I S S U E
97
Medicographia
Vol 30, No. 4, 2008
ISSN 0243-3397
N ew A pproaches and C hallenges
in O steoporosis
L. G. RAISZ, USA
EDITORIAL
NEW CONCEPTS IN BONE BIOLOGY: HOW INNOVATION
TODAY WILL HELP TOMORROW. NOUVEAUX CONCEPTS
EN BIOLOGIE OSSEUSE : COMMENT LES INNOVATIONS
305
ACTUELLES FONT LES PROGRÈS DE DEMAIN
E. SEEMAN, AUSTRALIA
THE OSTEOCYTE: CONDUCTOR OF ADAPTIVE AND
313
REPARATIVE REMODELING
D. W. DEMPSTER, USA
STRUCTURE AND FUNCTION OF THE ADULT SKELETON 320
ADVANCES IN BONE MACROSTRUCTURE AND MICROH. K. GENANT, K. ENS. PREVRHAL, STRUCTURE CT IMAGING IN OSTEOPOROSIS
USA AND GERMANY
326
P. AMMANN, SWITZERLAND ADVANCES IN THE ASSESSMENT OF BONE STRENGTH
334
GELKE, AND
P. GARNERO, FRANCE
ADVANCES IN BONE TURNOVER ASSESSMENT WITH
339
BIOCHEMICAL MARKERS
A journal of
medical information
and international
communication
from Servier
Available online at
www.medicographia.com
E. SORNAY-RENDU AND
P. D. DELMAS , FRANCE
ADVANCES IN OSTEOPOROSIS DIAGNOSIS: THE USE OF 350
O. BRUYÈRE AND
J.-Y. REGINSTER,
BELGIUM
CORRELATION BETWEEN INCREASED BONE MINERAL
DENSITY AND DECREASED FRACTURE RISK: BONE
MINERAL DENSITY AS A TOOL TO MONITOR POST-
CLINICAL RISK FACTORS
355
MENOPAUSAL OSTEOPOROSIS TREATMENT
Contents continued overleaf...
Medicographia
Vol 30, No. 4, 2008
I S S U E
97
...Contents continued from cover page
N ew A p p r o a c h e s a n d C h a l l e n g e s
in O s t e o p o r o s is
A. S. HEPGULER, TURKEY / CONTROVERSIAL QUESTION
T. P. TORRALBA,
IS BONE MINERAL DENSITY MEASUREMENT USEFUL
PHILIPPINES /
IN PATIENTS WHO HAVE ALREADY FRACTURED?
G. MAALOUF, LEBANON /
C. A. F. ZERBINI, BRAZIL /
C. V. ALBANESE, ITALY /
J. C. ROMEU, PORTUGAL /
K. BRIOT, FRANCE /
P. GEUSENS, NETHERLANDS / E. PASCHALIS,
P. ROSCHGER, P. FRATZL,
AND K. KLAUSHOFER,
AUSTRIA / C.-H. WU AND
R.-M. LIN, TAIWAN
P. HALBOUT, FRANCE
PROTELOS
STRONTIUM RANELATE AS AN INNOVATION IN THE
360
373
TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS:
SCIENTIFIC EVIDENCE AND CLINICAL BENEFITS
J. B. CANNATA-ANDÍA AND INTERVIEW
J. B. DÍAZ-LÓPEZ, SPAIN TREATING OSTEOPOROSIS ACROSS ITS STAGES
C. ROUX AND
J. FECHTENBAUM,
FRANCE
FOCUS
WHEN SPINAL OSTEOPOROSIS AND OSTEOARTHRITIS
S. BOONEN,
BELGIUM
UPDATE
MANAGING OSTEOPOROSIS IN THE ELDERLY
C. RÉGNIER, FRANCE
D. CAMUS, FRANCE
384
388
COEXIST
A TOUCH OF FRANCE
MOUNTAINS, BALLOONS, AND FLYING MACHINES:
PAUL BERT AND THE BIRTH OF AVIATION MEDICINE
IN FRANCE
A TOUCH OF FRANCE
ANTOINE DE SAINT EXUPÉRY, PILGRIM OF THE STARS
PILOT, WRITER, POET
393
399
409
E
D I T O R I A L
New concepts in bone biology:
how innovation today
will help tomorrow
by L. G. Raisz, USA
T
Lawrence G. RAISZ, MD
University of Connecticut
Health Center
Farmington, CT USA
www.medicographia.com
Address for correspondence:
University of Connecticut Health
Center, 263 Farmington Avenue,
Farmington, CT 06030-3920, USA
(e-mail: [email protected])
Medicographia.
2008;30:305-312.
O APPRECIATE THE REMARKABLE IMPACT OF NEW CONCEPTS
in bone biology, it is instructive to look at what we knew about bone
50 years ago. There was one regulatory hormone, parathyroid hormone, and there was debate over whether or not estrogen was important. The hormonal role of vitamin D had not yet been recognized. The concepts of local regulation and of bone remodeling were just beginning to emerge. In the last 50 years there has been
a series of breakthroughs in bone biology and metabolic bone disease that has revolutionized
our understanding of bone pathogenesis and our approach to diagnosis, prevention, and therapy. In the 1960s and 1970s, controlled trials established the role of estrogen deficiency in bone
loss and of estrogen replacement to prevent that loss,1 although the antifracture efficacy of estrogen has only recently been proven. Bone densitometry was developed, which permitted us to
diagnosis osteoporosis and initiate treatment before fractures occurred.2 The hormonal role of
vitamin D was established, as well as the existence of local factors, initially interleukin-1 and
prostaglandin E2, that could stimulate bone resorption.3 The existence of both local and systemic regulation of bone formation by bone morphogenetic proteins and insulin-like growth
factor was also recognized.4,5 Thus it was possible to discuss the “interaction of local and systemic
factors in the pathogenesis of osteoporosis.” 6 Bone-specific therapy with bisphosphonates was
introduced, although the demonstration of clear-cut antifracture efficacy did not occur until the
1990s.7 Remarkably, it took almost 70 years to develop a clinically effective anabolic therapy,8
based on an observation from the early 1930s that intermittent low-dose parathyroid hormone
could increase bone mass in experimental animals.
Estrogen
Estrogen deficiency is important in the pathogenesis of bone loss in both men and women.3,9,10
However, the large Women’s Health Initiative (WHI) trial, while it clearly demonstrated the antifracture efficacy of estrogen, came to the conclusion that the risks of hormone replacement
therapy outweigh the benefits.11 This has resulted in a marked decrease in the use of estrogen in
osteoporosis. Doses of estrogen much lower than those used in the WHI trial can decrease bone
resorption and increase bone mass,12 but studies have not been large enough to assess any reduction in fractures or increase in breast cancer, heart disease, and stroke, as was shown for fulldose hormone replacement therapy. The precise mechanisms of estrogen action on bone are not
fully understood, but estrogen affects both hematopoietic osteoclast precursors and osteoblastic cells.13
Vitamin D
Recent studies have demonstrated an expanding role for vitamin D in bone health.14-16 When given with adequate amounts of calcium, higher levels of vitamin D supplementation can decrease
secondary hyperparathyroidism and the risk of fracture and falls in elderly patients and improve
New concepts in bone biology: how innovation today will help tomorrow – Raisz
MEDICOGRAPHIA, VOL 30, No. 4, 2008 305
EDITORIAL
physical performance.17 The optimal levels of the circulating precursor, 25-hydroxyvitamin D,
should be substantially higher than the minimum levels required to prevent rickets and osteomalacia.18
Mechanical force
There have been great advances in our understanding of the mechanisms by which the skeleton
responds to mechanical forces.19 The rapid bone loss that occurs with immobilization, and the
more subtle effects of decreased physical activity, have highlighted the need to understand this
process. The response to mechanical forces appears to be mediated by the osteocyte-osteoblast
network of canaliculi and cell processes.20 A number of triggers for this response have been identified, including nitric oxide, prostaglandins, and ATP. They may act through a disinhibition of
the Wnt signaling pathway (see below). An interesting innovation is the development of low-intensity vibration systems that might replace the usual recommended physical activities of walking and other weight-bearing exercises. Although the efficacy of the approach has not yet been
fully validated, it may have the added benefit of inhibiting adipogenesis.21
Macroarchitecture and microarchitecture
An important clinical concept that has received increasing attention is the need to assess bone
strength by methods other than measurement of bone mineral density.22 The effect of macroarchitecture—that is, such variables as hip axis length and cortical width, can be measured using
available radiological imaging techniques. Newer techniques are required, however, to assess
microarchitecture such as the proportion of plate or rod-like structures in trabecular bone and
the porosity of cortical bone. Both micro–magnetic resonance imaging and micro–computed
tomography imaging can accomplish this, but only at peripheral sites such as the distal radius
or tibia.
Genetics
Since the finding that genetic polymorphisms of the vitamin D receptor gene could affect bone
mass, there have been numerous other regulatory genes identified.23 In addition, there are quantitative trait loci that affect bone mass and strength at various sites, but for which the specific
gene has not yet been determined. Several polymorphisms have been shown to affect fracture risk
independent of bone density. This finding suggests that there may be subtle alterations in the
composition of minerals or matrix in bone that may affect fragility, but this has not yet been precisely elucidated.
Biochemical markers
The availability of biochemical markers to assess resorption or formation has accelerated the
understanding of bone pathogenesis and the evaluation of therapy.24 For resorption, the major
markers are collagen breakdown products or enzymes from osteoclasts, such as cathepsin K and
tartrate resistant acid phosphatase. Bone formation can be measured from the products of the
procollagen molecule that are released during collagen deposition, as well as via osteocalcin and
bone-specific alkaline phosphatase. While these measurements have not been fully accepted for
general clinical use, they are often employed to assess the response to therapy.
Osteoclast function
The complex signaling and subsequent biochemical changes that are required for osteoclastic
bone resorption have been largely elucidated. Osteoclastic resorption is dependent on an interaction between receptor activator of nuclear factor–kappa B (NF-κB) ligand (RANKL) located
on osteoblastic cells, and its receptor RANK located on osteoclastic cells.4,25 This can be blocked
by the decoy receptor, osteoprotegerin.26 RANKL antibodies are being tested as antiresorptive
drugs.27 Drugs that block adhesion, acid secretion, and release of the critical enzyme cathepsin K from osteoclasts are also being explored.28,29 Theoretically these agents, which block activity but do not destroy osteoclasts, could have a positive function if these cells are a source of factors that enhance bone formation.29
Transcriptional regulation
The discovery that Runx-2 (Cbfa-1) was a critical transcription factor for osteoblast differentiation was followed by a remarkable expansion of our understanding of this process.30 Perhaps the
most important discovery has been that the Wnt signaling pathway is critical not only for os306 MEDICOGRAPHIA, VOL 30, No. 4, 2008
New concepts in bone biology: how innovation today will help tomorrow – Raisz
EDITORIAL
teoblast differentiation and function, but also for steering precursor cells toward the formation
of osteoblasts and away from adipocytes.31 Increased Wnt signaling may also decrease osteoclastic activity and hence result in a substantial gain in bone mass. Following the finding that an
activating mutation of the coreceptor LRP-5 could result in a high bone mass phenotype and its
deletion in early onset osteoporosis,32,33 extensive studies have been carried out on the regulation of Wnt signaling. Factors that bind the ligands or the receptors, such as soluble frizzled related protein, dickkopf, and sclerostin, can suppress Wnt signaling. Disinhibition of the Wnt pathway could produce the ideal therapeutic effect in osteoporosis—increased bone formation and
decreased resorption.
Osteoimmunology
Clear evidence that the hematopoietic system could affect bone came from the finding that peripheral blood mononuclear cells stimulated by antigens or mitogens could produce an osteoclast activating factor.6 Subsequent studies have shown that many different cytokines can either
stimulate or inhibit osteoclastic bone resorption and also regulate osteoblast function.34 An interaction between estrogen and cytokines has been suggested; deletion or inhibition of cytokines
such as interleukin-1 or tumor necrosis factor–α can decrease or even abrogate the response to
estrogen deficiency.35-38
Neural regulation
Neuropeptides have been shown to affect bone cells,39 and central neural pathways involved in
skeletal regulation have been identified, although they have yet to be fully defined.40 Leptin as
well as β-adrenergic and cannabinoid receptor pathways have been implicated. Neural pathways
may link skeletal regulation with energy metabolism and may be responsible for both diurnal
and seasonal effects on bone.41
Stem cells and tissue engineering
Autologous transplantation of cells for bone repair has been used for many years.42 The development of stem cells or other stromal cells is being explored for orthopedic and dental repair.43
Transfection of precursor cells with factors that would enhance bone formation or inhibit bone
resorption could accelerate healing and could be used in the treatment of fractures and other
bone defects.
How innovation today will help tomorrow
There are many ways in which current knowledge of bone physiology and pathophysiology could
be used to help maintain or restore skeletal integrity and prevent fractures. Genetic analysis
could identify individuals at high risk of fracture and give pointers toward appropriate therapy.
Lifestyle changes can limit the negative impact of an individual’s genetic makeup. Prevention of
fractures will depend on the ability to block the two main pathogenetic mechanisms; increased
bone-resorption and decreased bone-formation response during remodeling. New approaches to
interfering with the RANKL/RANK pathways or blocking osteoclast activity are being explored as
well as new anabolic pathways, particularly those involving Wnt signaling. The effects of strontium ranelate, statins, and prostaglandins suggest that there may be other anabolic pathways.44-46
Strontium ranelate is already used in the treatment of osteoporosis,47 but a statin that can be
targeted to bone has not yet been developed clinically. The use of prostaglandins for local repair
is being tested.48
A major problem has been the failure to apply current advances to the vast majority of those
at risk.49 In addition, more attention must be paid to the risk of falls, which have a substantial
impact on fracture incidence, independent of skeletal fragility.50 Until these problems are solved,
today’s innovations will not have the impact that they should. Thus there is a critical need for
developing ways to increase awareness and enhance the application of appropriate diagnosis,
prevention, and therapy in osteoporosis. (see references on page 308)
New concepts in bone biology: how innovation today will help tomorrow – Raisz
MEDICOGRAPHIA, VOL 30, No. 4, 2008 307
EDITORIAL
REFERENCES
1. Lindsay R, Hart DM, Aitken JM, MacDonald EB, Anderson JB,
Clarke AC. Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet. 1976;1:1038-1041.
2. Hui SL, Slemenda CW, Johnston CC Jr. Age and bone mass as
predictors of fracture in a prospective study. J Clin Invest.1988;
81:1804-1809.
3. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and
prospects. J Clin Invest. 2005;115:3318-3325.
4. Raisz LG, Kream BE. Regulation of bone formation. N Engl J
Med. 1983;309:29-35.
5. Urist MR, Mikulski AJ, Nakagawa M, Yen K. A bone matrix calcification-initiator noncollagenous protein. Am J Physiol.1977;
232:C115-C127.
6. Raisz LG. Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med. 1988;318:818-828.
7. Black DM, Cummings SR, Karpf DB, et al; Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348:1535-1541.
8. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid
hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:
1434-1441.
9. Falahati-Nini A, Riggs BL, Atkinson EJ, O'Fallon WM, Eastell
R, Khosla S. Relative contributions of testosterone and estrogen
in regulating bone resorption and formation in normal elderly
men. J Clin Invest. 2000;106:1553-1560.
10. Syed F, Khosla S. Mechanisms of sex steroid effects on bone.
Biochem Biophys Res Commun. 2005;328:688-696.
11. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
12. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17beta-estradiol and bone density and
bone metabolism in older women: a randomized controlled trial.
JAMA. 2003;290:1042-1048.
13. Taxel P, Kaneko H, Lee SK, Aguila HL, Raisz LG, Lorenzo JA.
Estradiol rapidly inhibits osteoclastogenesis and RANKL expression in bone marrow cultures in postmenopausal women: a pilot
study. Osteoporos Int. 2008;19:193-199.
14. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al.
Effect of Vitamin D on falls: a meta-analysis. JAMA. 2004;291:
1999-2006.
15. Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P. Need for additional calcium to reduce
the risk of hip fracture with vitamin D supplementation: evidence
from a comparative meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2007;92:1415-1423.
16. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures
and therapeutic implications. Endocr Rev. 2001;22:477-501.
17. Wicherts IS, van Schoor NM, Boeke AJ, et al. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab. 2007;92:2058-2065.
18. Bischoff-Ferrari HA, Dawson-Hughes B. Where do we stand
on vitamin D? Bone. 2007;41:S13-S19.
19. Rubin J, Rubin C, Jacobs CR. Molecular pathways mediating
mechanical signaling in bone. Gene. 2006;367:1-16.
20. Bonewald L. Osteocytes as dynamic, multifunctional cells.
Ann N Y Acad Sci. 2007;1116:281-290.
21. Rubin CT, Capilla E, Luu YK, et al. Adipogenesis is inhibited
by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals. Proc Natl Acad Sci U S A. 2007;104:
17879-17884.
22. Kleerekoper M. Osteoporosis prevention and therapy: preserving and building strength through bone quality. Osteoporos
Int. 2006;17:1707-1715.
23. Ralston SH. Genetics of osteoporosis. Proc Nutr Soc. 2007;
66:158-165.
24. Cremers S, Garnero P. Biochemical markers of bone turnover
in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls. Drugs. 2006;66:
2031-2058.
25. Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption—a hypothesis. Calcif Tissue Int.1981;33:
349-351.
26. Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin-defi-
cient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12:1260-1268.
27. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in
postmenopausal women with low bone mineral density. N Engl
J Med. 2006;354:821-831.
28. Kumar S, Dare L, Vasko-Moser JA, et al. A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone
turnover in vivo in monkeys. Bone. 2007;40:122-131.
29. Karsdal MA, Martin TJ, Bollerslev J, Christiansen C, Henriksen K. Are nonresorbing osteoclasts sources of bone anabolic
activity? J Bone Miner Res. 2007;22:487-494.
30. Lian JB, Stein GS, Javed A, et al. Networks and hubs for the
transcriptional control of osteoblastogenesis. Rev Endocr Metab
Disord. 2006;7:1-16.
31. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone
mass by Wnt signaling. J Clin Invest. 2006;116:1202-1209.
32. Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell.
2001;107:513-523.
33. Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the
LDL receptor-related protein 5 gene results in the autosomal
dominant high-bone-mass trait. Am J Hum Genet.2002;70:11-19.
34. Horowitz MC, Lorenzo JA. IL-10, IL-4, the LIF/IL-6 family,
and additional cytokines. In: Bilezikian JP, Raisz LG, Rodan GA,
eds. Principles of Bone Biology.San Diego, Calif: Academic Press;
2002:961-977.
35. Ammann P, Rizzoli R, Bonjour JP, et al. Transgenic mice expressing soluble tumor necrosis factor-receptor are protected
against bone loss caused by estrogen deficiency. J Clin Invest.
1997;99:1699-1703.
36. Kawaguchi H, Pilbeam CC, Vargas SJ, Morse EE, Lorenzo JA,
Raisz LG. Ovariectomy enhances and estrogen replacement inhibits the activity of bone marrow factors that stimulate prostaglandin production in cultured mouse calvariae. J Clin Invest.
1995;96:539-548.
37. Pacifici R. Estrogen deficiency, T cells and bone loss. Cell Immunol. 2007 Sept 19. Epub ahead of print.
38. Weitzmann MN, Cenci S, Rifas L, Haug J, Dipersio J, Pacifici
R. T cell activation induces human osteoclast formation via receptor activator of nuclear factor kappaB ligand-dependent and
-independent mechanisms. J Bone Miner Res. 2001;16:328-337.
39. Lerner UH. Neuropeptidergic regulation of bone resorption
and bone formation. J Musculoskelet Neuronal Interact. 2002;2:
440-447.
40. Sato S, Hanada R, Kimura A, et al. Central control of bone
remodeling by neuromedin U. Nat Med. 2007;13:1234-1240.
41. Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab. 2006;4:341-348.
42. Connolly JF. Clinical use of marrow osteoprogenitor cells to
stimulate osteogenesis. Clin Orthop Relat Res.1998;355:S257S266.
43. Phinney DG, Prockop DJ. Concise review: mesenchymal stem/
multipotent stromal cells: the state of transdifferentiation and
modes of tissue repair—current views. Stem Cells. 2007;25:28962902.
44. Gutierrez GE, Lalka D, Garrett IR, Rossini G, Mundy GR.
Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations. Osteoporos
Int. 2006;17:1033-1042.
45. Marie PJ. Strontium ranelate: a physiological approach for optimizing bone formation and resorption. Bone. 2006;38:S10-S14.
46. Paralkar VM, Borovecki F, Ke HZ, et al. An EP2 receptor-selective prostaglandin E2 agonist induces bone healing. Proc Natl
Acad Sci U S A. 2003;100:6736-6740.
47. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium
ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468.
48. Li M, Ke HZ, Qi H, et al. A novel, non-prostanoid EP2 receptor-selective prostaglandin E2 agonist stimulates local bone formation and enhances fracture healing. J Bone Miner Res. 2003;
18:2033-2042.
49. Solomon DH, Katz JN, Finkelstein JS, et al. Osteoporosis
improvement: a large-scale randomized controlled trial of patient
and primary care physician education. J Bone Miner Res. 2007;22:
1808-1815.
50. Tinetti ME, Gordon C, Sogolow E, Lapin P, Bradley EH. Fallrisk evaluation and management: challenges in adopting geriatric
care practices. Gerontologist. 46:717-725.
Keywords: bone resorption; bone formation; hormones; cytokines; osteoporosis
308 MEDICOGRAPHIA, VOL 30, No. 4, 2008
New concepts in bone biology: how innovation today will help tomorrow – Raisz
ÉDITORIAL
Nouveaux concepts en biologie
osseuse : comment les innovations
actuelles font les progrès de demain
par L. G. Raisz, USA
A
FIN D’APPRÉCIER L’IMPACT CONSIDÉRABLE DES NOUVEAUX
concepts en biologie osseuse, il est intéressant de revenir à ce que
nous savions des os il y a environ 50 ans. Il existait une seule hormone régulatrice, la parathormone, et les débats portaient sur
l’importance du rôle des œstrogènes. Le rôle hormonal de la vitamine D n’avait pas encore été
établi. Les concepts de régulation locale et de remodelage osseux commençaient à peine à faire
leur apparition. Au cours des 50 dernières années, une série d’avancées dans les domaines de la
biologie osseuse et des maladies métaboliques osseuses ont révolutionné notre compréhension
de la pathogenèse osseuse et notre approche du diagnostic, de la prévention et du traitement.
Au cours des années 1960 et 1970, des études contrôlées établirent le rôle du déficit en œstrogènes sur la perte osseuse, et l’intérêt de l’œstrogénothérapie substitutive dans sa prévention 1,
l’efficacité des œstrogènes dans la prévention des fractures n'ayant été pour sa part que récemment démontrée. La densitométrie osseuse fut développée, ce qui nous permit de diagnostiquer
l’ostéoporose et de mettre en œuvre le traitement avant la survenue des fractures 2. Le rôle hormonal de la vitamine D fut démontré, ainsi que l’existence de facteurs locaux, initialement
l’interleukine-1 et la prostaglandine E2 , capables de jouer un rôle dans la stimulation de la
résorption osseuse 3. L’existence d’une régulation locale et systémique de la formation osseuse
par les protéines morphogénétiques osseuses et le facteur de croissance analogue à l’insuline
(insulin-like growth factor, IGF) fut également mise en évidence 4,5. Il a été ainsi possible de discuter de « l’interaction des facteurs locaux et systémiques dans la pathogenèse de l’ostéoporose » 6. Les traitements spécifiquement osseux par les bisphosphonates firent leur apparition,
bien que la démonstration nette de leur efficacité contre les fractures n’ait été apportée que
dans les années 1990 7. Il est intéressant de noter qu’il a fallu près de 70 ans pour développer un
traitement anabolisant cliniquement efficace 8, sur la base d’une observation remontant au début des années 1930 selon laquelle l’administration intermittente de parathormone à faible dose
pouvait augmenter la masse osseuse chez des animaux d’expérimentation.
Œstrogènes
Le déficit en œstrogènes joue un rôle important dans la pathogenèse de la perte osseuse chez
la femme comme chez l’homme 3,9,10. Cependant, l’étude à grande échelle WHI (Women’s Health
Initiative), alors qu’elle démontrait clairement l’efficacité antifracturaire des œstrogènes, a conclu
que les risques d’une hormonothérapie substitutive dépassaient ses bénéfices 11. Ces conclusions
ont conduit à une diminution marquée de l’utilisation des œstrogènes dans l’ostéoporose. Des
doses d’œstrogènes très inférieures à celles utilisées dans l’étude WHI permettent de réduire la
résorption osseuse et d’augmenter la masse osseuse 12, mais les études n’étaient pas d’échelle suffisante pour évaluer une éventuelle prévention antifracturaire ou une augmentation du cancer
du sein, des maladies cardiaques, et des accidents vasculaires cérébraux, comme cela avait été
démontré avec les hormonothérapies substitutives à doses élevées. Les mécanismes précis de
l’action des œstrogènes sur l’os ne sont pas entièrement élucidés, mais il est établi que les œstrogènes affectent à la fois les précurseurs hématopoïétiques des ostéoclastes et les cellules ostéoblastiques 13.
Nouveaux concepts en biologie osseuse : comment les innovations actuelles font les progrès de demain – Raisz
MEDICOGRAPHIA, VOL 30, No. 4, 2008 309
ÉDITORIAL
Vitamine D
De récentes études confirment le rôle grandissant de la vitamine D dans la santé osseuse 14-16.
Lorsqu’elle est administrée avec des quantités adéquates de calcium, une supplémentation renforcée en vitamine D permet de diminuer l’hyperparathyroïdie secondaire ainsi que le risque
de fractures et de chutes chez les patients âgés, mais également d’améliorer les performances
physiques 17. Les concentrations optimales du précurseur circulant, la 25-hydroxyvitamine D,
doivent être substantiellement plus élevées que les niveaux minimums nécessaires pour prévenir le rachitisme et l’ostéomalacie 18.
Forces mécaniques
Des avancées considérables ont été effectuées dans notre compréhension des mécanismes permettant au squelette de répondre aux forces mécaniques 19. La perte osseuse rapide qui survient
au cours d’une immobilisation et les effets plus subtils d’une diminution de l’activité physique
ont souligné la nécessité d’approfondir notre connaissance de ce processus. La réponse aux forces
mécaniques semble être assurée par la médiation du réseau des canalicules et des prolongements cellulaires des ostéocytes et des ostéoblastes 20. Un certain nombre de facteurs déclenchant
cette réponse ont été identifiés, notamment le monoxyde d’azote, les prostaglandines et l’ATP.
Ils pourraient agir par l’intermédiaire d’une désinhibition de la voie de signalisation Wnt (voir
ci-dessous). Une innovation intéressante a été apportée par le développement de systèmes de
vibration de faible intensité qui pourraient remplacer l’activité physique habituellement recommandée (par exemple la marche et les autres exercices physiques en appui). Bien que l’efficacité de cette approche n’ait pas encore été entièrement validée, elle pourrait également présenter l’avantage supplémentaire d’inhiber l’adipogenèse 21.
Macroarchitecture et microarchitecture
Un concept clinique important ayant fait l’objet d’une attention croissante est la nécessité d’évaluer la résistance osseuse par d’autres méthodes que la mesure de la densité minérale osseuse 22.
Les caractéristiques de la macroarchitecture – par exemple des variables comme la longueur
de l’axe de la hanche et l’épaisseur corticale, peuvent être mesurées en utilisant les techniques
d’imagerie radiologique disponibles. Cependant, de nouvelles techniques sont nécessaires pour
évaluer la microarchitecture, en particulier la proportion des structures en plaques et en bâtonnets dans l’os trabéculaire et la porosité de l’os cortical. La micro-imagerie par résonance magnétique et la microtomodensitométrie pourraient répondre à ces besoins, mais uniquement au
niveau de sites périphériques, par exemple l’extrémité distale du radius ou du tibia.
Génétique
La découverte que la présence de polymorphismes génétiques du gène codant pour le récepteur
de la vitamine D est susceptible d’affecter la masse osseuse a conduit à l’identification de nombreux autres gènes régulateurs 23. En outre, il existe des loci de caractères quantitatifs affectant
la masse et la résistance osseuse à différentes localisations, mais pour lesquels le gène spécifique
n’a pas encore été déterminé. Il a été montré que plusieurs polymorphismes exerçaient une influence sur les risques de fractures, indépendamment de la densité osseuse. Ce résultat suggère
qu’il pourrait exister des altérations subtiles de la composition minérale ou de la matrice osseuse ayant un impact sur la fragilité, mais cela n’a pas encore été précisément élucidé.
Marqueurs biochimiques
La découverte de marqueurs biochimiques permettant d’évaluer la résorption ou la formation
a permis d’accélérer la compréhension de la pathogenèse osseuse et d’affiner l’évaluation des
traitements 24. Pour ce qui concerne la résorption, les principaux marqueurs sont constitués par
les produits de dégradation du collagène ou les enzymes ostéoclastiques, notamment la cathepsine K et la phosphatase acide résistante au tartrate. La formation osseuse peut être mesurée
par les produits de la molécule de procollagène qui sont libérés au cours du dépôt du collagène,
ainsi que par l’ostéocalcine et la phosphatase alcaline osseuse. Bien que ces mesures ne soient
pas entièrement intégrées à la pratique clinique générale, elles sont fréquemment employées
pour évaluer la réponse au traitement.
Fonction ostéoclastique
La signalisation complexe et les changements biochimiques résultants qui sont nécessaires à
la résorption osseuse ostéoclastique ont été largement élucidés. La résorption ostéoclastique
310 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Nouveaux concepts en biologie osseuse : comment les innovations actuelles font les progrès de demain – Raisz
ÉDITORIAL
dépend de l’interaction entre l’activateur du récepteur du ligand du facteur nucléaire κB‚ (receptor activator of nuclear factor-kappa B [NF-κB‚] ligand, RANKL) situé sur les ostéoblastes, et
son récepteur RANK qui se trouve sur les ostéoclastes 4,25. Ce système peut être bloqué par un
récepteur leurre, l’ostéoprotégérine 26. Les anticorps anti-RANKL sont actuellement testés comme
médicaments antirésorptifs 27. Les médicaments bloquant l’adhésion, la sécrétion acide et la
libération de la cathepsine K, cette enzyme essentielle issue des ostéoclastes, font également
l’objet d’investigations 28,29. Théoriquement, ces substances qui bloquent l’activité mais ne détruisent pas les ostéoclastes pourraient avoir une action positive si ces cellules constituent une
source de facteurs favorisant la formation osseuse 29.
Régulation transcriptionnelle
La découverte de Runx-2 (Cbfa-1), un facteur de transcription essentiel pour la différenciation
des ostéoblastes, a été suivie par une progression remarquable dans notre compréhension de ce
processus 30. La découverte peut-être la plus importante a été le rôle essentiel joué par la voie de
signalisation Wnt non seulement pour la différenciation et la fonction des ostéoblastes, mais
également sa capacité de diriger les cellules précurseurs vers la formation d’ostéoblastes, et de
les éloigner des adipocytes 31. Une intensification de la signalisation par la voie Wnt pourrait également diminuer l’activité ostéoclastique, et par conséquent permettre d’obtenir un gain substantiel de masse osseuse. Après la découverte qu’une mutation activant le corécepteur LRP-5
pouvait produire un phénotype à masse osseuse importante et que sa délétion provoquait un déclenchement précoce de l’ostéoporose 32,33, de nombreuses études ont été effectuées sur la régulation de la voie de signalisation Wnt. Les facteurs qui se lient aux ligands ou aux récepteurs,
par exemple la protéine soluble de type frizzled, la protéine dickkopf et la sclérostine, ont la
capacité de supprimer la voie de signalisation Wnt. La désinhibition de la voie Wnt pourrait
produire un effet thérapeutique idéal dans l’ostéoporose – c’est-à-dire une augmentation de la
formation osseuse et une diminution de la résorption osseuse.
Ostéoimmunologie
La preuve incontestable que le système hématopoïétique était capable d’affecter l’os a été apportée par la mise en évidence que des cellules mononucléées du sang périphérique stimulées
par des antigènes ou des mitogènes pouvaient produire un facteur activant les ostéoclastes 6. Des
études ultérieures ont montré que de nombreuses cytokines différentes pouvaient soit stimuler soit inhiber la résorption osseuse ostéoclastique, mais également réguler la fonction ostéoblastique 34. L’existence d’une interaction entre les œstrogènes et les cytokines a été suggérée ;
la délétion ou l’inhibition des cytokines, par exemple l’interleukine-1 ou le facteur de nécrose
tumorale–, peut diminuer ou même supprimer la réponse à un déficit en œstrogènes 35-38.
Régulation neurale
Il a été montré que les neuropeptides avaient une influence sur les cellules osseuses 39, et des voies
neurales centrales participant à la régulation du squelette ont été identifiées, bien qu’elles n’aient
pas encore été entièrement définies 40. Les rôles de la voie de la leptine et de la voie des récepteurs
-adrénergiques et cannabinoïdes ont été évoqués. Les voies neurales pourraient établir un
lien entre la régulation squelettique et le métabolisme énergétique, et être responsables d’effets
diurnes et saisonniers sur l’os 41.
Cellules souches et génie tissulaire
La transplantation autologue de cellules pour la réparation osseuse est utilisée depuis de nombreuses années 42. Le développement de cellules souches et d’autres cellules stromales est actuellement exploré dans le domaine de la réparation orthopédique et dentaire 43. La transfection
de cellules précurseurs avec des facteurs susceptibles de stimuler la formation osseuse et d’inhiber la résorption osseuse pourrait accélérer la cicatrisation et être utilisée dans le traitement
des fractures et des autres atteintes osseuses.
Comment les innovations d’aujourd’hui font les progrès de demain
Les voies par lesquelles les connaissances actuelles de la physiologie et de la physiopathologie
osseuse peuvent être utilisées pour maintenir ou restaurer l’intégrité squelettique et prévenir
les fractures sont multiples. L’analyse génétique permettrait d’identifier des individus exposés
à des risques importants de fractures et de fournir des orientations sur le traitement approprié.
Il est possible de limiter l’impact négatif du patrimoine génétique d’un individu par des chanNouveaux concepts en biologie osseuse : comment les innovations actuelles font les progrès de demain – Raisz
MEDICOGRAPHIA, VOL 30, No. 4, 2008 311
ÉDITORIAL
gements du style de vie. La prévention des fractures dépendra de la capacité à bloquer les deux
principaux mécanismes pathogénétiques : l’augmentation de la résorption et la diminution de
la formation osseuses au cours du remodelage. De nouvelles approches visant à interférer avec
les voies RANKL/RANK ou à bloquer l’activité des ostéoclastes sont actuellement explorées, ainsi
que de nouvelles voies anaboliques, en particulier celles portant sur la signalisation Wnt. Les
effets du ranélate de strontium, des statines et des prostaglandines suggèrent qu’il pourrait exister d’autres voies anaboliques 44-46. Le ranélate de strontium est déjà utilisé dans le traitement
de l’ostéoporose 47, mais aucune statine dont l’action pourrait être ciblée sur l’os n’a été développée en pratique clinique. L’utilisation des prostaglandines pour la réparation locale est en
cours d’expérimentation 48.
L’un des problèmes majeurs a été l’incapacité à faire bénéficier de ces avancées actuelles
la grande majorité des patients à risque 49. En outre, une attention plus soutenue doit être apportée au risque de chutes, qui ont un impact substantiel sur l’incidence des fractures, indépendamment de la fragilité squelettique 50. Tant qu’une solution n’aura pas été apportée à ces problèmes, les innovations actuelles ne pourront pas avoir l’impact qu’elles devraient avoir. Par
conséquent, il existe un besoin urgent de trouver des moyens d’augmenter la prise de conscience
et d’améliorer l’application de méthodes appropriées de diagnostic, de prévention et de traitement dans l’ostéoporose.
312 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Nouveaux concepts en biologie osseuse : comment les innovations actuelles font les progrès de demain – Raisz
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
he study of bone as a mineralized “hard” tissue has led to the misconception that it is an
impenetrable lifeless rock. It is mineralized,
it is hard, but it is neither impenetrable nor lifeless.
Bone is constructed rapidly during growth, changing its size, shape, and architecture, and then reconstructed—remodeled throughout the whole of
adult life. It is traversed by a myriad of canals and
canaliculi that make it no less intricate in design
than the hepatobiliary, bronchoalveolar or glomerulotubular systems (Figure 1, page 314).
The structure of bone determines the loads it can
tolerate. This is obvious, but the reverse is less obvious—the loads on bone determine its structure.1-4
This is adaptation, a phenomenon achieved by the
cellular machinery of bone modeling and remodeling. Bone modeling is the construction of the
skeleton by bone formation without prior bone resorption. Bone remodeling is the focal reconstruction of the skeleton by bone resorption followed by
bone formation at discrete points on the three components of the inner or endosteal envelope (endocortical, trabecular, intracortical) and to a lesser extent, on the outer or periosteal envelope.5
Bone remodeling is not a duet for osteoclasts and
osteoblasts. This notion falls short of the name given to this cellular machinery—the basic multicellular unit (BMU).2,4,6 Many cells participate in remodeling, and the osteocyte, the most numerous
cell of bone, is one of the most important members
of this orchestra, if not the conductor.7,8 There are
about 10000 cells per cubic millimeter and 50 processes per cell,9 each within a canaliculus forming
a lacelike communicating network of fluid-filled
channels like the Paris metro (Figures 2 and 3,
page 314 and 315). No part of bone is more than a
few microns from an osteocyte, an anatomical feature suggesting that these cells and their processes
within the canaliculi wall relay information about
their surroundings. This osteocytic-canalicular system functions in damage prevention by orchestrating adaptive remodeling, and in damage removal,
by orchestrating reparative remodeling. Osteocytes
detect strain and initiate modeling and remodeling
to adapt bone’s material properties and structural
design to offset the strain that will otherwise damage bone.10-12 Adaptation can be viewed as a damage-prevention mechanism. The change in bone
size, shape, and mass distribution during growth
achieved by modeling and remodeling is successful
adaptation; it is damage prevention by pre-emptive
modification of structural strength in response to increasing stresses imposed by growth. Microdamage,
when it accumulates, compromises bone strength
and must be removed.13 The second important function of the osteocyte is the detection of damage and
initiation of focal remodeling to remove and replace
damage with this new bone.14
T
Ego SEEMAN, MD
Austin Health
University of Melbourne
Melbourne, AUSTRALIA
The osteocyte:
conductor of adaptive and
reparative remodeling
by E. Seeman, Australia
ttainment of peak structural strength during growth and maintenance
of this strength during aging depend on the integrity of the cellular
machinery of bone modeling and remodeling. This machinery functions
well during growth, adapting bone’s material composition and structural design to prevailing loading circumstances. Loading and unloading are sensed by
osteocytes, which then orchestrate adaptive remodeling by the cells of the basic
multicellular unit (BMU) to focally deposit bone in one location or remove it
from another, modifying bone size, shape, and mass distribution according to
the dictates of local loading circumstances and a genetic program. The young
adult skeleton is the product of successful adaptation. Roads, buildings, and
bridges develop damage with time and so does bone. The size and location of
damage is identified by osteocyte apoptosis, which initiates reparative remodeling with resorptive removal of damage and subsequent new bone formation,
restoring the pristine state of the skeleton—for a while. Strength maintenance
by damage detection and removal eventually fails because of accumulating
age-related abnormalities in the remodeling machinery and the osteocyte population. Aging is associated with (i) a decline in periosteal bone formation;
(ii) a decline in bone formation, and continued resorption by the BMU producing a negative BMU balance; (iii) increased remodeling with worsening of the
negative BMU balance after menopause; and (iv) a decline in osteocyte numbers probably due to reduced osteocytogenesis and increased apoptotic death.
Thus, aging compromises the cellular machinery of bone modeling and remodeling and the osteocyte-lacunar mechanism that localizes damage and orchestrates its removal. Bone fragility results because each remodeling event in adulthood, whether adaptive or reparative, produces a deficit in bone volume and
structural decay. Recognition of the central role of the osteocyte in adaptive
modeling and remodeling for damage prevention, and reparative remodeling
for damage removal, is an important advance in the study of bone biology.
A
Medicographia. 2008;30:313-319.
(see French abstract on page 319)
Keywords: bone formation; bone strength; adaptation; modeling; remodeling,
osteocyte; osteoblast, osteoclast; aging
www.medicographia.com
Address for correspondence: Ego Seeman, Austin Health, University of Melbourne, Melbourne, Australia
(e-mail: [email protected])
The osteocyte: conductor of adaptive and reparative remodeling – Seeman
SELECTED
BMU
BRC
PTH
RANKL
ABBREVIATIONS AND ACRONYMS
basic multicellular unit
bone remodeling compartment
parathyroid hormone
receptor activator of nuclear factor–
kappa B ligand
MEDICOGRAPHIA, VOL 30, No. 4, 2008 313
NEW APPROACHES
Figure 1. Cortical bone is
composed of osteons with
a central haversian canal
and obliquely running
Volkmann canals, as
shown in the central
cartoon and high resolution images. Courtesy of
M. Knackstedt, Australian
National University,
Canberra, Australia.
AND
CHALLENGES
IN
OSTEOPOROSIS
Modeling and remodeling
during growth — osteocytes
in adaptation and damage prevention
The osteocyte is likely to participate in the attainment of bone’s peak structural strength during
growth by facilitating focal changes in bone size,
shape, and mass distribution to accommodate loading at that point.15 Long bones are not drinking
straws with the same dimensions throughout their
length. Diameters differ at each degree around the
perimeter of a cross section, creating differences in
the external shape of the cross section (Figure 4).
Differences in the medullary diameters at corresponding points around the perimeter of a cross
section determine the shape of the marrow cavity,
while the proximity of the periosteal and endocor-
tical envelopes at each point around the perimeter determines the cortical thicknesses around the
perimeter and so the cortical mass, its spatial distribution, and the distance this irregularly and
uniquely-shaped cortical mass is placed from the
neutral axis.16
The diversity in the spatial organization of bone
so critical for determining the diversity of bone
strength from individual to individual is achieved by
differing degrees of modeling point by point around
the periosteal perimeter, depositing bone in locations where it is needed, and remodeling on the endocortical surface at the corresponding points, with
removal of bone from where it is not needed by net
resorption. Bone strength is optimized not necessarily by using more and more mass, but by strategically modifying bone size, shape, and the distribution of mass using the minimum net amount of
bone needed.17
Local loading influences bone shape, but bone
shape is also genetically “programmed.” Fetal limb
buds removed in utero and grown in vitro develop
the shape of the proximal femur.18 The relative contributions of genetic and loading influences to the
variance in bone traits such as shape of a cross section remain uncertain, but it is likely that most of
the variance is due to differences in genetic factors
rather than loading circumstances.19 Whether genetically programmed, a response to local loading
or both, the final common pathway to the establishment of peak structural strength is the cellular
machinery of modeling and remodeling.
Osteocytes are likely to orchestrate modeling and
remodeling by detecting strain and facilitating bone
formation by modeling and removal of bone by remodeling, in order to modify the distribution of bone
Figure 2. Cracks arise
mostly in the interstitial
bone between the osteons
(upper and lower left-most
panels) and less in the
osteon, because of the latter’s alternating high and
low mineral density lamellae
forming a composite that is
resistant to crack occurrence and propagation
(upper middle panel).
Osteocytic lacunae can be
seen in the lamellae and
these contain osteocytes.
Courtesy of M. Schaffler.
314 MEDICOGRAPHIA, VOL 30, No. 4, 2008
The osteocyte: conductor of adaptive and reparative remodeling – Seeman
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
Figure 3. Osteocytes communicate with flattened
lining cells on the periosteal
and endosteal surfaces (upper and lower left panels)
and with each other (right
panel). Upper and lower left
panels, courtesy of A. Boyde
and G. Marotti; right panel,
courtesy of L. Bonewald.
focally so that it is adapted to, and accommodates,
prevailing stresses. In doing so, this cell is likely to
be instrumental in facilitating the construction of
the diversity of contours of a long bone cross section at each point along its length, conferring the
unique shape of all 206 bones of the skeleton.
The enormous capacity of this cellular machinery to modify structure during growth is seen in the
morphological differences in the playing and nonplaying arms of tennis players. Modeling and remodeling modify bone size, shape, and mass distribution of the humerus of the playing arm without
necessarily changing its mass.20,21 For example, in
tennis players, periosteal apposition with concurrent adjacent endocortical resorption shifts the cortical mass at that point outward away from the neutral axis of the shaft; there is no change in mass but
resistance to bending increases.
Sclerostin — the conductor’s baton
The osteocyte participates in this process of adaptation, facilitating focal bone formation at one point
yet bone resorption at another, in part by modulating sclerostin output. Sclerostin, a product of the
Sost gene, is found in osteocytes and inhibits bone
formation. Osteocytes adjust sclerostin output to
modulate Wnt signaling. Robling et al report that
loading reduces Sost transcripts and sclerostin levels.22 More greatly strained portions of the cortex
of the ulna have a greater reduction in Sost staining and sclerostin-positive osteocytes. Hindlimb unloading increases Sost expression in the tibia. Thus,
modulation of sclerostin appears to be a mechanism by which osteocytes coordinate osteogenesis
in response to increased loading in one region and
inhibition of bone formation or bone resorption
in unloaded regions. Li et al report that sclerostin
knockout male and female mice have increased bone
formation, high bone mass, and increased bone
strength. Femur bone volume was increased in trabecular and cortical compartments due to increased
osteoblast surfaces without change in osteoclast surfaces. Bone formation rate was increased on trabecular, endocortical, and periosteal surfaces.23
Ablating osteocytes in vivo results in structural
abnormalities and loss of mechanotransduction.
Tatsumi et al report that ablating 80% of osteocytes
in mice produces cortical porosity, disruption of trabecular architecture, and microfractures. Impairment of adaptation to unloading was also observed,
with failure of the normally observed loss of bone
produced by tail suspension.24 No osteocytes—no
bone resorption in response to unloading. Osteocytes appear to exert an inhibitory influence on
bone resorption; when this inhibitory influence is
removed, osteoclastogenesis and bone resorption
proceed. Osteocytes may modulate receptor activator of nuclear factor–kappa B ligand (RANKL) expression in preosteoblasts and restrain RANKL gene
expression, which is released when osteocytes die.
The osteocyte: conductor of adaptive and reparative remodeling – Seeman
Figure 4. Femoral neck
shape is elliptical adjacent
to the femoral shaft but
more circular at its center and adjacent to the
femoral head, features that
are achieved by differences
in bone modeling and
remodeling around the
bone’s periosteal and
endocortical perimeter.
Likewise, at each point
along the tibia, the external and marrow shape
and mass distribution
differ along the length
of the bone. Courtesy of
R. Zebaze and Q. Wang,
Melbourne, Australia.
MEDICOGRAPHIA, VOL 30, No. 4, 2008 315
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
(1)
(2)
Figure 5. Reparative remodeling is initiated when (i) microdamage severs osteocyte
processes (courtesy of J. Hazenberg), (ii) apoptotic osteocytes surround the damaged
region initiating osteoclastogenesis (courtesy of M. Schaffler), (iii) resorption (R) is
targeted to the damage (courtesy of D. Burr), (iv) osteocytes are released by resorption
(courtesy of A. Boyde), (v) osteocytes are engulfed by osteoclasts, (vi) bone formation
follows formation of a cement line, and (vii) osteocytes are formed from osteoblasts
entombed within the matrix they synthesize. OB, osteoblast; OC, osteocyte. Central
cartoon illustrates theses remodeling events with microdamage, formation of the bone
remodeling compartment, osteoclasts removing damage and imbibing osteocytes,
formation of a cement line, and bone formation by osteoblasts and restoration of bone
structure.
Bone modeling and
remodeling during adulthood —
osteocytes in damage repair
The purpose of modeling and remodeling during
adulthood is to maintain bone strength achieved
during growth, but in accordance with the prevailing loading circumstances. Part of the notion of
“maintaining” strength is the detection and removal
of damaged bone. Bone, like roads, buildings, and
bridges, accumulates microdamage by repeated
loading.13,14 Microcracks are a means of dissipating
energy, like the small eruption on the side of a volcano before the big bang. These microcracks allow
energy dissipation to avoid the alternative means
of dissipating energy— complete fracture—making two pieces of bone from one. But accumulation
of microdamage compromises whole bone strength,
so microdamage must be detected and removed.25
Only bone has the ability to define the location
and the extent of the damage, and only bone has effective mechanisms in place to remove that damage and restore bone’s material composition, its
microarchitecture and macroarchitecture, to its
pristine state—for a while at least. Bone resorption
is not bad for bone unless it becomes excessive. On
the contrary, the resorptive phase of the remodeling cycle removes damaged bone and is essential to
bone health. Indeed, prolonged suppression of remodeling with potent antiresorptive therapy may
result in microdamage accumulation, fractures,
and reduced bone healing.26,27 The formation phase
of the remodeling cycle restores the structure of
316 MEDICOGRAPHIA, VOL 30, No. 4, 2008
bone, provided that the volume of damaged bone
removed is replaced by the same volume of normal
bone. The osteocyte plays a pivotal role in bone
modeling and remodeling by sacrificing itself. Microcracks sever osteocyte processes in their canaliculi, producing osteocyte apoptosis (Figure 5).14
Apoptotic osteocytes may be a form of damage
themselves or may produce damage by altering the
surrounding bone matrix, which then becomes liable to damage production or damage propagation.
For example, corticosteroid-treated mice have large
osteocyte lacunae surrounded by matrix with a
40% reduction in mineral and reduced elastic modulus.28 Estrogen deficiency and corticosteroid therapy produce osteocyte apoptosis.29 Increased osteocyte apoptosis following menopause may be partly
responsible for the increased remodeling rate midlife in women. Prevention of osteocyte death is an
attractive therapeutic target if dead osteocytes represent damage or produce damage.29,30 If osteocyte
death is a means of detecting and removing damage, preventing osteocyte death may not be appropriate. However, prevention of fragility associated
with corticosteroid-induced osteocyte apoptosis has
been reported using antiapoptotic agents.31
Irrespective of whether apoptotic osteocytes are
a consequence of damage, are the damage itself or
produce matrix damage, the number of dead osteocytes provides the topographical information needed to identify the location and size of that damage.7,32,33 Osteocyte apoptosis is likely to be one of
the first events signaling the need for remodeling.
It precedes osteoclastogenesis.34 In vivo, osteocyte
apoptosis occurs within 3 days of immobilization
and is followed within 2 weeks by osteoclastogenesis.35 In vitro, death of the osteocyte-like MLO-Y4
cells induced by scratching results in the formation
of TRACP-positive (osteoclast-like) cells along the
scratching path.36
The pivotal role of the bone remodeling canopy
in bone remodeling
Thus, the need for reparative remodeling is likely to
be signaled by osteocyte death via their processes
connected by gap junctions to flattened osteoblasts
lining the inner or endosteal surface of bone where
remodeling takes place. Damage, whatever its nature, occurs within the mineralized bone matrix of
osteons or the interstitial bone (between osteons),
but the cellular machinery of remodeling responsible for its removal occurs on the endocortical, trabecular, and intracortical components of the endosteal envelope. The endocortical and trabecular
surfaces are adjacent to marrow. The intracortical
surfaces line the haversian canals traversing the
intracortical compartment of bone.
The location and size of damage within the matrix deep to the surface must be relayed to the surface upon which remodeling is initiated. Remodeling must then be directed deep from the surface
into the bone matrix to the site of damage. So, information concerning the location and size of damage must reach the bone surface, and cells involved
in remodeling must reach the site of damage beneath the surface.
The osteocyte: conductor of adaptive and reparative remodeling – Seeman
NEW APPROACHES
AND
CHALLENGES
Thus the flattened lining cells are likely to be
conduits, transmitting the health status of the mineralized matrix to the bone marrow, one of the
sources of the cells of the BMU.37,38 Apoptotic osteocytes signal the location and size of the damage
within the bone matrix to the flattened lining cells
of the endosteal surface, leading to the formation of
a bone remodeling compartment (BRC) that confines and targets remodeling to the damage, minimizing removal of normal bone.39
The regulatory steps between osteocyte apoptotic death and creation of the BRC are not known.
Bone lining cells express collagenase mRNA.40 An
early event in the creation of the BRC may be collagenase digestion of unmineralized osteoid, exposing mineralized bone, a requirement for osteoclastic bone resorption to proceed. The lining cells are
flattened osteoblasts. They express markers of the
osteoblast lineage, particularly those forming the
canopy over the BRC.39 These canopy cells also express markers for a range of growth factors and regulators of osteoclastogenesis such as RANKL, suggesting that the canopy has a central role in the
differentiation of precursor cells of marrow stromal
origin, monocyte-macrophage origin, and vascular
origins toward their respective osteoblast, osteoclast
or vascular phenotypes.
differentiation and function may then be regulated
by products of newly synthesized osteoclasts, again,
before bone resorption has taken place. Once resorption has occurred, the products of bone resorption and/or cell-cell contact between osteoclasts and
osteoblasts may then further determine the final
volumes of bone resorbed and formed, and so the
final BMU balance.41-44
Adding to this complexity is the likelihood that
osteoblastogenesis and osteoclastogenesis are regulated by osteocytes and their products. For example, in the MLO-Y4 cell line, damaged osteocyte-like
cells secrete M-CSF and RANKL.36 Whether this occurs in human subjects in vivo is not known but it
raises the possibility that osteocytes participate in
the differentiation of monocyte-macrophage precursor cells toward the osteoclast lineage.
How this cellular and molecular traffic is orchestrated from beginning to end is far from clear, but
the canopy of the BRC is of central significance in
bone remodeling. It is not the only source of the
cells driving bone remodeling. Both osteoblast and
osteoclast precursors circulate and so may arrive at
the BRC via the circulation and via capillaries penetrating the canopy.45-47
Once differentiated, teams of osteoclasts resorb a
volume of damaged bone, but little is known of the
The multidirectional steps of the
factors determining the volume of bone resorbed,
and particularly how resorption stops after the damaged region has been resorbed. Osteoclasts phagocytose osteocytes and this may be one way the signal for resorption is removed (see Figure 5).48,49
After the reversal phase, the function of which
remains unknown, osteoblasts deposit osteoid, partly or completely filling the trench in cross section
(which establishes the size of the negative BMU balance in that cross section) on a trabecular surface,
and partly or completely filling a resorption tunnel
within the cortex forming the lamellae that then
undergo primary and secondary mineralization. In
a given cross section, how the osteoblasts change
polarity to produce the differently orientated collagen fibers from lamella to lamella is not known.
Most osteoblasts die, others become lining cells,
while others are entombed in the osteoid they form,
leading to reconstruction and “rewiring” of the osteocytic canalicular communicating system for later mechanotransduction, damage detection, and
repair.12 How this “rewiring” occurs is not understood.
remodeling cycle
While resorption of a volume of bone by osteoclasts
precedes formation of a similar volume of bone by
osteoblasts, the cellular and molecular events leading to these two differentiated cell functions may
not be sequential; on the contrary, they may occur
simultaneously and be multidirectional, forming a
servo-feedback system that tailors the volumes of
bone resorbed and formed appropriate to the structural need.
For example, signaling from apoptotic osteocytes
to cells expressing the osteoblast phenotype in the
canopy of the BRC may influence further differentiation of these lining cells toward osteoblast precursors expressing RANKL that then go on to participate in osteoclastogenesis.22 Other cells go on to
be fully differentiated osteoblasts able to produce
osteoid. So regulation of osteoclastogenesis and osteoblastogenesis may be occurring simultaneously
through osteoblast precursors in the canopy. Thus,
osteoblast precursors may be being synthesized before resorption has even occurred and their further
The osteocyte: conductor of adaptive and reparative remodeling – Seeman
IN
OSTEOPOROSIS
Figure 6. Osteocyte
numbers are reduced in
patients with vertebral
fractures.51 The fewer the
osteocyte numbers the
higher the microcrack
density in bone.51
Osteocyte numbers are
lower in bone deep to a
surface as this bone is remodeled less frequently.
MEDICOGRAPHIA, VOL 30, No. 4, 2008 317
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
Age-related changes
in remodeling,
the osteocyte population,
and emerging bone fragility
Osteocytes as targets for therapy
If osteocyte death is a step in the pathway toward
bone fragility, then these cells may be a target for
prevention of bone fragility or restoration of bone
strength. There is evidence that bisphosphonates
and sex steroids mediate their benefits in part by
reducing apoptosis in osteocytes.29 Parathyroid hormone (PTH) may, in part, produce benefits by preventing osteocyte apoptosis. Keller and Kneissel report that PTH inhibits Sost transcription in vivo
and in vitro, suggesting that Sost regulation mediates PTH action in bone.30
While bone can accommodate loading by adaptive
modeling and remodeling during growth, this capacity diminishes with age because several changes
in the cellular machinery of bone modeling and remodeling compromise bone’s material properties
and structural design50: there is a reduction in periosteal bone formation, a reduction in the volume
of bone formed in each BMU, continued resorption
by each BMU, and an increase in the rate of bone
remodeling after menopause, with worsening of the
negative bone balance produced by each BMU as
a result of osteoclast lifespan increases and osteoblast lifespan decreases.
Age-related changes in osteoblastogenesis and osteoblast lifespan may also reduce osteocytogenesis,
while increased osteocytic apoptosis may compromise osteocyte numbers. Consequently, bone’s ability to conduct adaptive and reparative remodeling
becomes impaired. Every time a remodeling event
occurs, whether it occurs in response to loading or
damage repair, there is loss of bone and structural
decay. The effects of osteocyte deficiency on bone
fragility are seen by experimental deletion of osteocytes in mice.23 Patients with fragility fractures have
lower osteocyte density than controls (Figure 6,
page 317).51 Microdamage dominates in the interstitial bone between osteons, and this region has
fewer osteocytes and a higher tissue mineral density, because it is older less recently remodeled bone.
Lacunae adjacent to microdamage under about
700/mm 2 have a fourfold higher microdamage burden, and 79% of cracks are associated with empty
lacunae.52 Cancellous bone is made with more osteocytes in black people because of diminished osteoblast apoptosis; this could contribute to increased
bone strength.53 In black women, as in white women, there are fewer osteocytes and total lacunae,
and more empty lacunae in deep than superficial
bone.
Attainment and maintenance of bone strength depends on the integrity of the cellular machinery of
bone modeling and remodeling, the final common
pathway mediating genetic and environmental
influences on bone morphology. This machinery
adapts bone’s material composition and structural
design to central, systemic, and local hormonal signals and local loading circumstances throughout
life. The osteocyte is likely to orchestrate the cells
of this machinery to add and remove bone focally,
adapting bone morphology to loading to prevent
damage occurrence. Adaptation is a means of damage prevention. When microdamage does occur, osteocytic apoptosis identifies the demographics of
the damage and initiates reparative remodeling to
remove the damage and replace it with the same
volume of new bone. Strength maintenance is damage detection and removal. These mechanisms fail
with time because of age-related abnormalities in
the remodeling machinery and a decline in the osteocytic defense system due to reduced osteocytogenesis and increased apoptotic death; each remodeling event, whether adaptive or reparative, leaves
a deficit in bone volume, producing structural decay. Bone fragility is the product of failed adaptation.
Recognition of the central role of the osteocyte in
adaptive and reparative modeling is an important
advance in the study of bone biology.54 REFERENCES
1. Wolf J. Das Gesetz der Transformation der Kochen. Berlin,
Germany: Springer-Verlag; 1892.
2. Frost HM. Bone Remodeling Dynamics. Springfield, Ill:
Charles C Thomas; 1963.
3. Currey JD. Bones. Structure and Mechanics. Princeton, NJ:
Princeton University Press; 2002;1-380.
4. Parfitt AM. Skeletal heterogeneity and the purposes of bone
remodelling: implications for the understanding of osteoporosis.
In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San Diego,
CA: Academic Press; 1996:315-339.
5. Orwoll ES. Toward an expanded understanding of the role of
the periosteum in skeletal health. J Bone Mineral Res. 2003;18:
949-954.
6. Lorenzo J. Interactions between immune and bone cells: new
insights with many remaining questions. J Clin Invest. 2000;106:
749-752.
7. Verborgt O, Gibson GJ, Schaffler MB. Loss of osteocyte integrity in association with microdamage and bone remodeling after
fatigue damage in vivo. J Bone Miner Res. 2000;15:60-67.
8. Burger EH, Klein-Nulend J, Smit TH. Strain-derived canalicular fluid flow regulates osteoclast activity in a remodeling osteon—a proposal. J Biomech. 2003;36:1453-1459.
9. Marotti G, Cane V, Palazzini S, Palumbo C. Structure-function
relationships in the osteocyte. Ital J Min Electro Metab. 1990;4:
93-106.
10. Bakker A, Klein-Nulend J, Burger E. Shear stress inhibits
while disuse promotes osteocyte apoptosis. Biochem Biophys
Res Commun. 2004;20:1163-1168.
11. Aarden EM, Burger EH, Nijweide PJ. Function of osteocytes
in bone. J Cell Biochem. 1994;55:287-299.
12. Han Y, Cowin SC, Schaffler MB, Weinbaum S. Mechanotransduction and strain amplification in osteocyte cell processes. Proc
Nat Acad Science. 2004;101:16689-16694.
13. Frost HM. Presence of microscopic cracks in vivo in bone.
Henry Ford Hosp Med Bull. 1960;8:25-34.
14. Hazenberg JG, Freeley M, Foran M, Lee TC, Taylor D. Microdamage: a cell transducing mechanism based on ruptured osteocyte processes. J Biomechanics. 2006;39:2096-2103.
15. Warden SJ, Hurst JA, Sanders MS, Turner CH, Burr DB, Li J.
Bone adaptation to a mechanical loading program significantly
increases skeletal fatigue resistance. J Bone Miner Res. 2005;20:
809-816.
16. Ruff CB, Hayes WC. Sex differences in age-related remodeling of the femur and tibia. J Orthop Res. 1988;6:886-896.
17. Zebaze RM, Jones A, Knackstedt M, Maalouf G, Seeman E.
Construction of the femoral neck during growth determines its
strength in old age. J Bone Miner Res. 2007;22:1055-1061.
18. Murray PDF, Huxley JS. Self-differentiation in the grafted limb
bud of the chick. J Anat. 1925;59:379-384.
19. Seeman E, Hopper JL, Young NR, Formica C, Goss P, Tsala-
318 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Conclusion
The osteocyte: conductor of adaptive and reparative remodeling – Seeman
NEW APPROACHES
mandris C. Do genetic factors explain associations between muscle strength, lean mass, and bone density? A twin study. Am J
Physiol. 1996;270:E320-E327.
20. Haapasalo H, Kontulainen S, Sievanen H, Kannus P, Jarvinen
M, Vuori I. Exercise-induced bone gain is due to enlargement in
bone size without a change in volumetric bone density: a peripheral quantitative computed tomography study of the upper arms
of male tennis players. Bone. 2000;27:351-357.
21. Bass SL, Saxon L, Daly R, Turner CH, Robling AG, Seeman E.
The effect of mechanical loading on the size and shape of bone
in pre-, peri- and post-pubertal girls: a study in tennis players.
J Bone Miner Res. 2002;17:2274-2280.
22. Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of SOST?
Sclerostin. J Biol Chem. In press.
23. Li X, Ominsky MS, Niu QT, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone
strength. J Bone Miner Res. In press.
24. Tatsumi S, Ishii K, Amizuka N, et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 2007;5:464-475.
25. Danova NA, Colopy SA, Radtke CL, et al. Degradation of bone
structural properties by accumulation and coalescence of microcracks. Bone. 2003;33:197-205.
26. Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC,
Burr DB. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical
properties in dog rib. J Bone Miner Res. 2000;15:613-620.
27. Odvina CV, Zerwekh JE, Rao DS, Maaloof N, Gottschalk FA,
Pak CYC. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:
1294-1301.
28. Lane NE, Yao W, Balooch M, et al. Glucocorticoid-treated
mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J Bone Miner Res. 2006;
21:466-476.
29. Manolagas SC. Choreography from the tomb: an emerging
role of dying osteocytes in the purposeful, and perhaps not so purposeful, targeting of bone remodeling. Bone Key Osteovision.
2006;3:5-14.
30. Keller H, Kneissel M. SOST is a target gene for PTH in bone.
Bone. 2005;37:148-158.
31. O’Brien CA, Jia D, Plotkin LI, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and
reduce bone formation and strength. Endocrinology. 2004;145:
1925-1941.
32. Taylor D. Bone maintenance and remodeling: a control system based on fatigue damage. J Orthop Res. 1997;15:601-606.
33. Schaffler MB, Majeska RJ. Role of the osteocyte in mechanotransduction and skeletal fragility. In: Proceedings of the meeting “Bone Quality: What is it and Can we Measure It?”; May 2May 3, 2005; Besthesda, Md. Abstract 20.
34. Clark WD, Smith EL, Linn KA, Paul-Murphy JR, Muir P, Cook
ME. Osteocyte apoptosis and osteoclast presence in chicken radii
0-4 days following osteotomy. Calcif Tissue Int. 2005;77:327-336.
35. Aguirre JI, Plotkin LI, Stewart SA, et al. Osteocyte apoptosis
is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss. J Bone Miner Res. 2006;21:605-615.
36. Kurata K, Heino TJ, Higaki H, Väänänen HK. Bone marrow
cell differentiation induced by mechanically damaged osteocytes
in 3D gel-embedded culture. J Bone Miner Res. 2006;21:616-625.
37. Parfitt AM. Targeted and non-targeted bone remodeling: relationship to basic multicellular unit origination and progression. Bone. 2002;30:5-7.
38. Parfitt AA. The bone remodelling compartment: a circulatory
function of bone lining cells. J Bone Miner Res. 2001;16:15831585.
39. Hauge EM, Qvesel D, Eriksen EF, Mosekilde I, Melsen F. Cancellous bone remodelling occurs in specialized compartments
lined by cells expressing osteoblastic markers. J Bone Miner Res.
2001;16:1575-1582.
40. Fuller K, Chambers TJ. Localisation of mRNA for collagenase
in osteocytic bone surface and chrondrocytic cells but not osteoclasts. J Cell Sci. 1995;106:2221-2230.
41. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by
the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 1999;20:345-357.
42. Martin TJ, Sims NA. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med. 2005;11:
76-81.
43. Lorenzo J. Interactions between immune and bone cells: new
insights with many remaining questions. J Clin Invest. 2000;106:
749-752.
AND
CHALLENGES
IN
OSTEOPOROSIS
44. Zhao C, Irie N, Takada Y, et al. Bidirectional ephrinB2-EphB4
signalling controls bone homeostasis. Cell Metab.2006;4:111-121.
45. Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel DA, Riggs
BL, Khosla S. Circulating osteoblast lineage cells in humans.
N Engl J Med. 2005;352:1959-1966.
46. Eghbali-Fatourechi GZ, Moedder UI, Charatcharoenwitthaya
N, et al. Characterization of circulating osteoblast lineage cells
in humans. Bone. 2007;40:1370-1377.
47. Fujikawa Y, Quinn JMW, Sabokbar A, McGee JO, Athanasou
NA. The human osteoclast precursor circulates in the monocyte
fraction. Endocrinology. 1996;137:4058-4060.
48. Elmardi AS, Katchburian MV, Katchburian E. Electron microscopy of developing calvaria reveal images that suggest that
osteoclasts engulf and destroy osteocytes during bone resorption.
Calcif Tiss Int. 1990;46:239-245.
49. Suzuki R, Domon T, Wakita M. Some osteocytes released from
their lacunae are embedded again in the bone and not engulfed
by osteoclasts during remodelling. Anat Embrol. 2000;202:119128.
50. Qui S, Rao RD, Saroj I, Sudhaker 1, Palnitkar S, Parfitt AM.
Reduced iliac cancellous osteocyte density in patients with osteoporotic vertebral fracture. J Bone Miner Res. 2003;18:1657-1663.
51. Seeman E, Delmas PD. Bone quality–the material and structural basis of bone strength and fragility. N Engl J Med. 2006;
354:2250-2261.
52. Qiu S, Rao DS, Fyhrie DP, Palnitkar S, Parfitt AM. The morphological association between microcracks and osteocyte lacunae in human cortical bone. Bone. 2005;37:10-15.
53. Qiu S, Rao DS, Palnitkar S, Parfitt AM. Differences in osteocyte and lacunar density between black and white American
women. Bone. 2006;38:130-135.
54. Bonewald LF, Johnson ML. Osteocytes, mechanosensing and
Wnt signalling. Bone. In press.
L’OSTÉOCYTE : CHEF D’ORCHESTRE
DU REMODELAGE ADAPTATIF ET RÉPARATEUR
L’
acquisition de la solidité osseuse structurelle maximale au cours de la
croissance et son maintien pendant le vieillissement sont conditionnés
par l’intégrité de la machinerie cellulaire responsable du modelage et
du remodelage osseux. Cette machinerie fonctionne bien pendant la croissance,
en adaptant le matériau et la structure de l’os aux conditions prédominantes
de charge. Les ostéocytes détectent la charge et la décharge et orchestrent un
remodelage adaptatif via les cellules de l’unité multicellulaire de base (UMB),
sous le contrôle d’un programme génétique, pour former de l’os à un endroit
précis ou l’éliminer ailleurs. La taille, la forme et la distribution de la masse
osseuse sont ainsi modifiées pour s’adapter aux conditions locales de charge.
Le squelette du jeune adulte est le résultat d’une adaptation réussie. L’os –
comme les routes, les immeubles et les ponts – s’abîme avec le temps. Taille et
localisation des lésions sont détectées grâce à l’apoptose des ostéocytes, ce qui
met en route le remodelage réparateur par résorption des lésions puis formation d’os nouveau, reconstituant – pour un certain temps – l’état d’origine du
squelette. À terme, le maintien de la solidité grâce à la détection et à la suppression de la lésion échoue à cause de l’accumulation des anomalies liées à l’âge
affectant tant le remodelage que les ostéocytes en général. Le vieillissement
s’associe à : 1) une diminution de la formation osseuse au niveau du périoste ;
2) une diminution de la formation osseuse et une résorption permanente générées par l’UMB, aboutissant à un équilibre négatif de ce dernier ; 3) une augmentation du remodelage avec une aggravation de l’équilibre négatif de l’UMB
après la ménopause ; 4) une diminution du nombre des ostéocytes, probablement due à une réduction de l’ostéocytogenèse et à une augmentation de l’apoptose. Le vieillissement compromet donc la machinerie cellulaire de modelage
et remodelage osseux ainsi que le mécanisme lié aux lacunes ostéocytaires qui
détecte la lésion et assure son élimination. Chaque épisode de remodelage à l’âge
adulte, qu’il soit adaptatif ou réparateur, aboutit à un déficit du volume osseux
et à une dégradation structurale responsables de la fragilité osseuse. La reconnaissance du rôle central de l’ostéocyte dans le modelage et le remodelage
adaptatifs pour la prévention des lésions et dans le remodelage réparateur pour
supprimer les accidents osseux représente une avancée importante dans l’étude
de la biologie osseuse.
The osteocyte: conductor of adaptive and reparative remodeling – Seeman
MEDICOGRAPHIA, VOL 30, No. 4, 2008 319
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
David W. DEMPSTER
Regional Bone Center
Helen Hayes Hospital
West Haverstraw
Department of Pathology
College of Physicians and
Surgeons of Columbia University
New York, NY USA
Structure and function
of the adult skeleton
b y D . W. D e m p s t e r, U S A
est recognized for its mechanical supportive and protective functions,
the skeleton is actually a prototype for multitasking. It fulfills roles extending from maintenance of mineral homeostasis and acid-base balance to production of cytokines and growth factors, including some crucial to
hematopoietic stem-cell differentiation and survival. Bone has evolved to satisfy requirements that, in engineering terms, are often contradictory: strong
but light, rigid yet flexible and tough. This is thanks partly to its mineral/collagen mix, but also to the continuous remodeling by which it replaces fatigued
bone. Bone even senses areas of local weakness and repairs them before failure
occurs, with no loss of function. These properties are ensured via a four-phase
process (activation, resorption, reversal, and formation) involving the sequential action of osteoclasts and osteoblasts working under overall osteocyte control within linked bone remodeling units. Osteocytes buried in a mineralizing
matrix form a syncytial neuron-like network of mechanotransducers, sensing
load changes in the surrounding bone and, via such messengers as sclerostin,
the product of the Sost gene, transmitting this information to surface cells to
initiate or regulate remodeling. This elegant mechanism confirms Dr Alexander Cooke’s intuition, expressed in the prehistory of bone studies, in 1955, that
the “immutability of dry bones and their persistence for… millions of years
after the soft tissues have turned to dust give us a false impression of bone…
Its fixity after death is in sharp contrast to its ceaseless activity during life.”
B
Medicographia. 2008;30:320-325.
(see French abstract on page 325)
Keywords: skeleton; modeling; remodeling; mechanical adaptation;
osteoblast; osteoclast; osteocyte
he adult human skeleton is made up of 213
separate bones, each of which is sculpted by a
process called modeling and each of which is
constantly renewed by a process termed remodeling. Bone is a remarkable material. It has evolved
to satisfy a number of requirements that, in engineering terms, are often contradictory. Thus, bone
is strong but very light; it is rigid but flexible and
extremely tough. Bone accomplishes this delicate
balancing act through a variety of mechanisms.
These include the manner in which its mass is distributed in space (macroarchitecture and microarchitecture), the fact that bone is formed of a composite material consisting of mineral—which is
rigid—and collagen—which is flexible and tough,
the hierarchical structure of bone, which enables
toughening to occur at a number of different structural levels, and its ability to undergo remodeling.
Depending on its location, each bone supports one
or more specific functions. These include structural
support, locomotion and movement, protection of
vital organs, and maintenance of mineral homeostasis. The process of bone remodeling plays a vital
role in the latter, at least over the long term, and
at the same time also provides a mechanism for
preservation of mechanical strength by replacing
old, fatigued bone with new mechanically-sound
bone. Remodeling is achieved by the sequential action of osteoclasts and osteoblasts and the process
is initiated and regulated by osteocytes. The rate of
remodeling and the balance between resorption and
formation in each remodeling unit differs depending on anatomical location and also as a function
of age and disease states. Knowledge of the fundamental principles of modeling and remodeling provides an excellent framework for understanding
age-related changes in bone structure, as well as
the impact of mechanical loading.
T
Macroscopic anatomy
There are two principal classifications of bones: flat
bones, such as the skull, mandible, and scapula, and
long bones such as the femur, tibia, and radius. The
former develop by membranous bone formation,
while the latter are formed by a combination of
membranous bone formation and endochondral
bone formation. Long bones consist of a hollow tube
(shaft or diaphysis), which flairs at the ends to form
the cone-shaped metaphyses — the regions below
the growth plate—and the epiphyses—the regions
above the growth plate (Figure 1). The shaft is composed mainly of cortical bone, whereas the metaphysis and epiphysis contain cancellous bone surrounded by a shell of cortical bone. About 80% of
the adult skeleton is composed of cortical bone and
SELECTED
www.medicographia.com
Address for correspondence: David W. Dempster, Regional Bone Center, Helen Hayes Hospital,
Route 9W, West Haverstraw, NY USA
(e-mail: [email protected])
320 MEDICOGRAPHIA, VOL 30, No. 4, 2008
BRU
PTH
RANKL
TGF-β
ABBREVIATIONS AND ACRONYMS
bone remodeling unit
parathyroid hormone
receptor activator of nuclear factor–
kappa B ligand
transforming growth factor–β
Structure and function of the adult skeleton – Dempster
NEW APPROACHES
20% is cancellous, but the relative proportions of
the two types of bone vary considerably among different skeletal sites. In humans, the cancellous:cortical bone ratio is approximately 75:25 in the human vertebra, 50:50 in the femoral head, and 95:5
in the shaft or diaphysis of the radius. All bones are
ensheathed in a fibrous structure called the periosteum, and the inner surface, which is in direct contact with the marrow, is referred to as the endosteum. The periosteum contains the blood vessels
that nourish the bone, as well as nerve endings, osteoblasts, and osteoclasts. The periosteum is anchored to the bone by Sharpeys’ fibers that penetrate
into the bone tissue. The endosteum is a membranous sheath that also contains blood vessels, osteoblasts, and osteoclasts. In addition to lining the marrow cavity, the endosteum also envelops the surface
of cancellous bone and lines the blood vessel canals
(Volkman’s canals) that run through the bone.
AND
CHALLENGES
IN
OSTEOPOROSIS
flat bones, such as the ribs and those of the skull,
provide armor-like protection for the vital organs
that they surround. It is well known that the skeleton serves as the body’s main repository for calcium
and plays a key role in homeostatic regulation of
serum calcium concentration. It is less appreciated
that the skeleton plays a similar role with regard to
acid-base balance,3 and also serves as a rich source
of growth factors and cytokines. A good example of
this is the osteoblastic production of several factors
that are crucial for the differentiation and survival
of neighboring hematopoietic stem cells.4 Cancellous bone is often considered to be more metabolically active than cortical bone, which is mainly
viewed as fulfilling a mechanical function. However, this is likely to be a misconception and may also
be species-, and situation-dependent. For example,
the cancellous, medullary bone in birds serves as
a labile source of calcium that is mobilized during
eggshell calcification.5 On the other hand, it is the
cortical bone that supplies the necessary extra calcium during antler formation in deer.6 Increased
demands for calcium during pregnancy and lactation in humans are met primarily from non–weightbearing bone,7 but in primary hyperparathyroidism,
bone is removed predominantly from cortical sites.8
Modeling and mechanical adaptation
Figure 1. Scanning electron micrograph of the proximal tibia of a rat.
Abbreviations: Cn, cancellous bone; Ct, cortical bone; Epi, epiphysis; GP, growth plate; Met, metaphysis.
Reproduced from reference 1: Dempster DW. Anatomy and functions of the adult skeleton. In: Favus MJ, et al, eds. Primer on the
Metabolic Bone Diseases and Disorders of Mineral Metabolism.
6th ed. Washington, DC: The American Society for Bone and Mineral Research; 2006:7-11. Copyright © 2006, American Society for
Bone and Mineral Research.
Cortical and trabecular
bone structure and function
At the macroscopic level, cortical bone appears
dense and solid, whereas cancellous bone is a lacelike structure of interconnected trabecular plates
and bars surrounding marrow-filled cavities. At the
light microscope level, both cortical and cancellous
bone is composed of basic structural units or osteons. In cortical bone, the osteons are most often
referred to as Haversian systems after Clopton Havers, the 17th-century English anatomist who first
observed the canals that run through the center of
the structures. Haversian systems are cylindrical in
shape, and form an anatomizing network like the
branches of a tree.2 Their walls are formed from concentric sheaths or lamellae, which when cut in cross
section resemble the rings in a tree trunk. Trabecular osteons, also referred to as packets, are saucershaped and are also composed of stacks of lamellae.
When we consider function, the skeleton can be
considered as a prototype for multi-tasking. The
long bones serve as levers for the muscles, supporting locomotion and all other forms of motion. The
Structure and function of the adult skeleton – Dempster
One of the most remarkable features of mammalian
bone is its ability to adapt its shape and size in response to the prevailing mechanical load. The first
description of this phenomenon is usually attributed to the 19th-century German anatomist/surgeon
Julius Wolff (1835-1902), who stated that every
change in the function of a bone is followed by
changes in its internal architecture and its external
conformation. Imagine if a man-made object, such
as a bridge, could accomplish such a feat. As the
traffic density increased over time, the mass and
strength of the bridge would increase to accommodate it. In the unlikely event that the bridge became
less traveled, its mass would reduce. Mechanical
adaptation of bone is accomplished by a process
called modeling, in which bones are shaped or reshaped by the independent action of osteoblasts and
osteoclasts. Modeling occurs during growth, or in
the adult, to change the shape of the bone in response to mechanical loads. For example, the radius
in the playing arm of competitive, young tennis
players has a thicker cortex and a greater external
diameter than the contralateral radius as a result of
modeling.9 Conversely, unloading of the skeleton
during bed-rest or space flight, for example, results
in rapid bone loss. Bone modeling is distinguished
from remodeling by the fact that bone formation
is not tightly coupled to prior bone resorption. In
adult humans, bone modeling occurs less frequently than bone remodeling, particularly in cancellous bone, but it does occur in normal subjects10
and may be increased in disease states such as hypoparathyroidism and renal bone disease.11,12 Anabolic agents for the treatment of osteoporosis, such
as parathyroid hormone (PTH), have also been
shown to stimulate modeling.13
MEDICOGRAPHIA, VOL 30, No. 4, 2008 321
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
Bone remodeling
Half a century ago, Dr Alexander Cooke wrote eloquently that:
The skeleton, out of site and often out of mind,
is a formidable mass of tissue occupying about
9% of the body by bulk and no less than 17% by
weight. The stability and immutability of dry
bones and their persistence for centuries, and
even millions of years after the soft tissues have
turned to dust, give us a false impression of
bone during life. Its fixity after death is in sharp
contrast to its ceaseless activity during life.14
Figure 2. Cross-sectional diagrams of the bone remodeling unit (BRU)
in cancellous bone (upper) and cortical bone (lower). The arrow indicates
the direction of movement through space. Note that the cancellous BRU
is essentially one half of the cortical BRU.
Reproduced from reference 1: Dempster DW. Anatomy and functions of the adult skeleton. In: Favus MJ, et al, eds. Primer on the Metabolic Bone Diseases and Disorders of
Mineral Metabolism. 6th ed. Washington, DC: The American Society for Bone and Mineral
Research; 2006:7-11. Copyright © 2006, American Society for Bone and Mineral Research.
Figure 3. Bone remodeling unit in human iliac crest
bone biopsy.
Abbreviations: MB, mineralized bone; MC, mononuclear cells in
reversal phase; Ob, osteoblast; Oc, osteoclast; Os, osteoid.
Reproduced from reference 20: Roodman GD. Mechanisms of bone
metastasis. N Engl J Med. 2004;350:1655-1664. Copyright © 2004,
Massachusetts Medical Society.
In the adult skeleton, the “ceaseless activity” largely refers to the process of bone remodeling, which
is another remarkable feature of mammalian bone.
This process allows the skeleton to constantly renew itself and to selectively repair damage before it
reaches the point where function is compromised.
Let’s take the bridge analogy a little further. Imagine if a bridge was able to sense areas of local weak322 MEDICOGRAPHIA, VOL 30, No. 4, 2008
ness and repair them before failure occurred, and
to do this without interrupting traffic flow. Remodeling is accomplished by a group of different cell
types collectively termed the bone remodeling unit
(BRU) (Figures 2 and 3).15-19 Remodeling occurs in
four distinct phases: activation, resorption, reversal, and formation.
Activation
Activation refers to the event that transforms a previously quiescent bone surface into a remodeling
one. This phase involves recruitment of circulating
mononucleated osteoclast precursors,21 penetration
of the bone lining cell layer, and fusion of the mononuclear cells to form multinucleated preosteoclasts.
The degree to which remodeling activation at a particular site on the bone surface is targeted and the
extent to which it is random is uncertain. Some data
suggest that a proportion of the remodeling is directed toward specific sites that need to be repaired
(see below), but the site of most remodeling is likely to be arbitrary.22,23 The osteoclasts attach firmly to the bone matrix via avid binding between integrin receptors in their plasma membranes and
arginine-glycine-aspartic acid (RGD)-containing
peptides in the organic matrix, forming an annular sealing zone surrounding the resorbing compartment.
Resorption
Osteoclastic resorption is regulated by local cytokines such as receptor activator of nuclear factor–
kappa B ligand (RANKL), interleukins -1 and -6
(IL-1 and IL-6), and colony-stimulating factors, and
systemic hormones such as PTH, 1,25-dihydroxyvitamin D3, and calcitonin.20,21,24-26 During the resorption phase of the cycle, specific types of proton
pumps and other ion channels in the osteoclast
membrane transfer hydrogen ions to the resorbing
compartment, decreasing its pH to values as low as
4.0.27 This acidic solution dissolves the mineral
component of the matrix. Acidification is accompanied by secretion of a number of lysosomal enzymes
such as tartrate-resistant acid phosphatase and
cathepsin K, as well as matrix metalloproteases
(MMPs) including MMP-9 (collagenase) and gelatinase.28 These enzymes, which have pH optima in
the acidic range, digest the organic phase of the matrix. By this two-step process, the osteoclasts create saucer-shaped resorption cavities called Howship’s lacunae on the surface of the cancellous bone
and cylindrical tunnels within the cortex (Figure 2).
At first, resorption is accomplished by multinucleated osteoclasts, but later, resorption may be accomplished by monucleated cells.29,30 The resorption phase concludes with osteoclast apoptosis31 and
is followed by reversal.
Reversal
During the reversal phase, the resorption lacuna is
inhabited by mononuclear cells including monocytes, osteocytes that have been liberated from the
bone by osteoclasts, and preosteoblasts recruited to
initiate the formation phase of the cycle.32 It is during the reversal phase that crucial coupling signals
Structure and function of the adult skeleton – Dempster
NEW APPROACHES
are sent out to beckon osteoblasts into the resorption cavities. In the absence of an efficient coupling
mechanism, each remodeling transaction would
result in a net loss of bone. The nature of the coupling signal(s) is currently unknown, but there are
a number of theories. One theory is that osteoclasts
release growth factors from the bone matrix during the resorption phase and that these factors
serve as chemoattractants for osteoblast precursors
and stimulate osteoblast proliferation and differentiation. This hypothesis is attractive in that it accounts for recruitment of the osteoblasts at the correct location and in appropriate numbers to replace
the amount of bone that has been removed, which
presumably is related to the amount of growth factor released. Bone matrix–derived growth factors,
such as transforming growth factor–β (TGF-β),
insulin-like growth factors -I and -II (IGF-I and
IGF-II), bone morphogenetic proteins, platelet-derived growth factors, and fibroblast growth factor
could all serve as coupling factors.33-38 TGF-β prolongs osteoblast lifespan in vitro by inhibiting apoptosis, and the concentration of TGF-β in human
bone is positively correlated with histomorphometric indices of bone resorption and bone formation,
and with serum levels of osteocalcin and bone-specific alkaline phosphatase.39 In addition to possibly
stimulating formation during the reversal phase,
TGF-β released from bone may also play a role in
inhibiting resorption by decreasing RANKL production by osteoblasts.40
Another postulated mechanism for the coupling
of formation to resorption is that it is a strain-regulated phenomenon.41 In this theory, it is posited
that as the BRU traverses through cortical bone,
strain levels are reduced ahead of the osteoclasts
and are increased behind them. Likewise, strain is
thought to be higher at the base of Howship’s lacunae in cancellous bone and reduced in the bone
surrounding the lacunae. It is suggested that such
strain gradients cause sequential activation of osteoclasts and osteoblasts, with osteoclasts being activated in response to reduced strain and osteoblasts
in response to increased strain. This hypothesis also
has the potential to account for alignment of osteons to the dominant load direction.42 Another recently-proposed notion is that the osteoclast itself
plays a role in coupling.43,44 Bidirectional osteoclast
to osteoblast signaling via ephrin receptors has also
been implicated in this coupling process.45
Formation
Similar to resorption, formation is a two-step process in which the osteoblasts initially synthesize
the organic matrix and then regulate its mineralization. Once the collagenous, organic matrix is secreted, the osteoblasts initiate its mineralization by
releasing small, membrane-bound vesicles called
matrix vesicles, which establish suitable conditions
for mineral deposition by concentrating calcium
and phosphate ions and enzymatically degrading
inhibitors of mineralization, such as pyrophosphate
and proteoglycans that are present in the extracellular matrix.46 As bone formation continues, osteoblasts are buried in the matrix, becoming os-
Structure and function of the adult skeleton – Dempster
AND
CHALLENGES
IN
OSTEOPOROSIS
teocytes. Although incarcerated in the matrix, the
osteocytes maintain intimate contact with one another, as well as with the cells on the bone surface,
by means of gap junctions between the cytoplasmic
processes that extend through canaliculae. Each osteocyte becomes part of a large, three-dimensional,
functional syncitium, which can “sense” a change
in the mechanical properties of the surrounding
bone and transmit this information to the cells on
the surface to initiate or regulate bone remodeling
when necessary.47,48 It has therefore been suggested
that, from this perspective, bone cells behave like a
neuronal network.49
Osteocyte regulation of bone remodeling
Recent progress has been made in our understanding of how the osteocyte regulates bone remodeling. Osteocytes produce sclerostin, the protein product of the Sost gene, the loss of which leads to the
sclerosing bone disorders, sclerosteosis and Van
Buchem disease.50 Sclerostin antagonizes Wnt/Lrp5
receptor signaling, a pathway that is known to play
an important role in the mechanical stimulation of
bone formation. Robling and colleagues51 showed
that mechanically unloading bone increases Sost
expression by osteocytes, and that loading has the
opposite effect. These experiments delineate an elegant mechanotransduction mechanism by which
the osteocyte is able to act as a mechanosensor and
to regulate surface bone formation by modulation
of Sost expression.
When the osteoblasts have completed their matrix-forming function, approximately 50% to 70%
die by apoptosis, and the remainder is either incorporated into the matrix as osteocytes or remains on
the surface as bone lining cells. It used to be thought
that lining cells served primarily to regulate the
flow of ions into and out of the bone extracellular
fluid and, in so doing, constituted the anatomical
basis of the blood-bone barrier. However, it has
recently been shown that under certain circumstances, for example stimulation by PTH or mechanical force, bone lining cells can revert back to
osteoblasts.52,53 Another potentially important function of the lining cells is to create specialized compartments on the surface of trabecular bone in
which bone remodeling occurs.54
At the conclusion of each remodeling cycle a new
osteon has been created. Note that the process of
bone remodeling is essentially equivalent in cancellous and cortical bone. The BRU in cancellous bone
can be visualized as a cortical BRU split in half longitudinally (Figure 2).55 The difference between the
volume of bone excavated by the osteoclasts and
that formed by the osteoblasts is referred to as the
“bone balance.” BRUs on the periosteal surface of
cortical bone produce a slightly positive bone balance so that, with aging, the periosteal circumference increases as the effect of the small positive balance in each BRU accumulates. On the other hand,
remodeling units on the endosteal surface of cortical bone are in negative balance so that the marrow
cavity enlarges with age. Furthermore, the balance
is more negative on the endosteal surface than it is
on the periosteal surface and, as a result, cortical
MEDICOGRAPHIA, VOL 30, No. 4, 2008 323
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
thickness declines with age. The bone balance on
cancellous surfaces is also negative, resulting in a
gradual thinning of the trabecular plates with the
passage of time.15
Functions of bone remodeling
Although two principal functions of bone remodeling are appreciated, it has been suggested that
there must be other, as yet unknown, functions or
reasons why the human skeleton undergoes such
extensive remodeling.56 The main functions of bone
remodeling are acknowledged to be, first, the preventive maintenance of mechanical strength by
continuous rejuvenation of the bone matrix, and
second, an important role in mineral homeostasis
by the provision of access to the aforementioned
skeletal depot of calcium and phosphorus. While the
turnover rate of 2% to 3% per year in cortical bone
seems consistent with preservation of mechanical
strength, the turnover rate in cancellous bone is
much higher than would be required for this purpose, suggesting that the rate here is driven more
by the role of cancellous bone in mineral metabolism or by other unknown factors.19 In situations
where the requirement to mobilize mineral is high,
activation of new remodeling units may be required,
but it has been suggested that short-term mineral
homeostasis may only require the presence of a
minimum number of osteoclasts whose activity can
be regulated. Constant remodeling therefore ensures the presence of this contingent of osteoclasts.
Remodeling also provides for a continuous supply
of new bone of low mineral density, which is required for ionic exchange at quiescent surfaces.19
The most convincing evidence to date for a role
of bone remodeling in the maintenance of mechanical integrity comes from studies in dogs.57,58 Suf-
ficient loads were applied to long bones in vivo to
induce fatigue damage, and the bones were then
studied histologically. There was a statistically significant relationship between microcracks and resorption, with up to six times as many cracks associated with resorption spaces as would be predicted
by chance. This could possibly be explained by a
tendency of microcracks to form close to resorption
spaces.
However, further experiments showed that the
activation of remodeling was in response to the appearance of microcracks.59 This was demonstrated
by loading the left forelimbs of dogs 8 days prior
to sacrifice and loading the right forelimbs immediately prior to sacrifice. If cracks simply formed
at sites of resorption, then the number of cracks associated with resorption spaces would be predicted to be identical in each limb. However, the data
showed that the same number of microcracks
formed in each limb, but that the limb that was
loaded a week earlier displayed more resorption
spaces and a greater association between microcracks and resorption than the limb that was loaded immediately prior to sacrifice. The reasonable
conclusion is that microcracks initiate resorption.
One suggested mechanism for this targeted remodeling is that microcracks cause debonding of cortical osteons,60 resulting in a decrease in stress and
strain in that region of the osteon. This could be detected by osteocytes and communicated to the surface lining cells. The lining cells trigger activation
of a BRU from the Haversian canal and this burrows
toward, and ultimately replaces, the damaged area
with a new osteon. Fatigue damage may also promote osteocyte apoptosis and it has been suggested that this may be the initial trigger for targeted
remodeling.61-65 REFERENCES
1. Dempster DW. Anatomy and functions of the adult skeleton. In:
Favus MJ, et al, eds. Primer on the Metabolic Bone Diseases and
Disorders of Mineral Metabolism. 6th ed. Washington, DC: American Society for Bone and Mineral Research; 2006:7-11.
2. Stout SD, Brunsden BS, Hildebolt CF, Commean PK, Smith
KE, Tappen NC. Computer-assisted 3D reconstruction of serial
sections of cortical bone to determine the 3D structure of osteons.
Calcif Tissue Int. 1999;65:280-284.
3. Arnett T. Regulation of bone cell function by acid-base balance.
Proc Nutr Soc. 2003;62:511-520.
4. Taichman RS. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood.
2005;105:2631-2639.
5. Whitehead CC. Overview of bone biology in the egg-laying hen.
Poult Sci. 2004;83:193-199.
6. Banks WJ Jr, Epling GP, Kainer RA, Davis RW. Antler growth
and osteoporosis. I. Morphological and morphometric changes in
the costal compacta during the antler growth cycle. Anat Rec.
1968;162:387-398.
7. Bowman BM, Miller SC. Skeletal adaptations during mammalian reproduction. J Musculoskelet Neuronal Interact. 2001;1:
347-355.
8. Bilezikian JP, Brandi ML, Rubin M, Silverberg SJ. Primary hyperparathyroidism: new concepts in clinical, densitometric and
biochemical features. J Intern Med. 2005;257:6-8.
9. Haapasalo H, Kontulainen S, Sievanen H, Kannus P, Jarvinen
M, Vuori I. Exercise-induced bone gain is due to enlargement in
bone size without a change in volumetric bone density: a peripheral quantitative computed tomography study of the upper arms
of male tennis players. Bone. 2000;27:351-357.
10. Kobayashi S, Takahashi HE, Ito A, et al. Trabecular minimodeling in human iliac bone. Bone. 2003;32:163-169.
11. Ubara Y, Tagami T, Nakanishi S, et al. Significance of minimodeling in dialysis patients with adynamic bone disease. Kidney
Int. 2005;68:833-839.
12. Ubara Y, Fushimi T, Tagami T, et al. Histomorphometric features of bone in patients with primary and secondary hypoparathyroidism. Kidney Int. 2003;63:1809-1816.
13. Lindsay R, Cosman F, Zhou H, et al. A novel tetracycline labeling schedule for longitudinal evaluation of the short-term effects of anabolic therapy with a single iliac crest bone biopsy: Early actions of teriparatide. J Bone Miner Res. 2006;21:366-373.
14. Cooke AM. Osteoporosis. Lancet. 1955;1:878-882.
15. Frost HM. Intermediary Organization of the Skeleton. Boca
Raton, FL: CRC Press; 1986.
16. Parfitt AM. Physiologic and pathogenetic significance of bone
histomorphometric data. In: Coe FL, Favus MJ, eds. Disorders of
Bone and Mineral Metabolism. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2002:469-485.
17. Dempster DW. Bone remodeling. In: Coe FL, Favus MJ. Disorders of Bone and Mineral Metabolism.2nd ed. Philadelphia, PA:
Lippincott Williams and Wilkins; 2002:315-343.
18. Dempster DW. Bone remodeling. In: Riggs BL, Melton LJ III,
eds. Osteoporosis: Etiology, Diagnosis, and Management.2nd ed.
New York, NY: Raven Press; 1995:67-91.
19. Parfitt AM. Problems in the application of in vitro systems to
the study of human bone remodeling. Calcified Tissue Int. 1995;
56(suppl 1)S5-S7.
20. Roodman GD. Mechanisms of bone metastasis. N Engl J Med.
2004;350:1655-1664.
21. Roodman GD. Cell biology of the osteoclast. Exp Hematol.
1999;27:1229-1241.
22. Burr DB. Targeted and nontargeted remodeling. Bone. 2002;
30:2-4.
23. Parfitt AM. Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression.
Bone. 2002;30:5-7.
24. Simonet WS, Lacey DL. Osteoclast differentiation and activa-
324 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Structure and function of the adult skeleton – Dempster
NEW APPROACHES
tion. Nature. 2003;423:337-342.
25. Troen BR. Molecular mechanisms underlying osteoclast formation and activation. Exp Gerontol. 2003;38:605-614.
26. Blair HC, Athanasou NA. Recent advances in osteoclast biology and pathological bone resorption. Histol Histopathol.2004;
19:189-199.
27. Silver IA, Murrills RJ, Etherington DJ. Microelectrode studies on the acid microenvironment beneath adherent macrophages
and osteoclasts. Exp Cell Res. 1988;175:266-276.
28. Delaisse JM, Andersen TL, Engsig MT, Henriksen K, Troen T,
Blavier L. Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activities. Microsc Res Tech.
2003;61:504-513.
29. Eriksen EF. Normal and pathological remodeling of human
trabecular bone: three-dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease. Endocrine Rev. 1986;7:379-408.
30. Dempster DW, Hughes-Begos C, Plavetic-Chee K, et al. Normal human osteoclasts formed from peripheral blood monocytes
express PTH type 1 receptors and are stimulated by PTH in the
absence of osteoblasts. J Cell Biochem. 2005;95:139-148.
31. Reddy SV. Regulatory mechanisms operative in osteoclasts.
Crit Rev Eukaryot Gene Expr. 2004;14:255-270.
32. Baron R, Vignery A, Tran Van P. The significance of lacunar
erosion without osteoclasts: studies on the reversal phase of the
remodeling sequence. Metab Bone Dis Rel Res. 1980;2S:35-40.
33. Bonewald LF, Mundy GR. Role of transforming growth factor
beta in bone remodeling. Clin Orthop Rel Res. 1990;250:261-276.
34. Mohan S, Baylink DJ. Insulin-like growth factor system components and the coupling of bone formation to resorption. Horm
Res. 1996;45(suppl 1):59-62.
35. Hock JM, Centrella M, Canalis E. Insulin-like growth factor I
(IGF-I) has independent effects on bone matrix formation and
cell replication. Endocrinology. 1998;122:254-260.
36. Fiedler J, Roderer G, Gunther KP, Brenner RE. BMP-2, BMP-4,
and PDGF-bb stimulate chemotactic migration of primary human mesenchymal progenitor cells. J Cell Biochem. 2002;87:
306-312.
37. Tanaka H, Wakisaka A, Ogasa H, Kawai S, Liang CT. Effects
of basic fibroblast growth factor on osteoblast-related gene expression in the process of medullary bone formation induced in
rat femur. J Bone Miner Metab. 2003;21:74-79.
38. Locklin RM, Oreffo RO, Triffitt JT. Effects of TGF beta and
bFGF on the differentiation of human bone marrow stromal fibroblasts. Cell Biol Int. 1999;23:185-194.
39. Pfeilschifter J, Diel I, Scheppach B, et al. Concentration of
transforming growth factor beta in human bone tissue: relationship to age, menopause, bone turnover, and bone volume. J Bone
Miner Res. 1998;13:716-730.
40. Fox SW, Lovibond AC. Current insights into the role of transforming growth factor-beta in bone resorption. Mol Cell Endocrinol. 2005;243:19-26.
41. Smit TH, Burger EH. Is BMU-coupling a strain-regulated phenomenon? A finite element analysis. J Bone Miner Res. 2000;15:
301-307.
42. Smit TH, Burger EH, Huyghe JM. A case for strain-induced
fluid flow as a regulator of BMU-coupling and osteonal alignment.
J Bone Miner Res. 2002;17:2021-2029.
43. Martin TJ, Sims NA. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med. 2005;11:
76-81.
44. Karsdal MA, Henriksen K, Sorensen MG, et al. Acidification
of the osteoclastic resorption compartment provides insight into
the coupling of bone formation to bone resorption. Am J Pathol.
2005;166:467-476.
45. Zhao C, Irie N, Takada Y, et al. Bidirectional ephrinB2-EphB4
signaling controls bone homeostasis. Cell Metab.2006;4:111-121.
46. Anderson HC. Matrix vesicles and calcification. Curr Rheumatol Rep. 2003;5:222-226.
47. Huiskes R, Ruimerman R, van Lenthe GH, Janssen JD. Effects
of mechanical forces on maintenance and adaptation of form in
trabecular bone. Nature. 2000;405:704-706.
48. Burger EH, Klein-Nulend J, Smit TH. Strain-derived canalicular fluid flow regulates osteoclast activity in a remodeling osteon—a proposal. J Biomech. 2003;36:1452-1459.
49. Turner CH, Robling AG, Duncan RL, Burr DB. Do bone cells
behave like a neuronal network? Calcif Tissue Int. 2002;70:435442.
50. Balemans W, Ebeling M, Patel N, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10:537-543.
51. Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283:5866-5875.
52. Dobnig H, Turner RT. Evidence that intermittent treatment
Structure and function of the adult skeleton – Dempster
AND
CHALLENGES
IN
OSTEOPOROSIS
with parathyroid hormone increases bone formation in adult rats
by activation of bone lining cells. Endocrinology.1995;136:36323638.
53. Chow JW, Wilson AJ, Chambers TJ, Fox SW. Mechanical loading stimulates bone formation by reactivation of bone lining cells
in 13-week-old rats. J Bone Miner Res. 1998;13:1760-1767.
54. Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F. Cancellous bone remodeling occurs in specialized compartments
lined by cells expressing osteoblastic markers. J Bone Miner Res.
2001;16:1575-1582.
55. Parfitt AM. Osteonal and hemiosteonal remodeling: the spatial and temporal framework for signal traffic in adult bone. J Cell
Biochem. 1994;55:273-276.
56. Currey JD. Bones: Structure and Mechanics. Princeton, NJ:
Princeton University Press; 2002.
57. Burr DB, Martin RB, Schaffler MB, Radin EL. Bone remodeling in response to in vivo fatigue microdamage. J Biomech.
1985;18:189-200.
58. Mori S, Burr DB. Increased intracortical remodeling following fatigue damage. Bone. 1993;14:103-109.
59. Burr DB, Forwood MR, Fyhrie DP, Martin RB, Schaffler MB,
Turner CH. Perspective: Bone microdamage and skeletal fragility
in osteoporotic and stress fractures. J Bone Miner Res. 1997;12:
6-15.
60. Martin RB, Burr DB. Structure, Function, and Adaptation of
Compact Bone. New York, NY: Raven Press; 1989.
61. Noble BS, Peet N, Stevens HY, et al. Mechanical loading:
biphasic osteocyte survival and targeting of osteoclasts for bone
destruction in rat cortical bone. Am J Physiol Cell Physiol. 2003;
284:C934-C943.
62. Verborgt O, Tatton NA, Majeska RJ, Schaffler MB. Spatial distribution of Bax and Bcl-2 in osteocytes after bone fatigue: complementary roles in bone remodeling regulation? J Bone Miner
Res. 2002;17:907-914.
63. Verborgt O, Gibson GJ, Schaffler MB. Loss of osteocyte integrity is associated with microdamage and bone remodeling after fatigue in vivo. J Bone Miner Res. 2000;15:60-67.
64. Noble BS, Stevens H, Loveridge N, Reeve J. Identification of
apoptotic changes in osteocytes in normal and pathological bone.
Bone. 1997;20:273-282.
65. Noble BS, Peet N, Stevens HY, et al. Mechanical loading:
biphasic osteocyte survival and targeting of osteoclasts for bone
destruction in rat cortical bone. Am J Physiol Cell Physiol. 2003;
284:C934-C943.
STRUCTURE
ET FONCTION DU SQUELETTE ADULTE
A
lors qu’il est avant tout reconnu pour ses propriétés de soutien et de protection mécaniques, le squelette est en fait l’exemple type de l’organe
« multitâche ». Il assure des rôles qui vont du maintien de l’homéostasie minérale et de l’équilibre acidobasique à la production de cytokines et de
facteurs de croissance, dont certains jouent un rôle capital dans la différenciation et la survie des cellules souches hématopoïétiques. L’os a évolué pour satisfaire des besoins qui, en termes d’ingénierie, sont souvent contradictoires : il est
solide mais léger, rigide mais flexible et résistant. Ces caractéristiques résultent
certes des proportions respectives de minéraux et de collagène qui le constituent,
mais également du remodelage continu qui permet le remplacement de l’os
ancien. L’os est capable de détecter les zones de faiblesse locale et de les réparer avant toute manifestation pathologique, sans perte de fonction. Ces propriétés sont assurés par un processus en quatre phases (activation, résorption,
inversion et formation) qui s’accomplit par l’action séquentielle des ostéoclastes et des ostéoblastes travaillant sous le contrôle des ostéocytes, au sein
d’unités de remodelage osseux reliées entre elles. Les ostéocytes, enfouis dans
une matrice minérale, forment un réseau de « mécanotransducteurs », à l’instar d’un syncytium de type neuronal. Ils détectent les modifications de charge
dans l’os environnant et, par des messagers tels que la sclérostine (produit du
gène Sost), transmettent cette information aux cellules de surface pour instaurer ou réguler le remodelage. Cet élégant mécanisme vient confirmer l’intuition du Dr Alexander Cooke, exprimée dès 1955, alors que les études sur l’os en
étaient encore à leurs balbutiements : « l’immuabilité des os secs et leur persistance pendant… des millions d’années après le retour à la poussière des tissus mous, nous donne une fausse impression de l’os… Sa fixité après la mort
contraste fortement avec son activité incessante au cours de la vie ».
MEDICOGRAPHIA, VOL 30, No. 4, 2008 325
AND
CHALLENGES
IN
OSTEOPOROSIS
NEW APPROACHES
Harry K. GENANT, MD
University of California, San Francisco
Synarc Inc., San Francisco, CA, USA
Klaus ENGELKE, PhD
Department of Medical Physics, University
of Erlangen-Nürnberg, Erlangen and Synarc
Inc., Hamburg, GERMANY
Sven PREVRHAL, PhD
Department of Radiology, University
of California, San Francisco
San Francisco, CA, USA
Advances in bone macrostructure and microstructure
CT imaging in osteoporosis
by H. K. Genant, K. Engelke,
and S. Prevrhal, USA and Germany
ual-energy x-ray absorptiometry (DXA) is the
current clinical standard for diagnosing osteoporosis and assessing the risk of sustaining an osteoporotic bone fracture. The measurement of bone mineral density (BMD) by this areal
projection technique is frequently applied at the
D
tructural information about bone can be provided by noninvasive and/
or nondestructive techniques beyond simple bone densitometry. While
the latter provides important information about the risk of osteoporotic
fracture, many studies indicate that bone mineral density is only partly able to
explain bone strength. Our ability to estimate bone strength may be improved
by quantitative assessment of the macrostructural and microstructural features of bone. In terms of macrostructure, beside the use of conventional radiography and dual-energy x-ray absorptiometry, noninvasive and nondestructive
quantitative assessment includes methods involving computed tomography
(CT)— in particular, volumetric quantitative CT (vQCT) at ~500 to 1000 m
spatial resolution and high-resolution CT (hrCT) at ~100 to 500 m—in addition to high-resolution magnetic resonance (MR [hrMR]), also at ~100 to
500 m. Noninvasive and nondestructive imaging of bone microstructure includes CT at ~1 to 100 m and µMR at ~50 to 100 m. vQCT, hrCT, and hrMR
are generally applicable in vivo to humans; CT and MR are principally applicable in vitro to animal and human bone specimens, and in vivo to animals.
In this review, the more commonly-used CT-based imaging modalities of vQCT,
hrCT, and CT will be addressed, since the special applications of MR for quantitatively imaging bone structure have been less well-developed to date.
S
Medicographia. 2008;30:326-333.
(see French abstract on page 333)
Keywords: bone strength; macrostructure; microstructure; volumetric
computed tomography; high-resolution computed tomography;
noninvasive; nondestructive; quantitative assessment
www.medicographia.com
Address for correspondence: Prof Harry K. Genant, Professor Emeritus of Radiology, Orthopedic
Surgery, Medicine, and Epidemiology, University of California, San Francisco, San Francisco,
CA 94143, USA (e-mail: [email protected])
326 MEDICOGRAPHIA, VOL 30, No. 4, 2008
spine and hip, the two skeletal locations most prone
to fracture. Age, low bone density, and prevalence
of fractures are the most important risk factors for
future fractures, but the predictive power of these
variables is still insufficient to predict who will
eventually sustain a fracture or to unambiguously
identify high-risk groups. The structure or spatial
arrangement of bone at the macroscopic and microscopic levels is thought to provide additional independent information beyond BMD, and may help
to predict fracture risk more accurately and to better assess response to drug intervention. Support
for this idea is provided by the large overlap of BMD
values among people with and without fractures,
and by differences in mechanical strength observed
in vitro that appear to be driven by variations in
structure.1,2
While many of the parameters that have been
developed to describe macrostructural and microstructural properties can easily be assessed in vitro,
nondestructive and noninvasive techniques for use
in vivo are at the forefront of radiological research
in osteoporosis. A variety of different modalities
ranging from plain x-rays and DXA-based hip structural analysis to computed tomography (CT) and
magnetic resonance imaging (MRI) have been developed to assess bone structure, both at the macro
and micro levels. However, the most dynamic development can be observed in the field of CT. Advances in this field are therefore the topic of this
overview.
Compared with other modalities, CT-based techniques have several advantages. In contrast to DXA,
volumetric quantitative CT (vQCT) offers 3D information, and cortical and trabecular bone can be
separately analyzed. In contrast to MRI, vQCT acquisition is much quicker and technically less de-
Advances in bone macrostructure and microstructure CT imaging in osteoporosis – Genant and others
NEW APPROACHES
manding. Also, standard whole body clinical CT
scanners can be used for acquisition; these are
more widely available and easier to operate than
MRI equipment. Dedicated peripheral CT scanners
are available for assessing BMD in the radius and
tibia, as well as for measuring trabecular structure
of the forearm. Currently, the imaging of specimens, bone biopsies, and small animals for the investigation of bone structure is almost exclusively
carried out with μCT scanners. Over the past decade,
several commercial companies have been offering
an increasing variety of μCT scanners for different
applications. In addition, active research using μCT
is going on at several academic institutions.
AND
CHALLENGES
IN
OSTEOPOROSIS
ing of baseline and follow-up scans has been suggested.8 Most analysis software is experimental; only
a few commercial programs are available.
One advantage of QCT compared with DXA, already advocated for the original 2D single slice applications, is the separate analysis of BMD for the
trabecular and cortical compartments. Whereas trabecular bone, in particular at the spine, is metabol-
Volumetric quantitative
computed tomography
Originally, QCT focused on measurement of trabecular BMD in single transverse CT slices at the lumbar midvertebral levels and at the forearm. The determination of BMD is still an application of the
new spiral QCT acquisition protocols (Figure 1).3-6
However, these new 3D data acquisition schemes
raise challenges and promises for the analysis. A
particular challenge is the reproducible location of
a given analysis volume of interest (VOI) in longitudinal scans. One approach is to position the VOI
relative to an anatomic coordinate system that can
be reliably determined.6,7 As an alternative, a matchSELECTED
BMD
BV/TV
CT
DXA
ECT
EFFECT
ABBREVIATIONS AND ACRONYMS
bone mineral density
bone volume fraction
computed tomography
dual-energy x-ray absorptiometry
elcatonin
European Femur Fracture study using
finite Element analysis and 3D CT
FEM
finite element modeling
hrCT
high-resolution computed tomography
MRI
magnetic resonance imaging
MrOS
Osteoporotic Fractures in Men Study
OVX
ovariectomy
PaTH
ParaThyroid Hormone and Alendronate
for Osteoporosis (study)
pQCT
peripheral quantitative computed
tomography
PTH
parathyroid hormone
QCT
quantitative computed tomography
SMI
structure model index
SOTI
Spinal Osteoporosis Therapeutic Intervention (study)
SR
strontium ranelate
Tb.N
trabecular number
Tb.Sp
trabecular separation
Tb.Th
trabecular thickness
TROPOS TReatment Of Peripheral OSteoporosis
(study)
VOI
volume of interest
vQCT
volumetric quantitative computed
tomography
Figure 1. Volumetric quantitative computed tomography of the spine (top) and
hip (bottom) may be used to analyze bone mineral density in various bone compartments and to accurately measure bone mineral density and geometry. Top left:
segmented vertebral body selected for analysis with removed processes. Top center
and right: integral (red) and trabecular and peeled trabecular volumes of interest
(dark blue), along with the traditional elliptical and Pacman volumes of interest
(light blue). Bottom left: segmented proximal femur. Bottom center and right: analysis of volumes of interest in the hip.
ically more active and may therefore serve as an
early indicator of treatment success, cortical bone,
in particular at the hip, may be more important for
the estimation of fracture risk.9 Almost isotropic
spatial resolution of about 0.5 mm significantly improves the 3D assessment of the cortex. Still, the
spatial resolution is not high enough to give accurate results regarding cortical thickness below values
of approximately 1.5 to 2 mm. However, as shown
by the authors of the present review,10 even below
these values, a 10% to 20% change in thickness can
still be measured accurately. In general, it is easier
to measure cortical thickness in the femur than in
the spine, where thicknesses of 200 to 500 μm are
encountered frequently, especially in the elderly.
The limited spatial resolution also results in an underestimation of cortical BMD on the order of 10%
to 30%. In addition to measuring the cortex, vQCT
is a sophisticated tool for determining geometrical
parameters of mechanical relevance such as cross
sectional moments of inertia.
At the spine, the cross-sectional area of the vertebral bodies is a macrostructural parameter of interest, since larger vertebrae are likely to be able
to sustain load better than smaller ones. Periosteal
apposition, which may occur at the spine and the
femur, has the potential to offset the increase in
fragility caused by loss of bone mass by increasing
the cross-sectional area. A cross-sectional vQCT
study by Riggs et al showed that women not only
start out with smaller vertebrae and lose bone mass
Advances in bone macrostructure and microstructure CT imaging in osteoporosis – Genant and others
MEDICOGRAPHIA, VOL 30, No. 4, 2008 327
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
faster than men, but also that their cross-sectional area increases slower than men.11 Although the
magnitude of the changes reported with vQCT are
inconsistent with DXA findings,12 the study indicates that measurement of spinal cross-sectional
area with vQCT may provide additional predictive
power for fracture risk. Another parameter potentially of interest is the polar mass moment of inertia, which one measures to characterize the bone
mineral distribution within the vertebral body.
Since the geometry of the proximal femur is more
complicated than that of the vertebral body, macrostructural parameters of interest include cross-sectional areas at the neck and greater trochanter, hip
axis length, and simple mechanical measures such
as cross-sectional moment of inertia and section
moduli at various cross sections along the femoral
neck axis. As in the spine, periosteal apposition
causes the cross-sectional areas of the femoral neck
and shaft to expand with age.11 The large Osteoporotic Fractures in Men Study (MrOS) confirmed
this and also found that cortical thinning occurs
with increasing age. However, whereas the neck
seemed to exhibit net cortical bone loss, periosteal
expansion seemed to offset shaft cortical thinning
to maintain cortical cross-sectional area.13 This
study also showed ethnic differences, with higher
femoral neck and lumbar spine volumetric BMD but
Axial hrCT
Nonfracture, 62 y/o F
L 2- 4 DXA: 1.001
Fracture, 62 y/o F
L 2- 4 DXA: 0.820
Figure 2. Multislice high resolution in vivo computed tomography (hrCT)
image of the spine rendered in original axial plane (center), and in 3D,
showing a normal woman (left) and an osteoporotic woman (right). DXA,
dual-energy x-ray absorptiometry. Courtesy of Masako Ito.
lower cross-sectional areas in African Americans,
which might contribute to some of the ethnic difference in hip and vertebral fracture epidemiology.
Lang and colleagues showed in a specimen study
using vQCT that these parameters explain femoral
strength partially independently of BMD.14
Only a few treatment studies have so far used
vQCT. The first one to do so, the ParaThyroid Hormone and Alendronate for Osteoporosis (PaTH)
study, investigated parathyroid hormone (PTH) and
alendronate treatment alone or in combination, and
found that femoral cortical volume increased with
1 year of treatment with PTH followed by 1 year
with alendronate.15,16 CT examination also showed
328 MEDICOGRAPHIA, VOL 30, No. 4, 2008
a substantial increase in volumetric trabecular BMD
at total hip and femoral neck in PTH-treated postmenopausal osteoporotic women (n=62) after 1 year
as well as after 2 years. Similar results were observed
in another PTH study.17
The overall advantages of the vQCT technique include high precision, on the order of 1% to 2% for
BMD of the spine, hip, and radius; nearly instant
availability of data, in a matter of seconds to minutes; widespread access, with many thousands of
systems available worldwide; and minimal user interaction. The major disadvantages for volumetric
BMD measurement are the use of modest radiation
exposure, the spine and hip requiring an effective
dose of approximately 500 to 3000 μSv and a dose
of about 10 μSv for the radius. These radiation doses compare favorably, however, with the average
annual background effective dose of 2500 μSv in
the US and Europe, and the effective dose of 50 μSv
for a roundtrip transatlantic flight between the US
and Europe.
High-resolution computed tomography
Another area of active research is high-resolution
CT (hrCT). As described above, modern CT scanners
for measurement of the axial skeleton offer isotropic spatial resolution of approximately 0.5 mm. However, given the typical dimensions of trabeculae
(100-400 µm) and trabecular spaces (200-2000 μm)
this resolution is still borderline for enabling a direct determination of trabecular architecture (Figure 2). Due to substantial partial volume artifacts,
the extraction of the quantitative structural information is difficult and the results vary substantially according to the threshold and image processing
techniques used. Instead of measuring structural
parameters directly, there is a trend to use textural
or statistical descriptors to characterize the trabecular architecture without requiring stringent segmentation of the individual trabeculae.
Older techniques involved, for instance, use of
the trabecular fragmentation index (length of the
trabecular network divided by the number of discontinuities),18 run-length analysis,19 a parameter
reflecting trabecular hole area analogous to star
volume,20-22 and co-occurrence texture measures.22
Newer approaches prefer gray-level analyses and
use for example Minkowsky functionals23 or Gabor
wavelets24 to quantify trabecular topology. Recently,
structural parameters of the spine were analyzed
in a longitudinal in vivo study of PTH. In the treated group, all structural variables showed significant improvements, with some independence from
BMD.25 In a different cross-sectional study, the use
of hrCT to measure vertebral trabecular structure
parameters could better distinguish between fracture cases and nonfracture controls than BMD measurements with DXA.26
Since the assessment of trabecular structure in
vivo is rather difficult, special-purpose peripheral
CT scanners have been developed to assess the distal forearm, where trabecular thickness ranges from
60 to 150 μm and trabecular separation from 300
to 1000 μm. The first to pursue this successfully
Advances in bone macrostructure and microstructure CT imaging in osteoporosis – Genant and others
NEW APPROACHES
were Rüegsegger and colleagues, who built a thinslice high-resolution laboratory peripheral QCT
(pQCT) scanner for in vivo measurements with an
isotropic voxel size of 170 μm3.27 Using a scanner
with further improved resolution, Müller et al reported a high in vivo reproducibility of about 1%
achieved by careful registration of the acquired 3D
datasets.28 When in vitro pQCT structure measurements were compared with μCT, the correlation of
various 3D structural parameters between the two
systems was r 2 >0.9, despite the lower resolution of
the pQCT system. Therefore a dedicated segmentation threshold can be obtained for pQCT by calibrating the pQCT bone volume fraction (BV/TV) to
the µCT BV/TV.29
This group also introduced a number of new parameters to quantify the trabecular network, such
as ridge number density30 and the structure model index (SMI).31 The work of the group around
Rüegsegger cumulated in the development of the
XtremeCT, a commercially available in vivo pQCT
scanner for the forearm and the tibia with specifications similar to those of the laboratory scanner
described above (Figure 3).32 A critical step in the
analysis of follow-up scans in order to detect longitudinal changes of bone structure within a given
subject is the registration of baseline and follow-up
scans with an accuracy that should be in the order
of 100 μm. Thus during the scans, even slight motion of the forearm must be avoided, which is not
an easy task given the scan time of several minutes.
Compared with the manufacturer-provided matching, advanced 3D registration of scans could reduce
the repositioning error by over 20%.33
Apart from technical studies,32-34 some clinical
studies using the XtremeCT have already been reported. The first indication that peripheral trabecular structure assessment is indeed useful to differentiate women with an osteoporotic fracture
history from controls and is better than DXA at the
hip or spine, came from Boutroy and colleagues.32
Khosla and colleagues examined age- and sex-related bone loss cross-sectionally, and speculated as to
the different patterns of bone loss in men and women.35,36 Finally, MacNeil and coworkers reported a
strong ability to predict bone apparent stiffness
and apparent Young’s modulus with morphological
and density measurements in the radius and tibia
(r 2 >0.8) using the XtremeCT.37
Micro–computed tomography
μCT denotes a CT technique with a spatial resolution of 1 to 100 μm; techniques with a resolution below this are typically termed microscopy. μCT offers the promise of replacing tedious serial staining
techniques required by histomorphometric analysis of thin sections, and the possibility of longitudinal in vivo investigations in small animals such as
mice and rats. Many of the early μCT approaches
used synchrotron radiation,38 which is still the
method of choice for ultra high resolution applications. Obviously the use of desktop laboratory scanners equipped with x-ray tubes is much more convenient than setting up an experiment at one of the
AND
CHALLENGES
IN
OSTEOPOROSIS
few synchrotron facilities available. Thus, after initial and still ongoing university-based research during the last decade, a variety of x-ray tube–based
commercial μCT scanners have been developed.
Some of them integrate sophisticated software for
the 3D analysis of bone structure31,39,40 including finite element modeling (FEM).
3D μCT in vivo of wrist
90 90 90 μm3
effective dose <5 μSv
Figure 3. In vivo micro computed tomography image of the distal radius
using the XtremeCT system, with images showing the region of the distal
radius imaged (left), the resulting 3D rendering (right), and associated
micro–finite element analysis. Courtesy of Bruno Koller and Ralph Mueller.
One area of research involves the investigation of
trabecular bone structure in human iliac crest biopsies. For example, iliac crest bone biopsy specimens
were taken and analyzed from women participating
in a placebo-controlled trial with a bisphosphonate,
risedronate. After 1 year, in the control group, BV/
TV decreased by 20% and trabecular number (Tb.N)
by 14% compared with baseline. Trabecular separation (Tb.Sp) increased by 13% and marrow star volume increased by 86%. In the same period, lumbar
spine BMD as measured by DXA decreased by only
3.3%. In the risedronate-treated group, the architectural parameters did not significantly change
during the same period.41 In another study by some
members of the same group, the effect of risedronate
was examined using ultra high-resolution synchrotron-based μCT to document the impact of treatment on the degree of bone mineralization at the
tissue level. They showed considerable reduction in
the amount and degree of lower mineralized trabecular bone from serial iliac crest biopsies, using
the unique capabilities of the monochromatic beam
emanating from the synchrotron radiation beam
(Figure 4, page 330).42 In another longitudinal study
of paired biopsies taken before and after treatment
with human PTH, μCT showed increased 3D connectivity density and confirmed the preservation of
2D histomorphometric BV/TV, Tb.N, and trabecular
thickness (Tb.Th).43 Similar results for PTH were
reported recently in a third biopsy study. After 19
months of PTH treatment, compared with placebo,
BV/TV increased by 44%, Tb.N by 12%, Tb.Th by
16%, and connectivity density by 25%. Tb.Sp decreased by 10% and SMI by 50%, demonstrating
Advances in bone macrostructure and microstructure CT imaging in osteoporosis – Genant and others
MEDICOGRAPHIA, VOL 30, No. 4, 2008 329
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
Risedronate 5m
Baseline
3 Years
Figure 4. Ultra-high resolution synchrotron-based images of serial iliac
crest biopsies showing a reduction in the lower mineralized trabecular
bone in response to an anti-resorber, bisphosphonate. Courtesy of Eric
E. Ritman and Babul Borah.
the usefulness of 3D parameters obtainable from
μCT.44 In a study in ovariectomized baboons, bisphosphonates preserved the microarchitecture in
thoracic vertebrae.45
Arlot and coworkers investigated the 3D bone
microstructure of postmenopausal osteoporotic
women treated with strontium ranelate (SR).46 Transiliac bone biopsies (Figure 5) were obtained in a
subset of patients from 2 large randomized doubleblind multicenter studies: SOTI (Spinal Osteoporosis Therapeutic Intervention; 1649 patients, for incident vertebral fracture) and TROPOS (TReatment
BV/TV (+13%; not significant), and increasing Tb.N
(+14%, P=0.05) based on plate model assumption
(Figure 6). SR treatment stimulates 3D trabecular
and cortical bone formation, which is not at the expense of intracortical porosity. These changes in 3D
trabecular and cortical microstructure, shown by
μCT, enhance bone biomechanical competence and
help explain the decreased fracture risk observed after SR treatment.
As it is rather difficult to obtain human bone biopsies, studies investigating drug and disease effects
are often performed during the preclinical phase
using laboratory animals. In an investigation of rat
tibiae 16 weeks after ovariectomy (OVX), BV/TV decreased by 69% and Tb.Th by 30% compared with a
sham-operated control group. Tb.Sp increased by
100% and SMI by 48%. This showed that with estrogen deficiency, the trabecular network consisted of more rod-shaped trabeculae.47 Treatment of
OVX rats with risedronate maintained the platelike trabecular structure and network connectivity.48 A study with either cathepsin K- or rolipramtreated OVX BALB/c mice showed that compared
with the sham-operated control group, in both
treatment arms, a decrease in BV/TV and a deterioration in trabecular structure was prevented.49 Another study with ovariectomized rats showed that
PTH and elcatonin (ECT), a synthetic derivative of
eel calcitonin, preserved bone architecture by different means. After 12 weeks of treatment, BV/TV was
greater in the ECT and PTH groups than in the OVX
group. The number of nodes per trabecular volume
(N.Nd/TV) and Tb.N were significantly greater in
the ECT group, whereas Tb.Th was greater in the
PTH group.50 3D μCT has also been used to quantify trabecular architecture in osteoarthritis.51-56
Finite element modeling
Figure 5. 3D micro computed tomography image showing microstructure of transiliac bone biopsies from two postmenopausal women at 36
months after therapy. Placebo (left), strontium ranelate therapy (right).
Reproduced from reference 46: Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric
and micro-CT analysis of bone biopsies from postmenopausal osteoporotic women treated
with strontium ranelate. J Bone Miner Res. 2008;23:215-222. © 2008, The American
Society for Bone and Mineral Research.
Of Peripheral OSteoporosis; 5091 patients, for nonspinal fractures). A total of 41 biopsies from the
iliac crests of patients treated with either placebo
(n=21) or SR at 2g/day (n=20) were examined with
μCT at an isotropic resolution of 20 μm. Compared
with placebo, SR treatment significantly improved
trabecular SMI (--22%; P=0.01), shifting trabeculae
from a rod-like structure to a plate-like pattern, decreasing trabecular separation (--16%; P=0.04) based
on plate model assumption, increasing cortical
thickness (+18%; P=0.008), increasing trabecular
330 MEDICOGRAPHIA, VOL 30, No. 4, 2008
FEM is a computer-based simulation of the strains
and stresses induced by mechanical loading of an
object, and is widely used in engineering. The object is described as a connected set of simply-shaped
elements, which are ascribed elastic properties. One
of its goals is to better predict load conditions that
lead to fracture and thus to improve fracture prediction. Currently, the models are typically derived
from vQCT scans, and the elastic properties of elements are computed from bone density at the position of the elements (Figure 7).14,57-60 Finite element
models mechanically integrate all of the anisotropic, inhomogeneous, and complex geometry of the
bone structure examined.
Keaveny, Hayes, and colleagues found that at the
spine in healthy subjects, the cortical shell does not
transfer much of the load.58 It has been claimed that
voxel-based FEM–derived estimates of strength are
better predictors of in vitro vertebral compressive
strength than clinical measures of bone density derived from QCT with or without bone size.59 However, this advantage of FEM may not pertain if more
sophisticated parameters than just midvertebral
trabecular BMD and bone size are measured.6 Although imaging resolution for FEM is not critical in
cross-sectional studies using clinical CT scanners,
Advances in bone macrostructure and microstructure CT imaging in osteoporosis – Genant and others
NEW APPROACHES
3
+13%
P=0.26
3
–22%
P=0.01
OSTEOPOROSIS
2
125
2
100
1
1
75
1
1
50
5
5
25
Strontium
ranelate
0
Placebo
Strontium
ranelate
+18%
P=0.008
150
2
Placebo
IN
SMI
2
0
CHALLENGES
modeling of individual trabeculae, which is computationally much more demanding than just using
voxels containing average gray values, has become
feasible. Full 3D models were first developed by van
Rietbergen.63 Prediction of overall bone strength
recorded during mechanical testing of small samples of trabecular bone with such models is indeed
longitudinal studies that seek to track more subtle
changes in stiffness over time should account for
the small but highly significant effects of voxel size.60
In the femur, vQCT-based FEM applications for
fracture prediction are still rare. One study in 51
women aged 74 years61 showed different risk factors
for hip fracture during single-limb stance and falls,
BV/TV
AND
0
Placebo
Strontium
ranelate
Figure 6. Analysis of bone volume fraction (BV/TV), structure model index (SMI) and cortical thickness (Ct.Th)
in transiliac bone biopsies from postmenopausal women after 36 months of strontium ranelate therapy. Placebo
n=21, strontium ranelate n=20.
Reproduced from reference 46: Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and micro-CT analysis of bone biopsies from
postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res. 2008;23:215-222. © 2008, The American Society
for Bone and Mineral Research.
which is in agreement with epidemiologic findings
of different risk factors for cervical and trochanteric fractures. In the in vitro arm of the European Femur Fracture study using finite Element analysis
and 3D CT (EFFECT), parameters predicted fracture load in fall and stance configuration as well as
FEM.62 Also, reproducibility may impose limits on
the usefulness of FEM analysis.
With the vast increases in computer power of the
last decade and the availability of μCT data, the application of FEM at spatial resolutions that allow
better than with macroscopic bone density measurements.59,64 However, only recently has μCT scanning offered the resolution to allow conversion of
the gray values of the individual pixels to elastic
moduli to further improve the accuracy of fracture
load prediction.65 Using this improved technique,
Homminga and colleagues for example showed that
while osteoporotic vertebrae could withstand daily
load patterns to a degree comparable with that of
normal bone, loading as occurs during forward
bending caused much higher stresses in the osteoporotic vertebra.1
Conclusion
Low
High
Figure 7. Distribution of Young’s modulus during simulated compression in a stance-loading configuration,
computed by finite element modeling based on volumetric quantitative computed tomography data. Courtesy
of Tony Keaveny.
Recent important developments in quantitative bone
imaging are creating new opportunities to assess
bone biology in osteoporosis and other diseases, and
to evaluate the effects of pharmacotherapy on bone
structure and function. These techniques are gaining widespread acceptance, and have been incorporated into recent clinical trials of osteoporosis
therapy. hrCT and vQCT are widely available, noninvasive, nondestructive methods that provide information about BMD, bone macrostructure, and
to some extent “microstructure.” There are important limitations regarding spatial resolution, which
reduce visualization to only larger trabecular plates
and preclude depiction of its finer structure. Also,
these techniques entail exposure to modest levels
of ionizing radiation and require nonstandardized
and specialized image processing software. μCT, on
the other hand, provides automated 2D and 3D
evaluations of the osseous structure of laboratory
animals or of bone specimens, and since it is nondestructive of the sample, allows for subsequent
Advances in bone macrostructure and microstructure CT imaging in osteoporosis – Genant and others
MEDICOGRAPHIA, VOL 30, No. 4, 2008 331
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
mechanical testing. It provides highly detailed visualization of bone microstructure, while its limitations include the need for an invasive biopsy or
applications limited to laboratory animals. With μCT,
there is also the potential for sampling errors, relatively high costs, and limited availability of the
equipment. Finally, for both vQCT and μCT, the advanced techniques of FEM can be applied to the acquired image datasets, which provide the capability
to measure important parameters of bone strength
and perhaps to improve our understanding of skeletal biomechanics and fracture propensity. REFERENCES
1. Homminga J, Van-Rietbergen B, Lochmuller EM, Weinans H,
Eckstein F, Huiskes R. The osteoporotic vertebral structure is
well adapted to the loads of daily life, but not to infrequent “error”
loads. Bone. 2004;34:510-516.
2. Homminga J, McCreadie BR, Ciarelli TE, Weinans H, Goldstein
SA, Huiskes R. Cancellous bone mechanical properties from normals and patients with hip fractures differ on the structure level,
not on the bone hard tissue level. Bone. 2002;30:759-764.
3. Kang Y, Engelke K, Kalender WA. A new accurate and precise
3-D segmentation method for skeletal structures in volumetric
CT data. IEEE Trans Med Imaging. 2003;22:586-598.
4. Lang TF, Guglielmi G, van Kuijk C, De Serio A, Cammisa M,
Genant HJ. Measurement of bone mineral density at the spine and
proximal femur by volumetric quantitative computed tomography and dual-energy X-ray absorptiometry in elderly women with
and without vertebral fractures. Bone. 2002;30:247-250.
5. Lang TF, Li J, Harris ST, Genant HK. Assessment of vertebral
bone mineral density using volumetric quantitative CT. J Comput
Assist Tomogr. 1999;23:130-137.
6. Mastmeyer A, Engelke K, Fuchs C, Kalender WA. A hierarchical 3D segmentation method and the definition of vertebral body
coordinate systems for QCT of the lumbar spine. Med Image Anal.
2006;10:560-577.
7. Kang Y, Engelke K, Fuchs C, Kalender WA. An anatomic coordinate system of the femoral neck for highly reproducible BMD
measurements using 3D QCT. Comput Med Imaging Graph.2005;
29:533-541.
8. Li W, Sode M, Saeed I, Lang T. Automated registration of hip
and spine for longitudinal QCT studies: integration with 3D densitometric and structural analysis. Bone. 2006;38:273-279.
9. Bousson V, Le Bras A, Roqueplan F, et al. Volumetric quantitative computed tomography of the proximal femur: relationships
linking geometric and densitometric variables to bone strength.
Role for compact bone. Osteoporos Int. 2006;17:855-864.
10. Prevrhal S, Engelke K, Kalender WA. Accuracy limits for the
determination of cortical width and density: the influence of object size and CT imaging parameters. Phys Med Bio.1999;44:751764.
11. Riggs BL, Melton Iii LJ 3rd, Robb RA, et al. Population-based
study of age and sex differences in bone volumetric density, size,
geometry, and structure at different skeletal sites. J Bone Miner
Res. 2004;19:1945-1954.
12. Duan Y, Beck TJ, Wang XF, Seeman E. Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has
its origins in growth and aging. J Bone Miner Res. 2003;18:17661774.
13. Marshall LM, Lang TF, Lambert LC, Zmuda JM, Ensrud KE,
Orwoll ES. Dimensions and volumetric BMD of the proximal femur and their relation to age among older US men. J Bone Miner
Res. 2006;21:1197-1206.
14. Lang TF, Keyak JH, Heitz MW, et al. Volumetric quantitative
computed tomography of the proximal femur: precision and relation to bone strength. Bone. 1997;21:101-108.
15. Black DM, Greenspan SL, Ensrud KE, et al. The effects
of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:
1207-1215.
16. Black DM, Bilezikian JP, Ensrud KE, et al. One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med. 2005;353:555-565.
17. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture
and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med. 2007;146:326-339.
18. Chevalier F, Laval-Jeantet AM, Laval-Jeantet M, Bergot C. CT
image analysis of the vertebral trabecular network in vivo. Calcif
Tissue Int. 1992;51:8-13.
19. Ito M, Ohki M, Hayashi K, Yamada M, Uetani M, Nakamura
T. Trabecular texture analysis of CT images in the relationship
with spinal fracture. Radiology. 1995;194:55-59.
20. Gordon CL, Webber CE, Adachi JD, Christoforou N. In vivo assessment of trabecular bone structure at the distal radius from
high-resolution computed tomography images. Phys Med Biol.
1996;41:495-508.
21. Gordon CL, Lang TF, Augat P, Genant HK. Image-based assessment of spinal trabecular bone structure from high-resolution CT images. Osteoporos Int. 1998;8:317-325.
22. Showalter C, Clymer BD, Richmond B, Powell K. Three-dimensional texture analysis of cancellous bone cores evaluated at
clinical CT resolutions. Osteoporos Int. 2006;17:259-266.
23. Saparin P, Thomsen JS, Kurths J, Beller G, Gowin W. Segmentation of bone CT images and assessment of bone structure
using measures of complexity. Med Phys. 2006;33:3857-3873.
24. Xiang Y, Yingling VR, Malique R, Li CY, Schaffler MB, Raphan
T. Comparative assessment of bone mass and structure using texture-based and histomorphometric analyses. Bone. 2007;40:544552.
25. Graeff C, Timm W, Nickelsen TN, et al. Monitoring Teriparatide-Associated Changes in Vertebral Microstructure by HighResolution CT In Vivo: Results From the EUROFORS Study.
J Bone Miner Res. 2007;22:1426-1433.
26. Ito M, Ikeda K, Nishiguchi M, et al. Multi-detector row CT
imaging of vertebral microstructure for evaluation of fracture
risk. J Bone Miner Res. 2005;20:1828-1836.
27. Durand EP, Rüegsegger P. High-contrast resolution of CT
images for bone structure analysis. Med Phys.1992;19:569-573.
28. Muller R, Hildebrand T, Hauselmann HJ, Ruegsegger P. In
vivo reproducibility of three-dimensional structural properties
of noninvasive bone biopsies using 3D-pQCT. J Bone Miner Res.
1996;11:1745-1750.
29. Müller R, Koller B, Hildebrand T, Laib A, Gianolini S, Rüegsegger P. Resolution dependency of microstructural properties
of cancellous bone based on three-dimensional μ-tomography.
Technol Health Care. 1996;4:113-119.
30. Laib A, Hildebrand T, Hauselmann HJ, Ruegsegger P. Ridge
number density: a new parameter for in vivo bone structure analysis. Bone. 1997;21:541-546.
31. Hildebrand T, Rüegsegger P. Quantification of bone microarchitecture with the structure model index. CMBBE.1997;1:15-23.
32. Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2005;90:6508-6515.
33. Macneil JA, Boyd SK. Improved reproducibility of high-resolution peripheral quantitative computed tomography for measurement of bone quality. Med Eng Phys. 2007; December 27.
Epub ahead of print.
34. MacNeil JA, Boyd SK. Accuracy of high-resolution peripheral quantitative computed tomography for measurement of bone
quality. Med Eng Phys. 2007;29:1096-1105.
35. Khosla S, Riggs BL, Atkinson EJ, et al. Effects of sex and age
on bone microstructure at the ultradistal radius: a populationbased noninvasive in vivo assessment. J Bone Miner Res. 2006;
21:124-131.
36. Khosla S, Melton LJ 3rd, Achenbach SJ, Oberg AL, Riggs BL.
Hormonal and biochemical determinants of trabecular microstructure at the ultradistal radius in women and men. J Clin
Endocrinol Metab. 2006;91:885-891.
37. MacNeil JA, Boyd SK. Load distribution and the predictive
power of morphological indices in the distal radius and tibia by
high resolution peripheral quantitative computed tomography.
Bone. 2007;41:129-137.
38. Graeff W, Engelke K. Microradiography and microtomography. In: Ebashi E, Koch M, Rubenstein E, eds. Handbook on Synchrotron Radiation. Amsterdam, Holland: Elsevier; 1991:361-405.
39. Hildebrand T, Rüegsegger P. A new method for the model
independent assessment of thickness in three-dimensional images. J Microsc. 1997;185:67-75.
40. Odgaard A, Gundersen HJ. Quantification of connectivity in
cancellous bone, with special emphasis on 3-D reconstructions.
Bone. 1993;14:173-182.
41. Dufresne TE, Chmielewski PA, Manhart MD, Johnson TD,
Borah B. Risedronate preserves bone architecture in early postmenopausal women in 1 year as measured by three-dimensional
microcomputed tomography. Calcif Tissue Int. 2003;73:423-432.
42. Borah B, Ritman EL, Dufresne TE. The effect of risedronate
on bone mineralization as measured by micro-computed tomography with synchrotron radiation: correlation to histomorpho-
332 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Advances in bone macrostructure and microstructure CT imaging in osteoporosis – Genant and others
NEW APPROACHES
metric indices of turnover. Bone. 2005;37:1-9.
43. Dempster DW, Cosman F, Kurland ES, et al. Effects of daily
treatment with parathyroid hormone on bone microarchitecture
and turnover in patients with osteoporosis: a paired biopsy study.
J Bone Miner Res. 2001;16:1846-1853.
44. Fox J, Miller MA, Recker RR, Bare SP, Smith SY, Moreau I.
Treatment of postmenopausal osteoporotic women with parathyroid hormone 1-84 for 18 months increases cancellous bone formation and improves cancellous architecture: a study of iliac crest
biopsies using histomorphometry and micro computed tomography. J Musculoskelet Neuronal Interact. 2005 ;5:356-357.
45. Hordon LD, Itoda M, Shore PA, et al. Preservation of thoracic
spine microarchitecture by alendronate: comparison of histology and microCT. Bone. 2006;38:444-449.
46. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and
micro-CT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner
Res. 2008;23:215-222.
47. Yang J, Pham SM, Crabbe DL. High-resolution micro-CT
evaluation of mid- to long-term effects of estrogen deficiency on
rat trabecular bone. Acad Radiol. 2003;10:1153-1158.
48. Ito M, Nishida A, Aoyagi K, Uetani M, Hayashi K, Kawase M.
Effects of risedronate on trabecular microstructure and biomechanical properties in ovariectomized rat tibia. Osteoporos Int.
2005;16:1042-1048.
49. Xiang A, Kanematsu M, Kumar S, et al. Changes in micro-CT
3D bone parameters reflect effects of a potent cathepsin K inhibitor (SB-553484) on bone resorption and cortical bone formation in ovariectomized mice. Bone. 2007;40:1231-1237.
50. Washimi Y, Ito M, Morishima Y, et al. Effect of combined humanPTH(1-34) and calcitonin treatment in ovariectomized rats.
Bone. 2007;41:786-793.
51. Wachsmuth L, Engelke K. High-resolution imaging of osteoarthritis using microcomputed tomography. Methods Mol Med.
2004;101:231-248.
52. Patel V, Issever AS, Burghardt A, Laib A, Ries M, Majumdar S.
MicroCT evaluation of normal and osteoarthritic bone structure
in human knee specimens. J Orthop Res. 2003;21:6-13.
53. Ding M, Odgaard A, Hvid I. Changes in the three-dimensional microstructure of human tibial cancellous bone in early osteoarthritis. J Bone Joint Surg Br. 2003 ;85:906-912.
54. Batiste DL, Kirkley A, Laverty S, Thain LM, Spouge AR, Holdsworth DW. Ex vivo characterization of articular cartilage and
bone lesions in a rabbit ACL transection model of osteoarthritis
using MRI and micro-CT. Osteoarthritis Cartilage. 2004;12:986996.
55. Batiste DL, Kirkley A, Laverty S, et al. High-resolution MRI
and micro-CT in an ex vivo rabbit anterior cruciate ligament transection model of osteoarthritis. Osteoarthritis Cartilage. 2004;
12:614-626.
56. Chappard C, Peyrin F, Bonnassie A, et al. Subchondral bone
micro-architectural alterations in osteoarthritis: a synchrotron
micro-computed tomography study. Osteoarthritis Cartilage.
2006;14:215-223.
57. Keyak JH, Rossi SA. Prediction of femoral fracture load using
finite element models: an examination of stress- and strain-based
failure theories. J Biomech. 2000;33:209-214.
AND
CHALLENGES
IN
OSTEOPOROSIS
58. Silva MJ, Keaveny TM, Hayes WC. Load sharing between the
shell and centrum in the lumbar vertebral body. Spine.1997;22:
140-150.
59. Crawford RP, Cann CE, Keaveny TM. Finite element models
predict in vitro vertebral body compressive strength better than
quantitative computed tomography. Bone. 2003;33:744-750.
60. Crawford RP, Rosenberg WS, Keaveny TM. Quantitative computed tomography-based finite element models of the human
lumbar vertebral body: effect of element size on stiffness, damage,
and fracture strength predictions. J Biomech Eng. 2003;125:
434-438.
61. Ciarelli TE, Fyhrie DP, Schaffler MB, Goldstein SA. Variations
in three-dimensional cancellous bone architecture of the proximal femur in female hip fractures and in controls. J Bone Miner
Res. 2000;15:32-40.
62. Engelke K, Bousson V, Duchemin L, et al. EFFECT—The European Femur Fracture Study using Finite Element Analysis and
3D CT. J Bone Miner Res. 2006;21(Suppl 1)S86. Abstract F104.
63. Van Rietbergen B, Weinans H, Huiskes R, Odgaard A. A new
method to determine trabecular bone elastic properties and loading using micromechanical finite-element models. J Biomechanics. 1995;28:69-81.
64. Ulrich D, Hildebrand T, Van Rietbergen B, Muller R, Ruegsegger P. The quality of trabecular bone evaluated with microcomputed tomography, FEA and mechanical testing. Stud Health
Technol Inform. 1997;40:97-112.
65. Homminga J, Huiskes R, Van Rietbergen B, Ruegsegger P,
Weinans H. Introduction and evaluation of a gray-value voxel conversion technique. J Biomech. 2001;34:513-517.
PROGRÈS DANS L’IMAGERIE TOMODENSITOMÉTRIQUE
DE LA MACROSTRUCTURE ET DE LA MICROSTRUCTURE
OSSEUSES DANS L’OSTÉOPOROSE
A
u-delà de la simple densitométrie osseuse, des techniques non invasives
et/ou non destructrices peuvent fournir des informations sur la structure osseuse. Alors que la densitométrie apporte d’importants renseignements sur le risque de fractures ostéoporotiques, de nombreuses études
indiquent que la densité minérale osseuse n’explique qu’en partie la solidité osseuse. La mesure de la solidité osseuse pourrait être améliorée par l’évaluation
quantitative des éléments macrostructuraux et microstructuraux de l’os. En
ce qui concerne la macrostructure, à côté de la radiographie classique et de l’absorptiométrie biphotonique aux rayons X, la tomodensitométrie (TDM), en particulier la tomographie quantitative volumétrique (TQv) à résolution spatiale
à 500-1000 m et à haute résolution (Thr) à 100-500 m, ajoutée à la résonance magnétique à haute résolution (RM [RMhr]), à 100-500 m également,
permettent une évaluation quantitative non destructrice et non invasive. La
microstructure osseuse, quant à elle, peut être évaluée par la TDM à 1-100 m
et la RM à 50-100 m, qui sont également des méthodes d’imagerie non invasives et non destructrices. Les TQv, Thr et RMhr sont habituellement utilisées in vivo chez l’homme ; la TDM et la RM s’utilisent essentiellement in
vitro pour les échantillons osseux animaux et humains et in vivo pour les animaux. Les applications particulières de la RM pour l’imagerie quantitative de
la structure osseuse étant peu développées à ce jour, cet article se concentrera
sur les techniques d’imagerie tomodensitométriques de TQv, Thr et RMhr les
plus courantes.
Advances in bone macrostructure and microstructure CT imaging in osteoporosis – Genant and others
MEDICOGRAPHIA, VOL 30, No. 4, 2008 333
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
B
Patrick AMMANN, MD
Division of Bone Diseases
(WHO Collaborating Centre
for Osteoporosis Prevention)
Department of Rehabilitation
and Geriatrics
University Hospitals, Geneva
SWITZERLAND
Advances in
the assessment
of bone strength
b y P. A m m a n n , S w i t z e r l a n d
he ability of bone to withstand physiological stress depends on its intrinsic characteristics. Biomechanical tests of resistance to fracture provide
both an objective measure of overall bone quality and an objective index of fracture risk, but they are destructive and have no clinical application.
Determinants of bone strength include mass, geometry, microarchitecture, and
intrinsic bone tissue quality (itself dependent on the degree of mineralization
and matrix characteristics such as collagen fiber orientation and chemical structure). Indeed, the underlying determinants can be characterized in biopsies or
even by noninvasive methods. Measurement of intrinsic bone tissue quality,
combined with the ability of certain agents to act on its constituent parameters, opens up new prospects in elucidating the pathophysiology of osteoporosis
and developing specific treatments. Dual-energy x-ray absorptiometry remains
the conventional, routine, and noninvasive method for measuring fracture risk
and bone strength. Other methods such as micro–computed tomography and
measurement of intrinsic bone tissue quality remain research tools, but with
serious clinical potential.
T
Medicographia. 2008;30:334-338.
Bone mineral density and
dual-energy x-ray absorptiometry
(see French abstract on page 338)
Keywords: bone mineral density; bone strength; bone tissue quality; microarchitecture; micro–computed tomography; microindentation
www.medicographia.com
Address for correspondence: Patrick Ammann, Division of Bone Diseases, Department of
Rehabilitation and Geriatrics, University Hospitals, CH-1211 Geneva 14, Switzerland
(e-mail: [email protected])
334 MEDICOGRAPHIA, VOL 30, No. 4, 2008
one is programmed to withstand low-energy
trauma and repeated stimuli such as walking, running, and jumping. Fracture risk depends on the mechanical force of the trauma involved. The ability of bone to withstand physiological
stress is governed by its intrinsic characteristics,
and biomechanical tests of resistance to fracture
provide an objective measure of overall bone quality. Determinants of bone strength include mass,
geometry, and microarchitecture, but also intrinsic
bone tissue quality, which itself is governed by the
degree of mineralization and matrix characteristics such as collagen fiber orientation and chemical
structure. If we are to understand how bone adapts
to loss of mass and responds to treatment, all such
determinants need to be considered systematically
(Figure 1). Bone remodeling acts on these determinants and as such, is the target of the various treatments for osteoporosis.
During the menopause and during development
of osteoporosis, changes occur in the determinants
that predispose to fracture — fracture that can be
even from low-energy trauma within normal stress
limits — hence the importance of exploring these
changes using the methods available. Since most
such methods are invasive, studies tend to use animal models, which play a major role in evaluating the effects of osteoporosis treatments on the
mechanical properties of bone and their determinants.1,2 However, certain noninvasive methods now
make it possible to undertake such evaluations in
humans.
Before discussing these methods in detail, we
should note that in animal models, biomechanical
properties of intact cortical and trabecular bone are
investigated by axial compression of the vertebral
body and proximal tibia. Purely cortical bone is tested by flexion applied at three or four points. The
load/deflection curve is used to measure or extrapolate stiffness (the slope of the linear portion of the
curve) and maximal load (load at fracture).3 The departure from linearity representing the separation
between elastic (linear) deformation and plastic
(nonlinear) deformation is defined as the yield point.
The areas under these curves represent the energies
absorbed during elastic and plastic deformation.
The most widely used noninvasive method for diagnosing early osteoporosis is dual-energy x-ray absorptiometry (DXA) of the conventional determinant of mechanical properties, namely “areal” or
“surface” (ie, nonvolumetric) bone mineral density
(BMD). Osteoporosis is diagnosed using the World
Health Organization criteria that is based on the
SELECTED
ABBREVIATIONS AND ACRONYMS
BMD
BSU
CT
DXA
bone mineral density
bone structural unit
computed tomography
dual-energy x-ray absorptiometry
Advances in the assessment of bone strength – Ammann
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
Diameter (mm)
% vertebral fractures
ance of long bone mechanical properties
by up to 55%.12 Osteoanabolic agents,
eg, insulin-like growth factor-1,13 growth
3D Repartition
hormone, parathyroid hormone,14 and
• Geometry
• Microarchitecture
strontium ranelate in growing rats (Figure 3),12 stimulate periosteal apposition
and increase the external diameter of
Amount of material
Bone strength
Turnover
long bones, resulting in markedly enhanced mechanical properties. A 3% to
Material Quality
5% change in diameter can strengthen
• Mineralization
• Matrix
a long bone by 15% to 20%. Increased
• Organization
cortical thickness may also be observed
with antiresorptive treatments, which
add to bone strength by inhibiting endosteal resorption.13 Expansion of bone
Figure 1. Determinants of bone strength are altered by bone turnover
diameter is observed in humans. Duras an adaptation to mechanical forces, hormonal status, and antiing growth, diameter is influenced by
osteoporotic treatments.
nutrition, notably the intake of calcium,
proximal femur or lumbar BMD.4 DXA is widely
phosphate, and protein.15 Expansion of external bone
available and has proven predictive of both fracdiameter is also seen in elderly men, and in acroture risk and treatment response. In the absence of
megaly in response to excess growth hormone. Altreatment, ex-vivo studies show excellent correlathough bone dimensions may increase in adults,
tion between proximal femur BMD and the results
we do not know exactly how this contributes to
of biomechanical neck of femur flexion tests5 and
bone strength. No such expansion in diameter has
vertebral compression tests6; BMD predicts 66% to
yet been demonstrated in response to treatment in
74% of mechanical property variance. As a ratio between hydroxyapatite mineral content and scan sur20
RR: –37%
face, BMD incorporates bone dimensions in addiP =0.0001
tion to mineral quantity. Indeed, the proficiency of
18.2%
16
BMD in predicting bone strength is due, at least in
part, to its incorporation of bone size.
12
Most clinical studies of bone resorption inhibitors
11.5%
8
such as bisphosphonates, selective estrogen receptor modulators or estrogens, agents promoting bone
4
formation (parathyroid hormone), and strontium
ranelate, which both decreases bone resorption and
0
>0%
0%
increases bone formation, have shown associations
Change in femoral neck BMD
between increased BMD and decreased fracture risk,
after 1 year of treatment
but the relationship between these two parameters
Figure 2. The incidence of vertebral fractures is markedly
can be hazy.7 For example, such treatments differ
reduced at 3 years in patients with an increase in total
in their effect on BMD while having a similar imhip bone mineral density (BMD) at 1 year. For each 1%
pact on fracture risk. Nor are the changes in BMD
increase in femoral neck BMD after 1 year of treatment
observed at different skeletal sites proportional to
with strontium ranelate, there is a 3% decrease in clinical vertebral fracture risk after 3 years. For each 1%
the changes in fracture risk. Yet recent studies have
increase in total hip BMD after 3 years of treatment,
shown that a change in femoral neck BMD in rethere is a 4% decrease in clinical vertebral fracture risk
sponse to strontium ranelate can predict decreased
after 3 years. Based on data from reference 8.
vertebral fracture risk at 1 and 3 years (Figure 2),8
underlining the importance of this method not only
in diagnosis, but also in assessing treatment re3.5
sponse and the impact of treatment on the mechan*
9
ical properties of bone. We must also remember
3.4
*
that, according to the epidemiological evidence,
3.3
age and fracture history are independent determinants of fracture risk.10 This is a clear indication of
3.2
the importance of other determinants not apparent
on DXA.
3.1
Geometry
Dimensions such as external diameter and cortical
thickness are key determinants of bone strength.
Increasing the external diameter of a long bone
substantially increases its resistance to flexion. Increasing cortical thickness has a similar, if lesser,
effect.1-3,11 For example, in rats treated with strontium ranelate, external diameter predicted the vari-
Advances in the assessment of bone strength – Ammann
3.0
0
225
450
900
Strontium ranelate (mg/kg/d)
Stimulation of
periosteal apposition
Figure 3. Strontium ranelate administered in intact rats during the growing phase and adult life dose dependently increased the external diameter
of long bones as a result of a stimulation of periosteal apposition. Values
shown are mean ± standard error of the mean. *P<0.05 versus control
group. Based on data from reference 12.
MEDICOGRAPHIA, VOL 30, No. 4, 2008 335
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
humans. DXA and micro–computed tomography
(CT [μCT]) can be used to determine diameter, assisted by radiographs and conventional CT scans.
Indeed, algorithms are already available for deriving diameter, cortical thickness, and hence mechanical properties, from DXA data in the proximal
femur.16,17 These measures are difficult to use in clinical practice in the absence of reference values, but
they are extremely useful in the clinical research
setting.
Ex-vivo CT histomorphometry
By offering a three-dimensional (3D) window onto
bone microarchitecture, μCT appears better suited to evaluating trabecular connectivity, volume,
and thickness. It can also differentiate the trabecular morphology (plates versus columns) that plays
a determining role in the transmission and distribution of mechanical stress within bone tissue.
However, it cannot assess nonmineralized tissue
or bone cells. Being biopsy-based, it also remains
invasive.
Microarchitecture
In-vivo CT histomorphometry
The major features of bone microarchitecture are
trabecular bone volume, trabecular density, intertrabecular spacing, trabecular morphology (plate
versus column ratio), and the parameters of trabecular connectivity. Changes in any of these features
can affect bone strength. Thus changes in architecture account for the early decline in bone strength
after ovariectomy. Significant decreases in vertebral
strength antedate any significant decrease in BMD.
The dissociation between these two variables may be
due to an early change in microarchitecture (such
as perforation and/or disappearance of trabeculae),
with no major effect on BMD.1,2 Thus the mechanical properties of trabecular bone are dominated by
bone volume fraction and, to a lesser degree, by
structural trabecular anisotropy. Increased vertebral
fracture severity (measured semiquantitatively) is
associated with deterioration in bone microarchitecture.18 This continuous and progressive process
accounts for the accelerated cascade of fracture risk
observed in patients with severe vertebral fracture.
Osteoporosis treatments that act on bone remodeling are designed to prevent bone loss (anticatabolic agents) or induce a positive balance, either by
stimulating bone formation over bone resorption
(anabolic agents) or, in a two-pronged approach, by
promoting bone formation while inhibiting bone
resorption (strontium ranelate). It is therefore important to measure the microarchitectural impact
of these treatments if we are to understand exactly
how they reduce fracture risk. Various methods are
now available to this end.
Histomorphometry
Histomorphometry, normally performed on a horizontal transiliac crest core biopsy, offers a two-dimensional (2D) window onto microarchitecture and
bone quality. It provides data on the degree of mineralization, the lamellar organization (lamellar or
woven bone), and turnover, the latter determining
fracture risk independently of bone mass. It can
also be used to evaluate dynamic parameters, such
as bone formation, and to document bone formation upon treatment using tetracycline double labeling. In practice, histomorphometry is used to
rule out osteomalacia, detect high and low bone
turnover disease, and document the safety and effects on bone quality of various treatments. It is an
important technique for understanding how a treatment works, by providing information not only on
microarchitecture and tissue organization but also
on bone turnover.
336 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Newly-developed μCT systems have sufficient resolution for measuring human wrist and tibia microarchitecture noninvasively in vivo. Although the
resolution is lower than in ex-vivo studies, the technique provides data on trabecular connectivity and
morphology. Its major advantage is that it can be
used for serial microarchitecture monitoring. Initial reports have confirmed its accuracy, sensitivity, and reproducibility.19,20 Prospective studies will
test for a correlation between microarchitectural
changes and fracture risk. Until reference values are
established and the technique is fully validated, it
remains essentially a clinical research tool.
Miscellaneous
Magnetic resonance imaging histomorphometry is
a noninvasive radiation-free method for evaluating
bone tissue and characterizing its microarchitecture.21 However, resolution is lower than with radiographic methods. As for ultrasound, this may
add to the microarchitectural information supplied
by DXA but there is no consensus about interpreting its results.22
Intrinsic bone tissue quality
Most studies of bone quality have confined themselves to the analysis of geometry, microarchitecture, and morphology. Bone is a heterogeneous
tissue made up of a mineral component (hydroxyapatite) and an organic collagen component. Each
is theoretically capable of influencing the intrinsic
quality of bone tissue. The degree of mineralization
has been the more studied aspect of bone tissue
to date. Several methods for its study are available,
eg, quantitative backscattered electron imaging,23,24
synchroton radiation microtomography,25 and quantitative microradiography.26 All produce similar results.27 Studies of the organic component have focused on collagen fiber orientation and maturity.
Involvement of these parameters in tissue quality
is especially evident in osteogenesis imperfecta,
in which fiber disorganization causes a high fracture risk. Diseases resulting in the formation of
woven bone (disorganization of the collagen matrix), such as Paget’s, are also associated with decreased strength.
Various techniques are available for assessing and
quantifying intrinsic bone tissue quality at both
the bone structural unit (BSU) level (microindentation) and lamella level (nanoindentation). They
give an overall verdict on intrinsic quality, as influ-
Advances in the assessment of bone strength – Ammann
NEW APPROACHES
AND
CHALLENGES
OSTEOPOROSIS
involved. Protein intake can directly influence bone
matrix quality. Other work has shown the response
of intrinsic bone tissue quality to strontium ranelate
treatment, with increases in both elastic and plastic
parameters versus controls.33 This novel property,
namely the improvement in the intrinsic quality of
bone tissue newly formed in response to strontium
ranelate, could lead to a decrease in the development
and/or propagation of microcracks. Such activity
could become a new target for developers of osteoporosis treatments.
Although micro and nanoindentation are both
experimental and invasive, they could eventually
become tools for evaluating this major additional
determinant of bone strength, alongside geometry
and microarchitecture.
enced by the mineral and organic components, but
only nanoindentation selectively evaluates the influence of each. Microindentation is used to measure microhardness at the BSU or tissue level in
terms of resistance to indentation at a defined load
over a defined time.28,29 The types of indentation are
determined by the shape and material used in the
indenter. Nanoindentation measures hardness at
the individual lamella level thanks to the dimensions of the indenter generally used, the Berkovich
tip (a 3-sided pyramid).30 The method involves fixing the loading and unloading rates to obtain a
force displacement curve, which can then be used
to derive biomechanical parameters such as microhardness and Young’s elastic modulus.31-33 Microindentation uses a set load for a set time, with only
the depth, imprint, and hence the diameter of the
residual imprint, varying with the test material. The
dimensions of this residual imprint are used to calculate microhardness (kg/mm 2), with no differentiation between the elastic and plastic components.34
Indentation can be used to mimic an impact in
order to observe a material’s response.35,36 In studies of bone and dental tissue, microindentation using high test forces may generate macrodamage,
depending on ductility. The dimensions of such
damage (area and length) can be used to derive fracture toughness and to study damage propagation
through the tissue.37-39 This has the potential to become a valuable and dynamic approach to the study
of bone.
Current preliminary studies are revealing the
importance of intrinsic bone tissue quality, ie, the
quality of the bone-forming material itself. They
have shown tissue to be heterogeneous throughout the different phases of bone remodeling. They
have also found evidence of changes in response to
protein intake,31 hormone impregnation, and osteoporosis treatments. Specifically, an isocaloric reduction in protein intake in rats impairs cortical
and trabecular intrinsic bone tissue quality without
necessarily causing remodeling of the bone tissue
Direct measurement of bone strength provides an
objective index of fracture risk, but is destructive
and unsuited to clinical use. However, mechanical
property determinants, such as geometry, microarchitecture, and intrinsic bone tissue quality can be
objectively evaluated in bone biopsies or even by
noninvasive methods. DXA provides information on
BMD and indirectly on bone size, given that it is a
measure of areal density. Measurement of bone geometry is a useful noninvasive approach, in particular for determining external bone diameter. Microarchitecture can be evaluated in biopsies, but also by
noninvasive CT systems that can provide measurement in humans. Measurement of intrinsic bone
tissue quality and the response of its parameters
to treatment will accelerate understanding of the
pathophysiology of osteoporosis and assist in the
development of dedicated therapies. Nevertheless,
for the time being, DXA remains the routine noninvasive investigation for assessing fracture risk and
bone strength. Other techniques, such as μCT and
measurement of intrinsic bone tissue quality, remain
research tools but with serious clinical potential. REFERENCES
1. Ammann P, Rizzoli R, Bonjour JP. Preclinical evaluation of new
therapeutic agents for osteoporosis. In: Meunier PJ, ed. Osteoporosis: Diagnosis and Management. London, UK: Martin Dunitz;
1998:257-273.
2. Bonjour JP, Ammann P, Rizzoli R. Importance of preclinical
studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines. Osteoporos Int.
1999;9:379-393.
3. Turner CH. Biomechanics of bone: determinants of skeletal
fragility and bone quality. Osteoporos Int. 2002;13:97-104.
4. World Health Organization Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. WHO Technical Report
Series No. 843. Geneva, Switzerland: World Health Organization;
1994.
5. Dalen N, Hellstrom LG, Jacobson B. Bone mineral content and
mechanical strength of the femoral neck. Acta Orthop Scand.
1976;47:503-508.
6. Granhed H, Jonsson R, Hansson T. Mineral content and strength
of lumbar vertebrae: a cadaver study. Acta Orthop Scand.1989;60:
105-109.
7. Hauselmann HJ, Rizzoli R. A comprehensive review of treatments for postmenopausal osteoporosis. Osteoporos Int. 2003;
14:2-12.
8. Bruyère O, Roux C, Detilleux J, et al. Relationship between bone
mineral density changes and fracture risk reduction in patients
treated with strontium ranelate. J Clin Endocrinol Metab. 2007;
92:3076-3081.
9. Bruyère O, Roux C, Badurski J, et al. Relationship between
change in femoral neck bone mineral density and hip fracture
incidence during treatment with strontium. Curr Med Res Opin.
2007;23:3041-3045.
10. Kanis JA, Black D, Cooper C, et al; International Osteoporosis Foundation; National Osteoporosis Foundation. A new approach to the development of assessment guidelines for osteoporosis. Osteoporos Int. 2002;13:527-536.
11. Turner CH, Burr DB. Basic biochemical measurements of
bone: a tutorial. Bone.1993;14:595-608.
12. Ammann P, Shen V, Robin B, Mauras Y, Bonjour JP, Rizzoli R.
Strontium ranelate improves bone resistance by increasing bone
mass and improving architecture in intact female rats. J Bone
Miner Res. 2004;19:2012-2020.
13. Ammann P, Rizzoli R, Meyer JM, Bonjour JP. Bone density
and shape as determinants of bone strength in IGF-I and/or
pamidronate-treated ovariectomized rats. Osteoporos Int. 1996;
6:219-227.
14. Ejersted C, Andreassen TT, Oxlund H, et al. Human parathyroid hormone (1-34) and (1-84) increase the mechanical strength
and thickness of cortical bone in rats. J Bone Miner Res.1993;8:
1097-1101.
15. Bonjour JP, Chevalley T, Ammann P, Slosman D, Rizzoli R.
Gain in bone mineral mass in prepubertal girls 3.5 years after discontinuation of calcium supplementation: a follow-up study.
Lancet. 2001;358:1208-1212.
Advances in the assessment of bone strength – Ammann
IN
Conclusion
MEDICOGRAPHIA, VOL 30, No. 4, 2008 337
NEW APPROACHES
AND
CHALLENGES
16. Faulkner KG, Wacker WK, Barden HS, et al. Femur strength
index predicts hip fracture independent of bone density and hip
axis length. Osteoporos Int. 2006;17:593-599.
17. Le Bras A, Kolta S, Soubrane P, Skalli W, Roux C, Mitton D.
Assessment of femoral neck strength by 3-dimensional X-ray absorptiometry. J Clin Densitom. 2006;9:425-430.
18. Delmas PD. The use of bisphosphonates in the treatment of
osteoporosis. Curr Opin Rheumatol. 2005;17:462-466.
19. Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2005;90:6508-6515.
20. Boutroy S, Van Rietbergen B, Sornay-Rendu E, Munoz F,
Bouxsein ML, Delmas PD. Finite element analysis based on in vivo
HR-pQCT images of the distal radius is associated with wrist fracture in postmenopausal women. J Bone Miner Res. 2008;23:392399.
21. Krug R, Carballido-Gamio J, Banerjee S, Burghardt AJ, Link
TM, Majumdar S. In vivo ultra-high-field magnetic resonance
imaging of trabecular bone microarchitecture at 7 T. J Magn Reson Imaging. 2008;27:854-859.
22. Padilla F, Jenson F, Bousson V, Peyrin F, Laugier P. Relationships of trabecular bone structure with quantitative ultrasound
parameters: in vitro study on human proximal femur using transmission and backscatter measurements. Bone. 2008;42:1193-1202.
23. Roschger HP, Klaushofer K, Eschberger J. A new scanning
electron microscopy approach to the quantification of bone mineral distribution: Backscattered electron gray-levels correlated
to calcium Ka-line intensities. Scan Microsc. 1995;9:75-86.
24. Roschger P, Fratzl P, Eschberger J, Klaushofer K. Validation
of quantitative backscattered electron imaging for the measurement of mineral density distribution in human bone biopsies.
Bone. 1998;23:319-326.
25. Nuzzo S, Peyrin F, Cloetens P, Baruchel J, Boivin G. Quantification of the degree of mineralization of bone in three dimensions using synchrotron radiation microtomography. Med Physics.
2002;29:2672-2681.
26. Boivin G, Meunier PJ. The degree of mineralization of bone
tissue measured by computerized quantitative contact radiog-
IN
OSTEOPOROSIS
raphy. Calcif Tissue Int. 2002;70:503-511.
27. Boivin G, Meunier PJ. The mineralization of bone tissue: A
forgotten dimension in osteoporosis research. Osteoporos Int.
2003;14:19-24.
28. Bonser RH. Longitudinal variation in mechanical competence
of bone along the avian humerus. J Exp Biol. 1995;198:209-212.
29. Riches PE, Everitt NM, McNally DS. Knoop microhardness
anisotropy of the ovine radius. J Biomech. 2000;33:1551-1557.
30. Hengsberger S, Kulik A, Zysset P. Nanoindentation discriminates the elastic properties of individual human bone lamellae
under dry and physiological conditions. Bone. 2002;30:178-184.
31. Hengsberger S, Ammann P, Legrosa B, Rizzo R, Zysset P.
Intrinsic bone tissue properties in adult rat vertebrae: modulation by dietary protein. Bone. 2005;36:134-141.
32. Zioupos P. In vivo fatigue microcracks in human bone: material properties of the surrounding bone matrix. Eur J Morphol.
2005;42:31-41.
33. Ammann P, Badoud I, Barraud S, Dayer R, Rizzoli R. Strontium ranelate treatment improves trabecular and cortical intrinsic bone tissue quality, a determinant of bone strength. J Bone
Miner Res. 2007;22:1419-1425.
34. Wang XD, Masilamani NS, Mabrey JD, Alder ME, Agrawal
CM. Changes in the fracture toughness of bone may not be reflected in its mineral density, porosity, and tensile properties.
Bone. 1998;23:67-72.
35. Lube T. Indentation crack profiles in silicon nitride. J Eur
Ceram Soc. 2001;21:211-218.
36. Soraru GD, Tassone P. Mechanical durability of a polymer
concrete: a Vickers indentation study of the strength degradation process. Constr Build Mater. 2004;18:561-566.
37. Xu HH, Smith DT, Jahanmir S, et al. Indentation damage and
mechanical properties of human enamel and dentin. J Dent Res.
1998;77:472-480.
38. Phelps JB, Hubbard GB, Wang X, Agrawal CM. Microstructural heterogeneity and the fracture toughness of bone. J Biomed
Mater Res. 2000;51:735-741.
39. Sakar-Deliormanli A, Güden M. Microhardness and fracture
toughness of dental materials by indentation method. J Biomed
Mater Res Pt B Appl Biomater. 2006;76:257-264.
PROGRÈS
DANS L’ÉVALUATION DE
LA RÉSISTANCE OSSEUSE
L
e fait qu’un os résiste aux contraintes physiologiques va dépendre de ses
caractéristiques propres. La mesure objective de la qualité globale de
l’os est réalisée lors de tests biomécaniques permettant d’apprécier la
charge qui peut être appliquée sur l’os avant que la fracture survienne. Elle est
influencée par différents déterminants comme la masse, la géométrie, l’architecture et la qualité intrinsèque du tissu osseux. La qualité intrinsèque du tissu
osseux est liée au degré de minéralisation et aux caractéristiques de la matrice,
telles que l’orientation et la structure chimique des fibres de collagène. La mesure des propriétés mécaniques de l’os est une mesure objective du risque fracturaire, néanmoins elle est destructive et ne peut être appliquée en clinique.
En revanche, les déterminants des propriétés mécaniques comme la microarchitecture et la géométrie peuvent être envisagés soit à partir de biopsies osseuses soit par des méthodes non invasives. La mesure de la qualité intrinsèque
du tissu osseux et les possibilités de modification de ces paramètres sous traitement ouvrent une nouvelle perspective dans la compréhension de la physiopathologie de l’ostéoporose et dans le développement de traitements influençant
spécifiquement ce paramètre. Globalement, la mesure par l’absorptiométrie à
rayons X biphotonique reste l’approche clinique classique, non invasive, de l’investigation du risque fracturaire (respectivement des propriétés mécaniques de
l’os) et utilisée en routine. Les autres techniques comme la microtomodensitométrie et la mesure de la qualité intrinsèque du tissu osseux sont pour l’instant des outils de recherche mais avec de sérieux potentiels d’application clinique future.
338 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Advances in the assessment of bone strength – Ammann
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
steoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a
consequent increase in skeletal fragility and susceptibility to fracture.1 This definition implies that the
diagnosis should be performed before any fragility
fracture has occurred, which is a challenge for the
clinician. The level of bone mineral density (BMD)
can be assessed with adequate precision using dualenergy x-ray absorptiometry (DXA).
However, this measurement does not capture all
risk factors for fracture. Bone fragility also depends
on the morphology and architecture of bone, as
well as the material properties of the bone matrix
that cannot be readily assessed, all of these components being regulated by bone turnover (Figure 1,
page 340). Consequently, it has been suggested that
bone strength may be assessed, independently of
BMD level, by measuring bone turnover using specific serum and urinary markers of bone formation
and resorption. It has also been suggested that bone
turnover markers could be useful to monitor the efficacy of treatment—especially anticatabolic treatments — but also more recently, anabolic therapy
including parathyroid hormone (PTH). In this paper, we will review advances in biochemical markers of bone turnover and then discuss their use
for the management of postmenopausal and male
osteoporosis.
O
Patrick GARNERO, PhD
INSERM Research Unit 664
and CCBR-SYNARC, Lyon
FRANCE
Advances in bone
turnover assessment
with biochemical markers
b y P. G a r n e r o , F r a n c e
Current biochemical markers
of bone turnover
ystemic biochemical markers of bone formation and bone resorption can
now be easily measured with high precision using automated technology.
However, current markers have some limitations: (i) the within-patient
variability for type I collagen resorption markers is relatively large; (ii) current
markers provide an assessment of whole body turnover and do not enable the
contribution of the different skeletal envelopes to be distinguished; and (iii) they
only reflect quantitative changes of bone turnover, when changes in the properties of bone matrix are also an important determinant of bone strength. Research being undertaken to develop new biochemical markers that address some
of these limitations is in progress. Notably, the advances in our knowledge of
bone matrix biochemistry, including the posttranslational modifications of
type I collagen, may allow the identification of biochemical markers that reflect
changes in the material property of bone. A series of ex-vivo animal and cadaveric studies indicated that the extent of nonenzymatic collagen modifications
(eg, advanced glycation end products and isomerization) contributes to fracture resistance, especially bone toughness, independently of bone mineral density. Although it remains a challenge to assess these changes noninvasively, recent clinical studies have shown that the urinary ratio between nonisomerized
( CTX) and isomerized ( CTX) type I collagen telopeptide fragments may
provide information on bone matrix maturation, which is associated with fracture risk and, in postmenopausal women, is differently affected by the various
antiresorptive therapies. In this paper we describe the new biochemical markers
and briefly discuss their clinical uses in postmenopausal and male osteoporosis.
S
Medicographia. 2008;30:339-349.
(see French abstract on page 349)
Keywords: osteoporosis; fracture risk; type I collagen; bisphosphonates,
parathyroid hormone
www.medicographia.com
Address for correspondence: Patrick Garnero, CCBR-SYNARC, 16 rue Montbrillant,
69003 Lyon, France
(e-mail: [email protected])
Advances in bone turnover assessment with biochemical markers – Garnero
Bone remodeling is the result of two opposite activities, the production of new bone matrix by osteoblasts and the destruction of old bone by osteoclasts.
The rates of bone production and destruction can
be evaluated either by measuring predominantly
osteoblastic or osteoclastic enzyme activities or by
assaying bone matrix components released into the
bloodstream and excreted in the urine (Table I,
page 340). These have been separated into markers
of formation and resorption, but it should be kept
in mind that in disease states where both events are
coupled and change in the same direction, such as
osteoporosis, any marker will reflect the overall rate
of bone turnover.
At present, in postmenopausal osteoporosis the
most sensitive markers for bone formation are
serum total osteocalcin, bone alkaline phosphatase
(ALP), and the procollagen type I N-terminal propeptide (PINP) (for a review see reference 2). For
the evaluation of bone resorption, most assays are
based on the detection in serum or urine of type I
collagen fragments. These include the crosslinks
pyridinoline (PYD) and deoxypyridinoline (DPD),
the cathepsin K (C-terminal crosslinked telopeptide of type I collagen [CTX], N-terminal crosslinked
telopeptide of type I collagen [NTX]) and matrix
metalloprotease (MMP)–generated telopeptide peptides (CTX-MMP or ICTP), and fragments of the helical portion (helical peptide).2 The measurements
of most of these biochemical markers can be currently achieved with a high throughput and with
analytical precision on automated platforms.3,4
MEDICOGRAPHIA, VOL 30, No. 4, 2008 339
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
turnover and do not provide information on the
structural abnormalities of bone matrix properties,
which is an important determinant of bone fragility, especially toughness (Figure 1). Recently, new
biochemical markers have been investigated to address some of these limitations (Table II).
Bone
mass/density
Bone turnover:
Formation/Resorption
Architecture:
shape and
geometry
• Microarchitecture
Bone matrix properties:
• Mineral
• Collagen/crosslink
• Noncollagenous proteins
• Bone
Osteocyte
apoptosis
Microdamage
Figure 1. The different determinants of fracture resistance and the pivotal
role of bone turnover in their regulation.
Formation
Resorption
Serum
Total and bone ALP
Serum/plasma
NTX
Intact and total
osteocalcin
CTX
PICP and PINP
CTX-MMP (ICTP)
Urine
Total and free PYD
Total and free DPD
NTX
CTX
Type I collagen helical
peptide 620-633
Table I. Established biochemical markers of bone turnover. Markers with the most established performance
characteristics in postmenopausal osteoporosis are
shown in bold.
Abbreviations: ALP, alkaline phosphatase; CTX, C-terminal crosslinked telopeptide of type I collagen; DPD, deoxypyridinoline; MMP,
matrix metalloprotease; NTX, N-terminal crosslinked telopeptide
of type I collagen; PICP, C-propeptide of type I collagen; PINP, procollagen type I N-terminal propeptide; PYD, pyridinoline.
New biochemical markers
of bone metabolism
As reviewed below, currently-available biological
markers have been useful for the clinical investigation of various metabolic bone diseases and for
individual patient monitoring. However they do
have some limitations: biochemical markers of bone
resorption are mostly based on type I collagen,
which is not bone-specific; some of the type I collagen–based bone resorption markers are characterized by significant intra-patient variability, which
impairs their use in individual patients; the systemic levels of biochemical markers reflect global
skeletal turnover and do not provide distinct information on the remodeling of the different bone
envelopes, ie, trabecular, cortical, and periosteal,
although their relative contribution may vary with
aging, disease, and treatment; and finally, current
markers mostly reflect quantitative changes in bone
340 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Noncollagenous bone proteins
Although the vast majority of bone matrix is composed of type I collagen molecules, about 10% of
the organic phase is comprised of noncollagenous
proteins, some of which are almost specific for bone
tissue. It has been suggested that these proteins,
or fragments thereof, could constitute specific biochemical markers of bone turnover.
Bone sialoprotein
Bone sialoprotein (BSP) is an acidic, phosphorylated glycoprotein of 33 kDa (glycosylated: 70-80 kDa),
which contains an arginine-glycine-aspartic acid
(RGD) integrin binding site. Although BSP is relatively restricted to bone, it is also expressed by trophoblasts and is strongly upregulated in a variety
of human primary cancers, particularly those that
metastasize to the skeleton, including breast, prostate, and lung cancer.5 A recent case-control retrospective study showed that high expression of BSP
by non–small-cell lung tumor tissue was strongly
associated with the development of bone—but not
soft tissue—metastases.6 A small amount of BSP is
released into the circulation, and as such, is a potential marker of bone turnover.7 A high serum level of BSP has been shown to be associated with disease progression in patients with prostate cancer,
SELECTED
ABBREVIATIONS AND ACRONYMS
AGE
ALP
BMD
BSP
CTX
advanced glycation end product
alkaline phosphatase
bone mineral density
bone sialoprotein
C-terminal crosslinked telopeptide of
type I collagen
DPD
deoxypyridinoline
DXA
dual-energy x-ray absorptiometry
EPIDOS EPIDemiology of OSteoporosis (study)
FIT
Fracture Intervention Trial
HOS
Hawaii Osteoporosis Study
MORE
Multiple Outcomes of Raloxifene
Evaluation
MrOS
Osteoporotic Fractures in Men (study)
OFELY
Os des FEmmes de LYon (French study)
OPG
osteoprotegerin
PaTH
ParaThyroid Hormone and Alendronate
for Osteoporosis (study)
PTH
parathyroid hormone
PYD
pyridinoline
RANKL receptor activator of nuclear factorkappa B ligand
SOTI
Spinal Osteoporosis Therapeutic Intervention (study)
TRACP tartrate-resistant acid phosphatase
TROPOS TReatment Of Peripheral OSteoporosis
(study)
Advances in bone turnover assessment with biochemical markers – Garnero
NEW APPROACHES
and bone metastases development in patients with
localized breast carcinoma.8 Serum BSP levels have
also been reported to be increased in malignant
bone disease in postmenopausal osteoporosis, and
are decreased by antiresorptive treatment.7 However, accurate measurements of serum BSP with
currently available immunoassays remain challenging, especially because of its tight association with
circulating factor H.
Urinary osteocalcin fragments
Although most newly-synthesized osteocalcin is
captured by bone matrix, a small fraction is released into the blood where it can be detected by
immunoassays, and it is currently considered as a
specific bone formation marker. Circulating osteocalcin is composed of different immunoreactive
forms including the intact molecule, but also various fragments.9 The majority of these fragments
are generated from the in-vivo degradation of the
intact molecule and thus also reflect bone formation.9 In-vitro studies suggest, however, that some
osteocalcin fragments could also be released by osteoclastic degradation of bone matrix,10 and could
be resistant to glomerular filtration and accumulate in urine.11 Mass spectrometry analysis of urine
from patients with Paget’s disease and healthy children has shown that most urinary osteocalcin fragments consist of the mid-molecule portion.12 Elevated levels of urinary osteocalcin were reported in
osteoporotic postmenopausal women11 and values
decreased after 1 month of treatment with the bisphosphonate alendronate, contrasting with the absence of changes in serum total osteocalcin. A recent
study over 5 years evaluating 601 postmenopausal
women age 75 years and older, showed that increased urinary osteocalcin levels were associated
with BMD loss at the spine and the hip.13 In the
same population, in a large prospective study of elderly women, high levels of urinary osteocalcin—
but not serum total osteocalcin— were associated
with increased risk of clinical vertebral fracture independently of BMD.14 Theoretically, urinary osteocalcin fragments may constitute a more specific
bone resorption marker than type I collagen–related fragments, although their clinical value in osteoporosis remains to be more extensively evaluated.
Osteoclastic enzymes
Tartrate-resistant acid phosphatase 5b
(TRACP 5b)
Acid phosphatase is a lysosomal enzyme that is present primarily in bone, prostate, platelets, erythrocytes, and spleen. Bone acid phosphatase is resistant to L(+)-tartrate (TRACP), whereas the prostatic
isoenzyme is inhibited. Acid phosphatase circulates
in blood and shows higher activity in serum than
in plasma, because of the release of platelet phosphatase activity during the clotting process. In
normal plasma, TRACP corresponds to plasma isoenzyme 5. Isoenzyme 5 is represented by two subforms, 5a and 5b. TRACP 5a is derived mainly from
macrophages and dendritic cells, whereas TRACP
5b is more specific for osteoclasts.15,16 These two
forms differ in their carbohydrate content, optimum
pH, and specific activity. TRACP 5a is a monomer-
AND
CHALLENGES
IN
OSTEOPOROSIS
ic protein, whereas TRACP 5b is cleaved in two
subunits. In osteoclasts, TRACP 5b together with
cathepsin K is localized in transcytotic vesicles that
transport bone matrix degradation products from
the resorption lacunae to the opposite functional
secretory domain.17 In vitro, cathepsin K cleaves
TRACP, resulting in activation of TRACP to generate reactive oxygen species that can then participate in finalizing matrix degradation during transcytosis.
Total plasma TRACP activity is measured by colorimetric assays. However, the lack of specificity of
plasma TRACP activity for the osteoclast, its instability in frozen samples, and the presence of enzyme
Category
Candidate biochemical marker
Noncollagenous proteins of
bone matrix and fragments
Bone sialoprotein
Urinary mid-molecule osteocalcin fragments
Osteoclastic enzymes
TRACP 5b
Cathepsin K
Regulators of osteoclast or
OPG/RANKL (osteoclast)
osteoblast differentiation/activity Wnt signaling molecules (Dkk1/sFRP)
(osteoblast)
Sclerostin (osteoblast)
Markers of bone matrix properties
Nonenzymatic collagen crosslinks, eg,
pentoside
Type I collagen isomers (α/β CTX ratio)
Modifications to noncollagenous proteins,
eg, carboxylation and isomerization of
osteocalcin
Table II. New candidate biochemical markers of bone metabolism according to category.
Abbreviations: CTX, C-terminal crosslinked telopeptide of type I collagen; Dkk1, Dickkopf-1; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-kappa B ligand; sFRP, secreted Frizzled-related
protein; TRACP 5b, tartrate-resistant acid phosphatase isoenzyme 5b; Wnt, Wingless.
inhibitors in serum are potential drawbacks that
limit the development of clinically useful enzymatic TRACP assays in osteoporosis. To overcome these
limitations, two different immunoassays for serum
TRACP that preferentially detect the isoenzyme 5b
have been developed. The first one uses antibodies
that recognize both intact and fragmented TRACP
5a and 5b, selectivity for TRACP 5b being partly
achieved by performing the measurements at optimal pH for TRACP 5b.18 More recently, a new immunoassay using two monoclonal antibodies raised
against purified bone TRACP 5b has been described
that shows limited cross-reactivity for TRACP 5a.19
One antibody captures active intact TRACP 5b and
the other eliminates interference of inactive fragments. We found that this new enzyme-linked immunosorbent assay (ELISA) for TRACP 5b was more
sensitive than the previous one in detecting increased bone turnover following menopause and
its reduction by alendronate.20
Serum TRACP 5b is likely to mainly represent the
osteoclast number and the activity of the osteoclasts, and may thus provide complementary information on bone resorption compared with the
type I collagen–related markers.21 Another advantage of serum TRACP 5b relates to its limited diurnal variation and the negligible effect of food intake,
Advances in bone turnover assessment with biochemical markers – Garnero
MEDICOGRAPHIA, VOL 30, No. 4, 2008 341
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
resulting in a lower intrapatient variability than
with type I collagen biochemical markers of bone
resorption, although the magnitude of changes induced by antiresorptive therapy such as bisphosphonate in postmenopausal women is also lower.22
Cathepsin K
The enzyme cathepsin K is a member of the cysteine protease family that, unlike other cathepsins,
has the unique ability to cleave both helical and
telopeptide regions of collagen type I.23 The enzyme is produced as a 329 amino acid precursor,
procathepsin K, which is cleaved to its active form
with a length of 215 amino acids, a process that is
believed to occur in vivo in the bone resorption lacunae, having a low pH environment. Commercially, two assays are available for measuring cathepsin
K in serum, one measuring the enzymatic activity
and the other the protein concentration. Clinical
data are, however, limited. Increased cathepsin K
levels have been reported in patients with active
rheumatoid arthritis,24 patients with Paget’s disease,25 and postmenopausal women with fragility
fractures.26 However, the circulating concentration
of cathepsin K is very low, and currently-available
assays lack sensitivity to allow its accurate determination.
Regulators of osteoclastic and osteoblastic
activity
RANKL and OPG
The receptor activator of nuclear factor-kappa B
ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK)/osteoprotegerin (OPG) system
is one of the main regulators of osteoclast formation and function (for a recent review see reference
27). The relevance of this pathway in postmenopausal bone loss has been shown by Eghbali-Fatourechi et al,28 who analyzed RANKL expression
in bone marrow mononuclear cells and T and B
lymphocytes from premenopausal women, untreated postmenopausal women, and postmenopausal
women treated with estrogen. They found that the
levels of RANKL per cell were increased by two- to
threefold in untreated postmenopausal women
compared with premenopausal women, and correlated positively with serum and urine markers
of bone resorption, and negatively with circulating
estradiol. There was, however, no difference between groups in circulating levels of soluble RANKL
and OPG. More recently, it has been shown that the
bisphosphonate risedronate reduces the differentiation of peripheral blood mononuclear cells into
osteoclasts and their production of RANKL, although circulating levels again were found not to be
affected.29 At present, it remains unclear what proportion of circulating OPG is monomeric, dimeric
or bound to RANKL, and which of these forms is the
most biologically relevant to measure. The same
issues arise for the measurement of circulating
RANKL, which, in its free form, reaches barely detectable levels in healthy individuals. It is also unlikely that circulating levels of OPG and RANKL
adequately reflect local bone marrow production.
These limitations probably explain the conflicting
data available on the association of circulating OPG
342 MEDICOGRAPHIA, VOL 30, No. 4, 2008
and RANKL with BMD and biochemical markers of
bone turnover in postmenopausal women and elderly men.30
Wnt signaling molecules
The Wingless (Wnt) signaling pathway plays a pivotal role in the differentiation and activity of osteoblastic cells.31 There are 19 closely-related Wnt genes
that have been identified in humans. The primary
receptors of Wnt molecules are the seven-transmembrane Frizzled-related proteins (FRPs), each
of which interacts with a single transmembrane
low-density lipoprotein receptor-related protein 5/6
(LRP5/6). Different secreted proteins, including secreted FRP (sFRP), Wnt inhibitory factor-1 (WIF1),
and Dickkopfs (Dkk) 1 to 4, prevent ligand-receptor interactions and consequently inhibit the Wnt
signaling pathway. Alterations to the Wnt signaling pathway and its regulatory molecules, including Dkk-1 and sFRP, have been shown to play an
important role in bone turnover abnormalities associated with osteoporosis, arthritis, multiple myeloma, bone metastases from prostate and breast
cancer, and arthritis.32 Immunoassays for circulating Dkk-1 have been recently developed. In clinical
situations characterized by markedly depressed
bone formation such as multiple myeloma,33 and/or
increased focal osteolysis from multiple myeloma,33
bone metastases from breast34 or lung cancer,35 and
rheumatoid arthritis,36 increased circulating Dkk-1
levels have been reported. Conversely, in patients
with osteoarthritis of the hip characterized by focal subchondral bone sclerosis, decreased serum
Dkk-1 has been shown to be associated with a lower risk of joint destruction.37 However, in clinical situations characterized by systemic and relatively
modest changes of bone turnover such as postmenopausal osteoporosis, serum Dkk-1 was not
affected (personal observations). As for OPG and
RANKL, it is also possible that circulating Dkk-1
may not adequately reflect local bone contribution.
Posttranslational modifications of bone matrix proteins
Type I collagen
Type I collagen, the main organic component of
bone matrix, undergoes a series of enzymatic and
nonenzymatic intracellular and extracellular posttranslational modifications (Figure 2). Among the
enzymatic modifications, ex-vivo studies performed
on human and animal bone specimens have shown
that an overhydroxylation of lysine residues, an
overglycosylation of hydroxylysine, and a reduction
in the concentration of nonreducible crosslinks can
be associated with reduced bone resistance to fracture (for a review see reference 38). In human vertebral specimens, Banse et al39 showed that the ratio between the telopeptide crosslinks pyridinoline
(PYD)/deoxypyridinoline (DPD) was significantly associated with the compressive biomechanical properties of the vertebrae independently of BMD.
Non-enzymatic modifications including advanced
glycation end product (AGE) could also play a role
in the mechanical properties of bone tissue. AGEs
occur spontaneously in the presence of extracellular sugars (Figure 2). In contrast to enzymatic telo-
Advances in bone turnover assessment with biochemical markers – Garnero
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
β–Isomerization of the aspartate (D) residue in
the 1209AHDGGR1214 sequence (CTX) of the C-telopeptide of type I collagen is another non-enzymatic
posttranslational modification believed to reflect
bone matrix maturation (Figure 2). Histological
studies have shown a decreased degree of type I collagen isomerization within the woven bone—a tissue characterized by disorganized collagen fibers
and increased fragility — in patients with Paget’s
disease45 and in women with breast cancer and bone
metastases.46 Alterations of the degree of bone
type I collagen isomerization can be detected in vivo
peptide crosslinks whose concentration in bone tissue reaches a plateau with skeletal maturity, AGEs,
including the intercollagen molecule crosslink pentosidine, accumulate with age in human cortical
bone. Wang et al40 showed that the pentosidine concentration of human femoral bone increases with
age, and higher levels are associated with decreased
resistance to fracture, and more specifically, toughness. Indeed high AGE content is associated with
increased bone rigidity, reducing the capacity of
bone to deform upon mechanical load. Increased
bone pentosidine levels have also been shown to be
Isomerization
EKAH D GGR
CTX - CTX
N
C
Lys
CTX
Arg
C
N+
. Lys
. OH-Lys
Lysyl
oxydase
Immature divalent
crosslinks
. DHLNL
. HLNL
Advanced glycation end products
eg, Pentosidine
Mature trivalent
crosslinks
. PYD/DPD
. Pyrrole
Sugar
Figure 2. Schematic representation of the extracellular posttranslational modifications of type I collagen in bone matrix. Type I collagen
is formed from the association of two alpha 1 chains and one alpha 2 chain in triple helix apart from the two ends (N- and C-telopeptides). In bone matrix, type I collagen is subjected to different posttranslational modifications: the mature trivalent crosslinks, including involvement of pyridinoline (PYD), deoxypyridinoline (DPD) and pyrrole, which make bridges between two telopeptides and the
helicoidal region of another collagen molecule. These molecules result from the maturation of divalent crosslinking molecules (dihydroxylysinornorleucine [DHLNL] and hydroxylysinonorleucine [HLNL]), whose synthesis requires an enzymatic process (lysyl oxydase);
the advanced glycation end products (AGEs), which are formed by nonenzymatic glycation when sugar (eg, glucose) is present in the
extracellular matrix. Some AGEs such as pentosine are crosslinking molecules, although their precise location remains to be determined; the nonenzymatic isomerization of aspartic acid (D) occurring in the C-telopeptides of alpha 1 chains. Arg, arginine; CTX,
C-terminal crosslinked telopeptide of type I collagen; Lys, lysine.
associated with decreased bone fracture resistance
in human vertebral bone.41,42 In 432 elderly Japanese
women, increased urinary pentosidine was moderately associated with an increased risk of incident vertebral fracture independently of BMD and
bone turnover markers.43 A clinical situation in
which AGE may be particularly relevant is type 2
diabetes, a disease characterized by altered glucose
metabolism and increased bone fragility despite increased BMD. A recent study has shown an association between increased serum pentosidine levels
and the presence of prevalent vertebral fracture in
postmenopausal women with type 2 diabetes—but
not in men with type 2 diabetes—independently of
confounding factors, including levels of glycated albumin, BMD, and renal function.44 Pentosidine is
only one of several AGEs present in bone matrix and
is not specific for this tissue. The identification of
the major AGEs of bone tissue that directly affect
the mechanical properties of bone would be extremely useful to develop biological markers reflecting changes of bone matrix maturation.
by the differential measurement of native (α) and
isomerized (β) CTX fragments in urine. In adult patients with osteogenesis imperfecta, a genetic disorder caused by mutations in the type I collagen
genes, associated with abnormalities of type I collagen structure and increased bone fragility, we
recently found an increased urinary α/β CTX ratio.47 In patients with Paget’s disease of bone, we
have shown that the urinary excretion of α CTX was
markedly increased compared with β CTX, also resulting in an abnormal α/β CTX ratio.45 The relationships between these two isoforms can be normalized after treatment with bisphosphonates,48,49
a treatment that has been shown to result in the
formation of a bone matrix with normal lamellar
structure. The investigation of type I collagen isomerization may also be of clinical relevance in postmenopausal osteoporosis. In the Os des FEmmes
de LYon (OFELY) prospective study, we found that
the urinary ratio between native and β–isomerized
CTX was significantly associated with increased
fracture risk independently of both the level of hip
Advances in bone turnover assessment with biochemical markers – Garnero
MEDICOGRAPHIA, VOL 30, No. 4, 2008 343
NEW APPROACHES
AND
CHALLENGES
Urinary α/β
CTX ratio at baseline
OSTEOPOROSIS
IN
Relative risk* (95% CI) of fracture for α/β
CTX baseline values in the upper quartile
Nonvertebral
fractures only
All fractures
Unadjusted
2.0 (1.2-3.5)
2.5 (1.3-4.6)
Adjusted for bone ALP
1.8 (1.1-3.2)
2.2 (1.2-4.0)
Adjusted for femoral neck BMD
1.8 (1.03-3.1)
2.2 (1.2-4.0)
Adjusted for bone ALP & femoral neck BMD
1.7 (0.95-2.9)
2.0 (1.04-3.8)
*Adjusted for age, presence of prevalent fracture, and physical activity
Table III. Increased urinary a/b CTX ratio as an independent predictor of the risk of osteoporotic fractures. A total of 408 women participating in the Os des FEmmes de LYon
(OFELY) study were followed prospectively during 6.8 years. 55 nonvertebral fractures
and 16 incident vertebral fractures were recorded. The table shows the relative risks of
fracture for women with baseline levels of α/β CTX in the upper quartile.
After reference 50: Garnero P, Cloos P, Sornay-Rendu E, Qvist P, Delmas PD. Type I collagen racemization and isomerization and the risk of fracture in postmenopausal women: The OFELY prospective study.
J Bone Miner Res. 2002;17:826-833. Copyright © 2002, American Society for Bone and Mineral Research.
BMD and bone turnover rate measured by serum
bone ALP (Table III).50 More recently, the effects
of antiresorptive therapies on the non-enzymatic
modifications of collagen have been investigated in
animals ex vivo and in clinical studies in vivo. In vertebral trabecular bone from dogs, treatment with
alendronate and risedronate—but not raloxifene—
induced a decrease in the α/β CTX ratio, associated
with a marked increase in pentosidine, suggesting
increased bone collagen maturation with bisphosphonates.51 These animal data are consistent with
the decrease in the urinary α/β CTX ratio observed
in postmenopausal women receiving alendronate
Months
6
Mean change from baseline in
urinary α/β CTX ratio
25
12
18
24
0
–25
–50
**
*
***
***
–75
AL
IB
–100
HRT-T
RLX
*P <0.05 **P <0.01 ***P <0.001 vs placebo
Figure 3. Effects of different antiresorptive treatments on type I collagen
isomerization in postmenopausal women. The graph shows the mean
(standard error of the mean) changes from baseline of the urinary α/β
CTX (C-terminal crosslinked telopeptide of type I collagen) ratio in postmenopausal women receiving the bisphosphonates alendronate (AL;
10 mg/day [n=14] or 20 mg/day [n=13]), ibandronate (IB; 2.5 mg/day
[n=36], intermittent 20 mg every 2nd day for 24 days every 3 months
[n=36]), transdermal estradiol (HRT-T; 45 μg 17-β estradiol/day combined with 40 μg levonorgestrel [n=35]) or raloxifene (RLX; 60 mg/day
[n=30]). Because these were not head to head comparison trials, for each
treatment group, the changes from baseline were adjusted for the changes
in the corresponding placebo groups.
Reproduced from reference 52: Byrjalsen I, Leeming DJ, Qvist P, Christiansen C, Karsdal
MA. Bone turnover and bone collagen maturation in osteoporosis: effects of antiresorptive therapies. Osteoporos Int. 2008;19:339-348. Copyright © 2007, Springer London.
344 MEDICOGRAPHIA, VOL 30, No. 4, 2008
at 10 or 20 mg/day along with daily (2.5 mg) or intermittent oral ibandronate, whereas no significant
change was observed with raloxifene or estradiol
(Figure 3).52 In another study performed in postmenopausal women with osteoporosis participating
in the ParaThyroid Hormone and Alendronate for
Osteoporosis (PaTH) study, we could not however
find a significant change in the α/β CTX ratio after
1 or 2 years with the lower dose of 10 mg/day of alendronate.53 This suggests that a profound suppression of bone turnover may be required to induce
detectable changes in the urinary α/β CTX ratio.
Altogether, these data indicate that the degree of
posttranslational modification of collagen—more
specifically, that which is non–enzymatic age–related — plays an independent role in determining
the mechanical competence of bone, and the ratio
of α/β CTX may provide an in-vivo marker of bone
matrix maturation.
Noncollagenous proteins
Bone matrix also contains noncollagenous proteins
that can undergo posttranslational modifications.
Osteocalcin contains three residues of γ-carboxyglutamic acid (GLA). GLA results from the carboxylation of glutamic acid residues, an intracellular
posttranslational modification that is vitamin K–dependent. It was postulated that impaired γ-carboxylation of osteocalcin could be an index of both
vitamin D and vitamin K deficiency in elderly populations. In two prospective studies, one performed
in a cohort of elderly institutionalized women followed for 3 years54 and the other in a population of
healthy elderly women (the EPIDemiology of OSteoporosis [EPIDOS] study),55 levels of undercarboxylated osteocalcin—which can be evaluated indirectly by the method of incubation of serum with
hydroxyapatite—above the premenopausal range
were associated with a two- to threefold increase
in the risk of hip fracture, although total osteocalcin was not predictive. A decreased ratio of carboxylated and total osteocalcin, which is an index of
increased undercarboxylated osteocalcin, was associated with increased fracture risk in elderly women living at home.56 The mechanisms relating to
increased undercarboxylation of osteocalcin and
fracture risk is unclear. Serum undercarboxylated
osteocalcin,57 but not total osteocalcin, has been
found to be associated more strongly with ultrasonic transmitted velocity (which has been suggested to reflect, in part, changes in bone microarchitecture) at the os calcis and tibia than with BMD.
Osteocalcin also contains in its sequence five residues of aspartic acid that can undergo isomerization like type I collagen. Although not directly
analyzed in bone matrix, isomerized osteocalcin
fragments have recently been described in patients
with Paget’s disease of bone.58 The influence of the
isomerization of osteocalcin and other noncollagenous proteins on the mechanical competence of
bone matrix remains to be investigated. Finally, recent studies suggest that the degree of carboxylation may also be an important determinant of the
endocrine function of osteocalcin to regulate energy metabolism in mice,59 although its relevance in
humans remains undetermined.
Advances in bone turnover assessment with biochemical markers – Garnero
NEW APPROACHES
Postmenopausal osteoporosis
Markers of bone turnover to help with the
treatment decision
With the emergence of effective but rather expensive treatments, it is essential to detect those women at higher risk of fracture. Indeed, although several prospective studies have demonstrated a strong
association between BMD measurements and the
risk of hip, spine, and forearm fractures, as confirmed recently by a meta analysis including 29 082
women from 12 different cohorts,60 about half of patients with incident fractures have baseline BMD
assessed by DXA that is above the diagnostic threshold of osteoporosis, defined as a T-score of –2.5 standard deviations or more below the average value of
young healthy women. Clearly, there is a need for
improvement in the identification of patients at
risk of fracture.
Prospective studies investigating the relationships between bone formation markers and fracture risk have yielded conflicting and inconsistent
findings (for a review see reference 61). Conversely,
five prospective population studies (Rotterdam,
EPIDOS, OFELY, Hawaii Osteoporosis Study [HOS],
and Malmö) have consistently reported that high
bone resorption assessed by urinary or serum CTX,
urinary free deoxypyridinoline, serum TRACP 5b, or
urinary osteocalcin fragments (only one study for
these two latter markers) above the premenopausal
range, was associated with about a twofold higher
risk of hip, vertebral and nonhip, and nonvertebral
fractures over follow-up periods ranging from 1.8
to 5 years.16,61 A recent analysis of the Malmö cohort
in elderly women over the age of 75 years indicates
that some bone resorption markers may still be
predictive of fracture risk after 9 years,62 although
the association attenuates with time, which is also
the case for BMD. In all these analyses, the odds ratio of fracture was not modified after adjusting for
potential confounding factors such as mobility status, and was only marginally decreased after adjusting for BMD measured by DXA. The use of an odds
ratio is not ideal for clinical decision making, since
the risk may decrease or remain stable with age,
whereas absolute risk increases and calculating absolute risk such as 10-year probability is more appropriate. Based on the data from the EPIDOS and
OFELY studies, it was found that combining urinary
CTX with BMD or history of previous fracture results in a 10-year probability of hip fracture that
is about 70% to 100% higher than that associated
with low BMD alone, with a similar pattern for the
prediction of all fractures in younger postmenopausal women (Figure 4).63
The use of bone markers in individual patients
may be particularly useful in women who are not
detected to be at risk by BMD measurements. In the
OFELY study including 671 postmenopausal women followed prospectively over a median of 9 years,
48% of all fractures occurred in osteopenic women. Among these women, the combination of lower
BMD and/or prior fractures and/or bone ALP in the
CHALLENGES
IN
OSTEOPOROSIS
highest quartile could detect 85% of incident fractures with an age-adjusted hazard ratio of 5.3 (2.3;
11.8).64 Women at high risk of fracture may benefit
from therapeutic intervention, especially if risk factors are amenable to bone-specific agents. In the
Fracture Intervention Trial (FIT) with alendronate,
there was a greater reduction in the risk of nonspine
fracture in women with increased pretreatment
Low BMD (T< –2.5 SD)
Prior fracture
High CTX
Low BMD, high CTX
Prior fracture, high CTX
Low BMD, prior fracture
70
10-year probability of fracture (%)
Clinical uses of
bone markers in osteoporosis
AND
60
50
RR
6
5
*
* All of the above
4
3
40
2
30
20
1
*
10
0
50
60
70
80
Age (y)
Figure 4. The combination of clinical risk factors with bone mineral density (BMD)
and bone turnover measurements to identify women with the highest risk of fracture.
The figure shows the 10-year probability of hip fracture according to age and relative
risk. The symbols show the effect of risk factors on fracture probability derived from
women aged an average of 65 years (Os des FEmmes de LYon [OFELY] study) and 80
years (EPIDemiology of OSteoporosis [EPIDOS] study). The data from the OFELY
study are derived from information regarding all fractures. Low hip BMD was defined
as values 2.5 standard deviations (SD) from the mean in young adults. High urinary
CTX (C-terminal crosslinked telopeptide of type I collagen) corresponds to values above
the upper limit of premenopausal women (mean plus 2 SD).
Reproduced from reference 63: Johnell O, Oden A, De Laet C, Garnero P, Delmas PD, Kanis JA. Biochemical indices of bone turnover and the assessment of fracture probability. Osteoporos Int. 2002;13:523-526.
Copyright © 2002, Springer London.
bone turnover markers,65 although no such association was found in the smaller risedronate studies.66 Anabolic therapies and especially PTH have
been viewed as a particularly attractive therapeutic
agent for patients with low bone turnover. However
recent studies with both teriparatide (rhPTH 1-34)
and recombinant human PTH 1-84 indicate that
PTH therapy increases BMD and reduces fracture
risk, whether or not bone turnover is suppressed.
With both agents, the increase in spine BMD was
actually larger in those with higher pretreatment
bone turnover.67,68 In women treated with teriparatide, the absolute risk of spine fracture reduction
was also larger in those women with higher pretreatment levels of bone markers.69 Thus with both
anticatabolic and PTH treatments, higher pretreatment bone turnover appears to be associated
with a greater efficacy. Collete et al recently reported in a pooled analysis of the Spinal Osteoporosis
Therapeutic Intervention (SOTI) and TReatment Of
Peripheral OSteoporosis (TROPOS) randomized
studies that the anti–vertebral fracture efficacy of
strontium ranelate compared with placebo was similar across quartiles of baseline levels of bone alka-
Advances in bone turnover assessment with biochemical markers – Garnero
MEDICOGRAPHIA, VOL 30, No. 4, 2008 345
NEW APPROACHES
CHALLENGES
AND
IN
OSTEOPOROSIS
line phosphatase or CTX.70 These data suggest that
the antifracture efficacy of strontium ranelate is
largely independent of pretreatment bone turnover.
Bone markers for monitoring treatment of
osteoporosis
As for most chronic diseases, monitoring the efficacy of treatment of osteoporosis is a challenge. The
goal of treatment is to reduce the occurrence of
fragility fractures, but their incidence is low and the
absence of events during the first year(s) of therapy does not imply necessarily that treatment is effective. Thus, the use of surrogate markers with a
more rapid response is clearly needed for an efficient monitoring of treatment in osteoporosis. A
PTH bone formation markers
PTH bone resorption markers
Oral biphosphonates bone formation markers
Oral biphosphonates bone resorption markers
Change from baseline (%)
100
0
6
12
–100
18
24
30
36
Months
Figure 5. Schematic representation of the response of biochemical
markers of bone formation and resorption to intermittent parathyroid hormone (PTH) treatment and oral bisphosphonate.
surrogate marker can be defined as a laboratory
measurement or a physical sign that can be used as
substitute for a clinical meaningful end point that
measures directly how a patient feels, functions or
survives. Changes induced on a surrogate end point
by a therapy are expected to reflect changes in a clinical meaningful end point, ie, incidence of fracture.
The measurement of BMD as a surrogate marker of
treatment efficacy has been widely used in clinical
trials. Its use in the monitoring of treatment efficacy in the individual patient, however, has not been
validated.
Several randomized, placebo-controlled studies
have shown that resorption-inhibiting therapy, including that with bisphosphonates, estrogens, selective estrogen receptor modulators, the anti-RANKL
antibody denosumab, and cathepsin K inhibitors, is
associated with a prompt decrease in bone resorp346 MEDICOGRAPHIA, VOL 30, No. 4, 2008
tion markers that can be seen as early as after a few
weeks, with a plateau reached within 3 to 6 months
(for a recent review on the use of markers in clinical trials, see reference 71). The decrease in bone
formation markers is delayed, reflecting the physiological coupling of formation to resorption, and a
plateau is usually achieved within 6 to 12 months
(Figure 5). With inhibitors of cathepsin K, however, current evidence suggests there is only a small
change in bone formation markers during the first
year of therapy.
Recent studies have investigated the relationships
between bone marker changes and fracture risk in
several randomized studies of various antiresorptive
therapies. It was found that the changes in serum
osteocalcin, Bone ALP, and PINP with raloxifene
were associated with the subsequent risk of vertebral fractures in a subgroup of osteoporotic women enrolled in the Multiple Outcomes of Raloxifene
Evaluation (MORE), while changes in hip BMD were
not predictive.72 In postmenopausal women with osteoporosis treated with oral risedronate, changes
in urinary CTX and NTX after 3 to 6 months predicted the risk of subsequent incident vertebral fractures at 3 years.73 A significant association was also
found between changes in bone ALP, and vertebral,
hip, and nonspine fracture in women treated with
alendronate participating in FIT.74 In the risedronate
study, it was shown that the relationship between
vertebral fracture risk and the levels of CTX reached
after 3 to 6 months was not linear, and that there
may be a level of bone resorption reduction below
which there is no further fracture benefit.75 Although optimal cut-offs still need to be validated in
prospective studies, it has been proposed that the
goal of antiresorptive therapy is to reduce bone
turnover markers to within the lower half of the
reference range for healthy young premenopausal
women.73 This requires the determination of accurate reference intervals for the lower limit of bone
turnover markers in healthy premenopausal women, data that are now becoming available.76,77
Bone turnover markers may also be useful to
monitor the effects of anabolic treatments, including intermittent administration of PTH. For example, in the PaTH study with PTH 1-84 and with
teriparatide in the Fracture Prevention Trial,67,68 it
was shown that PTH produces a marked and rapid
(within a month) increase in markers of bone formation, followed by a delayed increase in bone resorption markers (Figure 5). In this situation, bone
formation markers, especially serum PINP,4,67,68 appear the most useful marker, although these data
will need to be confirmed in studies using incident
fracture as an end point.
Strontium ranelate has a unique mechanism of
action as it both stimulates bone formation and at
the same time decreases bone resorption, as documented by changes in biochemical markers in
clinical studies. However, because the magnitude
of these changes is relatively small,78 bone markers
are not useful to monitor its efficacy. Conversely,
changes in hip BMD with strontium ranelate have
been shown to be a strong predictor of its antivertebral fracture efficacy.79
Advances in bone turnover assessment with biochemical markers – Garnero
NEW APPROACHES
Male osteoporosis
About one quarter of all osteoporotic hip fractures
occur in men. In men, similar to postmenopausal
women, low BMD is associated with increased risk
of osteoporotic fracture. Two recent prospective
studies (the French MINOS study, with patients
aged 50 to 85 years, and the US Osteoporotic Fractures in Men [MrOs] study, in which patients were
>65 years)80,81 have shown that increased biochemical markers of bone turnover are significantly, although modestly, associated with BMD loss over
5 to 7.5 years.
An association between high levels of ICTP and
an increased risk of osteoporotic fracture in elderly men, independent of BMD has been reported in
the Australian Dubbo study.82 However, in the two
larger MINOS and MrOs studies, there was no significant association between a panel of biochemical markers of bone formation and bone resorption,
and incident risk of all (MINOS), hip, and nonspine
REFERENCES
1. No authors listed. Consensus development conference: diagnosis, prophylaxis and treatment of osteoporosis. Am J Med.
1993;94:646-650.
2. Garnero P, Delmas PD. Investigation of bone: biochemical
markers. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME,
Weisman MH, eds. Rheumatology. Vol 2. 4th ed. London, UK:
Harcourt Health Sciences Ltd; 2007:1943-1953.
3. Garnero P, Borel O, Delmas PD. Evaluation of a fully automated serum assay for C-Terminal cross-linking telopeptide of
type I collagen in osteoporosis. Clin Chem. 2001;47:694-702.
4. Garnero P, Vergnaud P, Hoyle N. Evaluation of a fully automated serum assay for total N terminal propeptide of type I collagen in postmenopausal osteoporosis. Clin Chem. 2008;54:188196.
5. Fedarko NS, Jain A, Karadag A, Van Eman MR, Fisher LW. Elevated serum bone sialoprotein and osteopontin in colon, breast,
prostate, and lung cancer. Clin Cancer Res. 2001;7:4060-4066.
6. Papotti M, Kalebic T, Volante M, et al. Bone sialoprotein is
predictive of bone metastases in resectable non-small-cell lung
cancer: a retrospective case-control study. J Clin Oncol. 2006;24:
4818-4824.
7. Seibel M, Woitge H, Pecherstorfer M, et al. Serum immunoreactive bone sialoprotein as a new marker of bone turnover in
metabolic and malignant bone disease. J Clin Endocrinol Metab.
1996;81:3289-3294.
8. Diel IJ, Solomayer EF, Seibel MJ, et al. Serum bone sialoprotein in patients with primary breast cancer is a prognostic marker for subsequent bone metastasis. Clin Cancer Res.1999;5:39143919.
9. Garnero P, Grimaux M, Seguin P, Delmas PD. Characterization
of immunoreactive forms of human osteocalcin generated in vivo
and in vitro. J Bone Miner Res. 1994;9:255-264.
10. Ivaska KK, Hentunen TA, Vääräniemi J, Ylipahkala H, Pettersson K, Väänänen HK. Release of intact and fragmented osteocalcin molecules from bone matrix during bone resorption in vitro.
J Biol Chem. 2004;279:18361-18369.
11. Srivastava AK, Mohan FR, Singer FR, Baylink DJ. A urine midmolecule osteocalcin assay shows higher discriminatory power
than a serum midmolecule osteocalcin assay during short-term
alendronate treatment of osteoporotic patients. Bone. 2002;31:
62-69.
12. Ivaska KK, Hellman J, Likojarvi J, et al. Identification of novel proteolytic forms of osteocalcin in human urine. Biochem
Biophys Res Com. 2003;306:973-980.
13. Lenora J, Ivaska KK, Obrant KJ, Gerdhem P. Prediction of
bone loss using biochemical markers of bone turnover. Osteoporos Int. 2007;18:1297-1305.
14. Gerdhem P, Ivaska KK, Alatalo SL, et al. Biochemical markers of bone metabolism and prediction of fracture in elderly women. J Bone Miner Res. 2004;19:386-393.
15. Esfandiari E, Bailey M, Stokes C, Cox TM, Evans MJ, Hayman
AR. TRACP influences Th1 pathways by affecting dendritic cell
function. J Bone Miner Res. 2006;21:1367-1376.
16. Janckila AJ, Parthasarathy RN, Parthasarathy LK, et al. Prop-
AND
CHALLENGES
IN
OSTEOPOROSIS
(MrOs) fractures after adjustment for confounding
factors. Thus, in contrast to postmenopausal osteoporosis, biochemical markers of bone turnover
have little value to assess fracture risk in elderly
men.
Conclusion
Consistent data have shown that some of the current biochemical markers may be useful to improve
prediction of fracture risk and to monitor the efficacy of antiresorptive and PTH therapies in postmenopausal women. New biochemical markers reflecting different biological pathways of osteoblastic
and osteoclastic activity and changes in the structural properties of bone matrix have more recently
been developed. Their respective value in the management of patients with osteoporosis alone or in
combination with existing markers should be further evaluated. erties and expression of human tartrate resistant acid phosphatase
isoform 5a by monocyte-derived cells. J Leukoc Biol. 2005;77:209218.
17. Vääräniemi J, Hallen JM, Kaarlonen K, et al. Intracellular
machinary for matrix degradation in bone-resorbing osteoclasts.
J Bone Miner Res. 2004;19:1432-1440.
18. Hallen JS, Alatalo SL, Suominen H, et al. Tartrate-resistant
acid phosphatase 5b: a novel serum marker of bone resorption.
J Bone Miner Res. 2000;15:1337-1345.
19. Ohashi T, Igarashi Y, Mochiuki Y, et al. Development of a novel fragments absorbed immunocapture enzyme assay system for
tartrate-resistant acid phosphatase 5b. Clin Chim Acta. 2007;
376:205-212.
20. Lhoste Y, Vergnaud P, Garnero P. A new specific immunoassay for intact serum TRACP5b demonstrates increased sensitivity in osteoporosis. J Bone Miner Res. 2007;22(suppl 1):S192.
21. Alatalo SL, Ivaska KK, Waguespack SG, Econs MJ, Väänänen
HK, Hallen JM. Osteoclast derived serum tartrate-resistant acid
phosphatase 5b in Albers-Schondberg disease (type II autosomal dominant osteopetrosis). Clin Chem. 2004;50:883-890.
22. Nenonen A, Cheng S, Ivaska K, et al. Serum TRACP5b is a
useful marker for monitoring alendronate treatment: comparison with other markers of bone turnover. J Bone Miner Res. 2005;
20:1804-1812.
23. Garnero P, Borel O, Byrjalsen I, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases.
J Biol Chem. 1998;273:32347-32352.
24. Skoumal M, Haberhauer G, Kolarz G, Hawa G, Woloszczuk W,
Klingler A. Serum cathepsin K levels of patients with longstanding rheumatoid arthritis: correlation with radiological destruction. Arthritis Res Ther. 2005;7:R65-R70.
25. Meier C, Meinhardt U, Greenfield JR, et al. Serum cathepsin K concentrations reflect osteoclast activity in women with
postmenopausal osteoporosis and patients with Paget’s disease
of bone. Clin Lab. 2006;21:1-10.
26. Holzer G, Noske H, Lang T, Holzer L, Willinger U. Soluble
cathepsin K: a novel marker for the prediction of nontraumatic
fractures? J Lab Clin Med. 2005;146:13-17.
27. Kearns AE, Khosla S, Kostenuik P. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone
remodeling in health and disease. Endocr Rev. 2008;29:155-192.
28. Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey
DL, Riggs BL. Role of RANK-ligand in mediating increased bone
resorption in early postmenopausal women. J Clin Invest. 2003;
111:1221-1230.
29. D’Amelio P, Grimaldi A, Di Bella S, et al. Risedronate reduces
osteoclast precursors and cytokine production in postmenopausal
osteoporotic women. J Bone Miner Res. 2008;23:373-379.
30. Rogers A, Eastell R. Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in
metabolic bone disease assessment. J Clin Endocrinol Metab.
2005;90:6323-6331.
31. Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chon-
Advances in bone turnover assessment with biochemical markers – Garnero
MEDICOGRAPHIA, VOL 30, No. 4, 2008 347
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
drocyte differentiation during vertebrate skeletogenesis. Dev Cell.
2005;8:739-750.
32. Johnson ML, Kamel MA. The Wnt signalling pathway and
bone metabolism. Curr Opin Rheum. 2007;19:376-382.
33. Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling
antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483-2494.
34. Voorzanger-Rousselot N, Goehrig D, Journe F, Body JJ, Clézardin P, Garnero P. Increased dickkopf-1 (Dkk-1) expression in
breast cancer bone metastases. Br J Cancer. 2007;97:964-970.
35. Yamabuki T, Takano A, Hayama S, et al. Dikkopf-1 as a novel
serologic and prognostic biomarker for lung and esophageal carcinomas. Cancer Res. 2007;67:2517-2525.
36. Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master
regulator of joint remodeling. Nat Med. 2007;13:156-163.
37. Lane NE, Nevitt MC, Lui LY, de Leon P, Corr M. Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian
women. Arthritis Rheum. 2007;56:3319-3325.
38. Viguet-Carrin S, Garnero P, Delmas P. The role of collagen in
bone strength. Osteoporos Int. 2006;17:319-336.
39. Banse X, Sims TJ, Bailey AJ. Mechanical properties of adult
vertebral cancellous bone: correlation with collagen intermolecular cross-links. J Bone Miner Res. 2002;17:1621-1628.
40. Wang X, Shen X, Li X, Agrawal CM. Age-related changes in
collagen network and toughness of bone. Bone. 2002;31:1-7.
41. Hernandez CJ, Tang SY, Baumbach BM, et al. Trabecular microfracture and the influence of pyridinium and non-enzymatic
glycation-mediated collagen cross-links. Bone. 2005;37:825-832.
42. Viguet-Carrin S, Roux JP, Arlot ME, et al. Contribution of
advanced glycation end product pentosidine and of maturation
of type I collagen to compressive biomechanical properties of human lumbar vertebrae. Bone. 2006;39:1073-1079.
43. Shiraki M, Kuroda T, Tanaka S, Saito M, Fukunaga M, Nakamura T. Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner
Metab. 2008;26:93-100.
44. Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto
T. Serum pentosidine levels are positively associated with the
presence of vertebral fractures in postmenopausal women with
type 2 diabetes. J Clin Endocrinol Metab. 2008;93:1013-1019.
45. Garnero P, Fledelius C, Gineyts E, Serre CM, Vignot E, Delmas
PD. Decreased β-isomerisation of C-telopeptides of type I collagen in Paget’s disease of bone. J Bone Miner Res.1997;12:14071415.
46. Leeming DJ, Delling G, Koizumi M, et al. Alpha CTX as a
biomarker of skeletal invasion of breast cancer: immunolocalization and the load dependency of urinary excretion. Cancer Epidemiol Biomarkers Prev. 2006;15:1392-1395.
47. Garnero P, Schott A, Meunier PJ, Chevrel G. Impaired type I
collagen C-telopeptide isomerization in patients with osteogenesis imperfecta. J Bone Miner Res. 2006;21(suppl 1):S429.
48. Garnero P, Gineyts E, Schaffer AV, Seaman J, Delmas PD.
Measurement of urinary excretion of nonisomerized and β–isomerized forms of type I collagen breakdown products to monitor the effects of the bisphosphonate zoledronate in Paget’s Disease. Arthritis Rheum. 1998;41:354-360.
49. Alexandersen P, Peris P, Guanabens N, et al. Non-isomerized
C-telopeptide fragments are highly sensitive markers for monitoring disease activity and treatment efficacy in Paget’s disease
of bone. J Bone Miner Res. 2005;20:588-595.
50. Garnero P, Cloos P, Sornay-Rendu E, Qvist P, Delmas PD.
Type I collagen racemization and isomerization and the risk of
fracture in postmenopausal women: The OFELY prospective
study. J Bone Miner Res. 2002;17:826-833.
51. Allen MR, Gineyts E, Leeming DJ, Burr DB, Delmas PD.
Bisphosphonates alter trabecular bone collagen cross-linking and
isomerization in beagle dog vertebra. Osteoporos Int. 2008;19:
329-337.
52. Byrjalsen I, Leeming DJ, Qvist P, Christiansen C, Karsdal MA.
Bone turnover and bone collagen maturation in osteoporosis:
effects of antiresorptive therapies. Osteoporos Int. 2008;19:339348.
53. Garnero P, Bauer DC, Mareau E, et al. The degree of type I collagen isomerization in postmenopausal women with osteoporosis after alendronate (ALN) or parathyroid hormone (PTH) administration: The PaTH Study. J Bone Miner Res. 2006;21(suppl
1):S233.
54. Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture
in elderly women. J Clin Invest. 1993;91:1769-1774.
348 MEDICOGRAPHIA, VOL 30, No. 4, 2008
55. Vergnaud P, Garnero P, Meunier PJ, Breart G, Kamilhagi K,
Delmas PD. Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the
EPIDOS study. J Clin Endocrinol Metab. 1997;82:719-724.
56. Luukinen H, Kakonen SM, Pettersson K, et al. Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin. J Bone Miner Res. 2000;15:24732478.
57. Liu G, Peakcock M. Age-related changes in serum undercarboxylated osteocalcin and its relationships with bone density,
bone quality, and hip fracture. Calcif Tissue Int.1998;62:286-289.
58. Cloos PAC, Christgau S. Characterization of aged osteocalcin
fragments derived from bone resorption. Clin Lab. 2004;50:585598.
59. Lee NK, Sowa H, Hinoi E, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130:456-469.
60. Johnell O, Kanis JA, Oden A, et al. Predictive value of BMD for
hip and other fractures. J Bone Miner Res. 2005;20:1185-1194.
61. Garnero P. Markers of bone turnover for the prediction of
fracture risk. Osteoporos Int. 2000;11(suppl 6):S55-S65.
62. Ivaska KK, Gerdhem P, Akesson K, Obrant KJ. Bone turnover
and prediction of fracture: nine year follow-up study of 1040 elderly women. J Bone Miner Res. 2007;22(suppl 1):S21.
63. Johnell O, Oden A, De Laet C, Garnero P, Delmas PD, Kanis
JA. Biochemical indices of bone turnover and the assessment of
fracture probability. Osteoporos Int. 2002;13:523-526.
64. Sornay-Rendu E, Munoz F, Garnero P, Duboeuf F, Delmas PD.
The identification of osteopenic women at high risk of fracture:
The OFELY study. J Bone Miner Res. 2005;20:1813-1819.
65. Bauer DC, Garnero P, Hochberg MC, et al. Pre-treatment bone
turnover and fracture efficacy of alendronate: the Fracture Intervention Trial. J Bone Miner Res. 2006;21:292-299.
66. Seibel MJ, Naganathan V, Barton I, Grauer A. Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic women treated with risedronate. J Bone Miner Res. 2004;19:323-329.
67. Chen P, Satterwhite JH, Licata AA, et al. Early changes in
biochemical markers of bone formation predict BMD response to
teriparatide in postmenopausal women with osteoporosis. J Bone
Miner Res. 2005;20:962-970.
68. Bauer DC, Garnero P, Bilezikian JP, et al. Short-term changes
in bone turnover markers and bone mineral density response to
parathyroid hormone in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2006;91:1370-1375.
69. Delmas PD, Licata AA, Reginster JY, et al. Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover. Bone. 2006;39:237-243.
70. Colette J, Reginster JY, Bruyère O, et al. Strontium ranelate
decreases vertebral fracture risk whatever the level of pretreatment bone turnover markers. Calcif Tissue Int. 2007;80(suppl 1):
S29-S30.
71. Cremers S, Garnero P. Biochemical markers of bone turnover
in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls. Drugs. 2006;66:
2031-2058.
72. Sarkar S, Reginster JY, Crans GG, et al. Relationship between
changes in biochemical markers of bone turnover and BMD to
predict vertebral fracture risk. J Bone Miner Res. 2004;19:394401.
73. Eastell R, Barton I, Hannon RA, Chines A, Garnero P, Delmas
PD. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res. 2003;
18:1051-1056.
74. Bauer DC, Black DM, Garnero P, et al. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronatetreated women: the fracture intervention trial. J Bone Miner Res.
2004;19:1250-1258.
75. Eastell R, Hannon RA, Garnero P, Campbell MJ, Delmas PD.
Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate: review of statistical analysis. J Bone Miner Res. 2007;22:1656-1660.
76. de Papp AE, Bone HG, Caulfield MP, et al. A cross-sectional
study of bone turnover markers in healthy premenopausal women. Bone. 2007;40:1222-1230.
77. Glover SJ, Garnero P, Naylor K, Rogers A, Eastell R. Establishing a reference range for bone turnover markers in young,
healthy women. Bone. 2008;42:623-630.
78. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium
ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468.
79. Bruyere O, Roux C, Detilleux J, et al. Relationship between
Advances in bone turnover assessment with biochemical markers – Garnero
NEW APPROACHES
bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab.
2007;92:3076-3081.
80. Szulc P, Montella A, Delmas PD. High bone turnover is associated with accelerated bone loss but not with increased fracture risk in men aged 50 and over—prospective MINOS study.
Ann Rheum Dis. 2007 Dec 7. Epub ahead of print.
PROGRÈS
AND
CHALLENGES
IN
OSTEOPOROSIS
81. Bauer DC, Garnero P, Harrison SL. Biochemical markers of
bone turnover, hip bone loss and non-spine fracture in men. A
prospective study. J Bone Miner Res. 2007;22(suppl 1):S21.
82. Meier C, Nguyen TV, Center JR, Seibel MJ, Eisman JA. Bone
resorption and osteoporotic fractures in elderly men: the Dubbo
osteoporosis epidemiology study. J Bone Miner Res. 2005;20:
579-587.
DANS L’ÉVALUATION DU RENOUVELLEMENT OSSEUX
PAR LES MARQUEURS BIOCHIMIQUES
I
l est maintenant facile de mesurer précisément les marqueurs biochimiques
systémiques de la formation et de la résorption osseuses grâce à l’automatisation des techniques. Les marqueurs actuels ont cependant certaines limites : (1) la variabilité interpatient pour les marqueurs de résorption du collagène de type I est relativement importante ; (2) les marqueurs actuels évaluent
le taux de renouvellement osseux du squelette entier mais ne permettent pas de
caractériser le rôle des différentes enveloppes squelettiques et (3) ils ne reflètent que les variations quantitatives du renouvellement osseux alors que les variations des propriétés de la matrice osseuse sont également un déterminant
important de la solidité osseuse. La recherche pour développer de nouveaux
marqueurs biochimiques remédiant à certains de ces inconvénients progresse.
Ainsi, notre meilleure connaissance de la biochimie de la matrice osseuse, et en
particulier des modifications post-translationnelles du collagène de type I, permet d’identifier les marqueurs biochimiques qui reflètent les modifications des
propriétés biomécaniques de l’os. Plusieurs études ex vivo ont montré que les
modifications non enzymatiques du collagène (par exemple, les produits de glycation avancée et l’isomérisation) participent à la résistance fracturaire, surtout
sa ductilité, indépendamment de la densité minérale osseuse. Des études cliniques récentes ont montré que le quotient urinaire entre les fragments non
isomérisés ( CTX) et isomérisés ( CTX) des télopeptides de collagène de type I
pouvait fournir des informations sur la maturation de la matrice osseuse. Cette
dernière est associée au risque fracturaire et, chez la femme ménopausée, varie
de façon différente selon le type de traitement antirésorptif. Cet article présente
une mise au point sur les nouveaux marqueurs biochimiques et analyse brièvement leur utilité clinique dans l’ostéoporose masculine et postménopausique.
Advances in bone turnover assessment with biochemical markers – Garnero
MEDICOGRAPHIA, VOL 30, No. 4, 2008 349
AND
CHALLENGES
IN
OSTEOPOROSIS
NEW APPROACHES
Elisabeth SORNAY-RENDU, MD
Pierre D. DELMAS, MD, PhD
INSERM Unit 831
E. Herriot Hospital, Lyon
FRANCE
Advances in
osteoporosis diagnosis:
the use of clinical risk factors
by E. Sornay-Rendu
a n d P. D . D e l m a s , F r a n c e
steoporosis and the consequent increase in fracture risk associated with
it are a major health concern for postmenopausal women and older men.
Osteoporosis is diagnosed on the basis of bone mineral density (BMD),
as epidemiological studies have shown low BMD to be a strong predictor of osteoporotic fracture. There is, however, a wide overlap of BMD values in fracture
cases and controls, because of the multiple determinants of skeletal fragility.
In addition, some recent studies have shown that up to one half of patients with
incident fractures have a baseline BMD that is above the World Health Organization (WHO) diagnostic threshold for osteoporosis (T-score <--2.5). The relatively poor sensitivity of BMD, contrasting with a high specificity, means that
many women who will fracture in their lifetime will not be identified as being
at high risk on the basis of BMD assessment alone. Studies found that less than
one third of patients who had had fragility fractures were appropriately evaluated and treated for osteoporosis, despite a high risk of future fractures. The
rates of diagnosis are even lower among those who have not yet had a fracture.
There is consequently a trend to recommend the identification of osteoporotic individuals based on fracture risk rather than BMD status. The incorporation of non-BMD risk factors has been demonstrated to improve the accuracy
of fracture risk prediction. Then, BMD would be one among other factors to
predict fracture risk. Over the past several years, the WHO collaborating center
led by John Kanis has conducted several meta-analyses of data from large-scale
prospective studies conducted in various countries to identify and quantify the
risk associated with several clinical factors (prior fracture in the patient or family, body mass index, smoking, and glucocorticoid treatment) independently
from BMD and age. These extensive studies should help to develop international guidelines for the clinical management of osteoporosis.
O
Medicographia. 2008;30:350-354.
(see French abstract on page 354)
Keywords: osteoporosis; diagnosis; clinical risk factor; fracture risk prediction;
absolute risk; bone mineral density; previous fracture; age; screening for
osteoporosis
www.medicographia.com
Professor Pierre Delmas died July 23, 2008.
Address for correspondence: Elisabeth Sornay-Rendu, INSERM Unit 831, Pavillon F,
Hôpital E. Herriot, 69437 Lyon Cedex 03, France
(e-mail: [email protected])
350 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Definition of osteoporosis
steoporosis is a disease characterized by low
bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. The diagnosis of osteoporosis is based on bone
mineral density (BMD), as low BMD has been shown
in epidemiological studies to be a strong predictor
of osteoporotic fracture.1-3 In 1994, an expert panel
of the World Health Organization (WHO) recommended thresholds of BMD in women to define osteoporosis.4 Thus, osteoporosis in postmenopausal
white women is defined as a BMD value assessed by
dual-energy X-ray absorptiometry of >2.5 standard
deviations below the average value in young women, ie, a T-score of --2.5 or lower. The definition of
severe osteoporosis (established osteoporosis) uses
the same threshold, but includes the presence of
O
SELECTED
ABBREVIATIONS AND ACRONYMS
ABONE Age BOdy size No Estrogen (risk assessment tool)
BMD
bone mineral density
BMI
body mass index
BTM
bone turnover marker
EPIDOS EPIDemiology of OSteoporosis (study)
HAS
High Health Authority (France)
NORA National Osteoporosis Risk Assessment
OFELY Os des FEmmes de LYon (study)
ORAI
Osteoporosis Risk Assessment Instrument
OST
Osteoporosis Self-Assessment Tool
SCORE Simple Calculated Osteoporosis Risk
Estimation
SOF
Study of Osteoporotic Fractures
WHO
World Health Organization
Advances in osteoporosis diagnosis: the use of clinical risk factors – Sornay-Rendu and Delmas
NEW APPROACHES
one or more prior fragility fractures. The term
“osteopenia” or “low bone mass” is applied when
T-scores are between --1.0 and --2.5. The preferred
site for BMD measurements for diagnostic purposes is the hip — either the total hip or the femoral
neck. In men, a similar T-score threshold is used
to diagnose osteoporosis, using sex-specific mean
peak bone mass values.
Limitations of bone mineral density
Based on the common definition of osteoporosis
(T-score <--2.5), the proportion of fractures attributable to osteoporosis is modest, ranging from 10%
to 44% in women 65 years of age and older.5 Indeed,
since there are many more people with osteopenia
than with osteoporosis, approximately half of all
fragility fractures occur in the osteopenic group, although the relative risk of fracture is higher in the
osteoporotic population. Data from the National Osteoporosis Risk Assessment (NORA)6 population
showed that in the space of 1 year, 52% of women
experiencing an incident osteoporotic fracture had
a T-score measured peripherally of between --1.0
and --2.5, and 82% had a T-score >--2.5. In the Rotterdam study, only 44% of all nonvertebral fractures occurred in women with a T-score below --2.5.7
Moreover, shortcomings of the T-score include lack
of standardization regarding which skeletal sites to
evaluate, lack of generalization to nonwhite groups,
and use of BMD as the only risk factor for osteoporosis that is evaluated. The relatively poor sensitivity of BMD, contrasting with a high specificity,
means that many women who will fracture in their
lifetime will not be identified to be at high risk on
the basis of BMD assessment alone. Thus, there is a
trend to recommend the identification of individuals based on fracture risk rather than BMD status
alone. Indeed, it has been shown that fewer than one
third of patients who have had fragility fractures are
currently appropriately evaluated and treated for osteoporosis,8,9 despite a high risk of future fractures.
Clinical risk factors
Age
Age is a major predictor of fractures. After menopause, an increase in the risk of fractures of the
wrist appears first, followed by an increase in the
risk of vertebral and then hip fractures. Fracture
prevalence continues to increase with advancing
age, with a notable increase in women around the
age of 75 years and a little later in men. It has been
shown that irrespective of BMD, the 10-year likelihood of sustaining a major osteoporotic fracture
(spine, humerus, wrist or hip) in women of 80 years
of age is twice as high as in women of 50 years of
age.10 Older women may be the most important
group to screen for osteoporosis.
The impact of other clinical risk factors may vary
with age. Indeed, the prevalence of prior fractures
increases with age. Results of a meta-analysis showed
that a familial history of fracture was more closely
associated with the fracture risk in younger women rather than older postmenopausal women.11 On
AND
CHALLENGES
IN
OSTEOPOROSIS
the other hand, factors associated with falls (eg, disorders of balance and vision) may be more relevant
in older women, in whom they are common and
predict hip fractures.12 Thus, age needs to be included in interpretations of BMD.
Prevalence of fractures
Another important risk factor for fracture, independent of BMD, is a previous fragility fracture.13 The
risk of subsequent fracture in women with a prior
fracture is double that of women without a fracture
history. In women with pre-existing vertebral fractures, the risk of subsequent fracture is approximately 4 times that of women without a fracture
history, and this risk increases with the number of
prior vertebral fractures. Both clinical and silent
vertebral fractures (identified radiologically) increase the risk, and should be looked for in patients
who have lost more than 2 cm in height.14 The risk
of a subsequent fracture is highest (up to 5 times
higher) in the first year after the original event.15,16
Family history of fracture
Several studies have shown clearly that there is a
substantial heritable component to both fracture
risk and adult bone density. A family history of fracture also appears to be a risk factor for fracture, independent of BMD. Hip fracture risk is increased
among daughters whose mothers have a prior history of fragility fractures after the age of 50 years.17
In the Study of Osteoporotic Fractures (SOF), the
risk of hip or wrist fracture was increased in those
women with a family history of wrist or hip fracture.
The increased risk of hip fracture was apparent with
a family history in mother, sister or brother.18 In a
recent meta-analysis from 7 large prospective population studies, Kanis et al reported that a parental
history of hip fracture was associated with a significant risk of both all osteoporotic fractures, and especially hip fracture.11
Weight and body mass index
Low weight, or low body mass index (BMI), is a welldocumented risk factor for future fracture, whereas a high BMI appears to be protective.12,19-21 A metaanalysis conducted with data from 12 prospective
population-based cohorts showed that low BMI is
associated with an increase in fracture risk of similar magnitude in men and women. This risk associated with a low BMI is present at most ages and
for all types of fracture studied, but is strongest for
hip fracture and is more marked at low BMI values.
After adjusting for BMD, a low BMI remains a significant risk factor only for hip fracture in women.22
Alcohol use and smoking
Studies from Europe, North America, and Australia
show that more than 2 units of alcohol per day can
increase the risk of osteoporotic and hip fractures
in both men and women. Smoking also increases
a person’s fracture risk. International studies have
shown that current smoking increases the risk for
hip fracture by up to 1.5-fold and that low BMD accounts for only 23% of the smoking-related risk of
hip fracture. A smoking history is also associated
Advances in osteoporosis diagnosis: the use of clinical risk factors – Sornay-Rendu and Delmas
MEDICOGRAPHIA, VOL 30, No. 4, 2008 351
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
with a significantly increased risk of fracture—but
lower than current smoking —compared with individuals with no smoking history.23
Frequent falls
Falls are another important predictor, particularly
for hip fracture in the elderly, as 90% of hip fractures result from falls. Visual impairments, loss of
balance, neuromuscular dysfunction, dementia,
immobilization, and use of sleeping pills, all of which
are quite common in elderly people, significantly
increase the risk of falling and the risk of fracture,
and should be assessed.24
Glucocorticoid use
The adverse effects of corticosteroids on bone fragility have been appreciated for many years. A major
mechanism relates to the progressive loss of bone
that occurs once corticosteroids are started, but the
underlying condition for which they are used is also
important to consider. Moreover, the alterations
in muscle strength and metabolism increase the
Survival probability
without fracture
1.00
Normal
Osteopenia RF–
0.75
Osteopenia RF+
Osteoporosis
0.50
0.00
0
20
40
60
80
100
120
Months
(671)
(627)
(502)
(555)
(517)
(463)
(308)
Number of
women
Figure 1. Survival probability without fracture in postmenopausal women according to the World Health Organization criteria for bone mineral density. Among
those with osteopenia, women were categorized into two groups: osteopenia with
one or more risk factor(s) (RF+) and osteopenia without risk factor(s) (RF--).
RF = low bone mineral density (--2.5< lowest T-score --2.0), prior fracture, high
level of bone turnover markers.
Reproduced from reference 35: Sornay-Rendu E, Munoz F, Garnero P, Duboeuf F, Delmas PD.
The identification of osteopenic women at high risk of fracture: The OFELY Study. J Bone Miner
Res. 2005;20:1813-1819. Copyright © 2005, the American Society for Bone and Mineral Research.
propensity for falling, thereby increasing fracture
risk. Epidemiological data suggest that the risk of
hip, forearm, and shoulder fractures is increased
about twofold with corticosteroids.25,26 The risk for
vertebral fracture may be somewhat higher.27 Current and previous glucocorticoid therapy are both
associated with an increased fracture risk even after
adjustment for BMD and previous fragility fracture.
The association is strongest for glucocorticoid treatment and hip fracture. The risk is similar in men
and women.28
Rheumatic disease
Patients with inflammatory rheumatic diseases,
ranging from rheumatoid arthritis to vasculitis,
have a high risk of fracture independent of their
BMD.29-31 Rheumatoid arthritis is an independent
risk factor for fracture that persists after adjustment for corticosteroid use.28
352 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Bone turnover markers
Several prospective studies have shown that bone
turnover markers (BTMs) are able to predict fracture
risk.32-34 In the Os des FEmmes de LYon (OFELY)
study, postmenopausal women with BMD values in
the osteopenic range had an increased risk of fracture in the subsequent 10 years if they had low BMD,
increased BTMs, or history of prior fracture. Thus,
the risk of fracture in osteopenic women with prior fractures or high BTMs is close to that of osteoporotic women. By contrast, osteopenic women with
no risk factors could be compared to normal women in terms of risk of fragility fracture (Figure 1).35
Screening for osteoporosis
before BMD measurement
In recent years, several risk assessment questionnaires incorporating body weight and/or age have
been developed and validated in a number of cohorts
to help better identify individuals who should undergo bone densitometry. These instruments are
used primarily to identify postmenopausal women
who may be at increased risk for osteoporotic fracture. The Osteoporosis Risk Assessment Instrument
(ORAI) is a 3-item risk assessment tool that consists of age, body weight, and current estrogen use.
In validation studies, a score of 9 on this instrument identified 90% of women with a BMD T-score
of 2 or more standard deviations below the mean.36
Age BOdy size No Estrogen (ABONE) is a similar but
simpler instrument using the same factors.37 The
Simple Calculated Osteoporosis Risk Estimation
(SCORE) is based on race, presence of rheumatoid
arthritis, low trauma fracture, estrogen use, age,
and weight.38 The Osteoporosis Self-Assessment Tool
(OST), which includes only age and body weight,
results in a recommendation for testing in 90% of
women who have osteoporosis but also in as many
as 60% of women who do not.39 Whereas these tools
use a single cut point for deciding whether to test
or not, it has recently been suggested that two cut
points be used to stratify the risk of osteoporosis as
low, moderate or high.40,41 As a risk index, women at
low risk would not require a BMD test, those with
moderate risk would be recommended for BMD
testing, and those at high risk could be treated to
prevent fracture without the need for BMD testing.
This is particularly interesting in countries where
BMD measurements are not widely available, because of cost or lack of equipment.
For clinical practice, several guidelines have been
established to select patients who should undergo
BMD measurement. The International Society for
Clinical Densitometry recommends BMD testing for
all women aged >65 years, postmenopausal women
aged <65 years with additional risk factors (prior
fragility fracture, medical conditions associated with
low bone mass or bone loss, such as hypogonadism
or hypothyroidism, medications associated with low
bone mass or bone loss, such as corticosteroids),
and men aged >70 years.42 The National Osteoporosis Foundation recommends BMD testing for postmenopausal women >65 years, as well as younger
Advances in osteoporosis diagnosis: the use of clinical risk factors – Sornay-Rendu and Delmas
NEW APPROACHES
postmenopausal women with one or more risk factors in addition to being white, postmenopausal,
and female. Major risk factors include personal history of fracture as an adult, parental history of
fragility fracture in a first-degree relative, low body
weight, and use of oral corticosteroid therapy for
more than 3 months. Additional risk factors are
impaired vision, estrogen deficiency at an early age
(<45 years), dementia, poor health/frailty, recent
falls, low calcium intake, low physical activity, and
alcohol intake in amounts of >2 drinks per day.43 In
France, the High Health Authority (HAS) recommends BMD testing in all men and women, regardless of age, in whom there are major clinical risk
factors (prior fragility fracture, initiation of corticosteroid therapy >7.5 mg/day, hyperthyroidism, hyperparathyroidism, hypogonadism, osteogenesis
imperfecta) and in postmenopausal women with the
following risk factors: parental history of hip fracture, low BMI, early menopause before the age of
40 years, corticosteroid use >7.5 mg/day for more
than 3 months at any point during their lifetime.
Assessment of fracture risk
with the use of BMD
The assessment of fracture risk has been largely
based on the relative risk measure, which is a population-based measure of risk that is not really applicable and useful for the individual. Indeed, the
interpretation of a relative risk or its change is highly dependent on the background risk. For instance,
doubling a minor risk is still minor, but doubling
a common risk is a significant risk. Therefore, a
statement such as “your risk of fracture is increased
twofold” is not informative for an individual, because the relative risk does not give the absolute
risk of fracture for the individual. An estimate of the
absolute risk of any fragility fracture during the subsequent 5 or 10 years appears desirable in the assessment of a patient at risk of fracture.9 For example, the absolute 10-year risk of a fragility fracture in
a postmenopausal woman with a T score --2.5 and
no other risk factors is less than 5% at the age of 50
but more than 20% at the age of 65. Absolute risk
increases further with additional independent risk
factors, particularly a previous fragility fracture.9
An example of this approach is the index developed by Black et al from the SOF,44 which includes
BMD, age, history of fracture after 50 years of age,
maternal hip fracture after 50 years of age, body
weight less than 57 kg, smoking status, and use of
the arms to stand up from a chair. Without the use
of BMD, women with scores in the lowest quintile
had a 5-year risk of hip fracture of 0.6% compared
with an approximate 14-fold increased risk of 8.2%
REFERENCES
1. Nguyen T, Sambrook P, Kelly P, et al. Prediction of osteoporotic fractures by postural instability and bone density. BMJ.1993;
307:1111-1115.
2. Cummings SR, Black DM, Nevitt MC, et al. Bone density at various sites for prediction of hip fractures. Lancet.1993;341:72-75.
3. Marshall D, Johnell O, Wedel H. Meta-analysis of how well
measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:1254-1259.
4. World Health Organization. Assessment of Fracture Risk and
AND
CHALLENGES
IN
OSTEOPOROSIS
for those with scores in the highest quintile. The
addition of BMD values to the models derived from
clinical variables alone improved performance, although not markedly. These performance characteristics were independently assessed against the
EPIDemiology of OSteoporosis (EPIDOS) French
study. International guidelines with algorithms for
clinical practice are currently established by the
WHO collaborating center. The aim is to develop a
standardized methodology for expressing fracture
risk and intervention threshold for men and women. The WHO tool for fracture prediction estimates
an individual’s probability of fracture in the next 10
years from clinical risk factors, with or without BMD
measurement. Seven clinical risk factors (prior fragility fracture, a parental history of hip fracture,
smoking, use of systemic corticosteroids, excess alcohol intake, low BMI, and rheumatoid arthritis)
are used, in addition to age and sex.9 Recently, a
risk assessment tool based on these clinical risk factors with and without hip BMD was developed from
nine population-based studies. Fracture risk was expressed as gradient of risk; ie, the increase in fracture risk per standard deviation increase in risk
score. For hip fracture, the use of BMD alone provided a higher gradient of risk than clinical risk factors alone and was increased with the combination.
For other osteoporotic fractures, the use of BMD
alone provided a similar gradient of risk as clinical
risk factors alone and the risk was not markedly increased by the combination. The performance characteristics of clinical risk factors with and without
BMD were validated in 11 independent populationbased cohorts.45
The validity of the use of clinical risk factors would
be strengthened by randomized controlled trials
that recruit patients on the basis of these risk factors. Indeed, efficacy of pharmacological intervention has been shown for patients selected on the
basis of low BMD, prior fracture or the use of oral
corticosteroids, but in no trials have patients been
selected on the basis of the other risk factors.
Conclusion
Prospective studies have consistently demonstrated that clinical risk factors such as age, prior fracture, a family history of fracture, and corticosteroid
use contribute to fracture risk, independent of bone
density as determined by absorptiometry. Thus the
use of BMD measurement alone to predict osteoporotic fracture risk is no longer appropriate. The
addition of clinical risk factors to risk factor assessment undoubtedly improves fracture risk prediction. Clinicians could then use the absolute fracture risk to guide treatment decisions. its Application to Screening for Postmenopausal Osteoporosis.
Technical Report Series 843. Geneva, Switzerland: World Health
Organization; 1994.
5. Stone KL, Seeley DG, Lui LY, et al. BMD at multiple sites and
risk of fracture of multiple types: long-term results from the Study
of Osteoporotic Fractures. J Bone Miner Res. 2003;18:1947-1954.
6. Siris ES, Miller PD, Barrett-Connor E, et al. Identification and
fracture outcomes of undiagnosed low bone mineral density in
postmenopausal women. Results from the National Osteoporo-
Advances in osteoporosis diagnosis: the use of clinical risk factors – Sornay-Rendu and Delmas
MEDICOGRAPHIA, VOL 30, No. 4, 2008 353
NEW APPROACHES
AND
CHALLENGES
sis Risk Assessment. JAMA. 2001;286:2815-2822.
7. Schuit SCE, van der Klift M, Weel AEAM, de Laet C. Fracture
incidence and association with bone mineral density in elderly
men and women. The Rotterdam Study. Bone. 2004;34:195-202.
8. Solomon DH, Finkelstein JS, Katz JN, Mogun H, Avorn J. Underuse of osteoporosis medications in elderly patients with fractures. Am J Med. 2003;115:398-400.
9. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture
risk. Osteoporos Int. 2005;16:581-589.
10. Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B.
Ten year probabilities of osteoporotic fractures according to BMD
and diagnostic thresholds. Osteoporos Int. 2001;12:989-995.
11. Kanis JA, Johansson H, Oden A, et al. A family history of fracture and fracture risk: a meta-analysis. Bone. 2004;35:1029-1037.
12. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for
hip fracture in white women. N Engl J Med. 1995;332:767-773.
13. Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA 3rd,
Berger M. Patients with prior fractures have an increased risk
of future fractures: a summary of the literature and statistical
synthesis. J Bone Miner Res. 2000;15:721-727.
14. Siminoski K, Jiang G, Adachi JD, et al. Accuracy of height loss
during prospective monitoring for detection of incident vertebral
fractures. Osteoporos Int. 2005;16:403-410.
15. Johnell O, Kanis JA, Black DM, et al. Associations between
baseline risk factors and vertebral fracture risk in the Multiple
Outcomes of Raloxifene Evaluation (MORE) Study. J Bone Miner
Res. 2004;19:764-772.
16. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. 2001;285:320323.
17. Bauer DC, Browner WS, Cauley JA, et al; Study of Osteoporotic Fractures Research Group. Factors associated with appendicular bone mass in older women. Ann Intern Med. 1993;118:657665.
18. Fox KM, Cummings SR, Powell-Threets K, Stone K; Study of
Osteoporotic Fractures Research Group. Family history and risk
of osteoporotic fracture. Osteoporos Int. 1998;8:557-562.
19. Johnell O, O’Neill T, Felsenberg D, et al; European Vertebral
Osteoporosis Study (EVOS) Group. Anthropometric measurements
and vertebral deformities. Am J Epidemiol. 1997;146:287-293.
20. Honkanen RJ, Honkanen K, Kroger H, Alhava E, Tuppurainen
M, Saarikoski S. Risk factors for perimenopausal distal forearm
fractures. Osteoporos Int. 2000;11:265-270.
21. Roy DK, O’Neill TW, Finn JD, et al. Determinants of incident
vertebral fracture in men and women: results from the European
Prospective Osteoporosis Study (EPOS). Osteoporos Int. 2003;14:
19-26.
22. De Laet C, Kanis JA, Oden A, et al. Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int. 2005;16:
1330-1338.
23. Kanis JA, Johnell O, Oden A, et al. Smoking and fracture risk:
a meta-analysis. Osteoporos Int. 2005;16:155-162.
24. Tinetti ME. Preventing falls in elderly persons. N Engl J Med.
2003;348:42-49.
25. Hooyman JR, Melton LJ, Melson AM, O’Fallon WM, Riggs BL.
Fractures after rheumatoid arthritis—a population based study.
Arthritis Rheum. 1984;27:1353-1361.
26. Cooper C, Coupland C, Mitchell M. Rheumatoid arthritis, corticosteroid therapy and the risk of hip fracture. Ann Rheum Dis.
1995;54:49-52.
27. Van Staa TP, Leufkens HGM, Cooper C. The epidemiology of
corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos
Int. 2002;13:777-787.
28. Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior
corticosteroid use and fracture risk. J Bone Miner Res. 2004;19:
893-899.
29. Orstavik RE, Haugeberg G, Mowinckel P, et al. Vertebral deformities in rheumatoid arthritis: a comparison with populationbased controls. Arch Intern Med. 2004;164:420-425.
30. Bultink IE, Lems WF, Kostense PJ, Dijkmans BA, Voskuyl AE.
Prevalence of and risk factors for low bone mineral density and
vertebral fractures in patients with systemic lupus erythematosus. Arthritis Rheum. 2005;52:2044-2050.
31. Goldring SR, Gravallese EM. Mechanisms of bone loss in inflammatory arthritis: diagnosis and therapeutic implications.
Arthritis Res. 2000;2:33-37.
32. Garnero P, Dargent-Molina P, Hans D, et al. Do markers of
bone resorption add to bone mineral density and ultrasonographic heel measurement for the prediction of hip fracture in elderly women? The EPIDOS prospective study. Osteoporos Int.1998;
8:563-569.
33. Ross PD, Kress BC, Parson RE, Wasnich RD, Armour KA,
Mizrahi IA. Serum bone alkaline phosphatase and calcaneus bone
density predict fractures: A prospective study. Osteoporos Int.
2000;11:76-82.
354 MEDICOGRAPHIA, VOL 30, No. 4, 2008
IN
OSTEOPOROSIS
34. Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD. Biochemical markers of bone turnover, endogenous hormones and
the risk of fractures in postmenopausal women: the OFELY study.
J Bone Miner Res. 2000;15:1526-1536.
35. Sornay-Rendu E, Munoz F, Garnero P, Duboeuf F, Delmas PD.
The identification of osteopenic women at high risk of fracture:
The OFELY study. J Bone Miner Res. 2005;20:1813-1819.
36. Cadarette SM, Jaglal SB, Kreiger N, et al. Development and
validation of the osteoporosis risk assessment instrument to facilitate selection of women for bone densitometry. CMAJ. 2000;162:
1289-1294.
37. Weinstein L, Ullery B. Identification of at-risk women for osteoporosis screening. Am J Obstet Gynecol. 2000;183:547-549.
38. Cadarette SM, Jaglal SB, Murray TM. Validation of the simple
calculated osteoporosis risk estimation (SCORE) for patient selection for bone densitometry. Osteoporos Int. 1999;10:85-90.
39. Koh LKH, Ben Sedrine W, Torralba TP, et al. A simple tool to
identify Asian women at increased risk of osteoporosis. Osteoporos Int. 2001;12:699-705.
40. Cadarette SM, McIsaac WJ, Hawker GA, et al. The validity of
decision rules for selecting women with primary osteoporosis for
bone mineral density testing. Osteoporos Int. 2004;15:361-366.
41. Sedrine WB, Chevallier T, Zegels B, et al. Development and
assessment of the Osteoporosis Index of Risk (OSIRIS) to facilitate selection of women for bone densitometry. Gynecol Endocrinol. 2002;16:245-250.
42. The writing group for the ISCD position development conference. Position statement: executive summary. J Clin Densitom.
2004;7:7-12.
43. National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003.
44. Black DM, Steinbuch M, Palermo L, et al. An assessment tool
for predicting fracture risk in postmenopausal women. Osteoporos Int. 2001;12:519-528.
45. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip
and osteoporotic fractures in men and women. Osteoporos Int.
2007;18:1033-1046.
PROGRÈS
DANS LE DIAGNOSTIC DE L’OSTÉOPOROSE
UTILISATION DES FACTEURS DE RISQUE CLINIQUES
:
L’
ostéoporose et l’augmentation du risque de fracture qui lui est associée
sont un problème majeur de santé pour les femmes post-ménopausées
et les hommes âgés. Le diagnostic de l’ostéoporose repose sur la densité
minérale osseuse (DMO), des études épidémiologiques ayant montré qu’une
faible DMO était un facteur prédictif puissant de fracture ostéoporotique. Cependant, les nombreux composants de la fragilité du squelette ne permettent pas
de différencier les DMO des cas de fracture et celles des témoins. Certaines études
récentes ont même montré que jusqu’à la moitié des patientes ayant eu une
première fracture avaient une DMO initiale supérieure au seuil de diagnostic
fixé pour l’ostéoporose par l’OMS (Organisation mondiale de la santé) (T-score
<--2,5). La sensibilité relativement faible de la DMO comparée à sa spécificité
élevée signifie que de nombreuses femmes qui subiront une fracture dans leur
vie ne pourront être définies à risque élevé sur la seule évaluation de la DMO.
Des études ont montré que moins d’un tiers des patientes ayant subi des fractures de fragilité étaient correctement évaluées et traitées pour l’ostéoporose
malgré un risque élevé de fractures dans l’avenir. Les taux de diagnostic sont
même plus faibles parmi celles qui n’ont pas encore eu de fracture. La tendance
est donc de recommander l’identification des sujets ostéoporotiques sur le risque
de fracture plutôt que sur la DMO. Il a été démontré que l’intégration de facteurs de risque différents de la DMO améliorait l’exactitude de la prévision du
risque de fracture. La DMO devrait donc n’être qu’un des facteurs de prévision
du risque fracturaire. Ces dernières années, le centre de John Kanis en collaboration avec l’OMS a conduit plusieurs métaanalyses sur les données de grandes
études prospectives menées dans différents pays pour identifier et quantifier le
risque associé à plusieurs facteurs cliniques indépendamment de la DMO et de
l’âge (antécédent de fracture chez la patiente ou sa famille, IMC, tabagisme et
traitement par glucocorticoïdes). Ces études de grande ampleur devraient faciliter la mise en place de recommandations internationales pour la prise en
charge clinique de l’ostéoporose.
Advances in osteoporosis diagnosis: the use of clinical risk factors – Sornay-Rendu and Delmas
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
Olivier BRUYÈRE, PhD
Department of Public Health, Epidemiology
and Health Economics, University of Liège
Liège, BELGIUM
Jean-Yves REGINSTER, MD, PhD
WHO Collaborating Center for Public Health
Aspects of Osteoarticular Disorders
University of Liège, Liège, BELGIUM
Correlation between increased bone
mineral density and decreased fracture risk
Bone mineral density as a tool
to monitor postmenopausal
osteoporosis treatment
by O. Bruyère and
J . - Y. R e g i n s t e r , B e l g i u m
steoporosis is a disease characterized by a
decrease in bone mass and deterioration in
skeletal microarchitecture, leading to increased fragility and susceptibility to fracture. The
final objective of osteoporosis treatment is the prevention of fractures. In clinical research, the assessment of the effect of a drug regarding new frac-
O
lthough low bone mineral density (BMD) is predictive of fracture risk in
untreated patients, there is currently debate about the extent to which
the antifracture efficacy of antiosteoporotic agents is related to BMD
changes. The goal of this article is to make an overview of studies dealing with
the association between BMD changes and fracture risk reduction. The percentage of the reduction in fracture risk attributable to changes in BMD after antiresorptive treatments (risedronate, alendronate, and raloxifene) varies from
4% to 28%. One study with a bone-forming agent (teriparatide) found that the
proportion of fracture risk reduction attributable to the increase in BMD ranged
from 30% to 41%. With strontium ranelate, the changes in femoral neck and
total hip BMD explained 76% and 74%, respectively, of the reduction in vertebral fractures observed during treatment. However, study designs as well as
statistical methods often differ, making the comparison between studies rather
difficult. Our review indicates that the association between BMD changes and
fracture risk is equivocal, but seems to be higher for strontium ranelate than
that reported for its competitors.
A
Medicographia. 2008;30:355-359.
(see French abstract on page 359)
Keywords: fracture risk; bone mineral density; surrogate marker; osteoporosis;
antiresorptive agent; bone-forming agent; strontium ranelate
www.medicographia.com
Address for correspondence: Olivier Bruyère, Department of Public Health, Epidemiology and
Health Economics, University of Liège, CHU Sart-Tilman, Bât B23, 4000 Liège, Belgium
(e-mail: [email protected])
tures is then of primary importance to assess its efficacy. However, evaluation of the antifracture effects of new agents requires large clinical trials with
durations of several years. When considering a population with a vertebral fracture incidence of 10%
to 20%, a study requires approximately 470 to 1000
analyzable patients per group in order to have 90%
power to detect a 40% risk reduction compared
with placebo.1 For an event with lower incidence,
such as hip fracture, the number of patients required to detect a statistically significant and clinically relevant difference increases dramatically. Because of this need for large clinical trials with several
years’ duration to evaluate the antifracture effects
of new agents, surrogate measures that may be more
quickly measured (ie, bone mineral density [BMD],
biochemical markers of bone turnover) are of interest. To be accepted, the quantitative relationship
between surrogates and the primary clinical end
point should be clearly established.
SELECTED
ABBREVIATIONS AND ACRONYMS
BMD
DXA
FIT
MORE
bone mineral density
dual-energy x-ray absorptiometry
Fracture Intervention Trial
Multiple Outcomes of Raloxifene
Evaluation (study)
SOTI
Spinal Osteoporosis Therapeutic Intervention (study)
TROPOS TReatment Of Peripheral OSteoporosis
(study)
Bone mineral density as a tool to monitor postmenopausal osteoporosis treatment – Bruyère and Reginster
MEDICOGRAPHIA, VOL 30, No. 4, 2008 355
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
Relationship between
bone loss and fracture risk
It is now widely accepted that one of the major determinants of skeletal weakness is the bone loss
that occurs after the menopause. As a matter of fact,
several epidemiologic studies of fracture incidence
have shown that in untreated patients, low BMD
is consistently correlated with increased fracture
risk.2-4 A meta-analytic approach suggests an increased relative risk (RR) of vertebral fracture and
hip fracture of 2.3 and 2.6, respectively, for 1 standard deviation (SD) reduction in spine and hip
BMD.4 Recently, the relationship between BMD and
fracture risk was assessed in a meta-analysis of data
from 12 cohort studies of approximately 39 000 men
and women.5 The results showed that BMD measurements at the femoral neck with dual-energy
x-ray absorptiometry (DXA) are a strong predictor
of future hip fractures, with a similar predictive ability in both men and women. At the age of 65 years,
risk ratios increased 2.94-fold (95% confidence interval [CI], 2.02-4.27) in men and 2.88-fold (95%
CI, 2.31-3.59) in women for each 1 SD decrease in
BMD. The authors conclude that assessment of hip
BMD provides a strong indicator of fracture risk,
largely independent of sex. Its predictive value is not
significantly attenuated with time after assessment
over a 10-year interval, suggesting that it can be
used to compute long-term fracture probabilities.
Prospective studies have also assessed the relationship between bone loss over time and fracture
risk. Recently, a study investigated the association
between bone density changes and incident new
fractures in the untreated population.6 This study
suggested that femoral neck bone loss is an independent predictor of future fracture risk, independent of baseline BMD levels and advancing age. It
was further shown in this study that 45% of fracture cases could be attributed to osteoporosis (based
on the most common definition of a BMD T-score
--2.5), high rate of bone loss, and advancing age.
The authors state that their results, if confirmed by
other studies, suggest that pharmacological intervention for primary prevention of bone loss may be
helpful in the reduction of fracture incidence in the
general population. In this study, each 0.12 g/cm2
loss in femoral neck BMD was associated with a
3.1-fold increase in hip fracture risk. The authors
also state that this association is somewhat lower
than that reported in cross-sectional BMD studies,
but it is consistent with earlier data from forearm
BMD measurement, which suggested that “fast bone
losers” (defined as loss of at least 3% per year) had
a higher risk of vertebral fractures.7
Effects of pharmacological agents
on bone mineral density and fracture risk
Several randomized controlled trials have demonstrated that pharmacological agents improve BMD
and reduce the risk of fracture.8-14 Although increases in BMD resulting from various pharmacological
treatments differ widely, reported reductions in vertebral fracture risk are rather similar.8-14
356 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Antiresorptive agents
Studies exploring the association between BMD
changes and fracture reduction have been mainly
conducted with antiresorptive agents; however, they
have provided contradictory results.15-19 In the Multiple Outcomes of Raloxifene Evaluation (MORE)
study, the increases in femoral neck BMD after
treatment were shown to account for only 4% of the
effect on vertebral fracture risk.16 Combining data
from three pivotal risedronate fracture end point
trials, Watts and colleagues showed that the increases in lumbar spine and femoral neck BMD account for only 18% and 11%, respectively, of the effect of risedronate on vertebral fracture incidence.20
The fracture risk was similar (about 10%) in risedronate-treated patients whose increases in BMD
were <5% and in those whose increases were 5%
(P=0.453). However, risedronate-treated patients
whose BMD decreased were at a significantly greater
risk of sustaining a vertebral fracture than patients
whose BMD increased. Another study found that
lumbar spine BMD changes accounted for about
28% of the overall risedronate treatment effect.21
Among women taking alendronate in the Fracture Intervention Trial (FIT), Hochberg et al found
that larger increases in total hip and spine BMD
were associated with a lower risk of new vertebral
fractures.22 Women with larger increases in total hip
BMD during the first 12 months of treatment had
a lower incidence of new vertebral fractures during
a 30-month follow-up period. Only 3.2% of women
with increases of 3% in total hip BMD experienced
new vertebral fractures, whereas twice as many
women (6.3%) whose BMD declined or remained
unchanged experienced new fractures (adjusted
odds ratio [OR], 0.45; 95% CI, 0.27-0.72). However, another study using a meta-analytic approach
showed that the percentage of the reduction in
vertebral fracture risk attributable to an increase
in spine BMD after alendronate treatment was only
16% in FIT.15 The reduction in fracture risk with
alendronate was greater than that predicted from
the improvement in BMD. For instance, based on
improvement in BMD, the meta-analytic model estimated that treatments predicted to reduce fracture risk by 20% (RR, 0.80), actually reduce the risk
of fracture by about 45% (RR, 0.55).
Meta-analysis, pooling different antiresorptive
agents, also produced conflicting results. It has been
reported that the risk of nonvertebral fractures decreased in patients with an increase in BMD during
treatment with antiresorptive agents.17 The authors
stated that antiresorptive agents that increase spine
BMD by at least 6% reduce nonvertebral fracture
risk by about 39%, and agents that increase hip
BMD by 3% or above, reduce nonvertebral fracture
risk by about 46%. Reanalysis of these data, however, using the same statistical methods, but correcting for discrepancies in the reported BMD and
person-year data, suggested that the magnitude of
reduction in fracture risk was not associated with
the increase in BMD.18 The authors infer that only
a small proportion of the risk reduction for vertebral and nonvertebral fractures observed with antiresorptive drug therapy is explained by the in-
Bone mineral density as a tool to monitor postmenopausal osteoporosis treatment – Bruyère and Reginster
NEW APPROACHES
Bone-forming agents
Very few studies have assessed the association between BMD changes and fracture reduction with
bone-forming agents. To the best of our knowledge,
the only study dealing with this topic found that an
approximately 9% to 14% increase in spine BMD
after treatment with teriparatide (ie, 0.09 g/cm2 in
women with a starting BMD of 0.64-1.01) was associated with a 30% to 41% fracture risk reduction.23
Strontium ranelate
The association between BMD changes and fracture
risk reduction seems to be more important with
strontium ranelate.24,25 Although its molecular mechanisms of action have not been unequivocally elucidated, evidence from several nonclinical models
supports a unique mechanism of action for strontium ranelate, which concomitantly reduces bone
resorption and increases bone formation. In two
large, placebo-controlled studies, ie, Spinal Osteoporosis Therapeutic Intervention (SOTI)13 and TReatment Of Peripheral OSteoporosis (TROPOS),14 3year treatment with strontium ranelate, 2 g per day
orally, was shown to reduce the risk of vertebral and
nonvertebral fractures by 41% and 16%, respectively, with a 36% reduction in the risk of hip fracture. Significant increases in lumbar spine and
femoral neck BMD have been consistently reported
in all populations exposed to strontium ranelate (at
3 years in SOTI and TROPOS, +12.7% and +9.8%
at the lumbar spine, and +7.2% and +8.2% at the
femoral neck, respectively).
However, caution is necessary in interpreting
changes in BMD during treatment with strontium
ranelate, as there is an adsorption of strontium at
the bone surface due to its bone-seeking property.
As a consequence, the clinical interpretation of a
BMD increase in patients who received strontium
ranelate treatment could be overestimated.26 It is
therefore of clinical interest to know the relationship between the observed increase in BMD and the
decreased incidence of fracture during treatment
with strontium ranelate.
When pooling the data of SOTI and TROPOS, an
association between changes in total hip or femoral
neck BMD, but not spine BMD, and vertebral fracture incidence has been shown for strontium ranelate–treated patients.24,25 For each 1% increase in
femoral neck BMD, the RR of new vertebral fracture decreases by 3% (1%-5%) (Figure 1), and for
each 0.010 g/cm2 increase in femoral neck BMD, the
risk of experiencing a new vertebral fracture is reduced by 6% (3%-10%). The results were quite similar when considering clinical vertebral fractures,
with a risk of a new fracture decreasing by 5% (2%7%) and 9% (5%-13%) for each 1% and 0.010 g/cm2
increase in femoral neck BMD, respectively. Patients experiencing new vertebral fractures gain
CHALLENGES
IN
OSTEOPOROSIS
less femoral neck BMD (+4.5% [9.1]) than patients
without vertebral fracture (+5.7% [7.4]) (P=0.03).
These data demonstrate that patients experiencing
an increase in BMD after 3 years of treatment have
a significant reduction in the risk of experiencing
a new vertebral fracture compared with patients
without an increase in BMD. Moreover, the 3-year
changes in femoral neck and total hip BMD explained 76% and 74%, respectively, of the reduction
in vertebral fractures observed during treatment
with strontium ranelate. The authors also showed
that, out of the patients treated with strontium
0.40
Risk of new vertebral fractures
crease in BMD. In conclusion, the predictive value
of changes in BMD regarding fracture risk reduction is still a matter for debate for antiresorptive
agents and, at this time, there is limited evidence
to support the use of BMD as a reliable indicator of
fracture risk reduction with antiresorptive agents.1,19
AND
Placebo
Strontium ranelate
0.35
0.30
0.25
0.20
0.15
0.10
0.05
–15
–10
–5
0
5
10
15
20
25
Percentage of femoral neck BMD change after 3 years
Figure 1. The relationship between change in femoral neck bone mineral
density (BMD) and the risk of new vertebral fracture with strontium ranelate.
Reproduced from reference 24: Bruyere O, Roux C, Detilleux J, et al. Relationship between bone
mineral density changes and fracture risk reduction in patients treated with strontium ranelate.
J Clin Endocrinol Metab. 2007;92:3076-3081. Copyright © 2007, The Endocrine Society.
ranelate, 45.7% experienced an absolute gain of
0.033 g/cm2 in femoral neck BMD after 3 years of
treatment, corresponding to the smallest detectable
difference in femoral neck BMD measurement.
Interestingly, the risk of a new vertebral fracture
in these patients was reduced by 24% (2%-41%)
(P=0.03), compared with patients without such a
gain in BMD. Not least, the authors also showed that
1-year changes in total hip or femoral neck BMD
predict future (3-year) vertebral fracture rate in patients treated with strontium ranelate. For each increase of 1% in femoral neck BMD after 1 year, the
risk of experiencing a new clinical vertebral fracture
after 3 years decreased by 3% (1%-6%).
Bone mineral density changes and nonvertebral fracture incidence
The relationships between change in BMD and nonvertebral fracture incidence during treatment with
strontium ranelate are also of interest. Recently, a
trend has been shown for the association between
change in femoral neck BMD (P=0.09) and total
proximal femur BMD (P=0.07), and the incidence
of new nonvertebral fractures.24,25 In strontium
ranelate–treated patients, the association between
changes in BMD and fracture risk reduction seems
to be stronger for vertebral fractures than for nonvertebral fractures. It could be hypothesized that
other factors, such as falls, have a substantial influence on this relation. However, another recent
Bone mineral density as a tool to monitor postmenopausal osteoporosis treatment – Bruyère and Reginster
MEDICOGRAPHIA, VOL 30, No. 4, 2008 357
NEW APPROACHES
AND
CHALLENGES
IN
OSTEOPOROSIS
study has shown a significant relationship between
neck BMD changes and hip fracture incidence during treatment with strontium ranelate.25
These results suggest that assessment of BMD at
the level of the hip (ie, femoral neck) is an appropriate tool for the monitoring of strontium ranelate–
treated patients.25 It should be pointed out that in
these studies, the association between BMD changes
and fracture incidence during 3 years of treatment
with strontium ranelate was obtained with unadjusted BMD values for strontium ranelate, since in
daily practice the clinician will deal with unadjusted BMD assessment. Moreover, if femoral neck BMD
data are available in patients treated with strontium ranelate, a positive change might be useful as
positive feedback to increase the long-term adherence to treatment. More studies are needed to assess
the clinical interest of repeated BMD measurements
to improve compliance and persistence.
Lumbar bone mineral density changes and
vertebral fracture incidence
The majority of studies (ie, with antiresorptive
agents or with strontium ranelate) have found no
clear association between lumbar BMD changes
and vertebral fracture incidence. This could be explained by the fact that in elderly subjects, the presence of degenerative conditions of the spine (eg, osteophytes or end plate sclerosis) contributes to the
artifacts in lumbar spine BMD measurement,27 leading to poor accuracy of fracture risk prediction. It
must also be pointed out that BMD measurement
includes contributions from the posterior elements,
joints, and calcification deposits in the aorta, and
could attenuate the changes observed if the measurement was limited to the vertebral body. The
change in lumbar BMD could thus be underestimated. Moreover, it has been shown that microarchitectural deformities in the vertebra, which are
not visually evident, could accumulate over time
and contribute to the apparent increase in the lumbar spine BMD and ultimately accumulate to fracture.28,29 However, it should be acknowledged that
these variations in BMD measurements would be
expected to affect both treatment groups equally.
Depending on the drug investigated, treatmentmediated BMD changes accounted for a small or
substantial part of the vertebral antifracture efficacy. The relationship between changes in BMD and
fracture risk may be different because these agents
interfere with bone strength through different
mechanisms of action at the tissue level (ie, improvement of bone quality parameters).30 The relationship between BMD changes and fracture risk is
confounded by other factors that contribute to the
etiology of a vertebral fracture. An important factor
is the change in bone microarchitecture that can be
REFERENCES
1. Li Z, Chines AA, Meredith MP. Statistical validation of surrogate endpoints: is bone density a valid surrogate for fracture?
J Musculoskelet Neuronal Interact. 2004;4:64-74.
2. Cummings SR, Black DM, Nevitt MC, et al; Study of Osteoporotic Fractures Research Group. Bone density at various sites
for prediction of hip fractures. Lancet. 1993;341:72-75.
3. Melton LJ 3rd, Atkinson EJ, O’Fallon WM, Wahner HW, Riggs
BL. Long-term fracture prediction by bone mineral assessed at
358 MEDICOGRAPHIA, VOL 30, No. 4, 2008
observed during antiosteoporotic treatment. These
positive effects on bone quality are essential to antifracture efficacy.31 In 3-D studies of bone microarchitecture in animals, bone architecture contributes
to vertebral strength beyond the contributions
made by bone quantity.32 Biomechanical competence of trabecular bone is dependent not only on
the absolute amount of bone present, but also on
the trabecular microstructure.28 Another factor that
could contribute to the reduction in fracture shown
with antiosteoporotic drugs, but also with strontium ranelate, is the decrease in bone resorption.
Bone resorption, which causes perforation of thin
trabeculae, results in loss of connectivity, ultimately
reducing the bone strength to a greater degree than
predicted by the loss of BMD alone.33,34 With an antiresorptive treatment, the reduction in bone resorption confers improvement in bone strength by
reducing the number and depth of resorption pits.35
Even if they have not been exhaustively developed
in the literature,18 all these elements also account
for the reduction in risk of vertebral fracture shown
with antiosteoporotic drugs. However, more studies are needed to assess the respective weight of
these mechanisms in fracture risk reduction.
Methodological differences
between studies investigating the
effects of pharmacological agents
It should also be pointed out that there are statistical differences between studies that have explored
the association between BMD changes and fracture
risk reduction, which contribute to the heterogeneity of the results. Some analyses are based on data
from individual patients, while others use meta-regression based on summary statistics. Some analyses also use logical regression models, since they
only use the dichotomic outcome for fracture event,
while others use the time-to-event methodology.
The magnitude of the variance of fracture risk reduction explained by BMD changes is calculated using different methods, some studies using the approach developed by Freedman et al,36 while others
use the method of Li et al.21 All these elements can
make the comparison between studies (and consequently drugs) more difficult.
Conclusion
In conclusion, our review indicates that BMD
changes are not always a reliable surrogate for assessing fracture risk reduction with antiosteoporotic drugs. The association between BMD changes and
fracture risk is highly challenged for antiresorptive
agents, but appears of greater magnitude for strontium ranelate. different skeletal sites. J Bone Miner Res. 1993;8:1227-1233.
4. Marshall D, Johnell O, Wedel H. Meta-analysis of how well
measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:1254-1259.
5. Johnell O, Kanis JA, Oden A, et al. Predictive value of BMD for
hip and other fractures. J Bone Miner Res. 2005;20:1185-1194.
6. Nguyen TV, Center JR, Eisman JA. Femoral neck bone loss predicts fracture risk independent of baseline BMD. J Bone Miner
Bone mineral density as a tool to monitor postmenopausal osteoporosis treatment – Bruyère and Reginster
NEW APPROACHES
Res. 2005;20:1195-1201.
7. Hansen MA, Overgaard K, Riis BJ, Christiansen C. Role of peak
bone mass and bone loss in postmenopausal osteoporosis: 12 year
study. BMJ. 1991;303:961-964.
8. Black DM, Cummings SR, Karpf DB, et al; Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348:1535-1541.
9. Reginster J, Minne HW, Sorensen OH, et al; Vertebral Efficacy
with Risedronate Therapy (VERT) Study Group. Randomized trial of the effects of risedronate on vertebral fractures in women
with established postmenopausal osteoporosis. Osteoporos Int.
2000;11:83-91.
10. Ettinger B, Black DM, Mitlak BH, et al; Multiple Outcomes of
Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis
treated with raloxifene: results from a 3-year randomized clinical trial. JAMA.1999;282:637-645.
11. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid
hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:
1434-1441.
12. Harris ST, Watts NB, Genant HK, et al; Vertebral Efficacy With
Risedronate Therapy (VERT) Study Group. Effects of risedronate
treatment on vertebral and nonvertebral fractures in women with
postmenopausal osteoporosis: a randomized controlled trial.
JAMA.1999;282:1344-1352.
13. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium
ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468.
14. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium
ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005;90:28162822.
15. Cummings SR, Karpf DB, Harris F, et al. Improvement in
spine bone density and reduction in risk of vertebral fractures
during treatment with antiresorptive drugs. Am J Med. 2002;112:
281-289.
16. Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper
KD. Relationships between bone mineral density and incident
vertebral fracture risk with raloxifene therapy. J Bone Miner Res.
2002;17:1-10.
17. Hochberg MC, Greenspan S, Wasnich RD, Miller P, Thompson
DE, Ross PD. Changes in bone density and turnover explain the
reductions in incidence of nonvertebral fractures that occur
during treatment with antiresorptive agents. J Clin Endocrinol
Metab. 2002;87:1586-1592.
18. Delmas PD, Seeman E. Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture
risk with anti-resorptive therapy. Bone. 2004;34:599-604.
19. Delmas PD, Li Z, Cooper C. Relationship between changes in
bone mineral density and fracture risk reduction with antiresorptive drugs: some issues with meta-analyses. J Bone Miner Res.
2004;19:330-337.
20. Watts NB, Cooper C, Lindsay R, et al. Relationship between
changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom. 2004;7:255-261.
21. Li Z, Meredith MP, Hoseyni MS. A method to assess the proportion of treatment effect explained by a surrogate endpoint.
Stat Med. 2001;20:3175-3188.
22. Hochberg MC, Ross PD, Black D, et al; Fracture Intervention
Trial Research Group. Larger increases in bone mineral density
during alendronate therapy are associated with a lower risk of
new vertebral fractures in women with postmenopausal osteoporosis. Arthritis Rheum. 1999;42:1246-1254.
AND
CHALLENGES
IN
OSTEOPOROSIS
23. Chen P, Miller PD, Delmas PD, Misurski DA, Krege JH. Change
in lumbar spine BMD and vertebral fracture risk reduction in
teriparatide-treated postmenopausal women with osteoporosis.
J Bone Miner Res. 2006;21:1785-1790.
24. Bruyere O, Roux C, Detilleux J, et al. Relationship between
bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab.
2007;23:3076-3081.
25. Bruyere O, Roux C, Badurski J, et al. Relationship between
change in femoral neck bone mineral density and hip fracture
incidence during treatment with strontium ranelate. Cur Med
Res Opin. 2007;23:3041-3045.
26. Blake GM, Lewiecki EM, Kendler DL, Fogelman I. A review of
strontium ranelate and its effect on DXA scans. J Clin Densitom.
2007;10:113-119.
27. Liu G, Peacock M, Eilam O, Dorulla G, Braunstein E, Johnston CC. Effect of osteoarthritis in the lumbar spine and hip on
bone mineral density and diagnosis of osteoporosis in elderly men
and women. Osteoporos Int. 1997;7:564-569.
28. Kleerekoper M, Villanueva AR, Stanciu J, Rao DS, Parfitt AM.
The role of three-dimensional trabecular microstructure in the
pathogenesis of vertebral compression fractures. Calcif Tissue Int.
1985;37:594-597.
29. Legrand E, Chappard D, Pascaretti C, et al. Trabecular bone
microarchitecture, bone mineral density, and vertebral fractures
in male osteoporosis. J Bone Miner Res. 2000;15:13-19.
30. Eastell R. Treatment of postmenopausal osteoporosis. N Engl
J Med. 1998;338:736-746.
31. Boonen S, Haentjens P, Vandenput L, Vanderschueren D.
Preventing osteoporotic fractures with antiresorptive therapy:
implications of microarchitectural changes. J Intern Med. 2004;
255:1-12.
32. Borah B, Dufresne TE, Cockman MD, et al. Evaluation of
changes in trabecular bone architecture and mechanical properties of minipig vertebrae by three-dimensional magnetic resonance microimaging and finite element modeling. J Bone Miner
Res. 2000;15:1786-1797.
33. Parfitt AM. Trabecular bone architecture in the pathogenesis
and prevention of fracture. Am J Med. 1987;82:68-72.
34. Recker RR. Architecture and vertebral fracture. Calcif Tissue
Int. 1993;53(suppl 1):S139-S142.
35. Cummings SR. How drugs decrease fracture risk: lessons
from trials. J Musculoskelet Neuronal Interact. 2002;2:198-200.
36. Freedman LS, Graubard BI, Schatzkin A. Statistical validation of intermediate endpoints for chronic diseases. Stat Med.
1992;11:167-178.
CORRÉLATION ENTRE L’AUGMENTATION DE LA DENSITÉ
MINÉRALE OSSEUSE ET LA DIMINUTION DU RISQUE DE FRACTURE
LA DENSITÉ MINÉRALE OSSEUSE COMME OUTIL DE SUIVI
DU TRAITEMENT DE L’OSTÉOPOROSE POST-MÉNOPAUSIQUE
:
B
ien qu’une densité minérale osseuse (DMO) basse soit prédictive du
risque de fracture chez les femmes non traitées, l’étroitesse de la relation entre les modifications de la DMO et l’efficacité antifracturaire des
agents antiostéoporotiques est actuellement controversée. Le but de cette revue est d’examiner les études sur les liens entre les modifications de la DMO et
la réduction du risque de fracture. Le pourcentage de réduction du risque de
fracture imputable aux modifications de la DMO après un traitement antirésorptif (risédronate, alendronate, raloxifène) varie de 4 % à 28 %. Une étude avec
le tériparatide, un médicament qui augmente la formation osseuse, a démontré que le pourcentage de réduction du risque de fracture imputable à l’augmentation de la DMO variait de 30 % à 41 %. Les modifications de DMO dues
au ranélate de strontium au niveau du col fémoral et de la hanche expliquent
respectivement 76 % et 74 % de la réduction des fractures vertébrales observée
pendant le traitement. La comparaison entre les études reste cependant difficile, les schémas et les méthodes statistiques étant souvent différents. Cet article montre que si les relations entre les modifications de la DMO et le risque
de fracture sont ambiguës, elles semblent néanmoins plus fortes pour le ranélate de strontium que pour ses concurrents.
Bone mineral density as a tool to monitor postmenopausal osteoporosis treatment – Bruyère and Reginster
MEDICOGRAPHIA, VOL 30, No. 4, 2008 359
C
O N T R O V E R S I A L
Q
U E S T I O N
Is bone mineral density
measurement useful in patients
who have already fractured?
1
A. S. Hepguler, Turkey
A
Asiye Simin HEPGULER, MD
Medical Faculty
Ege University
Izmir
TURKEY
(e-mail:
[email protected])
www.medicographia.com
lthough the prevalence of vertebral fracture varies according to the criteria used
to define fracture among different population studies, it increases with age in all communities and exceeds 50% among women over the
age of 85 years.1 It is already known from numerous cohorts, case-control studies, and crosssectional studies that a previous osteoporotic
fracture increases the risk of a subsequent fracture.2 The risk of having an incident vertebral
fracture, nonvertebral fracture or any fracture
at a given bone mineral density (BMD) T-score
in subjects with a previous vertebral fracture increased up to 12-, 2- and 7-fold, respectively, in
a study carried out by Siris et al.1 However, in a
study performed by Kanis et al,3 the predicted
gradient of risk for hip fracture with the use of
clinical risk factors was found to be 2.1/standard
deviation (SD) at the age of 50 years, and this
was demonstrated to decrease with age. Although
the gradient of risk was 3.7/SD with the use of
BMD alone, it increased to 4.2/SD with the combined use of clinical risk factors and the BMD
value. However, the gradient of risk for other osteoporotic fractures is lower than for hip fractures, and the addition of BMD does not change
the results significantly. A high-risk gradient
would improve sensitivity without influencing the
specificity in the prediction of fracture. For example, if 10% of women over the age of 50 years
are considered to be in the high-risk group, the
sensitivity and specificity of the test will be 26%
and 91%, respectively, when the gradient of risk
is only 2.0/SD; but when the gradient of risk is
4.0/SD, the sensitivity of the test will be 42% and
the specificity will be 92%, and the positive pre-
dictive value of the test will increase from 11% to
25%. This will facilitate the selection of people
with a higher possibility of fracture, resulting in
the improvement of both therapy and cost effectiveness.3 Bone strength is a reflection of bone
density and bone quality.4 A vertebral fracture
influences future fracture risk at all BMD values.
Imaging of the spine displays the quality of bone,
and vertebral fracture indicates an impaired bone
quality. Iliac biopsy studies among postmenopausal women demonstrated either worsening
histomorphometric assessment or micro–computer tomography results with increasing severity
of vertebral fractures.1 Assessment of BMD in
people with fracture is helpful for the estimation
of short-term fracture risk. Furthermore, the
International Society for Clinical Densitometry
(ISCD) recommends dual-energy x-ray absorptiometry scans for women under the age of 65
years who have risk factors for osteoporosis, and
for adults with fragility fracture.5 In addition, BMD
measurement is recommended by the International Osteoporosis Foundation,6 International
Society for Fracture Repair, and The Bone and
Joint Decade to determine the severity of osteoporosis and baseline pretreatment values and to
monitor the efficacy of treatment. Although densitometric assessment was not performed for some
of the patients in the studies with raloxifene 7 and
teriparatide,8 and these patients were included
in the studies only on the basis of the number of
previous vertebral fractures, a decrease in fracture risk with treatment was demonstrated, and
assessment of BMD alongside treatment is still
important. The ISCD also recommends BMD measurement for treatment monitoring. REFERENCES
1. Siris ES, Genant HK, Laster AJ, Chen P, Misurski DA, Krege
JH. Enhanced prediction of fracture risk combining vertebral
fracture status and BMD. Osteoporos Int. 2007;18:761-770.
2. Kanis JA, Johnell O, De Laet C, et al. A meta-analysis of
previous fracture and subsequent fracture risk. Bone. 2004;
35:375-382.
3. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk
factors enhances the performance of BMD in the prediction of
hip and osteoporotic fractures in men and women. Osteoporos
Int. 2007;18:1033-1046.
4. National Institutes of Health. NIH Consensus Development
Panel on Osteoporosis Prevention, Diagnosis, and Therapy.
Osteoporosis Prevention, Diagnosis, and Therapy. JAMA.
2001;285:785-795.
5. International Society for Clinical Densitometry Expert
Panel. International Society for Clinical Densitometry official position. http://www.iscd.org/Visitors/positions/Official
PositionsText.cfm. Accessed July 8, 2008.
6. International Osteoporosis Foundation.
www.iofbonehealth.org. Accessed July 8, 2008.
7. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis
treated with raloxifene. Results from a 3-year randomized
clinical trial. JAMA. 1999;282:637-645.
8. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone(1-34) on fractures and bone mineral density
in postmenopausal women with osteoporosis. N Engl J Med.
2001;344:1434-1441.
360 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Is bone mineral density measurement useful in patients who have already fractured?
CONTROVERSIAL QUESTION
2
T. P. Torralba, Philippines
I
Tito P. TORRALBA, MD
Makati Medical Center
Amorsolo Street
Makati City 1200
PHILIPPINES
(e-mail:
[email protected])
3
t is widely accepted that a previous fragility
fracture is among the strongest risk factors
for future fracture. Data indicate that patients with a history of prior or recent fracture
at any site have a two- to sixfold increased risk
of future fractures, and it then becomes imperative to assess the etiology and plan for appropriate therapy. Osteoporotic fractures beget future
osteoporotic fractures. Numerous reports have
demonstrated that prior or recent fractures are a
prelude to new fractures and are associated with
increased morbidity and mortality. With osteoporotic fractures of the spine, this increased risk
is shown to increase with the number and severity of prior fractures; in effect there is a high probability of a negative cascade of vertebral fractures. A very recent report from the Framingham
Heart Study 1 showed a “higher 1-year mortality
after a second hip fracture than the 1-year mortality after a first hip fracture,… that the first
hip fracture was an indicator for likelihood of a
second hip fracture.” With the evidence that bone
mineral density (BMD), advancing age, and prior
fractures are independent risk factors for future
fracture, and if circumstances directly related to
a fall highly indicate a fragility fracture, and
furthermore the 10-year fracture risk is high and
treatment is therefore clearly indicated, then a
BMD measurement becomes a very important
recommendation. Radiological evidence of a fracture, often the first imaging evidence gathered,
should be complemented by dual-energy x-ray
absorptiometry (DXA) measurements at the spine
and hip, and in special conditions and in the elderly, also the forearm. The DXA results can be
diagnostic of osteoporosis, predict future fracture
risk, and, with serial monitoring, predict the response to the overall management program. BMD
measurement is also of help in screening for
secondary causes of low bone mass or bone loss.
For that matter, all patients aged 50 years and
above presenting with fragility fracture should be
evaluated for osteoporosis by measurement of
BMD. Even orthopedists are urged to consider the
likelihood of osteoporosis as the background condition in fragility fractures. The evaluation for
this condition can lead to the start of appropriate
treatment that may improve the outcome of the
situation by reducing the risk of future fractures,
thereby significantly minimizing the deleterious
effects on health and quality of life in these patients.2 REFERENCES
1. Medscape Medical News. October 8, 2007. www.medscape.
com/viewarticle/563977. Accessed July 11, 2008.
2. American Academy of Orthopedic Surgeons Position Statement; June 2003. Recommendations for enhancing the care
of patients with fragility fractures. www.aaos.org/about/
papers/position/1159.asp. Accessed July 11, 2008.
G. Maalouf, Lebanon
I
Ghassan MAALOUF, MD
Saint George Hospital
Faculty of Medicine
Balamand University
BP 166378
Ashrafieh, Beirut
LEBANON
(e-mail: [email protected])
n the 1990s, osteoporosis was considered to
be closely related to low bone mass; indeed,
it was agreed that for each standard deviation decrease in bone mineral density (BMD),
the risk of fracture would double or significantly
increase. Today, however, it has become clear
that even with normal BMD or osteopenia, fragility fractures may occur. In fact, a recent study
by Ethel Siris demonstrated that most fragility
fractures happen to osteopenic patients. Over the
past few years, several concepts have emerged
regarding the pathogenesis of osteoporotic fractures, according to which, low or poor bone mass
does play a role, but another factor that has also
come to light is poor bone quality. As such, the
concept has changed: instead of only taking into
consideration bone mass, we should equally examine postmenopausal loss of bone strength,
age-related loss of bone strength, and probably
reduced peak bone strength, all of which may
lead to fragility fractures. Therefore, low bone
mass is one— and only one—factor in the occurrence of a fragility fracture. This factor combined with others increases the absolute risk of
fragility fracture. For instance, low BMD measurement coupled with high bone turnover dra-
Is bone mineral density measurement useful in patients who have already fractured?
matically increases the risk of further fractures.
Although a spinal fracture associated with normal BMD is in itself a risk factor for further fractures, when associated with osteopenia or osteoporosis diagnosed by BMD measurement, the risk
of further spine fractures significantly increases
as well as the risk of hip fractures. It is worth
noting that two women of the same age and BMD
can vary in their bone microarchitecture, one
with acceptable microarchitecture and the other
with severe microdamage, which can be detected
by high resolution computed tomography. We
should not ignore the fact that bone strength also
varies depending on the type of force it is subject
to; some of the most relevant types of impacting
forces are compression, bending, torsion, and
buckling. The rate of bone displacement is also of
relevance. While dual-energy x-ray absorptiometry (DXA) has strong predictive power, its performance in the assessment of treatment efficacy
is generally poor. The contribution of a BMD increase in the results of fracture reduction is less
than 20%, except for strontium ranelate and
parathyroid hormone treatment. In the case of
strontium ranelate treatment of postmenopausal
women, the increase in BMD at month 36 is
MEDICOGRAPHIA, VOL 30, No. 4, 2008 361
CONTROVERSIAL QUESTION
14.4% at the lumbar spine, which outreaches the
margin of error that can occur due to the machine performance. In the case of a fragility fracture occurring in a patient aged 80 years who has
a survival rate of 7 to 8 years, BMD measurement
will not be required for monitoring of treatment,
because the patient would most probably already
have previous fractures and should be treated for
the years to come. However the situation changes
if the fracture occurs at the age of 70 years: when
we start treatment, DXA measurement might
improve the predictive power regarding future
fractures, and if strontium ranelate or parathyroid hormone are prescribed, DXA measurement
might be of value to monitor the treatment or to
provide information about when to initiate treatment. Indeed, we know that only 5% of women
in the UK with a history of fractures have undergone a DXA scan, and even more important, less
than 10% receive treatment. So a DXA scan at
this stage might encourage patients to take medication in order to prevent further fractures; and
by monitoring the treatment through the same
method, this could improve compliance. In our
4
daily practice—and that is what really matters—
if BMD increases, we can tell the patient the
treatment is working; if it remains the same, we
can tell him/her that luckily, it has protected
them from further fractures, and finally if it decreases, then for the patient this means that it
won’t deteriorate any further, even though the
most important factor that will encourage the
patient to continue their treatment is the absence
of further fractures. Between 50 and 70 years of
age, which is when most fractures occur, BMD
measurement is crucial for determining the severity of the disease, and most importantly, for being able to tell the patient their absolute risk of
further fractures if not treated, in addition to
monitoring some treatments such as strontium
ranelate. Also, BMD measurement can definitely
help to improve the patient’s compliance if the
physician-patient relationship is well-developed
and the patient is given the correct information.
One final point: as new therapies may be developed within a decade or less, in young patients, it
could prove to be necessary to monitor the BMD
response to their current treatment. C. A. F. Zerbini, Brazil
S
Cristiano A. F. ZERBINI, MD
Department of
Rheumatology
Hospital Heliópolis
São Paulo, SP
BRAZIL
(e-mail:
[email protected])
ome years ago the definition of osteoporosis was modified to include the concept of
bone quality. The National Institutes of
Health Consensus Development in 2000 proposed
osteoporosis as a skeletal disorder characterized
by compromised bone strength predisposing to
increased risk of fractures.1,2 Bone strength comprises the association of bone quality and bone
density. Determination of the quality of bone is
not easily accessible in daily clinical practice, and
in this setting, osteoporosis continues to be defined by measurements of bone mineral density
(BMD) using the World Health Organization
(WHO) criteria.3 BMD accounts for 60% to 80%
of bone strength,4,5 and its measurement by dualenergy x-ray absorptiometry (DXA) is a strong
predictor of osteoporotic fractures in women and
men of any racial background.6,7 In industrialized
nations and even in developing countries, the incidence of osteoporosis and associated fractures
is becoming a huge problem for public health institutions. Recent data showed the occurrence of
2 million fractures in the US during 2005.8 A total
of 73% were at nonvertebral sites, 29% occurred
in men, and 14% occurred in the nonwhite population. The direct cost of these fractures in 2005
was US$ 16.9 billion and 94% of this cost was for
nonvertebral sites. This expenditure does not include lost productivity, unpaid caregiver time,
transportation, and social services. Future projections indicate that in the next 20 years since the
362 MEDICOGRAPHIA, VOL 30, No. 4, 2008
original observations (2005-2025), fractures will
increase from 2 to 3 million, cost will increase to
US$ 25.2 billion, and races other than white will
be the most affected group by new fractures.
Taking into account these concerning numbers,
it is reasonable to ask if it would be useful to
make a DXA measurement after a fracture. In
order to discuss this question, we should first
analyze the common denomination of fractures
in clinical practice.9 We can consider four types:
traumatic fracture, pathological fracture, stress
fracture, and osteoporotic (also fragility or lowtrauma) fracture. Traumatic fractures are caused
by high-impact trauma and are usually related
to accidents, violence or sports. Although some
may advocate that osteoporotic patients develop
this type of fracture more easily than healthy
individuals, traumatic fractures will occur in almost everyone submitted to a high-impact trauma. BMD testing is not indicated following this
type of fracture. Pathological fractures are usually associated with weaker bones affected by
neoplasia, and in this context, BMD testing is not
primarily indicated. Stress fractures are usually
caused by mechanical forces that accumulate
damage faster than it can be repaired. People who
are submitted to timely and repeated exercise,
such as athletes and military recruits, are more
prone to develop stress fractures. Much more than
low bone mass, these fractures are related to
bone geometry, angle of contact with the ground,
Is bone mineral density measurement useful in patients who have already fractured?
CONTROVERSIAL QUESTION
and poor physical conditioning. Their occurrence
does not indicate the need for BMD testing. Osteoporotic (fragility) fracture is defined as a fracture occurring in patients with low bone mass
submitted to a low-impact trauma, such as a
force equal to, or less than, falling from standing
height. Only about one third of vertebral fragility
fractures are clinical (ie, producing symptoms);
the others are occasionally discovered during
x-ray examinations carried out for other reasons.
The diagnosis of fragility fractures is important,
because their occurrence can predict new osteoporotic fractures independently of BMD. Clinical
vertebral fractures and also radiographic vertebral fractures (clinically identifiable or not) are
strongly associated with subsequent vertebral
fractures.10,11 Nonvertebral fractures are more
easily diagnosed than vertebral fractures, but
there is differentiation among them in predicting further occurrence of new osteoporotic fractures. Skull, finger, and toe fractures are not
considered in clinical research protocols and we
do not know their predictive capacity. Fractures
of ribs, scapula, sternum, and sacrum are sometimes included, but they are still poor predictors
of further fragility fractures. Clinical research
and epidemiological studies usually include fractures of the upper limb (clavicle, humerus, and
forearm), pelvis, and lower limb (femur and lower
leg). Some of them have been well-studied regarding the prediction of new fractures.12 Recently, Kanis and colleagues analyzed data from nine
prospective population-based cohorts to determine the impact of the addition of multiple risk
factors to BMD testing for the prediction of frac-
tures.13 In their analysis, fracture risk was expressed as gradient of risk (GR; risk ratio/standard deviation [SD] change in risk score). Their
results showed that at the age of 50 years, clinical risk factors alone predicted hip fracture with
a GR of 2.1/SD, BMD alone provided a GR of
3.7/SD, and combinations of clinical risk factors
and BMD gave a better GR of 4.2/SD. Compared
with hip fracture, for other osteoporotic fractures,
the GRs were lower. If one fragility fracture can
predict another one and if there are studies assessing the risk of a new fracture without the
inclusion of BMD testing, is it useful to carry out
a BMD measurement in a patient with a lowtrauma fracture? My answer to this question is
that BMD measurements in this setting will be
useful (i) to confirm the diagnosis of osteoporosis: low-trauma fractures may occur in postmenopausal women in the osteopenic range.14
This will have implications regarding treatment
decisions; (ii) to deter-mine the severity of osteoporosis; (iii) to determine the need to look for
secondary causes. A very low T-score (--2.0)
indicates the need for a thorough evaluation of
secondary causes of bone loss 15; and (iv) to help
in determining what type of treatment to prescribe. Very low bone mass may be an indication
for the use of an anabolic agent.16 If a DXA machine is not available, a patient with a fracture
that is clearly a fragility fracture must be treated. This treatment decision will be made much
easier with the availability of the 10-year fracture probability based on the WHO FRAX TM Fracture Risk Assessment Tool using the body mass
index approach.17 REFERENCES
1. National Institutes of Health. NIH Consensus Development
Panel on Osteoporosis Prevention, Diagnosis, and Therapy.
Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001;
285:785-795.
2. National Institutes of Health. Osteoporosis prevention,
diagnosis, and therapy. NIH Consensus Statement Online.
2000;17:1-36. http://consensus.nih.gov/2000/2000Osteoporosis
111html.htm. Accessed July 7, 2008.
3. World Health Organization Study Group. Assessment of fracture risk and its application to screening for postmenopausal
osteoporosis: report of a WHO study group. World Health
Organization Technical Report Series. 1994;843:1-129.
4. McBroom RJ, Hayes W, Edwards WT, Goldberg RP, White AA.
Prediction of vertebral body compressive fracture using quantitative computed tomography. J Bone Joint Surg Am. 1985;
67:1206-1214.
5. Mosekilde L, Mosekilde L, Danielson C. Biomechanical
competence of vertebral trabecular bone in relation to ash
density and age in normal individuals. Bone. 1987;8:79-85.
6. Johnell O, Kanis JA, Oden A, et al. Predictive value of BMD for
hip and other fractures. J Bone Miner Res. 2005;20:1185-1194.
7. Barrett-Connor E, Siris ES, Wehren LE, et al. Osteoporosis
and fracture risk in women of different ethnic groups. J Bone
Miner Res. 2005;20:185-194.
8. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A,
Tosteson A. Incidence and economic burden of osteoporosisrelated fractures in the United States, 2005-2025. J Bone
Miner Res. 2007;22:465-475.
9. Melton LJ III. Epidemiology of fractures. In: Riggs BL,
Melton LJ III, eds. Osteoporosis: Etiology, Diagnosis and Man-
agement. New York, NY: Raven Press; 1988:133-154.
10. Melton LJ III, Atkinson EJ, Cooper C, O’Fallon WM, Riggs
BL. Vertebral fractures predict subsequent fractures. Osteoporos Int. 1999;10:214-221.
11. Black DM, Arden NK, Palermo L, Pearson J, Cummings SR;
Study of Osteoporotic Fractures Research Group. Prevalent
vertebral deformities predict hip fractures and new vertebral
deformities but not wrist fractures. J Bone Miner Res. 1999;
14:821-828.
12. Johnell O, Kanis JA, Oden A, et al. Fracture risk following
an osteoporotic fracture. Osteoporos Int. 2004;15:175-179.
13. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk
factors enhances the performance of BMD in the prediction
of hip and osteoporotic fractures in men and women. Osteoporos Int. 2007;18:1033-1046.
14. Siris ES, Miller PD, Barret-Connor E, et al. Identification
and fracture outcomes of undiagnosed low bone mineral
density in postmenopausal women: results from the National
Osteoporosis Risk Assessment. JAMA. 2001;286:2815-2822.
15. Greenspan SL, Luckey MM. Evaluation of postmenopausal
osteoporosis. In Favus MJ, ed. Primer on the Metabolic Bone
Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, DC: American Society of Bone and Mineral Research;
2006:268-272.
16. Rosen CJ, Bilezikian JP. Anabolic therapy for osteoporosis. J Clin Endocrinol Metab. 2001;86:957-964.
17. WHO Collaborating Centre for Metabolic Bone Diseases,
University of Sheffield, UK. FRAX TM WHO Fracture Risk
Assessment Tool. Available at: http://www.shef.ac.uk/FRAX.
Accessed June 5, 2008
Is bone mineral density measurement useful in patients who have already fractured?
MEDICOGRAPHIA, VOL 30, No. 4, 2008 363
CONTROVERSIAL QUESTION
5
C. V. Albanese, Italy
O
Carlina V. ALBANESE, MD
Osteoporosis and
Skeletal Diseases Unit
Department of
Radiological Science
University of Rome Sapienza
Viale Regina Elena, 328
00161 Rome
ITALY
(e-mail: carlina.albanese@
uniroma1.it)
steoporosis is a common disease that
manifests itself as fragility fractures occurring at multiple skeletal sites, mostly the
spine, hip or wrist. Fractures affect up to onehalf of women and up to a third of men aged over
50 years, and are often associated with low bone
density.1 These numbers are likely to increase with
the increasing age of the population. According to
the World Health Organization 1994 guidelines,2
osteoporosis is defined as a bone mineral density
(BMD) that lies 2.5 standard deviations (SD) or
more below the average value for young healthy
women (ie, a T-score of <--2.5 SD). This criterion provides both a diagnostic and intervention
threshold. The most widely-validated technique
to measure BMD is dual-energy x-ray absorptiometry applied to sites of biological relevance,
including the hip, spine, and forearm. A diagnosis based on the BMD T-score is a recommended
clinical trial entry criterion for the development
of pharmaceutical interventions in osteoporosis.3
In addition, BMD tests have an important role
as a clinical tool for the evaluation of individuals
at risk of osteoporosis, and in helping clinicians
advise patients about the appropriate use of antifracture treatment.4 However, there are several
problems with the use of BMD tests alone for the
detection of individuals at high risk of fracture.
One of the major problems is that these tests have
high specificity but low sensitivity. While BMD
correlates strongly with fracture risk, the BMD
measurements of those who fracture and those
who do not overlap significantly. In addition,
the predictive value of BMD regarding fracture
risk reduction only partially explains the observed
reduction in fracture risk in treated patients.5
The impact on fracture risk of risk factors other
than BMD was recently studied, and results indicated that more patients should receive treatment.6 Candidate risk factors included age, sex,
glucocorticoid use, secondary osteoporosis, family history, prior fragility fracture, low body
mass index, smoking, excess alcohol consumption, and femoral neck BMD. The BMD test is
not only useful in the primary prevention of
fragility fracture, but also in the secondary prevention of spine and hip fractures in those who
have a history of fracture; it is also useful for
monitoring the response to therapy. Several clinical trials have demonstrated in particular for
postmenopausal women that treatment of patients
with fragility fractures improves BMD and reduces
the risk of future fractures. It was recently reported that an increase in BMD after 1 (femoral
neck) and 3 years (femoral neck and total proximal femur) was associated with a reduction in
vertebral fracture incidence during 3 years of
treatment with strontium ranelate.7 In this study,
applying the methodology recently used for antiresorptive agents, it was calculated that during
3 years of treatment with strontium ranelate,
the change in BMD measured at the total proximal femur or femoral neck explained more than
70% of the vertebral fracture risk reduction. Furthermore, it was reported that follow-up BMD
measurement during a pharmacological clinical
trial also provided a good tool to monitor improvement in the course of the disease and compliance with treatment, and helped motivate patients to continue their treatment after 5 years
of follow-up.8 However, although the safety and
efficacy of different drugs active in the prevention
of fragility fracture have been amply demonstrated, osteoporosis care is reported globally to be inadequate.9 Effective management of osteoporosis
has been widely available for many years, yet its
uptake remains poor, with BMD tested in fewer
than 8% of postmenopausal women, and therapy
prescribed in only 20% to 30% of women post–low
trauma fracture. Among the different factors
that are barriers to osteoporosis management,
improving patient understanding of osteoporosis
and increasing their perception of osteoporosis
risk plays an important role. In a recent study
aimed at determining if direct intervention at
orthopedic fracture clinics would improve postfracture management in patients, a low BMD
measurement was found to be the best factor associated with increased compliance.10 In conclusion, the BMD test is an useful tool in osteoporotic patients who have already fractured in order
to monitor the efficacy of therapy and to enhance their compliance during the therapy, both
in interventional trials and in clinical practice. REFERENCES
1. Cummings SR, Melton LJ. Epidemiology and outcomes of
osteoporotic fractures. Lancet. 2002;359:1761-1767.
2. World Health Organization Study Group. Assessment of fracture risk and its application to screening for postmenopausal
osteoporosis. Report of a WHO Study Group. WHO Technical
Report Series No. 843. Geneva, Switzerland: World Health
Organization; 1994.
3. Hochberg M. Preventing fractures in postmenopausal women with osteoporosis. A review of recent controlled trials of
antiresorptive agents. Drugs Aging. 2000;17:317-330.
4. Delmas PD, Li Z, Cooper C. Relationship between changes
in bone mineral density and fracture risk reduction with antiresorptive drugs: some issues with meta-analyses. J Bone
Miner Res. 2004;19:330-337.
5. Johnell O, Kanis JA, Oden A, et al. Predictive value of BMD for
hip and other fractures. J Bone Miner Res. 2005;20:1185-1194.
6. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk
factors enhances the performance of BMD in the prediction of
hip and osteoporotic fractures in men and women. Osteoporos
Int. 2007;18:1033-1046.
7. Bruyere O, Roux C, Detilleux J, et al. Relationship between
bone mineral density changes and fracture risk reduction in
patients treated with strontium ranelate. J Clin Endocrinol
Metab. 2007;92:3076-3081.
8. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with
postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468.
9. Watts NB, Cooper C, Lindsay R, et al. Relationship between
changes in bone mineral density and vertebral fracture risk
associated with risedronate: greater increases in bone mineral
density do not relate to greater decreases in fracture risk.
J Clin Densitom. 2004;7:255-261.
10. Kuo I, Ong C, Simmons L, Bliuc D, Eisman J, Center J.
Successful direct intervention for osteoporosis in patients
with minimal trauma fractures. Osteoporos Int. 2007;18:
1633-1639.
364 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Is bone mineral density measurement useful in patients who have already fractured?
CONTROVERSIAL QUESTION
6
J. C. Romeu, Portugal
T
José Carlos ROMEU, MD
Department of Rheumatology
& Metabolic Bone Diseases
Santa Maria Hospital
Lisbon
PORTUGAL
(e-mail:
[email protected])
o answer the question “Is bone mineral
density (BMD) measurement useful in
osteoporotic patients who have already
fractured?” it is crucial to analyze the following
points: (i) is BMD measurement useful for osteoporosis diagnosis in patients who have already
suffered a fragility fracture? (ii) is BMD measurement useful for osteoporosis management in osteoporotic patients who have already fractured?
(iii) is BMD measurement useful for treatment acceptance and compliance in osteoporotic patients
who have already fractured? and (iv) is BMD
measurement useful to determine treatment efficacy in osteoporotic patients who have already
fractured?
Is BMD measurement useful for osteoporosis
diagnosis in patients who have already
suffered a fragility fracture?
Osteoporosis is a systemic skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone
strength reflects the effect of BMD and bone quality.1 So, the presence of a fragility fracture, defined as a classical osteoporotic fracture (particularly vertebral, wrist or hip fracture) in patients
aged 50 years or older and associated with a traumatism of low energy, depicts compromised bone
strength and allows the diagnosis of osteoporosis
without BMD assessment. However, this concept
is not directly applicable to other fractures that
are less strongly associated with age, low bone
mass or mild trauma, such as fractures of the
proximal humerus, ribs, and pelvis.2 In patients
with fractures at these locations, the decision to
perform a BMD measurement must depend on the
presence of other risk factors for osteoporosis (eg,
age) and the energy of the underlying trauma
(ie, low impact); in this setting, BMD assessment
can effectively contribute to the diagnosis of osteoporosis. On the other hand, it is important to
consider that despite the fact that BMD is an independent risk factor for fracture, most osteoporotic
fractures occur in patients without an osteoporotic BMD T-score, reflecting its low sensitivity for
this condition.3,4 Thus, in patients who have already fractured, BMD measurement may not be
indispensable for the diagnosis of osteoporosis
and, when effectuated, its result must be carefully
interpreted and not overestimated.
Is BMD measurement useful for osteoporosis
management in osteoporotic patients who have
already fractured?
An osteoporotic fracture is a well-documented
independent risk factor for a new fracture, regardless of BMD, and the risk is highest immediately following the initial fracture.5-7 Moreover,
stronger evidence for therapy efficacy and a
higher absolute risk reduction of fractures (or
lower number of patients needed to treat) is observed in osteoporotic patients with prevalent
Is bone mineral density measurement useful in patients who have already fractured?
fractures,8-19 strengthening the clinical relevance
of treating these patients. In accordance, in addition to the evidence of efficacy in trials that
included patients selected on the basis of previous
fractures (without BMD as an inclusion criterion or including patients with a T-score above
--2.5),8,10-12,14-16,18,19 there are some observations that
suggest treatment efficacy in patients both with
previous fractures and with T-scores higher than
--2.5.20-22 Therefore, in osteoporotic patients who
have already fractured, BMD measurement is
not necessary for treatment decisions.
Is BMD measurement useful for treatment
acceptance and compliance in osteoporotic
patients who have already fractured?
In patients who have already suffered major osteoporotic manifestations (fractures), BMD measurement is not helpful for the reinforcement of
the need to treat—contrary to the situation in
patients without previous fracture.23 The presence
of a fracture assures the reliability of the diagnosis, predicts a high risk of new fractures, and
establishes the indication to treat. As in the treatment of other chronic diseases, there is a higher
discontinuation rate of osteoporosis treatment
in the first 3 to 6 months (more than 50%), decreasing progressively thereafter, and becoming
lower and stable after 2 years.24 The use of dualenergy x-ray absorptiometry has been considered as a possible strategy to increase compliance. However, this technique has a limited
capability to detect significant BMD changes over
time in individual patients, and the repetition
of the test is only recommended after 18 to 24
months. In fact, serial BMD measurements are
not really useful to prevent treatment discontinuation, as dropouts from treatment generally
occur before BMD assessment can be repeated.
Is BMD measurement useful to determine
treatment efficacy in osteoporotic patients
who have already fractured?
Although the definitive demonstration of therapeutic efficacy is fracture prevention, in clinical
practice it is not reasonable to wait for a fracture to confirm treatment inefficacy. As pointed
out before, there are limitations in the detection
of significant changes in BMD in individual patients on therapy (which often will fall within the
in-vivo precision error of the device), and a relatively weak correlation between reduction in
fracture rates and average changes in BMD.25-27
BMD readings are also further limited by the
“regression to the mean” effect, that is to say that
those who have higher increases in BMD in the
first year have higher decreases in BMD in the
second year, and vice versa.28 In spite of this controversy, serial BMD measurement is still the
most precise and useful technique for treatment
monitoring in clinical practice. However, it is
fundamentally important that serial measureMEDICOGRAPHIA, VOL 30, No. 4, 2008 365
CONTROVERSIAL QUESTION
ments are carried out with the same instrument,
with high performance in scanning and analysis,
application of the “Least Significant Change”
concept, and that all data should be judiciously
interpreted. In summary, in osteoporotic patients
who have already fractured and have accepted
treatment, BMD assessment can be useful to further monitor therapy efficacy. REFERENCES
1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis Prevention,
Diagnosis, and Therapy. JAMA. 2001;285:785-795.
2. Eastell R, Reid DM, Compston J, et al. Secondary prevention of osteoporosis: when should a non-vertebral fracture be
trigger for action? Q J Med. 2001;94:575-597.
3. Siris ES, Miller PD, Barret-Connor E, et al. Identification
and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women. JAMA. 2001;286:2815-2822.
4. Siris ES, Chen Y-T, Abbott TA, et al. Bone mineral density
thresholds for pharmacological intervention to prevent fractures. Arch Intern Med. 2004;164:1108-1112.
5. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for
hip fracture in white women. N Engl J Med. 1995;332:767-773.
6. Kanis JA, Jonhell O, De Laet C, et al. A meta-analysis of
previous fracture and subsequent fracture risk. Bone. 2004;35:
375-382.
7. Johnell O, Kanis JA, Odén A, et al. Fracture risk following
an osteoporotic fracture. Osteoporos Int. 2004;15:175-179.
8. Black DM, Cummings SR, Thompson DE, et al. Randomized trial of effect of alendronate on risk of fracture in women
with existing vertebral fracture. Lancet. 1996;348:1535-1541.
9. Ettinger B, Black DM, Mitlak BH, et al; Multiple Outcomes
of Raloxifene Evaluation (MORE) Investigators. Reduction of
vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282:637-645.
10. Harris ST, Watts NB, Genat HK, et al; Vertebral Efficacy
with Risedronate Therapy (VERT) Study group. Effects of
risedronate treatment on vertebral and nonvertebral fractures
in women with postmenopausal osteoporosis: a randomized
controlled trial. JAMA. 1999;282:1344-1352.
11. Reginster J, Minne HW, Sorensen OH, et al; Vertebral
Efficacy with Risedronate Therapy (VERT) Study Group. Randomized trial of effects of risedronate on vertebral fractures
in women with established postmenopausal osteoporosis.
Osteoporos Int. 2000;11:83-91.
12. Chesnut III CH, Silverman S, Andriano K, et al; PROOF
Study Group. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis:
the prevent recurrence of osteoporosis fractures study. Am J
Med. 2000;109:267-276.
13. McClung MR, Geusens P, Miller PD, et al; Hip Intervention
Program Study Group. Effect of risedronate on the risk of hip
fracture in elderly women. N Engl J Med. 2001;344:333-340.
14. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of
parathyroid hormone (1-34) on fractures and bone mineral
density in postmenopausal women with osteoporosis. N Engl
J Med. 2001;344:1434-1441.
15. Chesnut III CH, Skag A, Christiansen C, et al. Effects of
oral ibandronate administered daily or intermittently on frac-
ture risk in postmenopausal osteoporosis. J Bone Miner Res.
2004;19:1241-1249.
16. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with
postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468.
17. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium
ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) Study. J Clin Endocrinol Metab.
2005;90:2816-2822.
18. Black DM, Delmas PD, Esteall R, et al. Once-yearly zoledronic acid for treatment of osteoporosis. N Engl J Med. 2007;
356:1809-1822.
19. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1861-1862.
20. Quandt SA, Thompson DE, Schneidner DL, Nevitt MC,
Black DM. Effect of alendronate on vertebral fracture risk in
women with bone mineral density T scores of -1.6 to -2.5 at
the femoral neck: the Fracture Intervention Trial. Mayo Clin
Proc. 2005;80:343-349.
21. Roux C, Reginster J-Y, Fechtenbaum J, et al. Vertebral
fracture reduction with strontium ranelate in women with
postmenopausal osteoporosis is independent of baseline risk
factors. J Bone Miner Res. 2006;21:536-542.
22. Kanis JA, Johnell O, Black DM, et al. Effect of raloxifene
on the risk of new vertebral fracture in postmenopausal
women with osteopenia or osteoporosis: reanalysis of the Multiple Outcomes of Raloxifene Evaluation Trial. Bone. 2003;33:
293-300.
23. Gold T. Medication adherence: a challenge for patients
with postmenopausal osteoporosis and other chronic illnesses.
J Manag Care Pharm. 2006;12(suppl A):S20-S25.
24. Ortonali S. How can patient compliance with antiosteoporotic treatments be improved? Medicographia. 2004;26:
265-270.
25. Cranney A, Guyatt G, Griffith L, et al. Meta-analysis of
therapies for postmenopausal osteoporosis. IX: Summary of
meta-analysis of therapies for postmenopausal osteoporosis.
Endocr Rev. 2002;23:570-578.
26. Sarkar S, Mitlak BH, Wong M, et al. Relationships between
bone mineral density and incident vertebral fracture risk with
raloxifene therapy. J Bone Miner Res. 2002;17:1-10.
27. Cummings SR, Karpf DB, Harris F, et al. Improvement in
spine bone mineral density and reduction in risk of vertebral
fractures during treatment with antireasorptive drugs. Am J
Med. 2002;112:281-289.
28. Cummings SR, Palermo L, Browner W, et al; Fracture
Trial Research Group. Monitoring osteoporosis therapy with
bone densitometry: misleading changes and regression to the
mean. JAMA. 2000;283:1318-1321.
366 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Is bone mineral density measurement useful in patients who have already fractured?
CONTROVERSIAL QUESTION
7
K. Briot, France
O
Karine BRIOT, MD
René-Descartes University
Rheumatology Department
Cochin Hospital
27 rue du Faubourg
St Jacques, 75014 Paris
FRANCE
(e-mail:
[email protected])
steoporotic fractures represent a major
health problem worldwide, leading to
significant morbidity and mortality, and
major costs for healthcare systems. Early intervention is necessary to avoid the recurrence of
fracture.1 Is bone mineral density (BMD) measurement useful for diagnosis in patients with
fractures? Dual-energy x-ray absorptiometry
(DXA) is the most relevant method for BMD measurement, and is considered as the gold standard for the diagnosis of osteoporosis. The World
Health Organization definition of osteoporosis
is based on the results of BMD. Is BMD measurement useful for treatment decision-making in
patients with fractures? A low BMD is an important risk factor for future fractures 2; subjects
who have a BMD measurement that is one standard deviation below normal have twice the
fracture risk. However, the sensitivity of BMD
measurement is low, and approximately 50% of
all fractures would be missed if one relied on
BMD alone, because they occur in subjects who
have a BMD T-score in the osteopenic or normal
range.3,4 Clinical risk factors (such as age, previous fragility fracture, glucocorticoid use, low
weight, etc) can improve the prediction of fracture
risk.5 Fragility fracture is itself an important risk
factor, conferring a twofold increase in fracture
risk independently of BMD.6 For any given BMD
T-score, previous vertebral fractures have been
found to increase the risk of incident vertebral,
nonvertebral, and hip fractures, with this risk
increasing with the severity and number of prevalent vertebral fractures.7 Prior hip fracture increases the risk of vertebral, hip, and forearm fractures, independently of BMD.1 Other nonvertebral
fractures such as forearm fractures increase the
risk of new fractures,8 although this increased
risk is largely explained by low BMD.8 If the diagnosis of osteoporosis is based on assessment of
BMD by DXA, intervention thresholds should be
based on fracture probability, and a prevalent
fracture increases the probability of fracture substantially. However, has antiosteoporotic treatment been shown to be efficacious in patients
selected on the basis of prior fracture? Randomized trials have shown that antiosteoporotic
treatments such as bisphosphonates can reduce
the risk of fractures in postmenopausal women
selected solely on the basis of prior vertebral
fracture.9 The number of women aged an average
of 65 years who need to be treated to prevent 1
of them having a fracture, is an average of 10 if
patients have prevalent vertebral fractures, and
35 if they have no fractures but have a T-score
<--2.5 at the hip.10 An annual infusion of zoledronic acid performed after a hip fracture has been
shown to reduce the risk of new fractures. In one
study, women were selected on the basis of hip
fracture, and less than 50% of them had a femoral
neck T-score <--2.5.11 Because of the consequences
of vertebral and hip fracture, and because antiosteoporotic treatments have shown their efficacy
in patients selected on the basis of these fractures, antiosteoporotic treatment could be prescribed at any given BMD T-score. For other
nonvertebral fractures (forearm, ribs, shoulder,
and ankle fractures), the increased risk of new
fracture is largely mediated by a low BMD, and
treatments have not shown their effectiveness in
trials of postmenopausal women selected on the
basis of forearm or shoulder fractures. Consequently, antiosteoporotic treatment should be
allocated to postmenopausal women with a low
BMD (T-score <--2), and other clinical risk factors. Is BMD measurement useful for the follow-up
and management of patients with fractures? BMD
measurement is not recommended in France for
the monitoring of antiresorptive treatment until
the end of the first 5 years of treatment, but it can
be useful for the follow-up of strontium ranelate.12
Performing BMD measurement after a fracture
is useful for the re-evaluation of treatment (for
example, after 5 years of bisphosphonates). In
conclusion, a BMD measurement is useful in patients who have already fractured, for the diagnosis, for the prediction of future fracture, for the
treatment decision in the case of nonvertebral
fractures (hip excluded), and for the follow-up
and management of treated patients. REFERENCES
1. Johnell O, Kanis JA, Odén A, et al. Fracture risk following
an osteoporotic fracture. Osteoporos Int. 2004;15:175-179.
2. Marshall D, Johnell O, Wedel H. Meta-analysis of how well
measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:1254-1259.
3. Schuit SC, van der Klift M, Weel AE, et al. Fracture incidence
and association with bone mineral density in elderly men
and women: the Rotterdam Study. Bone. 2004;34:195-202.
4. Stone KL, Seeley DG, Lui LY, et al; Osteoporotic Fractures
Research Group. BMD at multiple sites and risk of fracture of
multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res. 2003;18:1947-1954.
5. Kanis JA. Osteoporosis: diagnosis of osteoporosis and assessment of fracture risk. Lancet. 2002;359:1929-1936.
6. Klotzbuecher CM, Ross PD, Landsmann PB, Abbott TA,
Berger M. Patients with prior fractures have an increased risk
of future fractures: a summary of the literature and statistical
synthesis. J Bone Miner Res. 2000;15:721-739.
7. Siris ES, Genant HK, Laster AJ, Chen P, Misurski DA, Krege
JH. Enhanced prediction of fracture risk combining vertebral
fracture status and BMD. Osteoporos Int. 2007;18:761-771.
8. Schousboe JT, Fink HA, Taylor BC, et al. Association between self-reported prior wrist fractures and risk of subsequent
hip and radiographic vertebral fractures in older women: a
prospective study. J Bone Miner Res. 2005;20:100-106.
9. Kanis JA, Barton IP, Johnell O. Risedronate decreases fracture risk in patients selected solely on the basis of prior fracture.
Osteoporos Int. 2005;16:475-482.
10. Harris ST, Watts NB, Genant HK. Effects of risedronate
treatment on vertebral and non vertebral fractures in women
with postmenopausal osteoporosis: a randomized controlled
trial. JAMA. 1999;282:1344-1352.
11. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic
acid and clinical fractures and mortality after hip fracture.
N Engl J Med. 2007;357:1799-1809.
12. Roux C, Garnero P, Thomas T, Sabatier JP, Orcel P, Audran
M. Recommendations for the monitoring of antiresorptive
therapies in postmenopausal osteoporosis. Joint Bone Spine.
2005;72:26-31.
Is bone mineral density measurement useful in patients who have already fractured?
MEDICOGRAPHIA, VOL 30, No. 4, 2008 367
CONTROVERSIAL QUESTION
8
P. Geusens, Netherlands
P
Piet GEUSENS, MD, PhD
Department of Internal
Medicine, Subdivision of
Rheumatology, University
Hospital Maastricht
Maastricht
NETHERLANDS
Biomedical Research Centre
University of Hasselt
BELGIUM
(e-mail:
[email protected])
ostmenopausal women with a fracture after the age of 50 years have twice the risk
of a subsequent fracture compared with
women without a fracture history.1 The risk of a
subsequent fracture after an initial fracture is even
higher during the first years after the initial fracture. In a short-term study, 25% of women with
a recent radiographic vertebral fracture had a
subsequent radiographic vertebral fracture within
1 year.2 The 2-year absolute risk for subsequent
fractures is more than 10% in women and men
with any clinical fracture after the age of 50 years.3
In long-term studies, half of subsequent clinical
fractures occurred within 5 years after an initial
clinical fracture.4,5 Therefore, all guidelines on
osteoporosis advocate that women with a fracture
after the age of 50 years need immediate attention and counseling for fracture prevention.6 This
increased risk for a subsequent fracture is independent of other fracture risk factors such as low
bone mineral density (BMD), BMD-independent
clinical risks for fractures (age, fracture history in
family, low body weight, smoking, excessive alcohol intake, rheumatoid arthritis, and glucocorticoid use), and BMD-independent fall-related
risk factors.1,7 Based on these risk factors, the
World Health Organization has developed algorithms that allow the calculation of the 5-year and
10-year absolute risk for fractures in individuals.1
In patients with many clinical risk factors, fracture risk can be high without measuring BMD,
but low BMD remains an additional risk factor
for fractures.1 When BMD is measured in postmenopausal women with a fracture, most patients
do not have BMD-defined osteoporosis (ie, a Tscore <--2.5), indicating that BMD measurement
by dual-energy x-ray absorptiometry (DXA) does
not capture all bone-related risks, such as microarchitecture.8 Even many patients with a socalled “osteoporotic” nonvertebral fracture have
no BMD-defined osteoporosis. In a systematic survey in 568 patients of 50 years and older with a
recent nonvertebral fracture, less than 50% had
BMD-defined osteoporosis.9 In a recent intervention study in patients who had suffered a hip
fracture during the last 3 months, only 40% had
BMD-defined osteoporosis.10 In postmenopausal
women with BMD-defined osteoporosis, 2 out of 3
were found to have known or newly-diagnosed
contributors to secondary osteoporosis, many of
which are correctable.11 In this context, the question arises as to the value of BMD measurement
in a patient with a fracture history. One way to
answer such a question is to take into account
the location of the fracture and to fit evidence
from fracture prevention studies to the fracture
risk of the patient with a fracture history.
Patients with a vertebral fracture
Patients with a vertebral fracture do not need
BMD measurement to decide about treatment.12
Their risk for fractures is high, and results of
368 MEDICOGRAPHIA, VOL 30, No. 4, 2008
randomized controlled trials on fracture prevention are available in patients selected on the basis
of a prevalent fracture, independent of BMD.
Once secondary osteoporosis is excluded or corrected,11 drug treatment can be started on top of
lifestyle recommendations.13 However, only one
in three vertebral fractures comes to clinical attention with signs and symptoms of an acute fracture. Still, all vertebral fractures, radiographic
or clinical, along with their number and severity,
are strong predictors of subsequent vertebral
and nonvertebral fractures.14 Underdiagnosis of
vertebral fractures is frequent, not only clinically,
but even when x-rays of the spine are available.15
There is a need for an universally-accepted gold
standard for the definition of vertebral deformities, and the value of new techniques for measuring vertebral deformities, such as instant vertebral assessment using DXA technology, needs
to be defined.16
Patients with a nonvertebral fracture
Patients with a nonvertebral fracture have risk
factors for fractures far beyond osteoporosis
alone, including BMD-independent bone- and
fall-related risk factors.9 Their risk for fractures
is high, and preventative measures to avoid new
fractures are advocated in all guidelines for such
patients.6 From an evidence-based medicine
point of view, it is advocated that patients with a
nonvertebral fracture have a BMD measurement
undertaken to decide about fracture prevention.6
If the T-score is <--2.5, drug treatment is indicated, as randomized controlled trials are available in this patient population. However, as the
presence of a fracture is a risk for future fracture,
many (but not all) guidelines on osteoporosis advocate treatment at even higher levels of T-score,
eg, <--1.0 or <--1.5 after a nonvertebral fracture
has already occurred.6 Such an approach is based
on the World Health Organization case-finding
strategy.1 One clinical consequence is that all
risk factors, including clinical risk factors and
BMD, need to be evaluated in order to not underestimate the absolute risk for fractures. On
the other hand, in the presence of many clinical
risks, the absolute risk for subsequent fractures
is already high without measuring BMD. Until
recently, no randomized controlled trials were
available on the antifracture effects of drugs in
patients selected only on the presence of a nonvertebral fracture, independent of BMD. Recently
it was shown that zoledronate given within 3
months after a hip fracture decreased the risk of
subsequent clinical fractures by 35% and mortality by 28% within 2 years, when around half
of patients were still available for follow-up.10
This is the first study to show that prevention of
a subsequent fracture is possible when patients
are selected solely on the basis of a history of
nonvertebral fracture (hip fracture in this study)
and independent of BMD. Indeed, only around
Is bone mineral density measurement useful in patients who have already fractured?
CONTROVERSIAL QUESTION
40% of the included patients with a recent hip
fracture had BMD-defined osteoporosis. Further
studies are necessary to test the hypothesis that
in patients solely selected on the basis of a prevalent nonvertebral fracture, fracture prevention
is possible, as has been shown in patients with a
prevalent vertebral fracture1 or recent hip fracture.10 In conclusion, postmenopausal women
with a fracture need immediate attention for
prevention of subsequent fractures. BMD mea-
surement contributes to fracture risk prediction
and is helpful in deciding about drug treatment.
However, in patients with a prevalent vertebral
fracture, BMD is not strictly necessary for the
treatment decision. The antifracture effect of
zoledronate in patients with a recent hip fracture
is the first indication that the same could be
true in patients with a nonvertebral fracture, a
hypothesis that needs to be tested for nonvertebral fractures at locations other than the hip. REFERENCES
1. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk
factors enhances the performance of BMD in the prediction of
hip and osteoporotic fractures in men and women. Osteoporos
Int. 2007;18:1033-1046.
2. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. 2001;
285:320-323.
3. van Helden S, Cals J, Kessels F, Brink P, Dinant GJ, Geusens
P. Risk of new clinical fractures within 2 years following a
fracture. Osteoporos Int. 2006;17:348-354.
4. van Geel TA, Geusens PP, Nagtzaam IF, et al. Risk factors for
clinical fractures among postmenopausal women: a 10-year
prospective study. Menopause Int. 2007;13:110-115.
5. Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of subsequent fracture after low-trauma fracture in men and women.
JAMA. 2007;297:387-394.
6. Geusens PP. Review of guidelines for testing and treatment
of osteoporosis. Curr Osteoporos Rep. 2003;1:59-65.
7. Kelsey JL, Browner WS, Seeley DG, Nevitt MC, Cummings
SR; Study of Osteoporotic Fractures Research Group. Risk factors for fractures of the distal forearm and proximal humerus.
Am J Epidemiol. 1992;135:477-489.
8. Khosla S, Melton LJ 3rd. Clinical practice. Osteopenia.
N Engl J Med. 2007;356:2293-2300.
9. S van Helden, A van Geel, P Geusens, et al. Bone- and fall-
related fracture risks in women and men with a recent clinical fracture. J Bone Joint Surg. In press.
10. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. The
HORIZON Recurrent Fracture Trial. Zoledronic acid and
clinical fractures and mortality after hip fracture. N Engl J
Med. 2007;357:1799-1809.
11. Tannenbaum C, et al. Yield of laboratory testing to identify
secondary contributors to osteoporosis in otherwise healthy
women. J Clin Endocrinol Metab. 2002;87:4431-4437.
12. Sambrook P, Cooper C. Osteoporosis. Lancet. 2006;367:
2010-2018.
13. US Department of Health and Human Services. Bone
Health and Osteoporosis: A Report of the Surgeon General.
Rockville, MD: US Dept of Health and Human Services,
Public Health Service, Office of the Surgeon General; 2004.
14. Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA,
Berger M. Patients with prior fractures have an increased risk
of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. 2000;15:721-739.
15. Gehlbach SH, Bigelow C, Heimisdottir M, et al. Recognition of vertebral fracture in a clinical setting. Osteoporos Int.
2000;11:577-582.
16. Lewiecki EM, Laster AJ. Clinical review: clinical applications of vertebral fracture assessment by dual-energy x-ray
absorptiometry. J Clin Endocrinol Metab. 2006;91:4215-4222.
9
E. Paschalis, P. Roschger, P. Fratzl, and K. Klaushofer, Austria
B
Klaus KLAUSHOFER, MD
Eleftherios PASCHALIS, MD
Paul ROSCHGER, MD
Peter FRATZL, MD
Ludwig Boltzmann Institute
of Osteology at the Hanusch
Hospital of WGKK & AUVA
Trauma Centre Meidling
4th Medical Department
Hanusch Hospital
Heinrich Collin Strasse 30
A-1140 Vienna
AUSTRIA
(e-mail: klaus.klaushofer@
osteologie.at)
efore one can answer the question as to
whether bone mineral density (BMD)
measurements are useful in osteoporotic
patients who have already fractured, one has to
put the worth of BMD in its proper perspective
with regard to its predictive value for bone strength
and thus fracture risk. Osteoporosis is a disease
that affects roughly 75 million people in Japan,
the US, and Europe.1 Although loss of bone mass,
measured clinically as a change in BMD, is considered an important risk factor for a reduction
in bone strength, in recent years, the definition of
osteoporosis has changed from a disease of low
BMD, to one of high bone fragility.2 It is clear
therefore that BMD is not the sole predictor of
whether an individual will experience fractures,3,4
as there is considerable overlap in BMD values
between populations that do and do not develop
fractures.5-7 It has been demonstrated that for a
given bone mass, an individual's risk of fracture
increases with age.8 Consistent with these findings, numerous investigators have shown that
mechanical variables directly related to fracture
risk are either independent of,9 or not totally ac-
Is bone mineral density measurement useful in patients who have already fractured?
counted for, by bone mass itself.10-14 Epidemiological evidence also shows considerable overlap of
bone density values between fracture and nonfracture groups, suggesting that low bone quantity alone is not the complete cause of fragility
fractures.15-17 It is evident then, that in addition
to BMD, bone quality should also be considered
when assessing bone strength. Bone quality is a
broad term encompassing a plethora of factors
such as geometry and bone mass distribution,
trabecular bone microarchitecture, microdamage, increased remodeling activity, along with
genetics, body size, environmental factors, and
changes in bone mineral and matrix tissue properties.6,7 In addition, new fracture risk factors are
emerging, and it is still unclear how these are
manifested in terms of BMD changes (if any). For
example, recent clinical/epidemiological data 18-21
show a definite correlation between homocysteine in the blood and fracture risk. Homocysteine is known to interfere with lysyl oxidase action,22 thus altering collagen post-translational
modifications and thus collagen cross-link profiles. Moreover, BMD measurements may not be
MEDICOGRAPHIA, VOL 30, No. 4, 2008 369
CONTROVERSIAL QUESTION
able to distinguish between bone volume and matrix mineralization changes, both of which play
an important role in determining fracture risk.23
Bone is a composite material of highly hierarchical structure consisting of organic matrix and
mineral, thus each component has a different,
yet intimately related, contribution to overall
bone strength.24 Utilizing techniques such as small
angle x-ray scattering, quantitative backscattered
electron imaging, and Fourier transform infrared
microspectroscopy and imaging, the analysis of
BMD distribution as well as the contribution of
mineral crystallite size, orientation, and maturity
(chemical composition) to bone strength is being actively pursued.24-31 Based on such studies,
models of the importance of mineral crystallite
shape and size in determining bone strength have
been put forth. Moreover, an important role for
the organic matrix in the determination of biomechanical properties is predicted. Specifically,
the matrix is proposed to play an important role
in alleviating impact damage to mineral crystallites and to matrix/mineral interfaces, behaving
like a soft wrap around mineral crystallites thus
protecting them from the peak stresses caused
by impact, and homogenizing stress distribution
within the bone composite.25,27 Again, when one
combines this proposed contribution of the organic matrix of bone with the recent clinical data,
one finds that it is impossible to discern through
BMD measurements. The drawback of the contribution of bone quality to bone strength is that
the majority of the relevant utilized techniques
for its measurement require an iliac crest biopsy,
a rather invasive and not so often practiced pro-
cedure. Considering all these aspects from a clinical perspective, we have to conclude that in a
patient with a “low-trauma” fracture, there is
something wrong with the biomechanical competence of the bone tissue, independent of BMD
value. This means that effective treatment is justified, independent of further diagnostic procedures. When a differential diagnosis of metabolic
bone diseases such as secondary osteoporosis is
needed, BMD is not helpful; this would require
a bone biopsy. Whether later on BMD measurements could be helpful to improve compliance or
show (with questionable precision) treatment effects after 2 to 3 years, is still a matter of debate,
entailing more commercial than scientific aspects. In summary, the posed question is a really
tough one, in that the clinically-available outcome (BMD) may not be informative enough in
predicting whether a patient will sustain a fracture, bearing in mind the well-documented technical recommended restrictions, diagnostic pitfalls, and biological variability, while the more
detailed techniques encompassing both bone
quantity and quality considerations offer a more
informed prediction, albeit at the expense of an
invasive procedure such as excision of an iliac
crest biopsy. It is our opinion that BMD should
continue to be considered as an outcome, but at
the same time its potential limitations in the absence of a biopsy should be emphasized. If a biopsy is available, then considerably less emphasis
should be placed on BMD. If clinical history and
pre-existing low-trauma fractures clearly indicate “fracture” disease, effective treatment rather
than BMD measurement is what is needed. REFERENCES
1. World Health Organization Scientific Group. Prevention and
Management of Osteoporosis. WHO Technical Report Series
No. 921. Geneva, Switzerland: World Health Organization; 2003.
2. Friedman A. Important determinants of bone strength: beyond bone mineral density. J Clin Rheumatol. 2006;12:70-77.
3. Boyce TM, Bloebaum RD. Cortical aging differences and
fracture implications for the human femoral neck. Bone. 1993;
14:769-778.
4. Marshall D, Johnell O, Wedel H. Meta-analysis of how well
measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:1254-1259.
5. Cummings SR. Are patients with hip fractures more osteoporotic? Review of the evidence. Am J Med. 1985;78:487-494.
6. McCreade RB, Goldstein AS. Biomechanics of fracture: is
bone mineral density sufficient to assess risk? J Bone Miner Res.
2000;15:2305-2308.
7. Manolagas SC. Corticosteroids and fractures: a close encoun-ter of the third cell kind. J Bone Miner Res. 2000;15:
1001-1005.
8. Hui S, Slemenda CW, Johnston CC. Age and bone mass
as predictors of fracture in a prospective study. J Clin Invest.
1988;81:1804-1809.
9. Jepsen KJ, Schaffler MB. Bone mass does not adequately
predict variations in bone fragility: a genetic approach. 47th
Annual Meeting of the Orthopedic Research Society; 2001;
San Francisco, CA. Trans Orthop Res Soc. 2001;114.
10. Parfitt AM. Bone remodeling and bone loss: understanding the pathophysiology of osteoporosis. Clin Obs Gynecol.
1987;30:789-811.
11. Mosekilde L, Mosekilde L, Danielsen CC. Biomechanical
competence of vertebral trabecular bone in relation to ash
density and age in normal individuals. Bone. 1987;8:79-85.
12. McCabe F, Zhou LJ, Steele CR, Marcus R. Noninvasive assessment of ulnar bending stiffness in women. J Bone Miner
Res. 1991;6:53-59.
13. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC,
Khaltaev N. Perspective: the diagnosis of osteoporosis. J Bone
Miner Res. 1994;9:1137-1142.
14. Kann P, Graeben S, Beyer S. Age-dependence of bone
material quality shown by the measurement of frequency of
resonance in the ulna. Calcif Tissue Int. 1994;54:96-100.
15. Schnitzler CM. Bone quality: a determinant for certain risk
factors for bone fragility. Calcif Tissue Int. 1993;53:S27-S31.
16. Ott SM. When bone mass fails to predict bone failure. Calcif
Tiss Int. 1993;53(suppl):S7-S13.
17. Cummings SR, Black DM, Nevitt MC, et al; Study of Osteoporotic Fractures Research Group. Appendicular bone density
and age predict hip fracture in women. JAMA. 1990;263:665-668.
18. Raisz LG. Homocysteine and osteoporotic fractures—
culprit or bystander? N Engl J Med. 2004;350:2089-2090.
19. McLean RR, Jacques PF, Selhub J, et al. Homocysteine as
a predictive factor for hip fracture in older persons. N Engl J
Med. 2004;350:2042-2049.
20. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, et al.
Homocysteine levels and the risk of osteoporotic fracture.
N Engl J Med. 2004;350:2033-2041.
21. Gjesdal CG, Vollset SE, Ueland PM, Refsum H, Meyer HE,
Tell GS. Plasma homocysteine, folate and vitamin B12 and
the risk of hip fracture. The Hordaland Homocysteine Study.
J Bone Miner Res. 2007;22:747-756.
22. Liu G, Nellaiappan K, Kagan HM. Irreversible inhibition
of lysyl oxidase by homocysteine thiolactone and its selenium and oxygen analogues. Implications for homocystinuria.
J Biol Chem. 1997;272:32370-32377.
370 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Is bone mineral density measurement useful in patients who have already fractured?
CONTROVERSIAL QUESTION
23. Fratzl P, Roschger P, Fratzl-Zelman N, Paschalis EP, Phipps
R, Klaushofer K. Evidence that treatment with risedronate in
women with postmenopausal osteoporosis affects bone mineralization and bone volume. Calcif Tissue Int. 2007;81:73-80.
24. Fratzl P, Gupta HS, Paschalis EP, Roschger P. Structure
and mechanical quality of the collagen-mineral composite in
bone. J Mater Chem. 2004;14:2115-2123.
25. Gao H, Ji B, Jager IL, Arzt E, Fratzl P. Materials become
insensitive to flaws at nanoscale: lessons from nature. Proc
Natl Acad Sci U S A. 2003;100:5597-5600.
26. Zizak I, Roschger P, Paris O, et al. Characteristics of mineral particles in the human bone/cartilage interface. J Struct
Biol. 2003;141:208-217.
27. Jager I, Fratzl P. Mineralized collagen fibrils: a mechanical model with a staggered arrangement of mineral particles.
10
Biophys J. 2000;79:1737-1746.
28. Roschger P, Paschalis EP, Fratzl P, Klaushofer K. Bone
mineralization density distribution in health and disease. Bone.
2008;42:456-466.
29. Paschalis EP, Betts F, DiCarlo E, Mendelsohn R, Boskey AL.
FTIR microspectroscopic analysis of human iliac crest biopsies from untreated osteoporotic bone. Calcif Tissue Int. 1997;
61:487-492.
30. Peterlik H, Roschger P, Klaushofer K, Fratzl P. From brittle to ductile fracture of bone. Nat Mater. 2006;5:52-55.
31. Fratzl P, Gupta HS, Roschger P, Klaushofer K. Bone nanostructure and its relevance for mechanical performance, disease and treatment. In Vogel V, ed. Nanotechnology — Nanomedicine and Nanobiotechnology. Weinheim, Germany:
Wiley-VCH. In press.
C.-H. Wu and R.-M. Lin, Taiwan
P
Chih-Hsing WU, MD
Ruey-Mo LIN, MD
Department of Orthopedics
National Cheng Kung
University Hospital
138 Sheng-Li Road
Tainan, 70428
TAIWAN
(e-mail:
[email protected])
revention of secondary fracture is the
major treatment goal for osteoporotic fracture. However, a large number of patients
remain untreated or receive inappropriate treatment even after a definite diagnosis of osteoporotic fracture.1,2 After 5 years in the Canadian
Multicenter Osteoporosis Study, 90% of men with
fragility fractures remained undiagnosed and
untreated for osteoporosis.3 No standard recommendation, the relatively high cost of long-term
medication, and the fear of adverse effects of
treatment might contribute to the poor adherence
to treatment.4 Recently, more concerns have been
focused on the role of bone mineral density (BMD).
What is the role of BMD measurement in these
osteoporotic fractured patients? To what extent
can we expect a beneficial effect when we arrange
dual-energy x-ray absorptiometry (DXA)? What
is the change in adherence to treatment of osteoporotic patients after they know their own BMD?
Do the different levels of BMD influence the treatment strategy? To answer these questions, we
need to assess them in a more evidence-based
manner. First, despite the argument regarding
BMD measurement methodology,5 BMD measurement is undoubtedly at the core of the concept of osteoporotic screening, diagnosis, and
prevention. The International Osteoporosis Foundation and National Osteoporosis Foundation
suggest that individuals with a history of fragility
fracture have high osteoporotic risk and should
receive BMD examination for the prevention of
osteoporotic fracture.6 Furthermore, for women
aged 70 to 80 years, the “BMD screening for all”
strategy was found to be more cost-effective than
no screening, or screening only for women with
at least one risk factor, in preventing hip fracture.7 Different levels of BMD, especially a relatively high Z-score (less than --2.0), also indicate
the possibility of secondary causes or underlying
risk factors for osteoporosis. Second, BMD may
influence different strategies regarding medication and management. In the case of low-trauma
fracture, during the 1-year follow-up in the
Is bone mineral density measurement useful in patients who have already fractured?
National Osteoporosis Risk Assessment (NORA)
study, a higher number of fractures observed in
women were osteopenic than osteoporotic.8 Although many trials have successfully demonstrated fracture prevention with pharmacological
interventions, the efficacy results regarding osteopenic individuals have been inconsistent.
Moreover, even a 50% reduction in fracture risk
would translate into only a modest effect on absolute risk reduction in osteopenic women.9,10
Percutaneous vertebroplasty is one treatment
choice for vertebral fracture. Improvement in
vertebral stiffness and strength after vertebroplasty has been found to depend highly on BMD.11
An ex-vivo biomechanical study suggested that
low-BMD (<0.7 g/cm2) patients may receive the
least amount of improvement in mechanical properties after vertebroplasty.11 Higher cement volume for relatively higher-BMD patients might
have a higher leakage rate. The cement volume
should be restricted to the amount needed for
fracture reduction only.11 Therefore, it might be
appropriate for osteoporotic fractured patients
with different BMDs to receive different treatment
strategies to prevent recurrent fracture 12 and
subsequent complications.11 Last, BMD is a good
indicator when monitoring treatment response.
The most responsive location is the lumbar spine,
with the hip neck or total hip being the second
choice. The forearm is not preferred,13 except
in cases of hyperparathyroidism. In one study,
women whose BMD increased by more than 3%
in the first 1 to 2 years of alendronate treatment
were found to have the lowest incidence of new
vertebral fracture.14 In the Spinal Osteoporosis
Therapeutic Intervention (SOTI) and TReatment
Of Peripheral OSteoporosis (TROPOS) studies,
the large increases in BMD reflected the promising effect of strontium ranelate.15,16 However, the
baseline BMD level is no different in teriparatide responders and nonresponders.17 Different
BMD levels may also help us to predict recurrent
fracture risk. A combination of clinical risk factors and BMD screening has a reasonable costMEDICOGRAPHIA, VOL 30, No. 4, 2008 371
CONTROVERSIAL QUESTION
effectiveness ratio in predicting osteoporotic
fracture.18 For the existing vertebral fracture patients of the Fracture Prevention Trial and the
Multiple Outcomes of Raloxifene Evaluation
(MORE),19 the 2-year predicted rate of recurrent
vertebral fracture was 12.3-fold for a T-score
of --2.0, 18.9-fold for a T-score of --3.0, and 28.0fold for a T-score of --4.0.20 In the Fracture Intervention Trial (FIT), each standard deviation
decrease in baseline spinal BMD was associated
with 1.5 to 2.1 times the fracture risk.21 Depending on the different BMD values, prevalent vertebral fracture status increased incident fracture
risk by up to 12 times.20 Finally, BMD is a practical tool to provide a means of communication
and increase compliance. Factors associated
with treatment nonadherence include adverse
effects, pain, and being unsure about BMD test
results.22 Correct DXA interpretation by physicians may lead to higher treatment rates and
better patient compliance, and patients who understand their BMD results also have a higher
rate of treatment continuity.4 In the Treatment
of Osteoporosis in Clinical Practice study, the
9851 Italian women who knew that their T-score
was less than --2.5 had a better compliance after
1 year of treatment, while those whose BMD was
not readily available had a 1.51-fold increased
risk of low compliance.23 Strategies to increase
adherence included reducing drug frequency
and monitoring patients via bone markers and
BMD testing.22 In conclusion, with the pleiotropic
role of BMD in osteoporotic management, the
arrangement of BMD measurement for osteoporotic patients who have already fractured is
warranted. REFERENCES
1. Kamel HK, Hussain MS, Tariq S, Perry HM, Morley JE.
Failure to diagnose and treat osteoporosis in elderly patients
hospitalized with hip fracture. Am J Med. 2002;109:326-328.
2. Castel H, Bonneh DY, Sherf M, Liel Y. Awareness of osteoporosis and compliance with management guidelines in patients with newly diagnosed low-impact fractures. Osteoporos
Int. 2001;12:559-564.
3. Papaioannou A, Kennedy CC, Ioannidis G, et al; CaMos
Research Group. The osteoporosis care gap in men with fragility fractures: the Canadian Multicentre Osteoporosis Study.
Osteoporos Int. 2008;19:581-587.
4. Pickney CS, Arnason JA. Correlation between patient recall
of bone densitometry results and subsequent treatment adherence. Osteoporos Int. 2005;16:1156-1160.
5. Bolotin HH. DXA in vivo BMD methodology: an erroneous
and misleading research and clinical gauge of bone mineral
status, bone fragility, and bone remodelling. Bone. 2007;41:
138-154.
6. Kanis JA, Black D, Cooper C, et al. A new approach to the
development of assessment guidelines for osteoporosis. Osteoporos Int. 2002;13:527-536.
7. Schott AM, Ganne C, Hans D, et al. Which screening strategy using BMD measurements would be most cost effective for
hip fracture prevention in elderly women? A decision analysis
based on a Markov model. Osteoporos Int. 2007;18:143-151.
8. Siris ES, Chen YT, Abbott TA, et al. Bone mineral density
thresholds for pharmacologic intervention to prevent fractures.
Arch Intern Med. 2004;164:1108-1112.
9. Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B.
Ten year probabilities of osteoporotic fractures according to
BMD and diagnostic thresholds. Osteoporos Int. 2001;12:
989-995.
10. Schousboe JT, Nyman JA, Kane RL, Ensrud KE. Cost-effectiveness of alendronate therapy for osteopenic postmenopausal
women. Ann Intern Med. 2005;142:734-741.
11. Graham J, Ahn C, Hai N, Buch BD. Effect of bone density
on vertebral strength and stiffness after percutaneous vertebroplasty. Spine. 2007;32:E505-E511.
12. Khosla S, Melton LJ 3rd. Osteopenia. N Engl J Med. 2007;
356:2293-2300.
13. Bouxsein ML, Parker RA, Greenspan SL. Forearm bone
mineral densitometry cannot be used to monitor response to
alendronate therapy in postmenopausal women. Osteoporos
Int. 1999;10:505-509.
14. Hochberg MC, Ross PD, Black D, et al; Fracture Intervention Trial Research Group. Larger increases in bone mineral
density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Arthritis Rheum. 1999;42:1246-1254.
15. Bruyère O, Roux C, Detilleux J, et al. Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab. 2007;92(8):3076-3081.
16. Bruyère O, Roux C, Badurski J, et al. Relationship between
change in femoral neck bone mineral density and hip fracture
incidence during treatment with strontium ranelate. Curr Med
Res Opin. 2007;23(12):3041-3045.
17. Gallagher JC, Rosen CJ, Chen P, Misurski DA, Marcus R.
Response rate of bone mineral density to teriparatide in postmenopausal women with osteoporosis. Bone. 2006;39:12681275.
18. Melton LJ 3rd, Atkinson EJ, Khosla S, Oberg AL, Riggs
BL. Evaluation of a prediction model for long-term fracture
risk. J Bone Miner Res. 2005;20:551-556.
19. Ettinger B, Black DM, Mitlak BH, et al; Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with
osteoporosis treated with raloxifene: results from a 3-year
randomized clinical trial. JAMA. 1999;282:637-645.
20. Siris ES, Genant HK, Laster AJ, Chen P, Misurski DA, Krege
JH. Enhanced prediction of fracture risk combining vertebral
fracture status and BMD. Osteoporos Int. 2007;18:761-770.
21. Nevitt MC, Ross PD, Palermo L, Musliner T, Genant HK,
Thompson DE; The Fracture Intervention Trial Research Group.
Association of prevalent vertebral fractures, bone density, and
alendronate treatment with incident vertebral fractures: effect
of number and spinal location of fractures. Bone. 1999;25:
613-619.
22. Papaioannou A, Kennedy CC, Dolovich L, Lau E, Adachi
JD. Patient adherence to osteoporosis medications: problems,
consequences and management strategies. Drugs Aging. 2007;
24:37-55.
23. Rossini M, Bianchi G, Di Munno O, et al; Treatment of
Osteoporosis in Clinical Practice (TOP) Study Group. Determinants of adherence to osteoporosis treatment in clinical
practice. Osteoporos Int. 2006;17:914-921.
372 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Is bone mineral density measurement useful in patients who have already fractured?
P
R O T E L O S
STRONTIUM RANELATE AS AN INNOVATION
IN THE TREATMENT OF POSTMENOPAUSAL
OSTEOPOROSIS: SCIENTIFIC EVIDENCE
AND CLINICAL BENEFITS
b y P. H a l b o u t , F r a n c e
one is a living tissue submitted to a continuous remodeling process necessary to maintain the integrity of the skeleton and to repair
local microdamage with the aim of ensuring maximal resistance to strains. Osteoporosis is a systemic
disease characterized by a low bone mass and an
impairment of bone microarchitecture, leading to
an increase in bone frailty and a subsequent increased risk of fracture. Bone loss occurs early in life
independently of gender, but it is dramatically increased in women after the menopause. Indeed, depletion of estrogens after the menopause increases the level of bone remodeling, resulting in an
increase in bone resorption. If low bone mineral
density (BMD) is highly predictive of the risk of fractures in postmenopausal women, other factors such
as low bone mass index, smoking addiction, or age
have now been identified as increasing the risk of
B
T
Philippe HALBOUT, PhD
International Scientific Project
Leader, Servier International
Neuilly-sur-Seine
FRANCE
he depletion in estrogens occurring in women after the
menopause increases bone remodeling with a net balance
in favor of resorption, leading to a dramatic bone loss coupled with a decrease in bone quality. The impairment of these
main components of bone strength increases bone fragility and
subsequently the risk of fractures, right from 50 years of age. Conventional therapeutic strategies are either based on the downregulation of bone resorption (anticatabolic agents, mainly represented by bisphosphonates) or on the upregulation of bone
formation (anabolic agents). These therapies are, however, unsatisfactory, as, due to a coupling effect, agents downregulating
bone resorption also decrease bone formation, and agents upregulating bone formation also increase bone resorption. Protelos
(strontium ranelate) is an innovative treatment for osteoporosis
developed and licensed by Servier, with a unique dual mechanism of action that increases bone formation while decreasing
bone resorption. Protelos decreases the risk of vertebral, nonvertebral, and hip fractures over 3 years, and as a consequence, has
been fully approved by the European Medicines Agency as a treatment of post-menopausal osteoporosis. Furthermore, Protelos is
the only treatment having demonstrated its efficacy on vertebral, nonvertebral, and hip fractures over 5 years in preplanned
studies. The superior efficacy of Protelos is independent of the
severity of the disease as assessed by levels of bone mineral den-
osteoporotic fracture. Elderly women have the highest prevalence of osteoporosis and the highest risk
of falls, making them likely to experience osteoporotic fractures. However, the treatment of the
youngest osteoporotic women, right from the occurrence of the menopause, has to be considered in
order to maximize the efficacy of antiosteoporotic
treatment in the long term and to avoid the most
devastating consequences when older. In accordance with the pathophysiology of osteoporosis, antiresorptive treatments were first developed to fix
the bone loss associated with osteoporosis. By a
coupling effect, antiresorptive agents also strongly
decrease bone formation and, eventually, do not allow the generation of new bone in osteoporotic patients. The same coupling effect is responsible for
an increase in bone resorption induced by anabolic treatments. An ideal treatment for osteoporosis
sity, bone turnover, and the number of prevalent fractures. Protelos is efficient in preventing osteoporotic fractures right from
50 years of age through to elderly patients. Basically, this superior efficacy is accounted for by the benefits of the mechanism of
action of Protelos on bone, improving both bone mineral density
and bone quality, thus increasing bone strength. Protelos has
good tolerability, good safety, and provides patients with readily
perceptible benefits in terms of their health status, thus supporting the good compliance observed in the phase III studies. The superior efficacy of Protelos has been acknowledged in the recentlypublished European guidance for the diagnosis and management
of osteoporosis in postmenopausal women, in which it is stated as
being the only treatment to have provided complete proof of efficacy on all kinds of fractures, whatever the severity of the disease,
making Protelos a logical first-line treatment.
Medicographia. 2008;30:373-383.
(see French abstract on page 383)
Keywords: bone turnover; bone formation; bone resorption;
fracture risk; osteoporosis; Protelos (strontium ranelate)
www.medicographia.com
Address for correspondence: Dr Philippe Halbout, Servier International,
192 avenue Charles de Gaulle, 92578 Neuilly-sur-Seine Cedex, France
(e-mail: [email protected])
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
MEDICOGRAPHIA, VOL 30, No. 4, 2008 373
PROTELOS
Prevention of vertebral fracture
Protelos
Alendronate
Risedronate
Ibandronate
Zoledronic acid
HRT
Raloxifene
Teriparatide and PTH
Prevention of nonvertebral fracture
Women with
osteoporosis
Women with
osteoporosis +
vertebral fracture
Women with
osteoporosis
+
+
+
NA
+
+
+
NA
+
+
+
+
+
+
+
+
+ (including hip)
NA
NA
NA
NA
+
NA
NA
* In subsets of patients only (post-hoc analysis).
† Mixed group of patients with or without prevalent vertebral fractures.
+ = effective drug.
would thus be one with a dual mechanism of action,
able to increase bone formation and to decrease bone
resorption, with a net gain of new and strong bone.
Protelos (strontium ranelate) is the first agent of
this new generation of treatment. This dual mechanism of action makes Protelos the first treatment
to have demonstrated a superior efficacy in decreasing the risk of vertebral, nonvertebral, and hip fractures in the long term, in all kinds of patients, whatever the severity of the disease.
Protelos decreases the
risk of vertebral, nonvertebral,
and hip fractures
The antifracture efficacy of Protelos has been investigated in a broad phase III clinical development
program, initiated in 1996. This program included
two extensive clinical trials for the treatment of
established osteoporosis involving 6740 women:
the Spinal Osteoporosis Therapeutic Intervention
(SOTI) study and TRreatment Of Peripheral Osteoporosis Study (TROPOS). Both studies were multinational, randomized, double-blind, and placebocontrolled with two parallel groups (strontium
ranelate 2 g/day versus placebo), involving 75 clinSELECTED
bALP
BMD
CaSR
DRESS
FIRST
OPG
OVX
RANKL
sCTX
SOTI
TROPOS
ABBREVIATIONS AND ACRONYMS
bone-specific alkaline phosphatase
bone mineral density
calcium-sensing receptor
Drug Rash with Eosinophilia and
Systemic Symptoms
Fracture International Run-in
Strontium ranelate Trial
osteoprotegerin
ovariectomized
receptor activator of nuclear factor–
kappa B ligand
serum type I collagen C-telopeptide
crosslinks
Spinal Osteoporosis Therapeutic Intervention (study)
TRreatment Of Peripheral Osteoporosis
Study
374 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Women with
osteoporosis +
vertebral fracture
+ (including hip)
+ (including hip)
+ (including hip)
+*
NA (+)†
+
NA
+
Table I. Protelos is the only
treatment to have demonstrated its efficacy on vertebral,
nonvertebral, and hip fractures,
whatever the severity of
osteoporosis.
Abbreviations: HRT, hormone
replacement therapy; NA, no evidence available; PTH, parathyroid
hormone.
Adapted from reference 5: Kanis JA,
Burlet N, Cooper C, et al. European
guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int.
2008;19:399-428. Copyright © 2008,
Springer London.
ical centers in 12 countries in Europe and Australia.
The study duration was 5 years, with a first statistical analysis planned after 3 years of follow-up. All
patients included in these two studies had previously participated in a run-in study, Fracture International Run-in Strontium ranelate Trial (FIRST),
aimed at starting the normalization of calcium and
Vitamin D. In parallel to the treatment, the patients
received a calcium/vitamin D supplement, which
was individually adapted according to their deficiencies (500 or 1000 mg of calcium, and 400 or 800 IU
of vitamin D3).1
The main goal of SOTI was the assessment of the
effect of Protelos on the risk of vertebral fractures.
SOTI included 1649 postmenopausal women with
a least one vertebral fracture, a mean of age of 69.3
years, a mean lumbar T-score of --3.6 standard deviations (SD) and a mean femoral neck T-score of
--2.8 SD. After 1 year of treatment with Protelos, the
risk of experiencing new vertebral fractures was decreased by 49% (relative risk [RR], 0.51; 95% confidence interval [CI], 0.36-0.74; P<0.001). This efficacy was similar after 3 years of treatment with
Protelos, with a decrease in the risk of a new vertebral fracture of 41% (RR, 0.59; 95% CI, 0.48-0.73;
P<0.001). The efficacy of Protelos was such that
only 9 patients needed to be treated for 3 years to
prevent 1 patient from having a vertebral fracture
(95% CI, 6-14).2
In parallel, TROPOS was conducted to assess the
effect of Protelos on nonvertebral fractures. This
study included 5091 postmenopausal women with
a mean of age of 76.7 years, a mean lumbar T-score
of --2.8 SD, a mean femoral neck T-score of --3.1 SD,
and a mean total hip T-score of --2.7 SD. Over 3
years, Protelos decreased the risk of nonvertebral
fractures by 16% (RR, 0.84; 95% CI, 0.702-0.995;
P<0.05) and the risk of major nonvertebral osteoporotic fractures by 19%, including hip, wrist, pelvis,
sacrum, ribs-sternum, clavicle, and humerus (RR,
0.81; 95% CI, 0.66-0.98; P<0.05).3 The efficacy of
Protelos in decreasing the risk of vertebral fractures was confirmed with a 45% reduced risk of experiencing a new vertebral fracture over 1 year (RR,
0.55; 95% CI, 0.39-0.77; P<0.001), and a 39% reduced risk over 3 years (RR, 0.61; 95% CI, 0.51-0.73;
P<0.001) by comparison with placebo.
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
PROTELOS
Protelos efficacy
is sustained over time
Osteoporosis occurring after the menopause is a
silent and chronic disease that leads to a progressive weakening of the bone structure by compromising both bone density and quality. The average
duration of treatment is set to escalate in line with
the increase in life expectancy. Moreover, it is recommended that treatments against osteoporosis
are taken over the long term in order to provide
maximal efficacy.
To date, Protelos is the only treatment for which
efficacy in decreasing vertebral and nonvertebral
fractures over 5 years has been proven in preplanned
studies (SOTI and TROPOS) (Figure 1). In TROPOS,
2714 patients (average age 77 years, lumbar T-score
--2.8 SD and femoral neck T-score --3.1 SD) completed the study over up to 5 years. The risk of nonvertebral fractures was reduced by 15% in patients
treated with Protelos compared with placebo (RR,
0.85; 95% CI, 0.73-0.99; P=0.032). This reduction
was similar to the 16% reduction seen in the main
analysis performed over 3 years. The number of patients needed to treat (NNT) to avoid one nonvertebral fracture was 44 (95% CI, 20-191). The risk of
new major nonvertebral osteoporotic fracture was
reduced by 18% with Protelos (RR, 0.82; 95% CI,
0.69-0.98; P=0.025) and the NNT for 5 years to prevent one such fracture was 46 (95% CI, 21-232).
Finally, in a subgroup of 1128 patients with a high
risk of hip fractures (74 years and more with a lumbar and femoral neck T-score --2.4 SD), Protelos
reduced the risk of experiencing a hip fracture by
43% over 5 years (RR, 0.57; 95% CI, 0.33-0.97;
P=0.036).6 In TROPOS, a sustained efficacy of Protelos in decreasing the risk of vertebral fractures was
also observed over 5 years, with a risk reduction
of 24% compared with placebo (RR, 0.76; 95% CI,
0.65-0.88; P<0.001).
Overall, Protelos decreased the risk of experiencing an osteoporotic fracture by 20% independently
of the location, compared with placebo (RR, 0.20;
95% CI, 0.71-0.90; P<0.001). Only 21 patients need
to be treated with Protelos to prevent 1 new osteoporotic fracture.6
Recently, the efficacy of Protelos was analyzed
over 8 years, thus providing unique data on the very
long-term efficacy of this antiosteoporotic treatment. At the end of the 5-year preplanned period, a
subgroup of patients from SOTI and TROPOS were
pooled and included in an additional 3-year openlabel extension study (Figure 2). Patients with previous fractures were not excluded from the extension study. At SOTI and TROPOS inclusion, patients
treated for 8 years (n=893) had an average age of
Placebo
Strontium ranelate
RR: --24%
30
*P <0.05
***P <0.001
RR: --15%
25
Patients (%)
Hip fractures have the most devastating consequences of osteoporosis in terms of morbidity and
mortality. Consequently, special attention has been
paid to the investigation of the efficacy of Protelos
in reducing hip fractures in postmenopausal women aged 74 years and more, who have the highest
probability of experiencing such fractures (femoral
neck BMD T score --3 SD). Over 3 years, Protelos
decreased the risk of hip fractures by 36% in these
patients (RR, 0.64; 95% CI, 0.412-0.667; P=0.046).3
On the basis of these clinical results, in 2004 the
European Medicines Agency fully approved the indication of Protelos in the treatment of postmenopausal osteoporosis to reduce the risk of vertebral
and hip fractures.4 Moreover, the recently published
European guidance for the diagnosis and management of osteoporosis in postmenopausal women,
acknowledged Protelos as the only treatment with
demonstrated efficacy in preventing both vertebral
and nonvertebral fractures, including hip fractures,
whatever the severity of the disease (Table I).5
***
20
*
RR: --43%
15
10
*
5
0
New vertebral
fracture
New nonvertebral
fracture
0-5 years
Hip fracture
Figure 1. As demonstrated in preplanned studies, Protelos decreases the risk of
vertebral, nonvertebral, and hip fractures over 5 years. RR, relative risk.
Adapted from reference 6: Reginster J, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of non-vertebral and vertebral fractures in postmenopausal
osteoporosis: results of a 5-year, randomized, placebo-controlled trial. Arthritis Rheumat. 2008;58:
1687-1695. Copyright © 2008, American College of Rheumatology.
74 years, with a lumbar spine and femoral neck
T- score of --3.01 SD. As there is no placebo group in
the extension study, the efficacy of Protelos has been
assessed by comparison of the incidence of fracture
over the first and the last 3 years of the 8-year period. The cumulative incidence of new vertebral fractures over the 3-year extension period was 13.7%,
compared with 11.5% over the first 3 years. In patients from TROPOS, the cumulative incidence of
new nonvertebral fractures over the 3-year exten-
Efficacy assessed by comparison of cumulative incidence
over 0-3 years and 5-8 years
SOTI
Strontium
ranelate
2 g/day
Baseline
0
1
2
3
4
5
6
7
8
TROPOS
Strontium
ranelate
2 g/day
Extension study
Strontium ranelate
2 g/day
2055 included patients
whatever previous
occurrence of fracture
1420
completers
(69%)
Figure 2. Study design of the extension study performed after the preplanned
5 years of the Spinal Osteoporosis Therapeutic Intervention (SOTI) study and
TRreatment Of Peripheral Osteoporosis Study (TROPOS).
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
MEDICOGRAPHIA, VOL 30, No. 4, 2008 375
PROTELOS
A
Vertebral fracture incidence (SOTI + TROPOS)
Cumulative incidence over 0-3 years
Cumulative incidence over 5-8 years*
11.5%
13.7%
10
Fracture incidence (%)
Fracture incidence (%)
10
8
6
4
2
0
1
2
8
6
4
2
0
3
6
Years
7
8
Years
Nonvertebral fracture incidence (TROPOS)
B
Cumulative incidence over 0-3 years
Cumulative incidence over 5-8 years*
9.6%
12%
10
Fracture incidence (%)
10
Fracture incidence (%)
Other results coming from SOTI and TROPOS
clearly demonstrated that age has no influence on
the efficacy of Protelos, which decreased the risk of
vertebral fractures over 3 years by 37% in women
<70 years (RR, 0.63; 95% CI, 0.46-0.85; P=0.003)
and by 42% in women aged 70 to 80 years (RR, 0.58;
95% CI, 0.48-0.68; P<0.001) (Figure 4).10
Women over 80 years of age represent about 8%
of the postmenopausal population, but contribute
to over 30% of fragility fractures and over 60% of
hip fractures due to the higher prevalence of osteoporosis and the higher risk of falls. Moreover,
elderly patients are particularly susceptible to complications after hip fracture, such as impaired function, loss of independence, need for nursing home
care, financial cost, and mortality. A preplanned
analysis of the pooled data from SOTI and TROPOS
recently documented the efficacy of Protelos in
women aged 80 years or more. Right from the first
year of treatment, Protelos reduced the relative risk
of experiencing vertebral fractures by 59% (RR,
0.41; 95% CI, 0.22-0.75; P=0.002) and nonvertebral fractures by 41% (RR, 0.59; 95% CI, 0.37-0.95;
P=0.027) in the elderly patients.11 Over 3 years, Protelos reduced the risk of vertebral fracture by 32%
(RR, 0.68; 95% CI, 0.50-0.92; P=0.013) and nonvertebral fracture by 31% (RR, 0.69; 95% CI, 0.520.92; P=0.011).11 The efficacy of Protelos is sustained
over 5 years, with a decrease of 31% in the risk of
vertebral fractures (RR, 0.69; 95% CI, 0.52-0.92;
P=0.010) and 26% in the risk of nonvertebral fractures (RR, 0.74; 95% CI, 0.57-0.95; P=0.019) compared with placebo (Figure 5).12
Protelos is the first antiosteoporotic treatment
with demonstrated early and sustained reduction
of vertebral and nonvertebral fractures in patients
aged 80 years. Protection against fractures occurred
within 12 months, and the benefit was sustained
throughout the 5 years of treatment. However, to
provide maximal benefit in the generation of new
bone of good quality with subsequent benefits in
terms of protection against osteoporotic fractures,
women should be treated right from the onset of
the menopause, ie, when osteoporosis starts setting in.
8
6
4
2
0
1
2
3
8
6
4
2
0
6
Years
7
8
Years
* First new fractures over the period
Figure 3. The efficacy of Protelos is sustained over 8 years on (A) vertebral and (B)
nonvertebral fractures, as demonstrated by the similar incidence of fractures over
the first and last 3 years of follow-up. Based on data from reference 7.
30
Protelos: efficient whatever the age
25
Osteoporosis is a chronic disease occurring consequent to menopause in patients as young as 50 years
of age. The first 10 years after the menopause are
known to be a phase of rapid bone loss due to the
dramatic increase in bone turnover that occurs following the decrease in estrogens. In postmenopausal
women aged between 50 and 65 years, Protelos reduced the risk of experiencing a vertebral fracture
over 3 years by 47% (RR, 0.53; 95% CI, 0.33-0.85;
P=0.006).8 This effect was sustained over 4 years,
with a significant relative risk reduction for vertebral fracture of 40% (RR, 0.60; 95% CI, 0.39-0.92;
P=0.017).9
376 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Fracture incidence (%)
sion was 11.9% compared with 9.6% over the first
3 years (Figure 3). In summary, the incidence of
vertebral and nonvertebral fractures in patients
treated with Protelos was similar over the first 3
years and the 3-year extension period, confirming
that efficacy was sustained over the very long term.
The efficacy of Protelos was directly related to a benefit on BMD over the 8 years.7
These results are unique data confirming a sustained efficacy of Protelos over time on both vertebral and nonvertebral fractures, directly linked with
a constant benefit on BMD.
20
RR: --37%
RR: --32%
RR: --42%
*
**
15
***
Placebo
Strontium
ranelate
*P <0.05
**P <0.01
***P <0.001
10
5
0
<70 years
70-80 years
>80 years
Age
Figure 4. Protelos decreases the risk of vertebral fractures over 3 years whatever
the patient’s age. Based on data from reference 10.
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
PROTELOS
Fracture incidence (%)
40
RR: --31%
Placebo
Strontium ranelate
*P <0.05
**P <0.01
RR: --26%
RR: --32%
30
**
*
RR: --31%
*
20
*
RR: --59%
RR: --41%
10
*
**
0
1
3
5
Vertebral fractures
1
3
5
Nonvertebral fractures
Treatment
period (years)
Figure 5. Protelos reduces the risk of vertebral and nonvertebral fractures, right from year 1 and over 5 years in elderly
patients. RR, relative risk.
Adapted from reference 11: Seeman E, Vellas B, Benhamou C, et al. Strontium ranelate reduces the risk of vertebral and nonvertebral fractures in
women eighty years of age and older. J Bone Miner Res. 2006;21:1113-1120. Copyright © 2006, The American Society for Bone and Mineral Research.
Also based on data from reference 12.
Protelos: efficient
whatever the risk factors
Osteoporosis is currently defined according to BMD
level, which is, however, not totally predictive of the
risk of experiencing an osteoporotic fracture. Indeed, other risk factors such as a low body mass index, smoking addiction, and family history of osteoporotic fractures, have been identified as increasing
the risk of fractures when combined with each other or with a low BMD. For clinicians, the only way
to accurately predict the risk of fracture in osteoporotic women according to all of these risk factors
is to use a special algorithm based on epidemiological data (FRAX TM).5
In daily practice, as the level of these risk factors
is different in each postmenopausal woman, it is
essential for clinicians to use a treatment having
demonstrated global efficacy independent of the
level of these risk factors. This approach was anticipated in the development of Protelos, as right from
2006, the results of a post-hoc study were published
assessing the efficacy of Protelos according to the
main determinants of vertebral fracture risk, ie,
BMD, prevalent fractures, family history of osteoporosis, body mass index, and addiction to smoking.10
Bone mineral density
The efficacy of Protelos is independent of the BMD
level at baseline. In osteopenic women (hip T-score
and lumbar spine T-score between --1 and --2.5 SD),
Protelos decreases the risk of vertebral fracture by
72% (RR, 0.28; 95% CI, 0.07-0.99; P=0.045). In osteoporotic women (hip T-score or lumbar spine Tscore --2.5 SD), this risk was decreased by 39%
(RR, 0.61; 95% CI, 0.53-0.70; P<0.001) with Protelos over 3 years.10
Prevalent fractures
Protelos has been shown to be efficient independent
of the number of prevalent vertebral fractures at
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
baseline. The risk of experiencing a vertebral fracture was thus reduced by 48% in patients without
prevalent fracture (RR, 0.52; 95% CI, 0.40-0.67;
P<0.001), by 45% in patients with one prevalent
fracture (RR, 0.55; 95% CI, 0.41-0.74; P<0.001), and
by 33% in patients with two and more prevalent
fractures (RR, 0.67; 95% CI, 0.55-0.81; P<0.001).10
Prevalent vertebral fractures in postmenopausal
women with osteopenia are highly predictive of
subsequent vertebral and nonvertebral fractures.
Protelos decreases the risk of vertebral fracture by
59% in osteopenic women with no prevalent fractures (RR, 0.41; 95% CI, 0.17-0.99; P=0.039) and
by 38% in osteopenic women with prevalent fractures (RR, 0.62; 95% CI, 0.44-0.88; P=0.008).13
Turnover
The depletion in estrogens occurring after the
menopause leads to an increase in bone remodeling whereby both bone formation and bone resorption are increased, with a net balance in favor of
bone resorption. Although the level of bone formation and bone resorption can now easily be determined by the assessment of the level of several bone
markers, there is no well-established relationship
between the level of bone remodeling and the increase in fracture risk. Hence, from a pragmatic
point of view, it is essential for clinicians to demonstrate that the efficacy of an antiosteoporotic treatment in reducing fracture risk is independent of
the level of bone turnover, and is therefore adapted
to treat all patient profiles.
The relationship between the efficacy of Protelos
in reducing fracture risk and the bone marker levels
before treatment was thus analyzed in the pooled
population from SOTI and TROPOS. The levels of
bone markers at baseline were stratified into quartiles for both bone-specific alkaline phosphatase
(bALP) and serum type I collagen C-telopeptide
crosslinks (sCTX). For bALP, Protelos significantly
and equally reduced the risk of vertebral fractures
MEDICOGRAPHIA, VOL 30, No. 4, 2008 377
PROTELOS
The benefits of Protelos on BMD have been
demonstrated on the lumbar spine, the femoral
neck, and the total hip over 3, 5, and 8 years in
SOTI and TROPOS. Over 3 years, Protelos increases BMD at the femoral neck by 8.2% (P<0.001),3
at the total hip by 9.8% (P<0.001),3 and at the lumbar spine by 14.4% (P<0.001).2 This efficacy was
sustained in the long term, as Protelos increased
BMD at the femoral neck by 11.3% (P<0.001), at
the total hip by 14.1% (P<0.001), and at the lumbar
spine by 20.2% (P<0.001) over 5 years.6 The benefit of Protelos on BMD was still significant over 8
years (P<0.001).7
The relationship between the BMD improvement
and the efficacy of Protelos in decreasing the vertebral and hip fracture risk has been established by
analyzing data from SOTI and TROPOS.
After 3 years of treatment with Protelos, each percentage point increase in femoral neck and total
proximal femur BMD was correlated with a 3% (95%
CI, 1%-5%) and 2% (95% CI, 1%-4%) reduction in
the risk of a new vertebral fracture, respectively. The
3-year changes in femoral neck and total proximal
femur BMD explained 76% and 74%, respectively,
of the reduction in vertebral fractures observed during the treatment. An increase in femoral neck BMD
after 1 year is predictive of the reduction in the incidence of new vertebral fractures observed after
3 years (P=0.04) (Figure 6).15 Interestingly, Protelos
decreased the risk of experiencing a hip fracture
after 3 years by 7% for each 1% increase in BMD at
the femoral neck (95% CI, 1-14; P=0.04).16
In summary, Protelos has a rapid and sustained
positive effect on vertebral and hip BMD that is both
predictive of and correlated with a decrease in fracture risk, thus providing an efficient tool for clinicians to monitor both the compliance of patients
and the efficacy of the treatment.
from the lowest quartile of bALP (bALP <9.3 ng/mL)
up to the highest quartile (bALP 14.5 ng/mL). For
sCTX, Protelos also significantly and equally reduced the risk of vertebral fractures from the lowest quartile (sCTX <2931 pmol/L) up to the highest
quartile (sCTX 5338 pmol/L). The efficacy of Protelos in decreasing the risk of vertebral fracture is
thus independent of the level of bone turnover at
the initiation of the treatment.14
Other risk factors
The efficacy of Protelos in decreasing the risk of
fracture is also independent of family history of osteoporosis, bone mass index, and addiction to smoking, which are other important risk factors.10
Protelos improves the two
main components of bone strength
The ability of the skeleton to resist strains is governed by two parameters: BMD, which roughly reflects the quantity of material, and the bone quality,
a general term that includes the bone microarchitecture, the intrinsic properties of the bone, and the
geometry of the bone (shape, dimension).
Decrease
in
fracture
risk
Risk of new vertebral fractures
Increase in BMD
0.20
0.15
0.10
Protelos
0.05
–15
–10
–5
0
5
10
15
20
Percentage of femoral
neck BMD changes after 3 years
Figure 6. The increase in bone mineral density (BMD) is highly predictive of
the efficacy of Protelos in decreasing the risk of vertebral fractures.
After reference 15: Bruyere O, Roux C, Detilleux J, et al. Relationship between bone mineral
density changes and fracture risk reduction in patients treated with strontium ranelate. J
Clin Endocrinol Metab. 2007;92:3076-3081. Copyright © 2007, The Endocrine Society.
Protelos increases bone mineral density
Bone loss occurs early in the life of women, and is
accelerated when the depletion in estrogens occurs
after menopause. Osteoporosis is currently defined
as a profound defect in bone mass, leading to a decrease in the ability of bone to resist strains and
consequently, an increase in fracture risk. A low
BMD in postmenopausal women is highly predictive of the experience of subsequent osteoporotic
fractures. Hence, the capability of an antiosteoporotic treatment to increase BMD reflects a direct and
beneficial effect on what remains the main determinant of the risk of fracture. Additionally, a close relationship between any benefits on BMD and decreases in fracture risk is a good tool for monitoring
the efficacy of the treatment in daily practice, which
could be helpful to motivate patients and increase
compliance.
378 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Protelos improves bone quality
More than half of osteoporotic fractures occur in
women with a BMD higher than --2.5 SD, ie, those
not considered as osteoporotic according to the definition from the World Health Organization. This
observation illustrates the importance of bone quality for bone strength, and the fact that any impairment of the bone quality can increase the risk of
fractures, independently of BMD. To provide the
maximal protection against fractures, an ideal antiosteoporotic treatment would thus first have to generate new bone, and second, improve bone quality.
Histomorphometric and micro–computed tomography analyses of biopsies from patients treated with Protelos over 3 years revealed an obvious
improvement in the bone microarchitecture. The
benefits of Protelos on bone microarchitecture were
both on cortical bone (+18% cortical thickness;
P=0.008) and on trabecular bone (+14% trabecular number; P=0.05; --16% trabecular separation;
P=0.004). Protelos also improved the structural
model index in favor of a stronger model based on
plates. The benefits of Protelos on bone microarchitecture resulted from an increase in osteoblast
activity, as reflected by an increase in the mineral
apposition rate (+9%; P=0.019) and in the osteo-
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
PROTELOS
95% CI, 0.47-0.83; P<0.001).2 In the patients aged
more than 80 years, Protelos also decreases the clinical fracture risk by 37% after 1 year (RR, 0.63; 95%
CI, 0.44-0.91; P=0.012), and by 22% over 3 years
(RR, 0.78; 95% CI, 0.61-0.99; P=0.040).
In parallel, Protelos increases the number of osteoporotic women free of back pain by 31% over
the first year of treatment (P=0.023), and by 30%
over 3 years (P=0.005).19 It has also been shown that
Protelos decreased the number of patients experiencing a loss of body height of at least 1 cm by 20%
over 3 years (P=0.003),2 and by 10% over 5 years
(P=0.003)6 in comparison with placebo (Figure 9).
Finally, the effect of Protelos on quality of life was
assessed using two questionnaires during phase III
development: a generic questionnaire SF36, and
QUALIOST®.20 QUALIOST® is a specific questionnaire for vertebral osteoporosis containing 23 items
assessing aspects of patients’ physical and emotional well-being, which gives an overall global score
on quality of life.21 After 3 years of treatment, a significant beneficial effect on health-related quality
of life was demonstrated in patients treated with
Protelos (global score P=0.016; emotional score
P=0.019; physical score P=0.032).19 The close rela-
Figure 7. Protelos improves bone microarchitecture at the cortical and
trabecular sites in postmenopausal women with osteoporosis.
Adapted from reference 17: Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric
and muCT analysis of bone biopsies from postmenopausal osteoporotic women treated
with strontium ranelate. J Bone Miner Res. 2008;23:215-222. Copyright © 2008, The
American Society for Bone and Mineral Research.
Superior efficacy
for better quality of life
A big challenge in the treatment of a chronic and
silent disease such as osteoporosis is to motivate
patients enough to adhere to their treatment. Obvious benefits to health, readily perceptible to the
patients, will have a good impact on their adherence, thereby maximizing the efficacy of the treatment and the prevention of fractures.
Clinical vertebral fractures are defined as a vertebral fracture associated with back pain and/or at
least 1 cm loss in body height. SOTI demonstrated
that Protelos reduces the number of patients experiencing a new clinical vertebral fracture by 52% as
early as over the first year (RR, 0.48; 95% CI, 0.290.80; P=0.003), and by 38% over 3 years (RR, 0.62;
Bone volume
Trabecular thickness
+30%
*P<0.05
*P<0.05
11
*
10
9
8
7
+10%
100
Tb.Th (μm)
Bone volume (%)
12
Before
treatment
96
92
88
84
After
treatment
*
Before
treatment
After
treatment
Figure 8. Protelos relaunches bone formation, even in patients in whom bone
turnover was strongly downregulated after long-term treatment with bisphosphonates. Tb.Th, trabecular thickness. Based on data from reference 18.
16
Patients free of back pain (%)
blast surface (+38%; P=0.047) (Figure 7).17 In addition, recent data have demonstrated that Protelos
improves bone microarchitecture in osteoporotic
patients with a suppressed bone turnover. Histomorphometric assessment of 10 paired bone biopsies of patients previously treated long term with
bisphosphonates, known to markedly decrease bone
turnover, showed that Protelos restarts bone formation. After 1 year of treatment, Protelos significantly increases bone volume by 30%, increases trabecular thickness by 10%, and improves trabecular
interconnection by --48%. These data show that
even if the bone turnover has been suppressed by
previous antiresorptive treatments, Protelos significantly improves bone microarchitecture, confirming that its efficacy is independent of bone turnover
(Figure 8).18
In summary, Protelos generates new bone and
improves microarchitecture at the cortical and trabecular sites. The improvement of the two main
components of bone strength illustrates the benefits of Protelos on bone status and ensures an optimal prevention of osteoporotic fractures in postmenopausal women.
14
RR: +31%
RR: +30%
**
RR: +28%
**
*
Placebo
Protelos
12
10
*P < 0.05
**P < 0.01
8
6
4
2
0
0-1 year
0-3 years
0-4 years
Figure 9. Protelos has direct benefits on back pain in the long term.
RR, relative risk.
Adapted from reference 19: Marquis P, Roux C, de la Loge C, et al. Strontium ranelate prevents
quality of life impairment in post-menopausal women with established vertebral osteoporosis.
Osteoporos Int. 2008;19:503-510. Copyright © 2008, Springer London. Also based on data from
reference 20.
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
MEDICOGRAPHIA, VOL 30, No. 4, 2008 379
PROTELOS
tionship between the increase in BMD with Protelos
and its efficacy in preventing osteoporotic fractures
is an additional asset for clinicians on one hand,
who can easily monitor the compliance of their patients and the efficacy of the treatment, and for the
patients on the other hand, who have an easily interpretable benefit regarding their bone status. From
a pragmatic point of view, the increase in BMD with
Protelos can motivate patients and increase their
compliance, which is one of the keys to the success
in the treatment of osteoporosis.
causative link has not been firmly established, as
the patients were polymedicated when DRESS was
diagnosed. However, it is recommended that strontium ranelate and other concomitant treatments
be stopped in the case of a rash occurring within
2 months from treatment initiation, and that adapted treatment and follow-up be initiated to avoid
systemic symptoms.
The benefits of Protelos in terms of health-related
quality of life of osteoporotic women, the relationship between BMD and the prevention of fracture,
and the good safety profile of Protelos are all strong
arguments that contribute to increasing compliance, and thereby to the efficacy of the treatment.
The superior efficacy of Protelos
is supported by a unique
mechanism of action
Figure 10. The unique mechanism of action of Protelos. Protelos increases
bone formation through an increase in osteoblast replication, differentiation, and activity. In parallel, Protelos decreases bone resorption via a
decrease in osteoclast differentiation and activity and the upregulation of
the osteoprotegerin/receptor activator of nuclear factor–kappa B ligand
(OPG/RANKL) ratio in osteoblasts. CaSR, calcium-sensing receptor.
Another advantage of Protelos is its mode of administration, which is easy and convenient with one
daily 2-g sachet diluted in water, to be taken at bedtime. As Protelos is very well tolerated at the upper gastrointestinal level, patients do not have to
follow any special requirements (unlike with the
bisphosphonates), which is a clear benefit for longterm use.
As a consequence of all these benefits, the compliance in the phase III program was high, ranging
between 80% and 83%, depending on the studies.2,3,6 Protelos was very well tolerated, not only in
the overall population but also in the elderly women included in SOTI and TROPOS.11 Over 5 years,
the safety profile of Protelos was similar to that observed over 3 years. Compared with placebo, the
following occurred more often in the Protelos group:
nausea (7.8% vs 4.8%), diarrhea (7.2% vs 5.4%),
headache (3.6% vs 2.7%), dermatitis (2.3% vs 2.0%)
and eczema (2.0% vs 1.5%).6 These effects were generally mild and transient. There was no difference
in the incidence of venous thromboembolic events
with Protelos compared with placebo (2.7% vs 2.1%;
odds ratio 1.30) over 5 years.6 Recently, postmarketing surveillance has identified several cases of
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome in patients treated with
strontium ranelate. The very low incidence (<20
cases for 570 000 patient-years of exposure) is in the
vicinity of what has been previously reported with
most of the other antiosteoporosis treatments. A
380 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Protelos has a unique mechanism of action, which
has been acknowledged worldwide, with the definition of a new therapeutic class in the Anatomical
Therapeutic Chemical (ATC) nomenclature for Protelos. Indeed, Protelos is the only antiosteoporotic treatment that simultaneously increases bone
formation and decreases bone resorption, thus rebalancing the bone turnover in favor of formation.
For several years, experimental studies have provided robust evidence demonstrating the dual mechanism of action of Protelos, which has been reviewed
elsewhere (Figure 10).22
Improvement of bone quality, improvement of
bone strength
The benefits of Protelos on bone remodeling have
notably been well demonstrated in osteopenic animals, a model mimicking the depletion in estrogens
occurring after the menopause.23 After short-term
(3 months) treatment, Protelos prevented trabecular bone loss in ovariectomized (OVX) rats, as
demonstrated by histomorphometric analysis in
the tibia metaphysis. This effect results from an increased osteoblast surface coupled with a decreased
osteoclast surface.23 The beneficial effects of Protelos on bone mass and microarchitecture in OVX rats
has been confirmed after 1 year of treatment.24 These
results clearly demonstrate that Protelos, by increasing bone formation and reducing bone resorption, improves bone microarchitecture with
subsequent benefits on bone strength in osteopenic
animals.
The benefits of Protelos on bone strength lead to
the prevention of osteoporotic fractures, as recently demonstrated in a unique model of mice experiencing spontaneous fractures. These transgenic
mice overexpressed Cbfa/Runx2 (Cbfa1), leading to
an increase in bone resorption. The severe osteoporosis occurring in these mice induces an increase
in bone fragility and the occurrence of spontaneous
fractures. After treatment for 9 weeks, Protelos decreased the number of new fractures by 60% in
comparison with controls. The prevention of spontaneous fractures was related to a net improvement
in the bone microarchitecture at both the trabecular and cortical sites (Figure 11).25 In addition to its
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
PROTELOS
properties on the bone microarchitecture, Protelos
improves the intrinsic properties of bone, as shown
after long-term treatment in rats.26 Long-term studies in monkeys and rodents have demonstrated that
the mineralization process and the degree of mineralization are normal with Protelos.27-30 In osteoporotic women treated with Protelos for up to 5
years, the analysis of bone biopsies showed no abnormalities in the bone structure nor in the mineralization process, thus supporting the very good
bone safety of this agent after long-term treatment.17
In summary, Protelos generates new bone and improves the bone microarchitecture with subsequent
benefits on bone strength, while having a good bone
safety profile.
Figure 11. Protelos improves bone mass and microarchitecture, thereby
preventing the occurrence of spontaneous fractures in a mouse model.
Based on data from reference 25.
Protelos: a unique treatment with a dual
mechanism of action
The dual mechanism of action of Protelos is due to
direct effects on both osteoblasts and osteoclasts.
Several independent studies in various models have
demonstrated that Protelos increases osteoblast replication, differentiation, and activity,31-33 while in
parallel, it downregulates osteoclast differentiation
and activity.34-36 A recent study has shown that Protelos increases the expression of bALP (osteoblast
differentiation) and the number of bone nodules
(osteoblast activity) of murine osteoblasts. In parallel, Protelos decreases tartrate-resistant acid phosphatase activity (osteoclast differentiation) and the
ability of murine osteoclasts to resorb (osteoclast
activity), probably by acting on the cytoskeleton of
these cells.37
In addition to these direct effects on osteoblasts
and osteoclasts, Protelos modulates the level of two
major factors strongly involved in the regulation of
osteoclastogenesis by osteoblasts. Osteoprotegerin
(OPG) and the receptor activator of nuclear factor–kappa B ligand (RANKL) are both expressed by
osteoblasts. The OPG/RANKL ratio governs osteoclastogenesis, with a low ratio promoting osteoclastogenesis and a high ratio downregulating it.
In human osteoblasts, Protelos was shown to increase mRNA expression of OPG, while it simultaneously decreased mRNA expression of RANKL. The
OPG/RANKL ratio in favor of OPG is highly predic-
Abbreviations: BV/TV, bone volume; C.Th, cortical thickness; Tb.N, trabecular number;
Tb.Sp, trabecular separation; Tb.Th, trabecular thickness; TG, transgenic mice; WT, wildtype mice.
tive of a subsequent downregulation of osteoclastogenesis by Protelos (Figure 12).38 In the same study,
Protelos increased the replication and the differentiation of human osteoblasts, parameters highly
predictive of subsequent positive effects on bone
formation. Overall, the results of this study were the
first demonstration that Protelos can modulate both
bone formation and bone resorption through a direct action on human osteoblasts, suggesting that
the osteoblast is a key player in the mechanism of
action of Protelos.
New clues to the receptor and signaling pathways
involved in the mechanism of action of Protelos
have recently come to light. Two independent studies have shown that Protelos is an agonist of the calcium-sensing receptor (CaSR),39,40 a receptor strongly involved in bone metabolism. In osteoblasts, the
activation of the CaSR is involved in the positive
effects of Protelos on osteoblast replication39 and the
increase in OPG expression.38 Likewise, the increase
in osteoclast apoptosis induced by Protelos is transduced by the CaSR expressed at the osteoclast surface.41 The CaSR thus plays an important role in the
mechanism of action of both osteoblasts and osteoclasts. Moreover, other mechanisms could also be
PRIMARY HUMAN OSTEOBLASTS
RANKL
OPG mRNA as % of control
***
200
***
**
150
100
50
0
Control 0.01
0.1
1
2
RANKL mRNA as % of control
Osteoprotegerin
250
120
100
80
60
***
40
**
***
***
20
0
Control 0.01
(mM Sr 2+)
0.1
1
2
(mM Sr 2+)
**P <0.01, ***P <0.001 vs control
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
Figure 12. Protelos
increases osteoprotegerin (OPG)
expression while
downregulating the
expression of receptor activator of nuclear factor–kappa B
ligand (RANKL),
which is predictive
of a subsequent
effect on osteoclastogenesis. Protelos
concentrations are
expressed in mMol of
strontium (mM Sr2+).
Based on data from
reference 38.
MEDICOGRAPHIA, VOL 30, No. 4, 2008 381
PROTELOS
1.2
E
***
***
**
bALP
(ng/mL)
*
0.8
*
0.4
SOTI
***P < 0.001; **P <0.01; *P <0.05
0
3 years.2,43 In addition, the analysis of bone biopsies
showed a significant increase in the osteoblast surface (+38% in cancellous and endocortical bone;
P=0.047) and a trend toward decreasing the osteoclast surface by 10% (Figure 13).17 These observations demonstrate the dual mechanism of action
of Protelos in postmenopausal women with osteoporosis, which, by increasing bone formation and
decreasing bone resorption, leads to subsequent
benefits by improving bone strength and decreasing fracture risk.
SCTX
(pmol/L)
–300
***
***
–600
*
**
***
0
M3
M6
M12
M24
M36
Months
Figure 13. In the Spinal Osteoporosis Therapeutic Intervention (SOTI) study, the analysis of bone markers confirmed the mechanism of action of Protelos, which increases
bone formation (bone alkaline phosphatase [bALP]) while decreasing bone resorption
(serum C-terminal crosslinked telopeptide of type I collagen [sCTX]). Similar results
were observed in TRreatment Of Peripheral Osteoporosis Study (TROPOS). E, estimate
of difference between Protelos and placebo groups, covariance analysis, baseline adjusted.
Adapted from reference 2: Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on
the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:
459-468. Copyright © 2004, Massachusetts Medical Society.
stimulated by Protelos in parallel with CaSR activation, which could account for the broad range of effects of Protelos in osteoblasts and osteoclasts.42
The dual mechanism of action of Protelos has
been demonstrated in phase III clinical trials
through the follow-up of the bone markers reflecting the level of bone remodeling. In both SOTI
and TROPOS, bALP—a marker of bone formation — increased in women treated with Protelos,
while sCTX — a marker of bone resorption — decreased. These effects were observed as soon as after
3 months of treatment (+8.1% for bALP; P<0.001;
--12.2% for sCTX; P<0.001) and were sustained over
REFERENCES
1. Reginster J, Diez-Perez A, Ortolani S, et al. Calcium-vitamin D supplementation in clinical trials of
osteoporosis should be titrated on the basis of prestudy assessments. Osteoporos Int. 2002;S1:S24. P69.
Abstract.
2. Meunier PJ, Roux C, Seeman E, et al. The effects of
strontium ranelate on the risk of vertebral fracture in
women with postmenopausal osteoporosis. N Engl J
Med. 2004;350:459-468.
3. Reginster JY, Seeman E, de Vernejoul MC, et al.
Strontium ranelate reduces the risk of nonvertebral
fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS)
study. J Clin Endocrinol Metab. 2005;90:2816-2822.
4. Protelos Summary of Product Characteristics. London, UK: EMEA; September 2004.
5. Kanis JA, Burlet N, Cooper C, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2008;
19:399-428.
6. Reginster J, Felsenberg D, Boonen S, et al. Effects
of long-term strontium ranelate treatment on the risk
of non-vertebral and vertebral fractures in postmenopausal osteoporosis: results of a 5-year, randomized,
placebo-controlled trial. Arthritis Rheumat. 2008;58:
1687-1695.
7. Reginster J, Sawicki A, Roces A, et al. Strontium
ranelate: 8 years efficacy on vertebral and nonverte-
382 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Conclusion
Protelos is the major innovation in the treatment
of osteoporosis. The unique mechanism of action of
Protelos has been demonstrated in nonclinical and
phase III clinical studies, rebalancing bone turnover
in favor of formation by both increasing bone formation and reducing bone resorption. By forming
new and strong bone, Protelos improves BMD and
bone quality, the two main components of bone
strength, thereby accounting for its superior efficacy in preventing osteoporotic fractures. Protelos is
the only treatment with proven efficacy in reducing
the risk of vertebral, nonvertebral, and hip fractures
in postmenopausal women with osteoporosis, whatever the age, the risk factors, and the severity of the
disease. This evidence supports the superior efficacy of Protelos, which has recently been acknowledged in the European guidance for the diagnosis
and management of osteoporosis in postmenopausal women, published in 2008, as the only treatment having provided total proof of efficacy in osteoporosis with and without prevalent fractures.
Protelos is a first-line treatment for postmenopausal osteoporosis with a quick and sustained efficacy, a very good safety profile, and which improves
quality of life. It is thus the ideal treatment for postmenopausal osteoporosis, from the youngest to the
oldest patients. bral fractures in post menopausal osteoporotic women. Osteoporos Int. 2008;P311. Abstract ECCEO 2008.
8. Devogelaer JP, Roux C, Isaia G, et al. Strontium
ranelate reduces the risk of vertebral fracture in young
postmenopausal women with severe osteoporosis.
J Bone Miner Res. 2007;22:S335. T412. Abstract.
9. Devogelaer J, Fechtenbaum J, Kolta S, et al. Strontium ranelate demonstrates efficacy over 3 and 4 years
against vertebral fracture in young postmenopausal
women (50-65 years) with severe osteoporosis. Osteoporos Int. 2008;19:S14-S15.
10. Roux C, Reginster JY, Fechtenbaum J, et al. Vertebral fracture risk reduction with strontium ranelate
in women with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res.
2006;21:536-542.
11. Seeman E, Vellas B, Benhamou C, et al. Strontium
ranelate reduces the risk of vertebral and nonvertebral fractures in women eighty years of age and older.
J Bone Miner Res. 2006;21:1113-1120.
12. Seeman E, Vellas B, Benhamou CL, et al. Sustained
5-year vertebral and non-vertebral fracture risk reduction with strontium ranelate in elderly women with
osteoporosis. Osteoporos Int. 2006;18. OC39. Abstract.
13. Seeman E, Devogelaer JP, Lorenc R, et al. Strontium ranelate reduces the risk of vertebral fractures
in patients with osteopenia. J Bone Miner Res. 2008;
23:433-438.
14. Collette J, Reginster JY, Bruyère O, et al. Strontium ranelate decreases vertebral fracture risk whatever the level of pretreatment bone turnover markers.
Osteoporos Int. 2007;18:S127-S128. P305. Abstract.
15. Bruyere O, Roux C, Detilleux J, et al. Relationship
between bone mineral density changes and fracture
risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab. 2007;92:3076-3081.
16. Bruyere O, Roux C, Badurski J, et al. Relationship
between change in femoral neck bone mineral density and hip fracture incidence during treatment with
strontium ranelate. Curr Med Res Opin.2007;23:30413045.
17. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and muCT analysis of bone biopsies from
postmenopausal osteoporotic women treated with
strontium ranelate. J Bone Miner Res.2008;23:215-222.
18. Busse B, Priemel M, Jobke B, et al. Effects of strontium ranelate therapy after long term bisphosphonate
treatment. Histomorphometric and μXRF/EDX analysis of paired iliac crest bone biopsies in 15 patients.
J Bone Miner Res.2007;22:S484-S485. W477. Abstract.
19. Marquis P, Roux C, de la Loge C, et al. Strontium ranelate prevents quality of life impairment in
post-menopausal women with established vertebral
osteoporosis. Osteoporos Int. 2008;19:503-510.
20. Marquis P, Roux C, Diaz-Curiel M, et al. Longterm beneficial effects of strontium ranelate on the
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
PROTELOS
quality of life in patients with vertebral osteoporosis
(SOTI study). Calcif Tissue Int.2007;80(suppl 1):S137S138(Abstract P377-T).
21. De La Loge C, Sullivan K, Pinkney R, et al. Crosscultural validation and analysis of responsiveness of
the QUALIOST: QUAlity of Life questionnaire In OSTeoporosis. Health Qual Life Outcomes. 2005;3:69.
22. Marie PJ, Ammann P, Boivin G, et al. Mechanisms
of action and therapeutic potential of strontium in
bone. Calcif Tissue Int. 2001;69:121-129.
23. Marie PJ, Hott M, Modrowski D, et al. An uncoupling agent containing strontium prevents bone loss
by depressing bone resorption and maintaining bone
formation in estrogen-deficient rats. J Bone Miner
Res.1993;8:607-615.
24. Bain S, Shen V, Zheng H, et al. Strontium ranelate
treatment prevents ovariectiomy induced bone loss in
rats by maintaining the bone formation at a high level. Calcif Tissue Int. 2004;74:S93-S94. P189. Abstract.
25. Geoffroy V, Marty C, Lalande A, et al. Strontium
ranelate reduces new vertebral fractures in a severe osteoporotic mice model with spontaneous fractures
by improving bone microarchitecture. Calcif Tissue
Int. 2006;78:S38. P003. Abstract.
26. Ammann P, Badoud I, Barraud S, et al. Strontium
ranelate treatment improves trabecular and cortical
intrinsic bone tissue quality, a determinant of bone
strength. J Bone Miner Res. 2007;22:1419-1425.
27. Farlay D, Boivin G, Panczer G, et al. Long-term
strontium ranelate administration in monkeys preserves characteristics of bone mineral crystals and
degree of mineralization of bone. J Bone Miner Res.
2005;20:1569-1578.
28. Boivin G, Deloffre P, Perrat B, et al. Strontium
distribution and interactions with bone mineral in
monkey iliac bone after strontium salt (S 12911) administration. J Bone Miner Res. 1996;11:1302-1311.
29. Ammann P, Shen V, Robin B, et al. Strontium
ranelate improves bone resistance by increasing bone
mass and improving architecture in intact female rats.
J Bone Miner Res. 2004;19:2012-2020.
30. Delannoy P, Bazot D, Marie PJ. Long-term treatment with strontium ranelate increases vertebral bone
mass without deleterious effect in mice. Metabolism.
2002;51:906-911.
31. Canalis E, Hott M, Deloffre P, et al. The divalent
strontium salt S12911 enhances bone cell replication
and bone formation in vitro. Bone.1996;18:517-523.
32. Choudhary S, Halbout P, Alander C, et al. Strontium ranelate promotes osteoblastic differentiation
and mineralization of murine bone marrow stromal
cells: involvement of prostaglandins. J Bone Miner
Res. 2007;22:1002-1010.
33. Zhu LL, Zaidi S, Peng Y, et al. Induction of a program gene expression during osteoblast differentiation with strontium ranelate. Biochem Biophys Res
Commun. 2007;355:307-311.
34. Baron R, Tsouderos Y. In vitro effects of S12911-2
on osteoclast function and bone marrow macrophage
differentiation. Eur J Pharmacol. 2002;450:11-17.
35. Takahashi N, Sasaki T, Tsouderos Y, et al. S 12911-2
inhibits osteoclastic bone resorption in vitro. J Bone
Miner Res. 2003;18:1082-1087.
36. Wattel A, Hurtel Lemaire A, Godin C, et al. Stron-
tium ranelate decreases in vitro human osteoclastic
differentiation. Bone. 2005;36:S400-S401. P585. Abstract.
37. Bonnelye E, Chabadel A, Saltel F, et al. Dual effect
of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and
resorption in vitro. Bone. 2008;42:129-138.
38. Brennan TC, Rybchin MS, Halbout P, et al. Strontium ranelate effects in human osteoblasts support
its uncoupling effect on bone formation and bone
resorption. J Bone Miner Res. 2007;22:S139. M014.
Abstract.
39. Chattopadhyay N, Quinn SJ, Kifor O, et al. The
calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation. Biochem Pharmacol. 2007;74:438-447.
40. Coulombe J, Faure H, Robin B, et al. In vitro effects of strontium ranelate on the extracellular calcium-sensing receptor. Biochem Biophys Res Commun.
2004;323:1184-1190.
41. Mentaverri R, Chattopadhyay N, Lemaire-Hurtel
AS, et al. The effects of strontium ranelate on osteoclasts are calcium-sensing receptor dependant. J Bone
Miner Res. 2005;(suppl):S309. SU511. Abstract.
42. Caverzasio J. Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. Bone. 2008;42:1131-1136.
43. Reginster JY, Collette J, Bruyere O, et al. Biochemical markers of bone turnover confirm the dual mode
of action of strontium ranelate: increase in bone formation and decrease in bone resorption. Arthritis
Rheum. 2006;54:S590. 1440. Abstract.
PERSPECTIVES
INNOVANTES DANS LE TRAITEMENT DE L’OSTÉOPOROSE POST-MÉNOPAUSIQUE
PAR LE RANÉLATE DE STRONTIUM : PREUVES SCIENTIFIQUES ET BÉNÉFICES CLINIQUES
a déplétion oestrogénique qui survient chez la femme postménopausée augmente le remodelage osseux entraînant
un déséquilibre important en faveur de la résorption, et
consécutivement, une perte osseuse majeure associée à une diminution de la qualité de l’os. Le déficit de ces composants de la
solidité osseuse augmente la fragilité osseuse et donc le risque de
fracture dès l’âge de 50 ans. Les stratégies thérapeutiques classiques sont basées soit sur la diminution de la résorption osseuse
(agents anti-cataboliques principalement représentés par les bisphosphonates) ou sur l’augmentation de la formation osseuse
(agents anaboliques, principalement représentés par les dérivés
de PTH). Ces traitements montrent cependant leurs limites car,
par un effet de couplage, les traitements diminuant la résorption
osseuse diminuent la formation osseuse, et les traitements augmentant la formation osseuse augmentent la résorption osseuse.
Protelos (ranélate de strontium) est un médicament innovant de
l’ostéoporose, découvert et développé par Servier, ayant un double
mécanisme d’action inédit puisqu’il augmente la formation osseuse tout en diminuant la résorption osseuse. Protelos diminue
le risque de fractures vertébrales, non vertébrales et de la hanche
sur 3 ans soutenant ainsi son indication dans le traitement de
l’ostéoporose post-ménopausique. De plus, Protelos est le seul
L
traitement ayant démontré son efficacité sur les fractures vertébrales, non vertébrales et de la hanche après 5 ans. L’efficacité
supérieure de Protelos est indépendante de la sévérité de la maladie évaluée par les niveaux de densité minérale osseuse, les marqueurs osseux ou le nombre de fractures prévalentes. Protelos
prévient les fractures ostéoporotiques tant chez la femme de 50
ans que chez la personne âgée. Cette supériorité d’efficacité s’explique par les bénéfices importants du mécanisme d’action de
Protelos sur l’os, qui à la fois augmente la densité minérale osseuse et améliore la qualité de l’os, avec un impact positif sur la
solidité osseuse. Protelos est bien toléré, a une bonne sécurité
d’emploi, et apporte aux patientes une amélioration de leur état
de santé facilement perceptible, expliquant la bonne observance
retrouvée dans les études de phase III. L’European guidance for
the diagnosis and management of osteoporosis in postmenopausal
women [Conseils pour le diagnostic et le traitement de l’ostéoporose chez la femme], publié récemment, fait état de la supériorité d’efficacité de Protelos, présenté comme le seul traitement
ayant fait la preuve complète de son efficacité sur tous les types
de fracture, quelle que soit la sévérité de la maladie, et faisant
logiquement de Protelos un traitement de première intention de
l’ostéoporose post-ménopausique.
Strontium ranelate as an innovation in postmenopausal osteoporosis treatment – Halbout
MEDICOGRAPHIA, VOL 30, No. 4, 2008 383
I
N T E R V I E W
TREATING OSTEOPOROSIS
ACROSS ITS STAGES
Interview with J. B. Cannata-Andía
and J. B. Díaz-López, Spain
Jorge B. CANNATAANDÍA, MD
José B. DÍAZ-LÓPEZ, MD
Department of Bone and
Mineral Metabolism
Hospital Universitario
Central de Asturias
Universidad de Oviedo
Oviedo, SPAIN
Could you define the different risk
factors for osteoporotic fractures?
irstly, let us clarify what we
should consider as a “risk factor” for osteoporotic fractures: any variable, state, or condition that has been
proven to be associated with a higher
probability of suffering the disease. According to the definition of osteoporosis,
the risks can be related to intrinsic skeletal factors, such as the quantity and quality of bone, but also to other extrinsic
skeletal factors.
Among the intrinsic factors, low bone
mineral density (BMD) has been consistently associated with an increase in bone
fractures.1,2 However, low BMD is not
the only important factor related to bone
F
T
fragility.3 Some risk factors are predictive of low BMD and hence predictive of
bone fractures, but others can be predictive of bone fractures for BMD-independent mechanisms.4 In fact, other risk
factors such as previous bone fractures
have been shown to have a strong predictive value for new fractures independently of BMD.5,6
In clinical practice, risk factors can be
categorized according to their importance into “major risk factors” and “other
risk factors” (Table I). In white women,
in which most studies have been conducted, the sum of several BMD-independent risk factors exponentially increases
the risk of having an osteoporotic bone
SELECTED
ABBREVIATIONS AND ACRONYMS
BMD bone mineral density
DXA dual-energy x-ray absorptiometry
EPOS European Prospective Osteoporosis Study
EVOS European Vertebral Osteoporosis
Study
WHO World Health Organization
he main goal in the treatment of osteoporosis is the prevention of bone fragility fractures. Knowledge of risk factors associated with the disease plays a key role in the
management of this condition: low bone mineral density is an important risk factor, but not the only one. Other risk factors such as
previous bone fracture have a strong independent predictive value for new bone fragility fractures. Several studies have demonstrated that one or more prevalent or incident vertebral fractures
increase the risk of having a new fragility fracture by 2 to 5 times.
Also, a greater mortality risk has been associated with vertebral
and hip fractures. Once the first bone fracture occurs, a true cascade of bone fractures can take place within a couple of years.
Thus, the pharmacological management of osteoporosis with
bone-active drugs is justified in order to reduce morbidity and
mortality. Despite the great amount of evidence relating to the advantages of the early management of osteoporosis, it is still only
a minority of patients diagnosed with a fragility fracture that re-
384 MEDICOGRAPHIA, VOL 30, No. 4, 2008
fracture, and this seems also to be the
case for men and for other races.4-13 The
combination of risk factors can help to
select patients at higher risk of osteoporosis, to determine the prognosis, and
to adequately implement treatment for
the disease.
In clinical practice, it is useful to identify those risk factors with higher predictive value, such as previous fragility
fractures, low BMD, older age, female
sex, and corticosteroid use. As an example, a postmenopausal woman who received long-term treatment with corticosteroids has a high risk of developing
osteoporosis, and she should receive
preventive treatment with bone-active
drugs, in addition to following a healthy
lifestyle and taking general preventive
measures.14,15 The clinical management
must be even stricter and last longer if
a low BMD and previous fragility fractures are concomitantly diagnosed.
The presence of one or more “other
risk factors,” as listed in Table I, such
as family history, low body mass index,
smoking, diabetes, and others, also provides an alert about a high risk of osteo-
ceives adequate pharmacological intervention. Antiosteoporotic
drugs can act efficiently and it is never too late to start the treatment. Antifracture efficacy in vertebral and nonvertebral bone
fractures has been clearly demonstrated by Protelos ® (strontium
ranelate), independently of baseline osteoporotic risk factors. As
a result, Protelos® is considered a first-option drug for the management of osteoporosis across all age groups.
Medicographia. 2008;30:384-387.
(see French abstract on page 387)
Keywords: bone mineral density; fragility fracture; risk factors;
risk prediction; fracture cascade; osteoporosis; strontium
ranelate
www.medicographia.com
Address for correspondence: Jorge B. Cannata-Andía, Head of Bone and Mineral
Metabolism, Full Professor of Medicine, Hospital Universitario Central de Asturias,
Universidad de Oviedo, Oviedo, Spain.
(e-mail: [email protected])
Treating osteoporosis across its stages – Cannata-Andía and Díaz-López
INTERVIEW
porosis16,17 and it justifies more specific
investigations including the measurement of BMD, and conductance of a careful examination for any possible previous
bone fragility fractures.
Could you detail the tools you use to
diagnose patients at risk?
he first and most important
tool to diagnose patients at risk
is a careful collection of the clinical data
of the patient, including a complete
questionnaire about all types of risk factors for osteoporotic fractures. When the
T
of the bone status including a BMD measurement. The gold standard technique
for BMD measurement is dual-energy xray absorptiometry (DXA) performed in
two main regions, the lumbar spine and
the hip. DXA measurement at these two
levels, together with the investigation of
vertebral deformities using a spine x-ray,
have been the techniques most used in
clinical trials and in all type of studies
on osteoporosis. They are also the most
important tools to evaluate the efficacy
of antiosteoporotic drugs.2,18-20
Although the measurement of BMD
using DXA is the most precise technique
Major risk factors
Other risk factors
Advanced agea
Female sex
Hypogonadism and early
menopause
Body mass index <20 kg/m 2 a
Family history of osteoporotic
fracturea
Vertebral fracture or deformitya
Previous fragility fracturea
Systemic glucocorticoid therapy
3 months a
Proneness to fallsa
Smokinga
White or Asian race
Low dietary calcium intake
Excess alcohol or caffeine intake
Low physical activity and daily living
functiona
Primary hyperparathyroidism
Clinical hyperthyroidism
Impaired vision, dementia, depression,
poor health, and being fraila
Malabsorption syndromea
Rheumatoid arthritisa
Diabetes mellitusa
Long-term anticonvulsant therapya
Long-term heparin therapy
High levels of bone turnover markersa
a
Bone mass–independent risk factors.
presence of concurrent risk factors—
mainly major risk factors— is found, a
BMD measurement should be performed.
Performing a BMD screening not on the
basis of the existence of risk factors is
not generally a currently accepted procedure.1,18,19
So far, several scales of risk factors
for osteoporotic fractures have been published, including those mentioned in
Table I.4,5,8,12-14,16-19 Moreover, the World
Health Organization (WHO) has recently
presented preliminary data on a new
scale that could be used in the near future for the diagnosis of osteoporosis.
Due to the fact that a previous fragility
fracture, particularly a vertebral fracture,
has been shown to be a strong risk factor for osteoporosis, the current spine
x-ray examination plays a key role in the
diagnosis and prognosis of osteoporosis.
The presence of vertebral deformities,
clinical vertebral fractures, loss of height,
and other types of bone fracture (pelvis,
humerus, ribs, etc) not associated with
important traumas is always suspicious
and should lead to a more specific study
Table I.
Risk factors
associated
with low
bone mineral
density and
fractures.
for the measurement of bone mass, other techniques used to assess peripheral
bone mass, such as ultrasound or radiogrammetry, may also provide additional
information related to the risk of osteoporotic fractures.21-24 Nevertheless, bone
mass values obtained with techniques
other than DXA cannot be used for the
diagnosis of osteoporosis when using
the WHO diagnostic criteria.25
It is important to stress that a great
number of fragility fractures occur not
only in osteoporotic patients, but also
in osteopenic patients. Independently of
the technique used, the risk of fragility
fracture increases as bone mass decreases.
This pattern is found for all ranges of
bone mass, independently of the diagnosis of osteopenia or osteoporosis.
Even though in the near future we may
have new and easily applicable risk factor scales for osteoporosis, in order to
estimate the absolute risk for osteoporosis in clinical practice, the most appropriate approach is to combine and integrate all general, clinical, radiological,
and BMD information.
Treating osteoporosis across its stages – Cannata-Andía and Díaz-López
Could you describe the fracture cascade
and justify the treatment of osteoporosis
as soon as possible for prevention of
this cascade?
o far, the existence of one or
more fragility fractures has
been widely accepted to be a strong risk
factor for future fragility fractures, even
independently of other major clinical risk
factors such as low BMD values.4,7,13,26,27
In the Oviedo cohort of the European
Union–supported European Vertebral
Osteoporosis Study (EVOS)/European
Prospective Osteoporosis Study (EPOS),
the presence of one prevalent or incident
vertebral fracture increased the possibility of sustaining a new vertebral fracture by 5 times and the risk of having a
Colle’s or hip fracture by 2 to 5 times.28
In agreement with these results, other
clinical trials performed in women have
also shown that one or more prevalent
vertebral fractures in the placebo group
increased by 5 times the risk of having a
new fracture during the first year of follow-up.29 Furthermore, patients who had
an incident vertebral fracture during
the first year showed a 19.2% absolute
risk increase for new fractures.29 A recent
2-year study also showed a 17.3% increase
in the absolute risk of new fractures in
patients who had more than one previous
fragility fracture. This risk decreased to
10.4% in those patients who had only
one previous fragility fracture.30
As several studies have demonstrated,
there is both a greater morbidity and
mortality associated with vertebral and
hip fractures.28,31-33 Thus, it seems reasonable to make every effort to diagnose
early all types of vertebral deformities
(including asymptomatic vertebral fractures); acting rapidly and efficiently may
not only prevent further fractures, but it
may also reduce mortality.
In summary, taking into account all
the previously discussed factors, their
interactions, the vicious circle created
when the first bone fracture occurs, and
the rapid occurrence of new fractures,
starting the pharmacological management of osteoporosis as soon as possible
is justified in order to prevent the fracture cascade.
S
In the case of osteoporosis diagnosed
following a first fracture, could you
comment on the need to still treat this
disease?
ll the experience gathered
through the large clinical trials designed to demonstrate the efficacy
of the main active drugs for osteoporo-
A
MEDICOGRAPHIA, VOL 30, No. 4, 2008 385
INTERVIEW
sis has shown a clear benefit in terms
of the relative risk reduction of vertebral
fractures in patients with or without
prevalent vertebral fractures. In addition,
the risk reduction for bone fractures has
been more marked in patients having at
least one prevalent vertebral fracture.34-41
Most of these trials have been carried
out in women, with fewer studies performed in men; however, the benefits of
active drugs have been shown to be similar in both sexes.42-44
Even though in the clinical trials that
have proved the efficacy of antiosteoporotic drugs a low BMD has been an important inclusion criterion, a preexisting
vertebral fracture, or even a hip fracture,41
has always been the most important inclusion criterion, while the reduction in
fragility fractures has been the most important end point. This fact emphasizes
the efficacy of active intervention when
a bone fragility fracture has been already
diagnosed.38-40
Consequently, it is important to stress
that in patients in whom a bone fragility
fracture has been already diagnosed,
clinical management along with general
measures such as following a healthy
lifestyle and taking calcium and vitamin D
supplements is not enough, and boneactive drugs should always be added to
the treatment to prevent further fractures.45 Despite the evidence gathered
from multiple studies in this field demonstrating the great advantage of the early
management of this condition, only a miREFERENCES
1. Osteoporosis prevention, diagnosis, and therapy.
JAMA. 2001;285:785-795.
2. Marshall D, Johnell O, Wedel H. Meta-analysis of
how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:
1254-1259.
3. Heaney RP. Bone mass, bone loss, and osteoporosis
prophylaxis. Ann Intern Med. 1998;128:313-314.
4. Espallargues M, Sampietro-Colom L, Estrada MD,
et al. Identifying bone-mass–related risk factors for
fracture to guide bone densitometry measurements:
a systematic review of the literature. Osteoporos Int.
2001;12:811-822.
5. Cummings SR, Nevitt MC, Browner WS, et al. Risk
factors for hip fracture in white women. N Engl J Med.
1995;332:767-773.
6. Dargent-Molina P, Favier F, Grandjean H, et al. Fallrelated factors and risk of hip fracture: the EPIDOS
prospective study. Lancet. 1996;348:145-149.
7. Albrand G, Munoz F, Sornay-Rendu E, DuBoeuf F,
Delmas PD. Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: the OFELY study. Bone. 2003;32:78-85.
8. Nevitt MC, Cummings SR, Stone KL, et al. Risk factors for a first-incident radiographic vertebral fracture
in women >/=65 years of age: the study of osteoporotic fractures. J Bone Miner Res. 2005;20:131-140.
9. Naves M, Diaz-Lopez JB, Gomez C, Rodriguez-Rebollar A, Serrano-Arias M, Cannata-Andia JB. Prevalence of osteoporosis in men and determinants of
changes in bone mass in a non-selected Spanish population. Osteoporos Int. 2005;16:603-609.
10. Nguyen ND, Eisman JA, Center JR, Nguyen TV.
Risk factors for fracture in nonosteoporotic men and
386 MEDICOGRAPHIA, VOL 30, No. 4, 2008
nority of patients who are diagnosed
with a fragility fracture are adequately
managed with active pharmacological
intervention.46
ciently in all ages. In summary, it is never too late, but this is particularly true
when a fragility bone fracture is already
present.
In the case of elderly patients, could
you describe why it is never too late to
treat osteoporosis?
As Protelos® has demonstrated a broad
range of antifracture efficacy in a
variety of patient profiles, could you
comment on its place of choice in the
treatment of postmenopausal osteoporosis?
s has been previously mentioned, increasing age is a
strong independent predictive risk factor for bone fragility fractures. The majority of bone fractures occur in people
older than 65 years. In fact, in the main
clinical trials from which most of the
evidence for the prevention and treatment
of osteoporosis has been obtained, the
patients included have always been older than 55 years, with a mean age close
to 70 years.34-44
The paper from Chapuy et al47 demonstrating the efficacy of calcium and vitamin D supplements in the prevention of
hip and nonvertebral fractures in healthy
ambulatory women with a mean age of
84 years old was important to “refresh
this concept”; it was around this time
that the popular expression “it is never
too late to treat osteoporosis” was coined.
Moreover, recent studies in people
older than 80 years have supported this
concept, demonstrating the efficacy of
all types of antiosteoporotic drugs in the
prevention of vertebral and nonvertebral
fractures.48,49 This reinforces the concept
that antiosteoporotic agents can act effi-
here is a high level of evidence
that Protelos® (strontium
ranelate) reduces vertebral fractures in
women with osteopenia, osteoporosis,
and severe osteoporosis. The percentage
reduction of vertebral fractures after
3 years of therapy is 41%, and the effect
can be detected as early as the first year.39
In addition, a reduction in nonvertebral
and hip fractures has been shown in elderly subjects with low BMD at the hip.40
The antifracture efficacy of Protelos®
has also been demonstrated in patients
older than 80 years,49 and its efficacy in
postmenopausal women is independent
of baseline osteoporotic risk factors.50
In addition, Protelos® is well tolerated,
and it does not require dosage adjustment according to age, nor does it produce mild-to-moderate reduction in renal function or liver impairment. Due
to all these characteristics, Protelos®
is considered a first-option drug for the
management of osteoporosis for patients
of all ages. women. J Clin Endocrinol Metab. 2007;92:955-962.
11. Lewis CE, Ewing SK, Taylor BC, et al. Predictors
of non-spine fracture in elderly men: the MrOS study.
J Bone Miner Res. 2007;22:211-219.
12. Cauley JA, Wu L, Wampler NS, et al. Clinical
risk factors for fractures in multi-ethnic women: The
Women s Health Initiative. J Bone Miner Res. 2007;
22:1816-1826.
13. Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk
of subsequent fracture after low-trauma fracture in
men and women. JAMA. 2007;297:387-394.
14. van Staa T-P, Geusens P, Pols HAP, de Laet C, Leufkens HGM, Cooper C. A simple score for estimating
the long-term risk of fracture in patients using oral
glucocorticoids. QJM. 2005;98:191-198.
15. Devogelaer JP, Goemaere S, Boonen S, et al. Evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: a consensus document of the Belgian Bone Club. Osteoporos Int. 2006;17:8-19.
16. Dargent-Molina P, Piault S, Breart G. A triage
strategy based on clinical risk factors for selecting elderly women for treatment or bone densitometry: the
EPIDOS prospective study. Osteoporos Int. 2005;16:
898-906.
17. Melton LJ 3rd, Atkinson EJ, Khosla S, Oberg AL,
Riggs BL. Evaluation of a prediction model for longterm fracture risk. J Bone Miner Res.2005;20:551-556.
18. Brown JP, Josse RG; Scientific Advisory Council of
the Osteoporosis Society of Canada. Clinical practice
guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ.2002;167(suppl 10):S1-S34.
19. Management of osteoporosis in postmenopausal
women: 2006 position statement of the North Ameri-
can Menopause Society. Menopause. 2006;13:340-367.
20. Cummings SR, Black DM, Nevitt MC, et al; the
Study of Osteoporotic Fractures Research Group. Bone
density at various sites for prediction of hip fractures.
Lancet.1993;341:72-75.
21. Marshall D, Johnell O, Wedel H. Meta-analysis of
how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:
1254-1259.
22. Miller PD, Siris ES, Barrett-Connor E, et al. Prediction of fracture risk in postmenopausal white women with peripheral bone densitometry: evidence from
the National Osteoporosis Risk Assessment. J Bone
Miner Res. 2002;17:2222-2230.
23. Khaw KT, Reeve J, Luben R, et al. Prediction of
total and hip fracture risk in men and women by
quantitative ultrasound of the calcaneus: EPIC-Norfolk prospective population study. Lancet. 2004;363:
197-202.
24. Diez-Perez A, Gonzalez-Macias J, Marin F, et al.
Prediction of absolute risk of non-spinal fractures using clinical risk factors and heel quantitative ultrasound. Osteoporos Int. 2007;18:629-639.
25. World Health Organization Study Group. Assessment of fracture risk and its application to screening
for postmenopausal osteoporosis. Report of a WHO
Study Group. WHO Technical Report Series No. 843.
Geneva, Switzerland: World Health Organization; 1994.
26. Ross PD, Davis JW, Epstein RS, Wasnich RD. Preexisting fractures and bone mass predict vertebral
fracture incidence in women. Ann Intern Med.1991;
114:919-923.
27. Klotzbuecher CM, Ross PD, Landsman PB, Abbott
TA 3rd, Berger M. Patients with prior fractures have
A
T
Treating osteoporosis across its stages – Cannata-Andía and Díaz-López
INTERVIEW
an increased risk of future fractures: a summary of
the literature and statistical synthesis. J Bone Miner
Res. 2000;15:721-739.
28. Naves M, Diaz-Lopez JB, Gomez C, Rodriguez-Rebollar A, Rodriguez-Garcia M, Cannata-Andia JB. The
effect of vertebral fracture as a risk factor for osteoporotic fracture and mortality in a Spanish population. Osteoporos Int. 2003;14:520-524.
29. Lindsay R, Silverman SL, Cooper C, et al. Risk of
new vertebral fracture in the year following a fracture.
JAMA. 2001;285:320-323.
30. van Helden S, Cals J, Kessels F, Brink P, Dinant GJ,
Geusens P. Risk of new clinical fractures within 2 years
following a fracture. Osteoporos Int. 2006;17:348-354.
31. Melton LJ 3rd. Adverse outcomes of osteoporotic
fractures in the general population. J Bone Miner
Res. 2003;18:1139-1141.
32. Hasserius R, Karlsson MK, Nilsson BE, RedlundJohnell I, Johnell O. Prevalent vertebral deformities
predict increased mortality and increased fracture
rate in both men and women: a 10-year populationbased study of 598 individuals from the Swedish cohort in the European Vertebral Osteoporosis Study.
Osteoporos Int. 2003;14:61-68.
33. Pongchaiyakul C, Nguyen ND, Jones G, Center JR,
Eisman JA, Nguyen TV. Asymptomatic vertebral deformity as a major risk factor for subsequent fractures
and mortality: a long-term prospective study. J Bone
Miner Res. 2005;20:1349-1355.
34. Black DM, Cummings SR, Karpf DB, et al; Fracture Intervention Trial Research Group. Randomised
trial of effect of alendronate on risk of fracture in
women with existing vertebral fractures. Lancet.1996;
348:1535-1541.
35. Reginster J, Minne HW, Sorensen OH, et al; Vertebral Efficacy with Risedronate Therapy (VERT)
Study Group. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int.
2000;11:83-91.
36. Chesnut IC, Skag A, Christiansen C, et al. Effects
of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249.
37. Seeman E, Crans GG, Diez-Perez A, Pinette KV,
Delmas PD. Anti-vertebral fracture efficacy of raloxifene: a meta-analysis. Osteoporos Int. 2006;17:313316.
38. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect
of parathyroid hormone (1-34) on fractures and bone
mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434-1441.
39. Meunier PJ, Roux C, Seeman E, et al. The effects
of strontium ranelate on the risk of vertebral fracture
in women with postmenopausal osteoporosis. N Engl
J Med. 2004;350:459-468.
40. Reginster JY, Seeman E, De Vernejoul MC, et al.
Strontium ranelate reduces the risk of nonvertebral
fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS)
Study. J Clin Endocrinol Metab. 2005;90:2816-2822.
41. Lyles KW, Colon-Emeric CS, Magaziner JS, et al.
Zoledronic acid and clinical fractures and mortality
after hip fracture. N Engl J Med. 2007;357:1799-1809.
42. Orwoll E, Ettinger M, Weiss S, et al. Alendronate
for the treatment of osteoporosis in men. N Engl J
Med. 2000;343:604-610.
43. Kaufman JM, Orwoll E, Goemaere S, et al. Teri-
TRAITER L’OSTÉOPOROSE
L
e but principal du traitement de l’ostéoporose est la prévention des fractures de fragilité osseuse. La connaissance
des facteurs de risque associés à la maladie joue un rôle
clé dans la prise en charge de cette pathologie : une faible densité
minérale osseuse est un facteur de risque important, mais pas le
seul. D’autres facteurs de risque, comme une fracture osseuse
antérieure, présentent une forte valeur prédictive indépendante
pour de nouvelles fractures de fragilité. Plusieurs études ont démontré qu’une ou plusieurs fractures vertébrales prévalentes ou
incidentes multiplient par 2 à 5 le risque d’avoir une nouvelle
fracture de fragilité. Un risque de mortalité plus élevé est également associé aux fractures vertébrales et de la hanche. Après la
première fracture osseuse, une véritable cascade de fractures peut
Treating osteoporosis across its stages – Cannata-Andía and Díaz-López
paratide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and
discontinuation of therapy. Osteoporos Int. 2005;16:
510-516.
44. Ringe JD, Faber H, Farahmand P, Dorst A. Efficacy of risedronate in men with primary and secondary
osteoporosis: results of a 1-year study. Rheumatol Int.
2006;26:427-431.
45. Supplementation of vitamin D and calcium: advantages and risks. Diaz-Lopez B, Cannata-Andia JB.
Nephrol Dial Transplant. 2006;21:2375-2377.
46. Feldstein A, Elmer PJ, Orwoll E, Herson M, Hillier
T. Bone mineral density measurement and treatment
for osteoporosis in older individuals with fractures: a
gap in evidence-based practice guideline implementation. Arch Intern Med. 2003;163:2165-2172.
47. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin
D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992;327:1637-1642.
48. Boonen S, McClung MR, Eastell R, El-Hajj Fuleihan G, Barton IP, Delmas P. Safety and efficacy of risedronate in reducing fracture risk in osteoporotic
women aged 80 and older: implications for the use of
antiresorptive agents in the old and oldest old. J Am
Geriatr Soc. 2004;52:1832-1839.
49. Seeman E, Vellas B, Benhamou C, et al. Strontium
ranelate reduces the risk of vertebral and nonvertebral fractures in women eighty years of age and older.
J Bone Miner Res. 2006;21:1113-1120.
50. Roux C, Reginster JY, Fechtenbaum J, et al. Vertebral fracture risk reduction with strontium ranelate in
women with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res. 2006;
21:536-542.
À TOUS SES STADES
intervenir dans les 2 ans qui suivent. Le traitement pharmacologique de l’ostéoporose avec des produits agissant sur l’os est
alors justifié pour réduire la morbidité et la mortalité. Malgré les
nombreux arguments en faveur du bénéfice d’une prise en charge
précoce de l’ostéoporose, seule une minorité de patientes ayant
une fracture de fragilité est traitée de façon pertinente. Les produits antiostéoporotiques sont efficaces et il n’est jamais trop tard
pour commencer le traitement. Protelos ® (ranélate de strontium) a clairement démontré son efficacité antifracturaire sur les
fractures osseuses vertébrales et non vertébrales, indépendamment des facteurs de risque ostéoporotiques initiaux. Protelos ®
est ainsi considéré comme un médicament de première intention
pour la prise en charge de l’ostéoporose quel que soit l’âge.
MEDICOGRAPHIA, VOL 30, No. 4, 2008 387
F
O C U S
WHEN SPINAL OSTEOPOROSIS AND
OSTEOARTHRITIS COEXIST
by C. Roux and J. Fechtenbaum, France
steoporosis and osteoarthritis are two common disorders in the elderly, both with similar symptoms of pain, physical limitation,
and disability. In both diseases, however, anatomical lesions do not always parallel the symptoms.
Epidemiological studies have observed an inverse
relationship between osteoporosis and osteoarthritis at the spine (see Figures 1 and 2), the latter being considered as possibly delaying the development of osteoporosis.1 However, vertebral fractures
and osteoarthritis can coexist, and each of these diseases must be recognized carefully because of the
different therapeutic consequences.
O
Christian ROUX, MD, PhD
Jacques FECHTENBAUM,
MD, PhD
Paris Descartes University
Cochin Hospital
Rheumatology Department
Paris, FRANCE
Prevalence of osteoarthritis
and back pain
On standard x-rays, the average prevalence of lumbar spine osteoarthritis is 50% in women in their
forties, increasing with age to 65% to 70% in women in their eighties.2 In asymptomatic volunteers
more than 60 years old, the prevalence of degenerative disc disease on magnetic resonance imaging of
the lumbar spine is 93%.3 In a cross-sectional study
of healthy postmenopausal women aged an average
of 68 years, the prevalence of osteoarthritis at the
spine was high: 75% of women had osteophytes, and
64% had at least one disc space–narrowing.4 HowSELECTED
BMD
ABBREVIATIONS AND ACRONYMS
bone mineral density
O
steoporosis and osteoarthritis are both common disorders
in the elderly. They cause similar symptoms: pain, physical limitations, and disability. Thoracic hyperkyphosis is
an example of a symptom that can be related to osteoporotic vertebral fractures, thoracic intervertebral disc degeneration or both.
There is debate over the relationship between osteoporosis and
osteoarthritis, the latter being considered as possibly delaying the
development of osteoporosis. Indeed, patients with osteoarthritis of the hands, hips, or knees have higher bone mineral density
than controls. However, disc space–narrowing has been reported
prospectively as a risk factor for vertebral fractures. In fact, osteoarthritis is not an homogenous disease. Some individuals with
osteoarthritis belong to a group with a trophic variant, with osteophytes and end-plate bone sclerosis, and they may be protect-
388 MEDICOGRAPHIA, VOL 30, No. 4, 2008
ever, not all of these patients observed in epidemiological studies had symptoms at the time of x-rays.
Two thirds of adults have low back pain at some
time, and even if cross-sectional imaging of the
spine shows anatomical lesions, it is not always easy
to establish their involvement in the symptoms,
which can be more related to structural changes.
On average, 42% of women aged 65 to 70 years who
do not have vertebral fractures report having experienced moderate or severe back pain during the
previous year, and 28% of these women have this
degree of pain most or all of the time.5 During follow-up, there is some association between radiological changes and past, but not present, symptoms.
Disc degeneration is more common in patients with
recurrent back pain, although it was shown in a 9year prospective study that such disc space–narrowing also occurs in 40% of asymptomatic women.6,7
In parallel to these observations, it is well-known
that not all vertebral osteoporotic fractures come to
clinical attention, and numerous prospective studies have shown that incident vertebral fractures can
occur without, or with very few, symptoms in osteoporotic postmenopausal women. Moreover, back
pain has been reported to be only linked to recent
(ie, less than 4 years) vertebral fractures.8
Radiological assessment of back pain
in postmenopausal women
Thus, the decision to determine the necessity of
spine radiography in postmenopausal women with
back pain is not easy. It is a balance between the
ed from fractures. Others who have an atrophic variant and display mainly joint- and disc space–narrowing may have low bone
mineral density. At the spine, the risk of vertebral fractures must
be assessed in this context, and assessment should incorporate
the mechanical and mobility conditions of the individual.
Medicographia. 2008;30:388-392.
(see French abstract on page 392)
Keywords: back pain; thoracic kyphosis; osteoarthritis;
osteoporosis; coexistence, bone mineral density; osteophyte;
disc space–narrowing; vertebral fracture
www.medicographia.com
Address for correspondence: Prof Christian Roux, MD, PhD, Paris Descartes
University, Cochin Hospital, Rheumatology Department, Paris, France
(e-mail: [email protected])
When spinal osteoporosis and osteoarthritis coexist – Roux and Fechtenbaum
FOCUS
the author suggests using it only on the two mostinvolved or worst-involved levels, from T4-T5 to
T12-L1, as subjectively determined by the reader.
There is a strong difference between these two scoring systems: the Kellgren scale requires the presence of osteophytes for the radiographic diagnosis
of osteoarthritis, yet isolated disc space–narrowing
can be present. Osteophytes and narrowing are two
independent features of joint osteoarthritis: Pye et
al showed recently that during follow-up, increasing severity of osteophytes and end-plate sclerosis
are linked, and that this association is stronger than
any other, including disc space–narrowing.14
Thoracic kyphosis
Figure 1. Osteoarthritis without
vertebral fracture.
Thoracic kyphosis, ie, an exaggerated forward curvature of the thoracic spine, is important when discussing the role of osteoarthritis and osteoporosis
in the development of clinical symptoms, and the
potential coexistence of osteoarthritis and osteoporosis of the spine. It is a frequent feature in the
elderly, and can be related to thoracic vertebral fractures, degenerative changes of the thoracic spine,
or both. Thoracic kyphosis can be assessed by examining the ability or inability of the patient to lie
flat without neck hyperextension, by measuring the
distance from the occiput to the horizontal, or by
using a flexicurve ruler in the upright position.15,16
Hyperkyphosis (dowager’s hump) is a well-known
consequence of osteoporotic fractures. However,
the Rancho Bernardo study showed that the majority of men and women with hyperkyphosis had
no evidence of osteoporosis, and that the most common finding associated with kyphosis is degenerative disc changes: in the higher quartile of the
kyphotic angle, only 37% of women (74 years old on
average) had prevalent thoracic vertebral fractures.17
Most of the studies have shown that kyphosis in-
Figure 2. Multiple vertebral fractures
without osteoarthritis.
concern over unnecessary radiation (if pain is related to degenerative changes) and the importance
of imaging the spine for making a treatment decision if there is a vertebral fracture. The necessity
for spinal x-rays can be based on age, height loss,
and history of fracture,9 but this is too remote from
the day-to-day care of patients. We analyzed back
pain in a cohort of 410 postmenopausal women with
osteoporosis, aged 74 years on average10: among the
different characteristics of the pain, those that were
most related to the presence of vertebral fractures
were the high intensity, the sudden occurrence, and
the thoracic localization of the pain. We suggest
that a tool that includes age, back pain intensity,
height loss, history of low trauma nonvertebral fractures, thoracic localization, and sudden occurrence
of back pain, is useful to identify women with osteoporosis and back pain who should have spine
x-rays undertaken.10
12
Disc space narrowing
No
Mild
Moderate
Severe
No
No
Slight
Pronounced
1
2
3
4
No/very small
Mild
Moderate
Large
Lane13
0
1
2
3
0
Moderate
Severe
Intervertebral bridge
Table I. Scoring
of osteoarthritis
of the spine.
When spinal osteoporosis and osteoarthritis coexist – Roux and Fechtenbaum
Sclerosis
Kellgren
Assessment and grading
of osteoarthritis
Osteoarthritis of the spine is assessed on lateral
spine x-rays, most often at the lumbar spine. The
grading of thoracic spine osteoarthritis can be done
in a similar way.11 It is not possible to assess facet
joint arthritis on lateral views, and this necessitates
antero-posterior views. The two main grading scores
used are Kellgren’s scoring scale,12 described in
1963, and Lane’s scoring scale,13 described 30 years
later (Table I).
For assessment involving the Kellgren score, it
is possible to combine grades 1 and 2 as “no-mild
osteoarthritis” and 3 and 4 as “moderate-severe osteoarthritis.” In Lane’s scoring scale, it is also possible to assess subchondral sclerosis as 0 (none) and
1 (present). However, interrater agreement is fair
for sclerosis at the lumbar vertebral end-plates, and
excellent for osteophytes and narrowing. Lane’s
score can be applied to the thoracic spine, although
Osteophytes
-
0
50% and <80%
Moderate/severe
80%
creases with age, and age may explain half of the
variation of the index of kyphosis.18 Degeneration of
the intervertebral disc occurs in the anterior fibers
of the annulus fibrosus, and these degenerative
changes can impact adjacent vertebral body morphology. Vertebral deformities are more frequent
at the midthoracic spine, in osteoarthritis, and because of osteoporotic fractures as well. Actually osteoarthritic changes occur only on the anterior part
of the vertebrae, and attention must be paid to the
depression of the central end-plates of the vertebrae
to recognize a fracture.19 The interpretation of isolated short anterior vertebral heights of the midMEDICOGRAPHIA, VOL 30, No. 4, 2008 389
FOCUS
thoracic spine must take into account adjacent disc
space–narrowing and the presence of deformities
of similar appearance on contiguous vertebrae, both
signs being more in favor of a nonosteoporotic
origin of the deformity. Vertebral fractures are unlikely to have identical aspects, and occur more frequently in noncontiguous vertebrae. Obviously
these signs are not specific to osteoporosis, but they
can be used in clinical practice. Ignorance of them
can lead to false diagnosis of fracture, as observed
sometimes with the use of quantitative tools for
spine x-ray interpretation. Thoracic kyphosis has
been associated with different complications, including height loss and decreased physical function,
impairments in pulmonary function, and presence
of esophageal hiatal hernia. The interesting point
is the increase in risk of incident fractures in elderly hyperkyphotic women,20 even after adjustment
for age, baseline fracture, and BMD. This may be related to other consequences of hyperkyphosis, ie,
alteration of balance with increasing risk of falls,
decrease in back extensor strength, slower gait, and
greater body sway.21 Hyperkyphosis may be considered as an example of an aging-related process,20 and
deserves clinical attention.
Debate regarding the coexistence of
osteoporosis and osteoarthritis
Beyond thoracic kyphosis, there is a debate regarding whether osteoporosis and osteoarthritis are exclusive or can coexist. Renier et al22 found a lower
prevalence of disc degeneration in 50 patients with
osteoporosis (proven by biopsy) than in controls,
and Foss and Byers23 showed the absence of osteoarthritis on femoral heads excised for hip fractures.
Most studies show high bone densities in patients
with hip, knee, or hand osteoarthritis. In elderly
women aged 75 years or more, bone mass is positively correlated with the severity of hand osteoarthritis, and osteoporotic fractures are less frequent
in women with a high degree of osteoarthritis.24 Patients with osteoarthritis of the hip have greater
bone mass than both normal controls and patients
with hip fractures. In the Framingham cohort
study, women with a low or intermediate grade of
knee osteoarthritis had higher femoral bone mineral density (BMD) compared with controls without
knee osteoarthritis. Interestingly, the difference was
related mainly to patients with osteophytes; there
was actually no difference when considering patients with knee space–narrowing only.25 For Dequeker,26 high bone mass is one of several factors
in the pathogenesis of disc joint degeneration. Elevated levels of insulin-like growth factors have been
measured in iliac crest bone of patients with osteoarthritis, and, moreover, serum insulin-like growth
factor is a prognostic factor for knee osteoarthritis.
Bone mineral density
At the spine, degenerative joint disease changes can
influence BMD measurements, and this potential
artifact must be taken into account in the interpretation of the relationship between osteoarthritis
and osteoporosis. BMD is increased by osteophytes,
390 MEDICOGRAPHIA, VOL 30, No. 4, 2008
by sclerosis related to disc degeneration, and by osteoarthritis of the facet joints.27 What is debated is
the potential relationship between these two findings: does high BMD preexist in patients with osteoarthritis, or is it only a consequence of the disease
in these patients? In 93 postmenopausal women
with at least one osteoporotic vertebral fracture,
the presence of even mild osteophytosis produced
on average a 24% increase in lumbar spine BMD;
but in the same study, the mean femoral neck density was 8% higher in the osteophyte group compared with the other groups.28
Actually, interpretation of these results must take
into account the different lesions related to osteoarthritis: joint or disc space–narrowing (destruction), and adjacent bone sclerosis and osteophytes
(formation). In a study of hip osteoarthritis, BMD
at both spinal and appendicular sites was associated with the presence and size of hip osteophytes;
isolated narrowing of the hip, without osteophytes,
was not linked to high bone density.29 In 250 women aged 65 years on average who were recruited
from a population register, there was an increase
in lumbar spine BMD with increasing grade of all
radiographic features of disc degeneration; this
stayed true after adjustment for age, and persisted
after adjustments for body mass index and physical
activity levels. Femoral neck BMD increases with
increasing grade of both osteophytes and sclerosis,
but not with disc space–narrowing.30
Two cross-sectional studies and one prospective
study suggested that spinal disc degeneration does
not protect against osteoporotic fractures (Figures 3 and 4), and that low BMD does not protect
against disc degeneration. In a cross-sectional study,
lumbar spine osteoarthritis and BMD were assessed
in 559 postmenopausal women.4 BMD of the spine,
hip, and whole body increased with the severity of
osteophytosis, and there was a link between severity of disc narrowing and higher BMD at the spine
(and not at other sites), as expected. There was no
association between spine osteoarthritis and fragility fractures. Unexpectedly, this study showed an
association between disc narrowing and risk of vertebral fractures. This result was confirmed prospectively: 634 women (61 years of age on average) were
followed for 11 years, and 42 vertebral fractures
occurred. There was no association between osteophytes and fractures.
In contrast, the presence of disc space–narrowing
at baseline was associated with an increased risk of
vertebral fractures, with an odds ratio (OR) of 6.9
(1.4-31.9). There was no relationship with the risk
of nonvertebral fracture, however, nor between vertebral fracture risk and the severity of disc narrowing.31 It is possible that a limitation of these studies
is that the magnitude of the association between
disc space narrowing and osteoporosis and fractures is dependent on subject selection, ie, the degree of BMD decrease at baseline. Indeed, we studied 410 postmenopausal osteoporotic women aged
an average of 74 years, of whom 52% had at least one
prevalent vertebral fracture. The prevalence of osteoarthritis was high in this elderly population,
with 90% of them having at least one osteophyte
When spinal osteoporosis and osteoarthritis coexist – Roux and Fechtenbaum
FOCUS
Figure 3. Vertebral fracture with adjacent disc space–
narrowing.
and 65% of them having at least one disc space–
narrowing. In this cross-sectional study, the risk of
having a vertebral fracture decreased in patients
with at least one osteophyte (OR, 0.38 [0.17-0.86]),
and in patients with more than two disc space–
narrowings (OR, 0.27 [0.16-0.46]). There was a statistically significant inverse correlation between
composite indexes of osteoarthritis and vertebral
fractures. Moreover, cluster analysis was able to distinguish three different clusters in this population,
including one characterized by both the absence of
disc space–narrowing and the presence of a high
number of vertebral fractures.11
Figure 4. Vertebral
fracture and remote disc
space–narrowing.
Other possible factors in the relationship
between osteoporosis and osteoarthritis
Beyond the differences in studied populations, other potential mechanisms underlying the occurrence
of osteoarthritis and osteoporosis must be discussed.
The increase in BMD in patients with hand osteoarthritis was recently confirmed in a large study
conducted in Norway.32 In this study there was no
correlation between BMD and osteoarthritis duration and health status, indicating that increased
BMD precedes the development of arthritis, rather
than being a consequence of it. The Rotterdam prospective study confirmed that radiographically evident osteoarthritis of the hips and knees is associated with high BMD, as well as with an increased
REFERENCES
1. Verstraeten A, Ermen HV, Haghebaert G, Nijs J,
Geusens P, Dequeker J. Osteoarthritis retards the development of osteoporosis: observation of the coexistence of osteoarthritis and osteoporosis. Clin Orthop.
1991;264:169-177.
2. Van Saase JL, Van Romunde LK, Cats A, Vandenbroucke JP, Valkenburg HA. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological
osteoarthritis in a Dutch population with that in 10
other populations. Ann Rheum Dis.1989;48:271-280.
3. Boden SD, Davis DO, Dina TS, Patronas NJ, Wiesel
SW. Abnormal magnetic resonance scans of the lumbar spine in asymptomatic subjects: a prospective investigation. J Bone Joint Surg Am.1990;72:403-408.
4. Sornay-Rendu E, Munoz F, Duboeuf F, Delmas PD.
Disc space narrowing is associated with an increased
vertebral fracture risk in post menopausal women: the
OFELY Study. J Bone Miner Res. 2004;19:1994-1999.
5. Ettinger B, Black DM, Nevitt MC, et al; Study of
Osteoporotic Fractures Research Group. Contribution
of vertebral deformities to chronic back pain and disability. J Bone Miner Res.1992;7:449-456.
rate of bone loss in the proximal femur.33
This suggests that the difference in BMD is
more pronounced earlier in life, and the role
of high BMD in the development of osteoarthritis may vary with age, acting through
changes in stiffness of the subchondral bone.
Alteration of the quality of bone in osteoarthritis has been studied by Schnitzler et
al using biopsies of the iliac crests34: lower
bone volume and thinner trabeculae have
been found in osteoarthritis patients compared with controls, contrasting with other
data showing an increased cancellous bone
area and trabecular thickness.35 Even an alteration in trabecular orientation in subchondral bone has been shown.36 The role
of regional rather than systemic factors in
the relationship between osteoarthritis and
osteoporosis is relevant at the spine. Both
the disc and the neural arch (facet joints)
resist compressive force acting down the
long axis of the spine. With age-related degenerative changes in intervertebral discs,
there is a concentration of loads onto the
anterior part of the vertebral body when the
spine is flexed.37 In upright posture, disc
degeneration transfers compressive load-bearing
to the posterior part of the spine, with a reduction
in BMD and trabecular architecture anteriorly,
leading to fragility of this part of the vertebral body.
On the other hand, however, an alteration of the
mobility of the spine induced by disc degeneration
has been described,38,39 and facet joint arthritis also
leads to a local stabilization of the spine. Both of
these lesions change the local mechanical conditions and can theoretically reduce the risk of vertebral fracture.
Osteoarthritis of the spine is not an homogenous
disease. Some osteoarthritic individuals have a predisposition to develop osteophytes, and having this
trophic variant of the disease may protect them
from fractures. Others have mainly joint and disc
space–narrowing, and they may have a different
risk in the form of low BMD. The risk of vertebral
fractures must therefore be assessed in the context
of local mechanical conditions. 6. Symmons DPM, Van Hemert AM, Vandenbroucke
JP, Valkenburg HA. A longitudinal study of back pain
and radiological changes in the lumbar spines of middle aged women. I. Clinical findings. Ann Rheum Dis.
1991;50:158-161.
7. Symmons DPM, Van Hemert AM, Vandenbroucke
JP, Valkenburg HA. A longitudinal study of back pain
and radiological changes in the lumbar spines of middle aged women. II. Radiographic findings. Ann Rheum
Dis. 1991;50:162-166.
8. Huang C, Ross PD, Wasnich RD. Vertebral fractures
and other predictors of back pain among older women. J Bone Miner Res. 1996;11:1026-1032.
9. Vogt TM, Ross PD, Palermo L, Musliner T, Genant
HK, Black D; Fracture Intervention Trial Research
Group. Vertebral fracture prevalence among women
screened for the Fracture Intervention Trial and a
simple clinical tool to screen for undiagnosed vertebral fractures. Mayo Clin Proc. 2000;75:888-896.
10. Roux C, Priol G, Fechtenbaum J, Cortet B, LiuLéage, S, Audran M. A clinical tool to determine the
necessity of spinal radiography in postmenopausal
When spinal osteoporosis and osteoarthritis coexist – Roux and Fechtenbaum
women with osteoporosis presenting with back pain.
Ann Rheum Dis. 2007;66:81-85.
11. Roux C, Fechtenbaum J, Briot K, Cropet C, LiuLéage S, Marcelli C. Inverse relationship between vertebral fractures and spine osteoarthritis in postmenopausal women with osteoporosis. Ann Rheum Dis.
2008;67:224-228.
12. Kellgren JH, Lawrence JS. Osteoarthrosis and disc
degeneration in an urban population. Ann Rheum Dis.
1958;17:388-396.
13. Lane NE, Nevitt MC, Genant HK, Hochberg MC.
Reliability of new indices of radiographic osteoarthritis of the hand and hip and lumbar disc degeneration.
J Rheumatol. 1993;20:1911-1918.
14. Pye SR, Reid DM, Lunt M, Adams JE, Silman AJ,
O’Neill TW. Lumbar disc degeneration: association between osteophytes, end-plate sclerosis and disc space
narrowing. Ann Rheum Dis. 2007;66:330-333.
15. Prince RL, Devine A, Dick IM. The clinical utility
of measured kyphosis as a predictor of the presence of
vertebral deformities. Osteoporos Int. 2007;18:621627.
MEDICOGRAPHIA, VOL 30, No. 4, 2008 391
FOCUS
16. Ettinger B, Black DM, Palermo L, Nevitt MC,
Melnikoff S, Cummings SR. Kyphosis in older women
and its relation to back pain, disability and osteopenia:
the Study of Osteoporotic Fractures. Osteoporos Int.
1994;4:55-60.
17. Schneider DL, von Mühlen DG, Barrett-Connor E,
Sartoris D. Kyphosis does not equal vertebral fractures:
the Rancho Bernardo Study. J Rheumatol. 2004;31:
747-752.
18. Milne JS, Williamson J. A longitudinal study of kyphosis in older people. Age Ageing.1983;12:225-233.
19. Ferrar L, Jiang G, Adams J, Eastell R. Identification of vertebral fractures: an update. Osteoporos Int.
2005;16:717-728.
20. Huang MH, Barrett-Connor E, Greendale GA,
Kado DM. Hyperkyphotic posture and risk of future
osteoporotic fractures: The Rancho Bernardo Study.
J Bone Miner Res. 2006;21:419-423.
21. Sinaki M, Brey RH, Hughes CA, Larson DR, Kaufman KR. Balance disorder and increased risk of falls
in osteoporosis and kyphosis: significance of kyphotic posture and muscle strength. Osteoporos Int. 2005;
16:1004-1010.
22. Renier JC, Bernat M, Fallah N. Etude correlative
de l’ostéoporose et de la discarthrose. Rev Rhum Mal
Osteoartic. 1981;48:323-330.
23. Foss MV, Byers PD. Bone density, osteoarthritis of
the hip, and fracture of the upper end of the femur.
Ann Rheum Dis. 1972;31:259-264.
24. Marcelli C, Favier F, Kotzki PO, Ferrazzi V, Picot
MC, Simon L. The relationship between osteoarthritis of the hands, bone mineral density, and osteoporotic fractures in elderly women. Osteoporos Int.
1995;5:382-388.
25. Hannan MT, Anderson JJ, Zhang Y, Levy D, Felson
DT. Bone mineral density and knee osteoarthritis in
elderly men and women. Arthritis Rheum. 1993;36:
1671-1680.
26. Dequeker J, Mohan S, Finkelman RD, Aerssens J,
Baylink DJ. Generalized osteoarthritis associated with
increased insulin-like growth factor types I and II and
transforming growth factor beta in cortical bone from
the iliac crest. Possible mechanism of increased bone
density and protection against osteoporosis. Arthritis
Rheum. 1993;36:1702-1708.
27. Yu W, Glüer CC, Fuerst T, et al. Influence of degenerative joint disease on spinal bone mineral measurements in post menopausal women. Calcif Tissue
Int. 1995;57:169-174.
28. Masud T, Langley S, Wiltshire P, Doyle DV, Spector TD. Effect of spinal osteophytosis on bone mineral density measurements in vertebral osteoporosis.
BMJ. 1993;307:172-173.
29. Nevitt MC, Lane NE, Scott JC, Hochberg MC,
Pressman AR, Genant HK; Study of Osteoporotic Fractures Research Group. Radiographic osteoarthritis of
the hip and bone mineral density. Arthritis Rheum.
1995;22:932-936.
30. Pye SR, Reid DM, Adams JE, Silman AJ, O’Neill
TW. Radiographic features of lumbar disc degeneration and bone mineral density in men and women.
Ann Rheum Dis. 2006;65:234-238.
31. Sornay-Rendu E, Allard C, Munoz F, Duboeuf F,
Delmas PD. Disc space narrowing as a new risk factor
for vertebral fracture. Arthritis Rheum. 2006;54:12621269.
QUAND L’ARTHROSE
L’
ET L’OSTÉOPOROSE RACHIDIENNES COEXISTENT
ostéoporose et l’arthrose sont deux maladies fréquentes
chez le sujet âgé, responsables de symptômes similaires,
avec douleur, limitations physiques et handicap. L’hypercyphose thoracique est un symptôme exemplaire en ce qu’il peut
être rapporté soit aux fractures vertébrales ostéoporotiques, soit
à la dégénérescence des disques intervertébraux thoraciques, ou
bien encore aux deux. Les relations entre l’ostéoporose et l’arthrose sont actuellement débattues, la possibilité ayant été invoquée que l’arthrose puisse retarder l’évolution de l’ostéoporose.
En effet, les patients souffrant d’arthrose des mains, des hanches
ou des genoux ont une densité minérale osseuse supérieure à
celle des témoins. À l’opposé, une étude prospective a montré que
392 MEDICOGRAPHIA, VOL 30, No. 4, 2008
32. Haugen IK, Slatkowsky-Christensen B, Orstavik R,
Kvien TK. Bone mineral density in patients with hand
osteoarthritis compared to population controls and
patients with rheumatoid arthritis. Ann Rheum Dis.
2007;66:1594-1598.
33. Burger H, Van Daele PLA, Odding E, et al. Association of radiographically evident osteoarthritis with
higher bone mineral density and increased bone loss
with age. Arthritis Rheum.1996;39:81-86.
34. Schnitzler CM, Mesquita JM, Wane L. Bone histomorphometry of the iliac crest, and spinal fracture
prevalence in atrophic and hypertrophic osteoarthritis of the hip. Osteoporos Int. 1992;2:186-194.
35. Jordan GR, Loveridge N, Power J, Clarke MT, Reve
J. Increased cancellous bone in the femoral neck of
patients with coxarthrosis (hip osteoarthritis): a positive remodeling imbalance favoring bone formation.
Osteoporos Int. 2003;14:160-165.
36. Kamibayashi L, Wyss UP, Cooke TD, Zee B.
Changes in mean trabecular orientation in the medial condyle of the proximal tibia in osteoarthritis.
Calcif Tissue Int. 1995;57:69-73.
37. Adams MA, Pollintine P, Tobias JH, Wakley GK,
Dolan P. Intervertebral disc degeneration can predispose to anterior vertebral fractures in the thoracolumbar spine. J Bone Miner Res. 2006;21:1409-1416.
38. Dai L. The relationship between vertebral body
deformity and disc degeneration in lumbar spine of
the senile. Eur Spine J. 1998;7:40-44.
39. Fujiwara A, Lim TH, An HS, et al. The effect of disc
degeneration and facet joint osteoarthritis on the segmental flexibility of the lumbar spine. Spine. 2000;25:
3036-3044.
le pincement discal lombaire bas était un facteur de risque de
fracture vertébrale. Ces constatations soulignent le fait que l’arthrose n’est pas une maladie homogène. Certains sujets présentent une variante trophique d’arthrose, caractérisée par la présence d’ostéophytes et d’une sclérose des plateaux vertébraux qui
pourraient les protéger des fractures. D’autres présentent une variante atrophique, avec principalement un pincement discal ou
articulaire, et chez ces sujets la densité minérale osseuse peut être
basse. C’est dans ce contexte que le risque de fractures vertébrales
doit être évalué, en prenant également en compte l’état mécanique et de mobilité de l’individu.
When spinal osteoporosis and osteoarthritis coexist – Roux and Fechtenbaum
U
P D A T E
MANAGING OSTEOPOROSIS
IN THE ELDERLY
by S. Boonen, Belgium
ecause of the aging of the population, the
number of individuals over the age of 80
years — who have the highest absolute risk
of fracture — will continue to increase steadily
throughout the world in the coming decades.1 As a
result, the number of fractures—particularly nonvertebral fractures like hip fractures—will continue to increase exponentially.2 Osteoporotic fractures
result in reduced quality of life and increased morbidity and mortality, particularly in patients over 80
years of age. Although hip fractures are considered
to be the most dramatic consequence of osteoporosis, other types of nonvertebral fractures contribute
significantly to the burden of the disease as well.3 In
older patients, nonvertebral fractures account for
more than 90% of the economic cost of osteoporosis (because of the need for hospitalization) and for
more than 90% of the disease-related mortality. Despite this public health burden, strategies for early
diagnosis and appropriate treatment have not been
widely implemented in this age group.
B
Steven BOONEN, MD, PhD
Leuven University Center for
Metabolic Bone Diseases &
Division of Geriatric Medicine
Leuven, BELGIUM
Consequences of
osteoporosis in old age
Vertebral fractures progressively increase with age
in both men and women.4 Overall, close to 50% of
women over the age of 80 years have one or more
vertebral deformities.5 Although vertebral fractures
do result in suffering and reduced quality of life,
these fractures contribute significantly less to the
burden of osteoporosis in the elderly population
when compared with hip fracture and other types
of nonvertebral fractures. Hip fractures in old age
constitute a challenge because of the size of the
O
steoporotic fractures in old age are a major public health
issue. Vertebral fractures result in suffering and a significant loss of quality of life, but in elderly individuals, nonvertebral fractures account for most of the morbidity, mortality,
and economic cost associated with osteoporosis. Although women over the age of 75 to 80 years have the highest risk of fracture,
osteoporosis in old age continues to be underdiagnosed and undertreated. Recent evidence with strontium ranelate indicates
that even in the oldest individuals, the benefits of current treatment options are achievable. In elderly patients, bone loss can be
inhibited and fracture risk reduced by calcium and vitamin D
supplementation and by pharmaceutical intervention with agents
such as bisphosphonates, teriparatide, and strontium ranelate.
Managing osteoporosis in the elderly – Boonen
problem. Because of the aging of the population,
the incidence of hip fracture will continue to increase dramatically. Even today, the cumulative incidence of hip fracture in women aged 80 years is
close to 30%. What this means is that by the age
of 80 years, 1 in 3 women will have sustained 1 or
more hip fractures, and 80 years of age is close to
the average life expectancy for women. A similar increase due to the aging of the population has been
observed for other types of nonvertebral fracture as
well, and this is because age is not only the main
determinant of the absolute risk of fracture, but
also one of the main determinants of the type of osteoporotic fracture. Between the ages of 55 and 70
SELECTED
ABBREVIATIONS AND ACRONYMS
BMD
FIT
FPT
HIP
MORE
bone mineral density
Fracture Intervention Trial
Fracture Prevention Trial
Hip Intervention Program
Multiple Outcomes of Raloxifene
Evaluation
RECORD Randomised Evaluation of Calcium OR
vitamin D
SOTI
Spinal Osteoporosis Therapeutic Intervention (study)
TROPOS TReatment Of Peripheral OSteoporosis
(study)
VERT MN Vertebral Efficacy with Risedronate
Therapy, Multinational (study)
VERT NA Vertebral Efficacy with Risedronate
Therapy, North America (study)
WHI
Women’s Health Initiative (study)
Prospective data support the concept that the treatment efficacy
and safety of strontium ranelate are not affected by age or by the
duration of the treatment, supporting its use as a first-line agent
in osteoporosis.
Medicographia. 2008;30:393-398.
(see French abstract on page 398)
Keywords: elderly; osteoporosis; underdiagnosis; treatment;
calcium supplementation; vitamin D supplementation;
bisphosphonates; teriparatide, strontium ranelate
www.medicographia.com
Address for correspondence: Steven Boonen, Professor of Medicine, Leuven
University Center for Metabolic Bone Diseases & Division of Geriatric Medicine,
Herestraat 49, B-3000 Leuven, Belgium (e-mail: [email protected])
MEDICOGRAPHIA, VOL 30, No. 4, 2008 393
UPDATE
years, postmenopausal women are more at risk of
sustaining a vertebral fracture than any other type
of osteoporotic fracture, but beyond the age of 70 to
75 years, they become increasingly at risk for hip
fracture and other types of nonvertebral fracture.
In elderly patients, nonvertebral fractures (including hip fracture) account for most of the morbidity and mortality associated with osteoporosis. Within 1 year after sustaining a hip fracture, mortality is
close to 20%, and of those who do survive the fracture, some 20% again will have to be institutionalized because of the fracture and because of its functional consequences.6 Similar observations have
been made for other types of nonvertebral fractures
in elderly patients as well.
lowing hip or vertebral fracture, and 37.2% and
1.2%, respectively, were treated following any first
fracture despite the increased risk of further fracture.12 Even supplementation with calcium and vitamin D is relatively rare in elderly patients following a fracture. In a recent report, only 6% of 170
patients (with a mean age of 80 years) were treated
with calcium and 3% were treated with vitamin D
at admission to hospital with hip fracture; the corresponding figures at discharge were 7% and 4%,
respectively.13
But the lack of awareness of osteoporosis in old
age, both among patients and physicians, is only
part of the problem. The problem is also that clinical trials have failed to address many of the relevant
questions on the management of osteoporosis in old
age. Guidelines from both the European Medicines
Agency and the US Food and Drugs Administration
have emphasized that there is no acceptable basis
for the exclusion of patients because of advanced
age alone or because of underlying comorbidities,
and that attempts should be made to include patients over 75 or even 80 years of age in trials, and
those with concomitant illness or medication. The
fact is, however, that many studies in osteoporosis
have not included patients over the age of 80 years,
or at least not a significant subset of patients over
80 years.
Osteoporosis in old age:
underdiagnosed and undertreated
The awareness of osteoporosis in old age continues
to be unacceptably low, not only among patients but
also among physicians. Numerous guidelines have
emphasized the need to diagnose and treat elderly patients with osteoporosis or those at risk of developing the disease,7,8 but osteoporosis in old age
continues to be underdiagnosed and undertreated.
90
Treatment
80
Medical management
of osteoporosis in old age
DXA
Proportion (%)
70
60
50
40
30
20
10
0
Women
50-64
Women
65-79
Women
80-89
Age (years)
Men
65-79
Men
80-89
Figure 1. The proportion of male and female patients admitted to hospital with
fractures that receives bone mineral density measurement by dual-energy xray absorptiometry (DXA) or pharmacological treatment, according to age.
After reference 10: Feldstein A, Elmer PJ, Orwoll E, Herson M, Hillier T. Bone mineral density measurement and treatment for osteoporosis in older individuals with fractures. Arch
Intern Med. 2003;163:2165-2172. Copyright © 2003, American Medical Association.
Even in older patients admitted to hospital with osteoporotic fractures, physicians continue to underuse the available dual-energy x-ray absorptiometry
equipment and, what is even worse, continue to underuse the available treatment options. Reported
treatment rates for osteoporosis in old age vary from
5% to 69%.9 The paradox is that although age is the
main determinant of the absolute risk of fracture,
treatment rates actually decrease with age (Figure 1).10 Not only have screening and preventative
measures not been incorporated into primary care
practice, many specialists do not even see the need
to investigate or treat osteoporosis in elderly patients.11 In one study conducted in women and men
aged 80 to 89 years, only 2.4% and 1.4%, respectively, had bone mineral density (BMD) scans fol394 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Prospective studies have provided compelling evidence that an excessive rate of bone remodeling is
one of the major determinants of bone loss, irrespective of age,14 and one of the main determinants
of fracture rate, regardless of bone density.15,16 Excessive bone remodeling is partly due to estrogen
and vitamin D deficiency,17-19 and it induces damage
to the microarchitecture of the bone and some
degree of hypomineralization,20 resulting in bone
fragility. While calcium and vitamin D are essential
to reduce bone loss and fractures in older individuals, elderly patients with documented osteoporosis need additional pharmacologic intervention21 to
provide benefit on top of the benefit already provided by calcium and vitamin D. Even in the very
elderly, pharmaceutical interventions seem to remain effective in reducing fracture risk. However,
it should be noted that few studies have specifically addressed the antifracture efficacy of osteoporosis treatment in patients over the age of 80 years
(Table I), because these very elderly patients constitute a frail subset of the elderly population with
the highest absolute risk of all types of osteoporotic
fractures. The notion of frailty is essential, because
it defines the need for treatment options that are
not only effective against vertebral and nonvertebral fractures, but also safe, even in individuals who
have an increased risk of adverse events. In fact,
most elderly patients with established osteoporosis
have multiple comorbid conditions such as gastrointestinal disease and renal insufficiency.24 Providing evidence that administered drugs are both effective and safe in this population is a challenge.
Managing osteoporosis in the elderly – Boonen
UPDATE
Methodology
Study
population
Medication
Dose/day
Duration
(months)
Incidence of fractures:
treatment vs control
Vertebral
Nonvertebral
Post-hoc
analysis
N=1392
Risedronate
age 80 years
(mean 83 years)22
oral 2.5 or
5 mg
12
2.5% vs
10.9%,
(P<0.001)
-
Post-hoc
analysis
N=1392
Risedronate
age 80 years
(mean 83 years)22
oral 2.5 or
5 mg
36
18.2% vs
24.6%,
(P=0.003)
14.0% vs
16.2% (NS)
Prospective
analysis
N=1488
age 80 years
(mean 83 years)23
Strontium
ranelate
oral 2 mg
12
3.5% vs
8.3%,
(P=0.002)
4.0% vs 6.8%
(P=0.027)
Prospective
analysis
N=1488
age 80 years
(mean 83 years)23
Strontium
ranelate
oral 2 mg
36
19.1% vs
26.5%
(P=0.013)
19.7% vs
14.2%
(P=0.011)
Calcium and vitamin D
Calcium and vitamin D are essential for skeletal
maintenance, and deficiencies are widespread in
older individuals.25 Numerous studies have provided compelling evidence that these deficiencies contribute to the increasing prevalence of osteoporosis
with age. As a result of a combination of low calcium intake and lack of vitamin D, many older individuals develop a negative calcium balance that in
turn stimulates the secretion of parathyroid hormone to enhance the production of 1,25 dihydroxyvitamin D, the physiologically active form of
vitamin D. This age-related secondary hyperparathyroidism maintains calcium homeostasis and
normocalcemia, but with excessive bone remodeling and an increased fracture risk as a consequence.
There is now considerable evidence that supplementation with calcium and vitamin D in the very
elderly will attenuate secondary hyperparathyroidism, help to maintain bone quality, and reduce fracture risk.21
The antifracture efficacy of calcium and vitamin D
has been assessed in both community-based and
institutionalized populations. Overall, studies of
supplementation of individuals in the community
have demonstrated smaller reductions in fracture
risk, but the baseline deficiencies in calcium and
vitamin D were less severe. In recent years, the
Randomised Evaluation of Calcium OR vitamin D
(RECORD) and Women’s Health Initiative [WHI]
studies have been among those to have received a
lot of attention, but to some extent, these studies
may have been misinterpreted. In RECORD, a study
involving elderly men and women with a previous
low-trauma fracture (n=5292), there was no difference in the occurrence of new fractures between
those receiving either supplementation or placebo.26
Similar negative results were obtained both for a
trial of oral vitamin D3 and calcium for prevention
of a secondary fracture in women with at least one
risk factor for hip fracture27 and for WHI.28 However, these studies, in particular WHI, involved
younger individuals who often had less severe—if
any — deficiencies of calcium and vitamin D, and
who were living in the community and generally
free of disability. The conflicting results are likely
Managing osteoporosis in the elderly – Boonen
Table I. Overview of
randomized, placebocontrolled clinical
trials of medication
for the prevention of
fractures in elderly
women over the age
of 80 years with documented osteoporosis.
NS, nonsignificant.
to be due, at least in part, to a lack of targeting of
those who do have calcium and vitamin D insufficiencies. The available evidence suggests that supplements should be directed to those individuals
with known insufficiencies or those at most risk of
insufficiencies; unrestricted supplementation in the
community may be unnecessary.21,29 Overall, the
available evidence is consistent with the recommendation to supplement older individuals with
calcium and vitamin D, particularly when their
serum 25-hydroxyvitamin D is less than 50 nmol/L.30
In addition to targeting of supplementation, using
the appropriate dose may be critical as well. Recent
meta-analyses of vitamin D supplementation suggest that a dose of 800 IU/day is required to produce
optimum benefit in terms of a reduction in fracture
risk,31 and that elderly individuals would benefit
most from a combination of calcium and vitamin D
supplementation.32 In an indirect comparison of
randomized controlled trials of vitamin D versus
placebo and vitamin D plus calcium versus placebo,
we recently found that adequate calcium additions
are required to reduce nonvertebral fracture risk
(including hip fracture risk) in older individuals receiving vitamin D.
Bisphosphonates
Although bisphosphonates are widely used in older
patients, few studies have addressed the effects of
these agents in very elderly patients with osteoporosis. In women over 80 years of age with well-defined
osteoporosis (a femoral neck BMD T-score below
2.5 and/or existing vertebral fractures), the efficacy
of risedronate in reducing fracture risk was demonstrated in a post-hoc analysis of data from three
randomized, double-blind, controlled, 3-year, fracture–end point trials (Hip Intervention Program
[HIP], Vertebral Efficacy with Risedronate Therapy,
Multinational [VERT MN], and Vertebral Efficacy
with Risedronate Therapy, North America [VERT
NA]).33-35 For women on risedronate (n=704; 2.5 or
5 mg/day) the risk of new vertebral fractures was
44% lower than for those treated with placebo
(n=688, P=0.003) after 3 years of treatment. Risedronate was well-tolerated and had a safety profile
similar to that of placebo.22 A treatment effect on
MEDICOGRAPHIA, VOL 30, No. 4, 2008 395
UPDATE
nonvertebral fractures could not be documented in
this analysis, although it should be noted that in
VERT and HIP, a statistically significant reduction
in nonvertebral fractures with risedronate treatment had been demonstrated prospectively in patients over a wide range of ages.33-35 Currently, no
analyses have directly documented the efficacy of
bisphosphonates in reducing the risk of nonvertebral fractures in women 80 years of age or older. In
the HIP trial with risedronate, women aged 70 to 79
years with osteoporosis and women aged 80 years
and over with at least one nonskeletal risk factor for
hip fracture, or a low BMD, were assessed. No nonvertebral fracture risk reduction was observed in
women over 80 years of age, but a proportion of
these women may not have been osteoporotic as
most of them had not been selected on the basis of
low BMD.35 The impact of age on the antifracture
efficacy of alendronate was analyzed using data from
a subset of individuals who had been enrolled in
the Fracture Intervention Trial (FIT) and had documented osteoporosis. There was no evidence for
an effect of age regarding the significant reductions
in the relative risk for clinical fractures seen in those
on alendronate (5 mg/day for 2 years followed by
10 mg/day for 1 to 2.5 years) compared with placebo. In fact, the absolute risk reductions for both vertebral and hip fractures in women aged 75 to 85
years with low BMD actually increased with age,
supporting an increase in the cost-effectiveness of
bisphosphonate treatment in older patients. However, a limitation of this analysis was the maximum age of women at entry to FIT (80 years); despite aging during the trial, women over 80 years
of age accounted for less than 8% of the patientyears on which the analysis was based.36 Overall, it
would seem that bisphosphonate treatment efficacy and safety is not affected by age, although compelling evidence to support the efficacy of bisphosphonates in reducing the risk of nonvertebral
fractures in women aged 80 years or more is not
available.
Selective estrogen receptor modulators
With raloxifene or any of the other selective estrogen
receptor modulators, antifracture efficacy has not
been assessed (or at least not reported) in patients
aged 80 years or more. In the large 3-year Multiple
Outcomes of Raloxifene Evaluation (MORE) trial,
postmenopausal women over the age of 80 years
were not enrolled.37 Because prospective evidence
for antifracture efficacy against nonvertebral fractures is not available, raloxifene is primarily used
in patients up to the age of 70 years to reduce the
risk of vertebral fractures.
Teriparatide
Teriparatide is an anabolic agent that enhances bone
formation, resulting in a positive bone balance; this
mechanism of action allows teriparatide to partly
restore damaged bone microarchitecture.38 Its effectiveness has been well-established for both vertebral and nonvertebral fractures in postmenopausal
women, but it has not been extensively studied in
individuals aged 80 years and over.
396 MEDICOGRAPHIA, VOL 30, No. 4, 2008
A post-hoc analysis of data from the randomized,
multicenter, double-blind, placebo-controlled Fracture Prevention Trial (FPT) compared the relative
treatment effect of teriparatide in women aged
younger than 75 years (n=841) and those over 75
years of age (n=244).39,40 Increases in biochemical
markers of bone formation were similar in both age
groups within 1 month after treatment commencement, supporting early bone formation with teriparatide, irrespective of age. Along with the changes
in bone turnover, the increase in BMD was similar in both age groups as well, suggesting that the
treatment response to teriparatide is not blunted
in elderly patients. In line with this, the relative effect of teriparatide in reducing the incidence of vertebral and nonvertebral fragility fractures was statistically indistinguishable in women aged 75 years
and over and those aged less than 75 years in a more
recent analysis.41 A significant reduction in nonvertebral fractures compared with placebo could not
be documented in women over 75 years of age, because the analysis was not sufficiently powered to
assess nonvertebral fracture risk reduction in this
age group. The number of events was relatively small
and the confidence limits correspondingly wide. No
major adverse events occurred in this older age
group, with no increase in the incidence of adverse
events.41
Overall, the data from these analyses support the
concept that the safety and efficacy of teriparatide
in postmenopausal women with osteoporosis is not
affected by age. Because of its ability to stimulate
cancellous and cortical bone formation and to partly restore the microarchitecture of the bone, teriparatide is targeted primarily at patients with a
severe degree of osteoporosis and existing fractures.
In these patients, 12- to 18-months of treatment
with teriparatide should be followed by continuous
treatment with another antiosteoporotic agent.
Strontium ranelate
Strontium ranelate has a distinct mechanism of action that is different from the mechanism of action
of antiresorptives or teriparatide. While antiresorptives inhibit bone turnover and teriparatide stimulates bone turnover, strontium ranelate is the first
agent to induce a dissociation of bone turnover and
to affect bone strength by increasing bone formation and reducing bone resorption.42
In two international, randomized, placebo-controlled, double-blind, fracture–end point studies
(Spinal Osteoporosis Therapeutic Intervention
[SOTI] and TReatment Of Peripheral OSteoporosis
[TROPOS]), strontium ranelate was shown to induce substantial reductions in vertebral and nonvertebral fracture risk, including hip fracture risk,
at different time points (over 1, 3, and 5 years) in
postmenopausal women and across a wide age range
(50-100 years of age).43-45
In a preplanned analysis of women over 80 years
of age (n=1488) who had been enrolled in these studies (Figure 2), strontium ranelate reduced the risk
of vertebral fracture by 59% (relative risk [RR], 0.41;
95% confidence interval [CI], 0.22-0.75; P=0.002)
after 1 year and 32% (RR, 0.68; 95% CI, 0.50-0.92;
Managing osteoporosis in the elderly – Boonen
UPDATE
A
RR: --59%
RR: --32%
P =0.002
P =0.013
Patients with new
vertebral fractures (%)
30
Over 1 year
Over 3 years
26.5 %
25
B
Placebo
Strontium
ranelate
2 g/day
19.1 %
20
15
10
5
0
8.3 %
3.5 %
RR, 0.41; 95% CI,
0.22-0.75
P=0.013) after 3 years, compared with placebo. For
nonvertebral fractures, including hip fractures,
there were substantial reductions of 41% (RR, 0.59;
95% CI, 0.37-0.95; P=0.027) after 1 year and 31%
(RR, 0.69; 95% CI, 0.52-0.92; P=0.011) after 3 years.
Similar findings were observed when combining
the major nonvertebral fractures of hip, wrist, pelvis
and sacrum, ribs-sternum, clavicle, and humerus,
with a RR compared with placebo of 37% (P=0.003)
after 3 years.23
Recent and unpublished data from continuous
blinding of women over 80 years of age participating in TROPOS provide evidence for sustained treatment efficacy over 5 years against vertebral and nonREFERENCES
1. Ettinger MP. Aging bone and osteoporosis: strategies for preventing fractures in the elderly. Arch Intern Med. 2000;163:2237-2246.
2. Palvanen M, Kannus S, Niemi S, Parkkari J. Secular trends in the osteoporotic fractures of the distal
humerus in elderly women. Eur J Epidemiol. 1998;
14:159-164.
3. Autier P, Haentjens P, Bentin J, et al; the Belgium
Hip Fracture Study Group. Costs induced by hip fractures: a prospective controlled study in Belgium. Osteoporos Int. 2000;11:373-380.
4. European Prospective Osteoporosis Study (EPOS)
Group. Incidence of vertebral fracture in Europe: results from the European Prospective Osteoporosis
Study (EPOS). J Bone Miner Res. 2002;29:517-522.
5. Pluijm SMF, Tromp AM, SMit JH, Deeg DJ, Lips P.
Consequences of vertebral deformities in older men
and women. J Bone Miner Res. 2000;15:1564-1572.
6. Boonen S, Autier P, Barette M, Vanderschueren D,
Lips P, Haentjens P. Functional outcome and quality
of life following hip fracture in elderly women: a prospective controlled study. Osteoporos Int. 2004;15:
87-94.
7. Gourlay M, Richy F, Reginster JY. Strategies for the
prevention of hip fracture. Am J Med. 2003;115:309317.
8. Cadarette SM, Jaglal SB, Kreiger N, McIsaac WJ,
Darlington GA, Tu JV. Development and validation of
the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry.
Can Med Assoc J. 2000;162:1289-1294.
9. Briancon D, de Gaudemar JB, Forestier R. Management of osteoporosis in women with peripheral osteoporotic fractures after 50 years of age: a study of
practices. Joint Bone Spine. 2004;71:128-130.
10. Feldstein A, Elmer PJ, Orwoll E, Herson M, Hillier
T. Bone mineral density measurement and treatment
for osteoporosis in older individuals with fractures.
Arch Intern Med. 2003;163:2165-2172.
11. Sheehan J, Mohamed F, Reilly M, Perry IJ. Sec-
Managing osteoporosis in the elderly – Boonen
RR: --41%
RR: --31%
P =0.027
P =0.011
25
19.7 %
20
14.2 %
15
10
6.8 %
5
0
RR, 0.68; 95% CI,
0.50-0.92
Over 3 years
30
Patients with new
nonvertebral fractures (%)
Over 1 year
4.0 %
RR, 0.59; 95% CI,
0.37-0.95
RR, 0.69; 95% CI,
0.52-0.92
Figure 2. Antifracture
efficacy of strontium
ranelate in a post–80year-old population for
(A) vertebral and (B)
nonvertebral fractures,
over 1 and 3 years.
RR, relative risk.
After reference 23: Seeman
E, Vellas B, Benhamou CL,
et al. Strontium ranelate reduces the risk of vertebral
and non-vertebral fractures
in women aged eighty years
and over. J Bone Miner Res.
2006;21:1113-1120. Copyright
© 2006, American Society for
Bone and Mineral Research.
vertebral fractures in these elderly patients.46 With
these results, strontium ranelate is the first antiosteoporotic treatment to demonstrate the ability
to provide an early and long-term sustained reduction in vertebral and nonvertebral fractures in very
elderly patients aged over 80 years. Even in these
frail elderly patients with underlying comorbidities,
no major safety issues could be identified. Taken together, these findings support the concept that the
treatment efficacy and safety of strontium ranelate
is not affected by age nor by the duration of the
treatment, thus supporting its use as a first-line
agent across the osteoporosis continuum, even in
the oldest of the old. ondary prevention following fractured neck of femur:
a survey of orthopaedic surgeons practice. Irish Med J.
2000;93:105-107.
12. Feldstein AC, Nichols GA, Elmer PJ, Smith DH,
Aickin M, Herson M. Older women with fractures:
patients falling through the cracks of guideline-recommended osteoporosis screening and treatment.
J Bone Joint Surg Am. 2003;85-A:2294-2302.
13. Kamel HK, Hussain MS, Tariq S, Perry HM, Morley JE. Failure to diagnose and treat osteoporosis in
elderly patients hospitalized with hip fracture. Am J
Med. 2000;109:326-328.
14. Bauer DC, Sklarin PM, Stone KL, et al. Biochemical markers of bone turnover and prediction of hip
bone loss in older women: the study of osteoporotic
fractures. J Bone Miner Res.1999;14:1404-1410.
15. Garnero P, Sornay-Rendu E, Claustrat B, Delmas
PD. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner
Res. 2000;15:1526-1536.
16. Garnero P, Hausherr E, Chapuy MC, et al. Markers of bone resorption predict hip fracture in elderly
women: the EPIDOS Prospective Study. J Bone Miner
Res. 1996;11:1531-1538.
17. Ettinger B, Pressman A, Sklarin P, Bauer DC, Cauley JA, Cummings SR. Associations between low levels
of serum estradiol, bone density, and fractures among
elderly women: the Study of Osteoporotic Fractures.
J Clin Endocrinol Metab. 1998;83:2239-2243.
18. Cummings SR, Black DM, Nevitt MC, et al; the
Study of Osteoporotic Fractures Research Group. Bone
density at various sites for prediction of hip fractures.
Lancet. 1993;341:72-75.
19. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for
bone loss and fractures and therapeutic implications.
Endocr Rev. 2001;22:477-501.
20. Mori S, Harruff R, Ambrosius W, Burr DB. Trabecular bone volume and microdamage accumula-
tion in the femoral heads of women with and without femoral neck fractures. Bone. 1997;21:521-526.
21. Boonen S, Vanderschueren D, Haentjens P, Lips P.
Calcium and vitamin D in the prevention and treatment of osteoporosis — a clinical update. J Int Med.
2006;259:539-552.
22. Boonen S, McClung MR, Eastell R, El-Haij Fulaihan G, Barton IP, Delmas P. Safety and efficacy of
risedronate in reducing fracture risk in osteoporotic
women aged 80 and older: implications for the use of
antiresorptive agents in the old and oldest old. J Amer
Geriatr Soc. 2004;52:1832-1839.
23. Seeman E, Vellas B, Benhamou CL, et al. Strontium ranelate reduces the risk of vertebral and nonvertebral fractures in women aged eighty years and
over. J Bone Miner Res. 2006;21:1113-1120.
24. Lindeman RD, Tobin J, Shock NW. Longitudinal
studies on the rate of decline in renal function with
age. J Am Geriatr Soc.1985;33:278-285.
25. Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitamin D insufficiency in an adult normal
population. Osteoporos Int.1997;7:439-443.
26. The RECORD Trial Group. Oral vitamin D and calcium for secondary prevention of low-trauma fractures in elderly people: a randomised placebo-controlled trial. Lancet. 2005;365:1621-1628.
27. Porthouse J, Cockayne C, King C, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention
of fractures in primary care. BMJ.2005;330:1003-1008.
28. Jackson RD, LaCroix AZ, Gass M, et al. Calcium
plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.
29. Boonen S, Bischoff-Ferrari A, Cooper C, et al. Addressing the musculoskeletal components of fracture
risk with calcium and vitamin D: a review of the evidence. Calcif Tissue Int. 2006;78:257-270.
30. Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al.
Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both
MEDICOGRAPHIA, VOL 30, No. 4, 2008 397
UPDATE
active and inactive persons aged 60 y. Am J Clin
Nutr. 2004;80:752-758.
31. Bischoff-Ferrari HA, Willett WC, Wong JB, et al.
Fracture prevention with vitamin D supplementation:
a meta-analysis of randomized controlled trials JAMA.
2005;294:2257-2264.
32. Boonen S, Lips P, Bouillon R, et al. Need for additional calcium to reduce the risk of hip fracture with
vitamin D supplementation: evidence from a comparative meta-analysis of randomized controlled trials.
J Clin Endocrinol Metab. 2007;92:1415-1423.
33. Harris ST, Watts NB, Genant HK, et al; the Vertebral Efficacy with Risedronate Therapy (VERT) Study
Group. Effects of risedronate treatment on vertebral
and nonvertebral fractures in women with postmenopausal osteoporosis: a randomised controlled trial.
JAMA.1999;282:1344-1352.
34. Reginster J, Minne HW, Sorensen OH, et al; the
Vertebral Efficacy with Risedronate Therapy (VERT)
Study Group. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int.
2000;11:83-91.
35. McClung MR, Guesens P, Miller PD, et al; the Hip
Intervention Program Study Group. Effect of rise-
PRISE
dronate on the risk of hip fracture in elderly women.
N Engl J Med. 2001;344:333-340.
36. Hochberg MC, Thompson DE, Black DM, et al. Effect of alendronate on the age-specific incidence of
symptomatic osteoporotic fractures. J Bone Miner Res.
2005;20:971-976.
37. Ettinger B, Black DM, Mitlak BH, et al; Multiple
Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with
raloxifene: results from a 3-year randomized clinical
trial. JAMA.1999;282:637-645.
38. Dempster DW, Cosman F, Parisien M, Shen V,
Lindsay R. Anabolic actions of parathyroid hormone
on bone. Endocr Rev. 1993;14:690-709.
39. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of
parathyroid hormone (1-34) on fractures and bone
mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434-1441.
40. Marcus R, Wang O, Satterwhite J, Mitlak B. The
skeletal response to teriparatide is largely independent
of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis. J Bone Miner Res. 2003;18:18-23.
41. Boonen SJ, Marin F, Mellstrom D, et al. Safety and
efficacy of teriparatide in elderly women with established osteoporosis: bone anabolic therapy from a geriatric perspective. J Am Geriatri Soc. 2006;54:782-789.
42. Marie PJ. Optimizing bone metabolism in osteoporosis: insight into the pharmacologic profile of
strontium ranelate. Osteoporos Int.2003;14(suppl 3):
S9-S12.
43. Meunier PJ, Roux C, Seeman E, et al. The effects
of strontium ranelate on the risk of vertebral fracture
in women with postmenopausal osteoporosis. N Engl
J Med. 2004;350:459-468.
44. Reginster JY, Seeman E, De Vernejoul MC, et al.
Strontium ranelate reduces the risk of non vertebral
fractures in postmenopausal women with osteoporosis: Treatment Of Peripheral Osteoporosis (TROPOS)
Study. Endocrinol Metab. 2005;90:2816-2822.
45. Reginster JY, Meunier PJ, Roux C, et al. Strontium
ranelate: an anti-osteoporotic treatment demonstrated vertebral and nonvertebral anti-fracture efficacy
over 5 years in post-menopausal osteoporotic women.
Osteoporos Int. 2006;17(suppl 2):S14(OC24).
46. Seeman E, Vellas B, Benhamou CL, et al. Sustained
5-year vertebral and non-vertebral fracture risk reduction with strontium ranelate in elderly women with
osteoporosis. Osteoporos Int. 2006;18:1-13(OC39).
EN CHARGE DE L’OSTÉOPOROSE CHEZ LE SUJET ÂGÉ
L
es fractures ostéoporotiques du sujet âgé sont un problème
majeur de santé publique. Les fractures vertébrales entraînent souffrance et perte significative de qualité de vie
mais, chez les sujets âgés, les fractures non vertébrales sont responsables de la majeure partie de la morbidité, la mortalité et des
coûts engendrés par l’ostéoporose. Bien qu’il soit connu que les
femmes âgées de 75 à 80 ans ont le plus gros risque de fracture,
l’ostéoporose à un âge élevé reste sous-diagnostiquée et sous-traitée. Les données récentes sur le ranélate de strontium montrent
398 MEDICOGRAPHIA, VOL 30, No. 4, 2008
que même des sujets très âgés pouvaient tirer bénéfice des options thérapeutiques actuelles. Chez les patients âgés, la perte osseuse peut être stoppée et le risque fracturaire diminué par un
apport en calcium et en vitamine D, et par un traitement pharmacologique par bisphosphonates, tériparatide ou ranélate de
strontium. Des données prospectives sont en faveur de l’utilisation du ranélate de strontium comme traitement de première intention, l’âge ou la durée du traitement n’influant pas sur son
efficacité et sa sécurité d’emploi.
Managing osteoporosis in the elderly – Boonen
A
T
O U C H
O F
F
R A N C E
Christian RÉGNIER, MD
Praticien Attaché Consultant, Hôtel-Dieu, Paris
Société Internationale d’Histoire de la Médecine
9 rue Bachaumont, 75002 Paris, FRANCE
(e-mail: [email protected])
Mountains, balloons, and flying machines
Paul Bert and the birth
of aviation medicine
in France
b y C . R é g n i e r, F r a n c e
T
here are two distinct emphases in the history of aviation medicine: (i) the identification and
elucidation of human physiological adaptation to the specific conditions of altitude, namely hypoxia and low atmospheric pressure; and (ii) the study of man’s physical ability to fly for extended
periods. Each technical advance in lighter and heavier-than-air flying machines subjected the human
body to fresh challenges that physicians and physiologists were forever seeking to resolve. But long before Icarus’ dream became true humans—or at least the bravest and most inquisitive among them—
got a first glimpse of the heavens by adventuring themselves on the slopes of mountains. Some came back
with strange tales.
From Olympus to the Andes: mountain sickness or the downside of going up
Writings attributable to Aristotle (384-322 BC) describe the difficulties experienced by his contemporaries
when climbing sacred Mount Olympus (2917 meters): “because the rarity of the air which was there did not
fill them with breath, they were not able to survive unless they applied moist sponges to their noses.”1
China under Emperor Ching-Te (37-32 BC) recognized two types of mountain: those causing a “great
headache” and those causing a “little headache.” A civil servant offered this warning to a general preparing
to march westward toward Tibet and Xinjiang:
T
he hot-air balloons of the late 18th century were the first step in man’s conquest of flight. These
lighter-than-air flying machines introduced humans to subnormal levels of oxygen, atmospheric pressure, and temperature. The second half of the 19th century, in particular with the work of Paul
Bert, saw the beginning of research into adaptation and survival at altitude, with physiological studies of the “mountain sickness” whose main features had been familiar for centuries. Aviation medicine
proper came into being in the early 20th century with the development of the first heavier-than-air machines. “Altitude sickness” became a major focus of study. The potential of the rapid advance in aircraft
development could only be exploited by pushing back the limits of human physiology with the aid of pilotprotective devices. Military imperatives in the First World War spurred progress in aircrew selection criteria, pilot performance, and the prevention of “aviation sickness.” It was natural that France, as perhaps
the leading country in the development of lighter and heavier-than-air machines, should also have been in
the forefront of aviation medicine. René Cruchet and René Moulinier’s Air sickness: its nature and treatment provided a clinical extension to Paul Bert’s pioneering physiological studies and rapidly became the
new specialty’s international reference work in the interwar years.
www.medicographia.com
Medicographia. 2008;30:399-408.
The history of aviation medicine in France – Régnier
(see French abstract on page 408)
MEDICOGRAPHIA, VOL 30, No. 4, 2008 399
A T
OUCH
OF
FRANCE
Mount Olympus, physical,
the tallest mountain in Greece
(2917 m), and spiritual abode of the
Greek Pantheon (Twelve Olympian
Gods). From Mont Olympus came
the first historically reported
reference to mountain sickness,
by Aristotle (4th century BCE).
Photo © Hervé Champollion/akgimages; Painting by Merry Blondel
Joseph (1781-1853), oil on canvas
4054 cm. Dispute between
Minerva and Neptune over the
fate of Athena. Musée du Louvre,
Paris. © RMN/ Gérard Blot.
On passing the Great Headache Mountain and the Little Headache Mountain, the Red Land and the Fever Slope,
men’s bodies become feverish, they lose color, and are attacked with headache and vomiting… Men lose their
faculties for understanding and are no longer capable of coming to each other’s assistance.
The syndrome experienced when crossing the mountains of Kashmir or Tibet—exhaustion, sleep disturbance, vomiting, swelling of the hands and feet—was known in Mongolian as yas. Tibetan has two terms
for mountain sickness: damgri (respiratory attack) and dugri (mountain poison).1,2
Observations of mountain sickness can be found scattered in the accounts of travelers’ to the Andes.
In 1590, the Spanish missionary José d’Acosta (1539-1600) reported his stay in Lima in his Naturall and
Morall Historie of the East and West Indies:
There is in Peru, a high mountaine which they call Pariacaca, and having heard speake of the alteration it bred,
I went as well prepared as I could, according to the instruction which was given me… but not withstanding
all my provision, when I came to mount the degrees, as they call them, which is the top of this mountain, I
was suddenly surprized with so mortall and strange a pang, that I was ready to fall from the top to the ground:
and although we were many in company, yet every one made haste (without any tarrying for his companion),
to free himself speedily from this ill passage. Being then alone with one Indian, whom I intreated to helpe to
stay me, I was surprised with such pangs of straining and casting, as I thought to cast up my heart too; for
having cast up meate, fleugme, & choller, both yellow and greene; in the end I cast up blood, with the straining of my stomacke… Some in the passage demanded confession, thinking verily to die; others left the ladders
and went to the ground, being overcome with casting, and going to the stoole: and it was tolde me, that some
have lost their lives there with this accident… And not only the passage of Pariacaca hath this propertie, but
also all this ridge of the mountaine, which runnes above five hundred leagues long… I therefore persuade
my selfe, that the element of the aire is there so subtile and delicate, as it is not proportionable with the breathing of man, which requires a more grosse and temperate aire.3
400 MEDICOGRAPHIA, VOL 30, No. 4, 2008
The history of aviation medicine in France – Régnier
A TOUCH
OF
FRANCE
Ascent of Mont Blanc (Savoie, France) by
Horace-Bénédict de Saussure in August 1787.
Color print by Christian von Mechel (1737-1817).
Fitzwilliam Museum, University of Cambridge, UK.
© Bridgeman Art Library.
On August 8, 1786, Jacques Balmat, a crystal collector and chamois hunter, and MichelGabriel Paccard, a Chamonix doctor, made the
first recorded ascent of Mont Blanc (4807 meters). They attributed their malaise during the
ascent to “the heat and stagnation of the air.”
The following year, the Genevan botanist, geologist, and physicist Horace-Bénédict de Saussure — who recounted his experience in his
4 volume and 2300 pp Voyage Dans les Alpes—ascended Mont Blanc to carry out several scientific experiments on the summit. He made seven trips into the Alps and stayed for 22 days in the Mont Blanc area.
On his third ascent, de Saussure experienced extreme fatigue:
When I began this ascent, I was already quite out of breath from the rarity of the air... The kind of fatigue which
results from the rarity of the air is absolutely unconquerable; when it is at its height, the most terrible danger
would not make you take a single step further… I… hoped to reach the crest in less than three quarters of
an hour; but the rarity of the air gave me more trouble than I could have believed… This need of rest was absolutely unconquerable; if I tried to overcome it, my legs refused to move, I felt the beginning of a faint, and
was seized by dizziness. [Once at the summit], when I had to get to work to set out the instruments and observe
them, I was constantly forced to interrupt my work and devote myself entirely to breathing.4
Lighter than air: the first hot air balloons
Altitude symptoms also afflicted balloonists. After the Montgolfier brothers’ first experiments in 1783,
ballooning rapidly caught the attention of physicians. Pioneers in the 18th century included the naturalist Jean-François Pilâtre du Rozier, the principal pharmacist of the Salpêtrière Hospital Louis Joseph
Proust, the American army surgeon John Jeffries, the Scottish ship surgeon James Tytler, and John Sheldon, professor of anatomy at the Royal Society of Medicine
in London. The balloons were capable of ascending to
3000 meters, and even way beyond. The record was set by
the English meteorologist James Glaisher and his copilot Henry Coxwell who in 1862 soared to 8840 meters, at
which point Glaisher passed out in the basket and was only
saved by Coxwell who, unable to use his frost-bitten fingers, released the gas valve with his teeth. The symptoms
experienced during balloon ascents resembled those reported by mountaineers: nausea, dizziness, barometric otitis, exhaustion, tachycardia, tachypnea, frostbite, transient
paralysis, and loss of consciousness.4,5
Paul Bert: science takes its first look at altitude
sickness
The French physiologist Paul Bert (1833-1886), who had
studied under Claude Bernard, conducted the first serious investigations into the cardiovascular effects of compression and decompression. He became celebrated for his
work on anesthetics, animal grafts, and respiratory physiology. Subsequently he went into politics, became minister of education in 1881, and 5 years later governor-general of Annam and Tonkin (former names of modern north
and central Vietnam).
The first hot-air balloon ascent by the Montgolfier brothers
(whence the French word derives from: montgolfière) on
19 September 1783 at the chateau of Versailles. Colored
engraving, Rothschild collection, Musée du Louvre, Paris.
© RMN/Michel Bellot.
The history of aviation medicine in France – Régnier
MEDICOGRAPHIA, VOL 30, No. 4, 2008 401
A T
OUCH
OF
FRANCE
French physiologist, physician, politician, and diplomat
Paul Bert (1833-1886). He made major discoveries concerning
barometric pressure and described the toxicity of oxygen at hyperbaric pressure. Other major discoveries concerned anesthesia.
His work made both aviation and diving medicine possible.
Portrait by Mascre Souville (19th century). Oil on canvas.
Musée du quai Branly. © Bridgeman Art Library.
His respiratory physiology studies focused on anoxemia.
On June 8, 1876, he lectured on Air pressure and living creatures at the Society of Friends of the Sciences. Around 1865,
Dr Denis Jourdanet had described the effects of altitude on
human health after conducting a number of scientific expeditions in the mountains of America and Asia. His hypothesis
was that mountain sickness was due to a decrease in atmospheric pressure at altitude and to the rarity of oxygen in the
air. Paul Bert referred to Jourdanet’s observations and those of
Montgolfier on the dizziness experienced by balloonists. Until
then, the prevailing belief was that altitude sickness was due solely to a decrease in barometric pressure.5,6
Paul Bert’s many experiments in his Sorbonne laboratory proved that the clinical symptoms of mountain
sickness were due to a decrease in the partial pressure of oxygen. His early work in birds showed a correlation between hemoglobin oxygen saturation and the partial pressure of oxygen in ambient air.
It is thus perfectly clear that it is not the decrease in mechanical pressure that causes these accidents, but
indeed the decrease in the oxygen tension of the expanded air. It is this decrease that prevents oxygen from
entering the blood in sufficient amounts.
Paul Bert investigated the effects of decreased barometric pressure and oxygen inhalation by perfecting
and standardizing a bell-jar chamber evacuated with a pump that had originally been introduced in 1848.
He fitted it with a device supplying controlled amounts of oxygen and tested it on himself.
I entered the chamber with a supply of oxygen in a large rubber bag. Then, as the [vacuum] pump began to
work, I experienced the classic decompression accidents… I felt myself becoming indifferent to everything
and incapable of thought or action… I tried to multiply by 3, but could not, and had to write on my pad “too
difficult!” Yet all these accidents disappeared as if by magic as soon as I breathed oxygen from my bag, and they
came back again when I breathed ordinary air.
Paul Bert recorded his pulse and respiratory rate at rest and after exertion while inhaling oxygen intermittently.
This is, let me say in passing, an experiment that I do not intend to repeat, having experienced mild congestive phenomena in the evening that I attributed to these sudden changes in cerebral circulation.5
Paul Bert’s landmark experiments on anoxemia. Left, with a bird in bell jar subjected to increasing depressurization to 18 cm H2O by suction of air through tube B. The bird “staggers, stumbles, and falls on its side.” Oxygen is
then introduced from pouch O through tube D, and the bird comes back to life, even though barometric pressure
inside the bell jar continues to fall. Tube C and mercury manometer E serve to set oxygen pressure in air to that
existing at specified altitudes. Right, Paul Bert tries same experiment on himself (see description in text). Engravings from the Traité de Physique Biologique [Treatise of Biological Physics], volume 1, by d’Arsonval, Chauveau,
Gariel, and Marey. Paris, France: Masson, 1901. © Bibliothèque Inter-Universitaire de Médecine (BIUM), Paris.
402 MEDICOGRAPHIA, VOL 30, No. 4, 2008
The history of aviation medicine in France – Régnier
A TOUCH
OF
FRANCE
Paul Bert did, however, repeat this experiment with two famous balloonists, Joseph Croce-Spinelli and
Théodore Sivel, who were preparing an attack on the altitude record. Paul Bert explained to them how
to combat the effects of hypoxia at altitude “by breathing oxygen.” Both men died of hypoxia on April 15,
1875 when their balloon the Zenith reached 8600 meters, leaving Gaston Tissandier as the sole survivor.
They had not consulted Paul Bert for that particular expedition, yet he suspected it would have probably
not helped if they had.
I was not in Paris, and unlike on the first occasion, I was unable to supervise the installation of the oxygen
bottles. I would certainly have made them take bigger ones; but in all likelihood I would have failed to predict
the cause of the catastrophe we now know of. The oxygen tube dangled some distance above their heads; knowing they had only a limited supply of this gaseous cordial, they kept it in reserve for the moment when the
sickness would strike most strongly; and when they tried to seize hold of the life-saving nozzle and bring it
to their mouths, their arms were already paralyzed.5
In 1878, Paul Bert published Barometric pressure. Researches in experimental physiology.5 As the first
study devoted exclusively to anoxemia, it enabled the “ascensionists” and “aeronauts” of the late 19th century to tackle summits (the Himalayas) and high altitudes (12 000 meters) with confidence.
Those magnificent men in their flying machines
Leonardo da Vinci began drawing flying machines
around 1485, inspired by his observations of birds.
They were designed to be propelled by human muscle
power, although there is no reliable evidence that any
were tested. Leonardo later devised a helical screw (or
prototype helicopter) which also remained at the sketch
and model stage.
Several types of glider were designed and built in the
early 19th century. Jean Le Bris patented a mobile-wing
contraption with albatross-inspired aerodynamics in
1857 and flew for some 60 meters in Douarnenez bay
(Brittany), earning himself, in the eyes of some, the title of first aviator. The journalist and novelist Gabriel
de La Landelle, himself the designer of a steam-engined
helicopter, described this first air flight in 1863 in his
book, Aviation or balloon-free air navigation, in which
he coined the neologism “aviation” from avis (bird) and
actio (action).7,8
Historians continue to debate whom to credit with
the first motorized flight. Even the term “flight” is not
clearly defined, other than the requirement that landing be at a level no lower than that of takeoff: absence
of contact with the ground over what distance? with/
without external assistance on takeoff? with/without
pilot control of the trajectory? Such uncertainties mean
that several candidates can claim to have pioneered
motor-powered flight:
On October 9, 1890, in the grounds of the château
Taking the leap: Clément Ader’s bat-winged plane, for which he coined
the word “avion.” This plane, one of the very first to deserve the name,
of Armainvilliers, east of Paris, Clément Ader flew the
can be seen in Paris, at the Musée des Arts et Métiers. Photo and photoÉole, a bat-winged contraption with a 4-blade propeller,
montage © Roby/© Musée des Arts et Métiers. All rights reserved.
20 cm above the ground over 50 meters. Financed by
the Ministry of Defense, he then built the Éole II powered by a 2-cylinder 20-hp steam engine weighing
35 kg. It has been claimed that Ader coined the French word “avion” (airplane) as an acronym for “appareil volant imitant l’oiseau naturellement” (flying machine imitating birds naturally).
On December 17, 1903, on the dunes of Kitty Hawk (North Carolina), Orville Wright flew the Flyer
39 meters for 12 seconds. Built with his brother Wilbur, the Flyer weighed 274 kg, and was powered by
a 12-hp motor driving two propellers. In some of the brothers’ subsequent flights, from 1904 onwards, takeoff was assisted (depending on wind conditions) by catapulting the contraption along a rail.
On March 18, 1906, at Montesson, near Paris, the Romanian pilot Traian Vuia flew for 12 meters at a
height of 1 meter in the Traian Vuia I, a machine weighing 195 kg powered by a 20-hp engine and a single
propeller, that was able to take off unassisted.
The history of aviation medicine in France – Régnier
MEDICOGRAPHIA, VOL 30, No. 4, 2008 403
A T
OUCH
OF
FRANCE
On October 23, 1906, in the Bagatelle park by the Porte Maillot in Paris, the Brazilian Alberto Santos-
Dumont flew 60 meters in the 14 bis, a biplane driven by a 50-hp gas-powered engine, also capable of unassisted takeoff. On November 12, 1906, he covered 220 meters in 21 seconds (41.3 km/h), setting the world’s
first aviation record.8,9
The French Aero Club was established in 1898 and the International Aeronautical Foundation in 1905.
Prizes, trophies, and competitions grew in number. The first international aviation meeting was held in
Reims from August 22 to 29, 1909; the greatest pilots took part, in front of almost 1 million spectators.
Paris was considered the capital of the aviation world. In 1911, 1350 flying machines were built worldwide,
and some 12 000 aviators notched up a total of 13 000 flights. That same year, as manufacturers began to
replace wood with metal, air power was put to military use for the first time, in the Tripolitanian war between Italy and the Ottoman Turks.2,8-10
Aviation research advanced in leaps and bounds up to the First World War in many countries. Endurance
records were constantly broken, altitudes of 3000 meters were commonly exceeded, and on-board instrumentation improved safety and navigation. Airplanes (as flying machines were coming to be known) began
carrying passengers and mail. Helmets and harnesses were developed to protect pilots from head injury
on landing or ejection from their machines. At the same time, faster ascents, improved accelerations, and
nosedive turns compounded the symptoms commonly experienced at altitude.8-11
Airplanes were increasingly used in the First World War. The leading combatants built up air forces consisting of production-line fighters, reconnaissance aircraft, and bombers. However, at the War’s outbreak,
airplanes were used only for reconnaissance, flying at 80 to 120 km/h and no higher than 3000 meters.
France entered the War with 158 airplanes and finished it with 11 836, manned by 150 000 aircrew, and capable of speeds exceeding 200 km/h and altitudes exceeding 6000 meters. Around 7800 French aviators died
during the 4 years of the War. In the same 4 years, the French built 51 040 airplanes and 92 000 engines
(many delivered to the British and Americans), and the Germans 48 537 airplanes and 41 000 engines.8-10,12
MILESTONES IN ALTITUDE PHYSIOLOGY
1648 Blaise Pascal (1623-1662) shows that atmospheric
pressure decreases with altitude.
1660 Sir Robert Boyle (1627-1691), the Irish physician,
chemist, and philosopher, publishes his New Experiments Physico-Mechanical, Touching the Spring of
the Air, and its Effects.
1777 The French chemist, Antoine Laurent de Lavoisier
(1743-1794), names and recognizes oxygen and describes its role in combustion and the respiration of
living creatures.
1784 In Montpellier Louis Leulier Duché publishes the first
study of medical conditions in balloonists.
1878 Paul Bert publishes La Pression Barométrique [Barometric Pressure], considered the first reference work
on the effects of decreased atmospheric pressure on
the body. He proves that the real cause of altitude
sickness is the fall in oxygen partial pressure.
1879 The British mountaineer Edward Whymper (1840-1911)
divides altitude sickness symptoms into those that
are “permanent” (loss of appetite, fatigue, increased
respiratory rate) and those that are “transient” (increases in blood pressure, body temperature, and
heart rate).
1890 François Gilbert Viault concludes from studies in the
Andes that altitude stimulates erythropoiesis.
1898 Angelo Mosso (1846-1910), professor of physiology in
Turin, builds an altitude laboratory on the summit of
Mount Rose (4553 meters). He believed that altitude
sickness was due to a fall in the partial pressure of
404 MEDICOGRAPHIA, VOL 30, No. 4, 2008
1919
1919
1920
1967
1979
1996
1997
1999
CO2 in the blood, and gave a complete clinical description of high-altitude pulmonary edema.
Alexander M. Kellas (1868-1921), a London physiologist
and professor of chemistry, takes part in eight Himalayan expeditions, and becomes the first physiologist
to analyze exercise-limiting factors at extreme altitudes.
Drs André Broca and Paul Garsaux devise a suit to
protect pilots’ abdominal walls from the effects of
centrifugal force.
Sir Joseph Barcroft (1872-1947) publishes the results
of a 6-day decompression chamber study he performed
on himself.
A permanent laboratory is set up at 5300 meters on
Mount Logan in Alaska.
J. L. Kobrick and J. B. Sampson devise an altitude
symptom questionnaire: the Environmental Symptoms Questionnaire (ESQ).
Dr Urs Scherrer shows that inhaling nitrous oxide in
high-altitude pulmonary edema lowers pulmonary
artery pressure, improves oxygenation, and shifts pulmonary blood flow toward the nonedematous region.
In Jean-Paul Richalet’s Everest III study in Marseille,
eight subjects live for a month in a chamber that is
incrementally depressurized until it reaches the virtual Everest summit.
Robert Roach, Charles Houston, Peter Hackett, and
Jean-Paul Richalet set up a Web site containing over
6000 literature references on altitude physiology and
medicine.
The history of aviation medicine in France – Régnier
A TOUCH
OF
FRANCE
World War I and the birth of aviation medicine
The German armed forces set up an air force health service in 1910. Aviation medicine research centers
were founded, such as the Royal Flying Corps Physiological Laboratory in London and the Air Medical Research Laboratory on Long Island. In 1910, two Bordeaux professors, the pathologist Jean-René Cruchet
and the naval surgeon René Moulinier, devoted an article solely to air sickness, a term which in various
forms (aviator’s/aviation sickness) became common in French and English-language works in the early
20th century. Aviation medicine was born, exploring six main avenues of research: physiology, clinical
medicine, psychology, cockpit/cabin habitability, ergonomics, and pilot selection. In their article, which
was subsequently expanded into a hugely influential and rapidly translated book,13 Cruchet and Moulinier
provided detailed descriptions of the effects of altitude on the nervous system, psychology, hemodynam-
Left: World War I pilot in 1914 donning an oxygen mask designed by Dr Paul Garsaux. The mask had an in-built
heating system to avoid the breathed-out water vapor turning to ice. Right: Oxygen regulator for Dr Paul Garsaux’s
automatic oxygen inhaler for air pilots. The oxygen breathing system consisted of a mask, a regulator, and oxygen
bottle. The first regulator (show here), built by Panhard et Levassor, was in two parts, a barometric capsule (left,
C), which moved a lever (L) that let in more or less oxygen from the bottle (attached to K) into the regulator
chamber (right, H). From: Garsaux P. Inhalateurs d’oxygène pour les hautes altitudes de l’aviation. La Nature,
22 March 1926; No. 2712. © La Nature.
ics, and cardiac, pulmonary, and vestibular function. Dr Paul Garsaux, head of the civil aviation medical
service, established a decompression chamber at Le Bourget airfield that mimicked variations in altitude
up to 12 000 meters at --10°C. His initial findings were that fat men coped less well with altitude than thin
wiry men, and that impulsive characters were the first to succumb to air sickness. Garsaux developed the
first automatic oxygen inhaler to be made in France, the Altitudo, fitted with a visual flow display and an
oronasal mask. It was taken up by all the allied air forces.12-15
In 1911, a study by Major Renard, one of Ader’s associates, revealed that 25% of flying accidents were
due to “poor natural ability on the part of the pilot.” It showed that physical ability was essential in piloting military aircraft. The ministerial circular of September 2, 1912, added conditions to the fitness for military service required of pilots: good eyesight, normal cardiorespiratory function, and a “robust aboveaverage constitution.” The circular was supplemented on January 23, 1914, by a directive on the physical
fitness required by aircraft and airship pilots. However, because of the lack of both specialist physicians
and a properly structured aviation medical service, these selective criteria were never enforced on French
pilots during the War.12,16,17
French pilots were recruited from army personnel unfit to serve in the infantry or artillery. At the start
of the War, the need to boost pilot numbers was such that all volunteers were accepted without any medical selection. A 1916 British study revealed that of 100 aviators killed on the front, three were downed in
battle, seven died as a result of mechanical failure, 30 as a result of pilot error, and 60 as a result of some
momentary physical failing.
Aviation medicine functioned precariously throughout the War. Two ministerial circulars in March and
December 1916 made an intensified medical selection mandatory, along with regular follow-up, including cardiovascular, cardiorenal, bronchopulmonary, gastrointestinal, and neurological examination. But
these measures were no more implemented than their predecessors. The only investigation that appears
to have been practiced routinely related to vision: visual fields, color vision, and binocular vision.2,12,16,18
By 1916, aviators were regularly exceeding altitudes of 5000 meters. Hypoxic reactions became more frequent and severe. On September 16, 1917, Dr Georges Ferry, a 3rd army pilot-physician, drafted a memo to
the undersecretary of state for aviation: Proposal for an air force medical service. Dr Ferry had already
carried out many studies of air sickness. He suggested making a clear distinction between pilot selection
criteria and pilot follow-up. The memo helped to establish an aviation investigation and physiological research unit under Nepper who, with Jean Camus, developed a test battery for candidate pilots consisting
of visual, auditory, and tactile reaction times (using stimuli such as gunshots, magnesium flares, or the sudden application of a cold towel to the head), emotion control, and fatigability.
The history of aviation medicine in France – Régnier
MEDICOGRAPHIA, VOL 30, No. 4, 2008 405
A T
OUCH
OF
FRANCE
FROM FLYING MACHINE TO AIRPLANE: 1907-1914
1907
July 1: The Wright brothers set up the first ‘air force’ unit in
the United States.
October 26: Henri Farman (1874-1958), born of British parents in Paris, breaks the speed and distance records by flying
770 meters in a Voisin.
November 9: Farman wins the Deutsch-Archdeacon Cup by
flying 1030 meters in a straight line in 1 minute 44 seconds.
1908
January 13: Farman wins the Deutsch-Archdeacon Grand
Prix for the first 1 km circuit, again in a Voisin.
May 14: In the United States, Wilbur Wright (1867-1912)
flies with a passenger for the first time. Farman pulls off the
same exploit in France 2 weeks later.
September 14: Wilbur Wright breaks the distance and endurance records by flying 67 km in 1 hour 31 minutes 25 seconds.
1909
July 25: Louis Blériot (1872-1936) is the first to fly the Channel, crossing from Calais to Dover in 38 minutes in a Blériot XI
at 75 km/h.
August 22: At the week-long aviation meet at the ReimsBetheny aerodrome: Hubert Latham (1883-1911) breaks the altitude record by flying at 155 meters, Farman breaks the endurance record (3 hours 5 minutes), and the American Glenn
Hammond Curtiss wins the Gordon Bennett cup at a record
speed of 75 km/h, beating Louis Blériot by 6 seconds.
October 10: Setting up of the first French aviation company,
the Compagnie Générale Trans-Saharienne.
Péquet (1888-1974) carries souvenir cards from the exhibition center in Allahabad to Naini, a distance of some 5 miles.
July 6: André Beaumont (pseudonym of Jean Louis Conneau,
1880-1937) wins the European circuit, a 17-stage air race across
France, Great Britain, and Belgium, beating Roland Garros
(1888-1918) into second place.
September 3: Roland Garros breaks the altitude record by
flying at 4960 meters in a Blériot XI.
November 1: First bombing from the air, by the Italian officer Guilio Guidotti on the Tripolitania (Libyan) front.
November 5: First transcontinental flight (of the United
States), by Cal Rodgers (1879-1912).
1912
March 1: First parachute jump, by the American Albert Berry.
April 13: The Frenchman Maurice Prévost (d. 1952) flies with
passengers from Paris to London in a Deperdussin.
May 31: The first international air regulation congress opens
in Paris.
August 7: Air traffic regulations for the Paris area ban landings in the capital.
September 9: In the United States, the Frenchman Jules
Vedrines (1881-1919) wins the Gordon Bennett Cup, breaking
the speed record in a Deperdussin (167.8 km/h).
October 26: Inauguration in Paris of the Aeronautics Exhibition where the showpiece is a biplane with a machine gun
mounted on the fuselage.
December 7: In Tunis, Roland Garros breaks the world altitude record by flying to 5610 meters.
1913
1910
March 10: First night flight, by Émile Aubrun (1881-1967)
near Buenos Aires.
March 28: First seaplane flight, by Henri Fabre (1882-1984)
on Lake Berre near Marseille.
May 18: First international conference on air navigation,
in Paris.
June 9: Launch of a French air force with its first raid, by officers Albert Féquant and Charles Marconet from the camp at
Châlons-sur-Marne (since renamed Châlons-en-Champagne)
to Vincennes, on board a Farman.
September 23: The Peruvian Geo Chavez, in a monoplane,
is the first to fly across the Alps, but he crash-lands and dies
from his injuries 4 days later.
December 3: The French pilot Géo Legagneux, in a Blériot,
breaks the altitude record by flying to 3100 meters.
December 18: At Étampes, Farman recaptures the endurance
record by flying for just over 8 hours.
December 30: At Étampes again, the Frenchman Maurice
Tabuteau (1884-1976) breaks the distance record by covering
525 km in a Farman.
1911
February: First mail flight: in India, the French pilot Henri
406 MEDICOGRAPHIA, VOL 30, No. 4, 2008
May 13: Igor Sikorsky pilots the first multiengine plane.
July 2: The French aviator Marcel Brindejonc des Moulinais
(1892-1916) receives a triumphant welcome in France after
flying 4820 km across Europe.
August 19: Adolphe Pégoud (1889-1915) makes a parachute
jump from 250 meters using an ejection system fitted to the
fuselage.
August 27: First loop the loop, by Petr Nikolaevich Nesterov
(1887-1914) in Russia in a Nieuport IV, followed by Pégoud 4
days later.
September 23: First crossing of the Mediterranean, from
Saint-Raphaël to Bizerte, by Roland Garros in a Morane-Saulnier H in 7 hours 53 minutes.
September 27-29: Marcel Prévost breaks the speed record by
flying at 204 km/h in a monoplane engineered by Béchereau.
1914
January 1: The St Petersburg-Tampa Airboat Line becomes
the world’s first provider of a regular air passenger service,
using the Benoist XIV seaplane.
June 9: The Frenchman Eugène Gilbert performs a 3000
km Tour de France in 39 hours 35 minutes 42 seconds.
July 10: The German Reinholt Bohm breaks the endurance
record by flying an Albatros for 24 hours 12 minutes.
The history of aviation medicine in France – Régnier
A TOUCH
OF
FRANCE
Three plates from the
Ishihara Color Vision
Charts. This test is used
to detect color blindness
in pilots (and, of course,
in anybody). The test was
published in 1918 by Dr
Shinobu Ishihara, an
army surgeon, then ophthalmologist in Japan. All
rights reserved.
Ferry was backed by General Maurice Duval, air force head at General HQ, who in 1917 was responsible
for reorganizing French aviation. The Air Force Health Service was established on May 19, 1918, with the
following remit from General Duval: “Please make sure that physicians and aviation panels subject all
aircrew candidates to absolutely rigorous examination.” Civil aviation fell into line: a doctor, Major Guillain,
was appointed Medical Inspector of Aviation with the remit to liaise with the Air Force Health Service.
Longvic in Burgundy became a research and data collection center for French pilot health; it comprised a
hospital for wounded or unwell pilots. It also developed a standard pilot examination battery, comprising
respiratory function tests, including the Flack test, a test of resistance to hypoxia in a decompression chamber, vision tests (resistance to dazzling), and tests of inner ear vestibular function. In 1918 André Broca
developed an oscillating revolving chair to test the deviation of perception in space.12,19 Remedies against air
sickness, a particular problem above 3500 meters, remained rudimentary, as reported by Dr Ferry himself:
I fight it: 1. by moving whenever I can, and by rubbing lotion into my forehead and temples; 2. by taking in
food: hot liquids, such as coffee or tea with a shot of spirits; biscuits; 3. by breathing very deeply and rhythmically and by singing, as a mechanical method of establishing a regular respiratory rate… As for the compulsion to sleep, I’ve never experienced it when flying, no doubt because I’m only too aware of its dangers.19
Aviation medicine: toward a fullfledged specialty
On October 13, 1919, 27 countries subscribed to the air traffic regulations contained in an annex to the
Treaty of Versailles, in particular a definition of the international standards determining the physical ability to pilot a plane.12 After demobilization, Major (surgeon) Pierre-Jules-Emile Beyne implemented the pilot
selection criteria, and established the Air Force Medico-Physiological Study Laboratory. He stated in 1922:
There is no evidence that excellent aviators need be athletes or supermen. It’s enough that they be men who
have passed a medical selection. This is because the specific conditions of life at altitude require particular
resistance by certain organ systems in the human body, while the professional necessities of aviation require
a minimum level of accuracy and precision in certain physiological functions. A number of air aces have been
found not to meet these criteria… Let us honor such exceptional pilots who proved themselves by their actions,
but before we sow more air ace grain, let us first have the good sense to sort it.
Heart rate,
beats/minute
Pulsations/5s
14
13
TYPE III
11
10
TYPE II
9
8
TYPE V
7
6
5
156
TYPE IV
12
TYPE I
0
144
132
120
108
96
84
72
5 10 15 20 25 30 35 40 45 50 55 60 65 s
Main types of response to the Flack test. This test was first
published in the Lancet in 1919, by Dr Martin Flack, who
from 1914 to 1919 was director of medical research at the
Royal Air Force. His test establishes the cardiovascular fitness
of pilots. Subjects must maintain a pressure of 40 mm Hg by
blowing in a tube while holding their breath after a forced
inspiration, for at least 40 seconds. Pulsations and heart
rate are measured. Types I and II pass. All rights reserved.
The history of aviation medicine in France – Régnier
In France, Germany, and overseas, Beyne set up a network of 21 aircrew
monitoring and selection centers next to military hospitals.12,17 In the interwar period, new higher-performance and more maneuverable aircraft produced hitherto unknown hemodynamic disturbances: g-forces drew blood
away from the head, causing vision to lose hue (the “brownout” and “grayout” that could precede blackout). Pressurized suits and cabins were required
as altitude records were pushed ever higher. The first suits consisted of rubberized parachute fabric glued to a chassis, boots of rubber and aluminum,
and a plastic helmet. Increased use of night flights raised awareness of the
risks of spatial disorientation, triggering the expansion of vestibular function testing. Civil and military aviation physicians sought solutions to most
of the clinical manifestations of air sickness: hypoxia, sudden decompression, cold, noise, hypocapnia, failing vision, fatigue, and the effects of drugs,
alcohol, and other substances.11,12,15,20
Shortly before the outbreak of the Second World War, military aviation
medicine began to apply more demanding pilot selection criteria than its
civilian counterpart. Military aircraft were capable of higher performance,
with particular respect to extended flights at high altitude. Aircraft acceleration doubled in 20 years, from 4.5 g to 9 g. In 1919, Broca and Garsaux
designed a prototype g suit to prevent blood flowing into the abdominal
MEDICOGRAPHIA, VOL 30, No. 4, 2008 407
A T
OUCH
OF
FRANCE
cavity during centrifugal acceleration. Pilots were supplied with oxygen reserves and customized
masks that could be worn in comfort over long periods, together with anti-g leggings (early models were filled with water). Pilot training included the use of decompression chambers. In France
the law of July 2, 1934, which set up the Air Ministry, also established the Air Health Service whose
remit extended over both civilian and military aviation. The Consultative Committee of Aeronautical Medicine was created in 1937.11,12,14,15,21,22
Epilogue
“Fabien needed all his strength to control the plane. His head ducked far down inside the cockpit,
he kept his eyes glued to the artificial horizon; for outside he could no longer distinguish earth
from sky, lost in a welter of primeval darkness. But now the instrument needles in front of him
began oscillating wildly, growing increasingly difficult to follow. Misled by their erratic readings,
he lost altitude. Slowly but surely he was sinking into a dark morass, a murky quicksand.”
Cover of recent
issue of the journal
of the French
aviation medicine
journal Médecine
Aéronautique
et Spatiale. With
kind permission.
© SOFRAMAS.
Night Flight (1931) 20 Antoine de Saint Exupéry.
REFERENCES
1. Ward MP, Milledge JS, West JB. High Altitude Medicine and
Physiology. 3rd ed. London, UK: Arnold; 2000.
2. Giroux JN. La médecine aérospatiale au cours de l’histoire.
Med Armees. 2000;28:489-494.
3. Acosta J. The naturall and morall historie of the East and West
Indies. In Major RH, ed: Classic Descriptions of Diseases. Springfield, Illinois: Charles C. Thomas, pp. 514–517, 1932. de Acosta
J. Natural and moral history of the Indies. Mangan JE, ed. Mignolo WD, introduction & commentary. Lopez-Morillas F, translator. Durham, NC; Duke University Press: 2002.
4. de Saussure HB. Voyage Dans les Alpes (1787-1795). Geneva,
Switzerland: Georg: 2002. English translation in: West JB. High
life: A History of High-Altitude Physiology and Medicine. New
York, NY: Oxford University Press; 59-60.
5. Bert P. Barometric Pressure. Researches in Experimental Physiology. English translation by Hitchcock MA, Hitchcock FA.
Columbus, Ohio: College Book Company; 1943. Available on-line
at http://www.archive.org/stream/barometricpressu00bert/
barometricpressu00bert_djvu.txt
6. Jourdanet D. Les Altitudes de l’Amérique Tropicale Comparées
au Niveau des Mers, au Point de Vue de la Constitution Médicale.
Paris, France: Baillière; 1861.
7. Peslin CY. Jean-Marie Le Bris – Marin Breton, Précurseur de
L’aviation. Paris, France: Les Ailes; 1944.
8. Marck B, Piccard B. Le Rêve de Vol ou les Origines de L’aviation. Toulouse, France: Le Pérégrinateur; 2006.
9. Noetinger J. L’aviation, une Révolution du XX e siècle. Paris,
France: NEL; 2005.
10. Douhet G. La Maîtrise de L’air. Paris, France: Éditions Economica; 2007.
11. Fulton JF. Aviation Medicine in its Preventive Aspects. London, UK: Oxford University Press; 1948.
12. Lefebvre P. Histoire de la Médecine aux Armées de 1914 à Nos
Jours. Vol 3. Paris, France: Lavauzelle; 1987.
13. Cruchet JR, Moulinier R. Le Mal des Aviateurs, ses Causes et
ses Remèdes. Paris, France: JB Baillière et fils; 1920. Cruchet R,
Moulinier R. Air Sickness: Its nature and Treatment. Translated
by Earp JR. London, UK: John Bale, Sons & Danielsson; 1920. Online at http://www.archive.org/stream/airsicknessitsna00crucuoft
14. Garsaux P. Histoire Anecdotique de la Médecine de L’air.
Paris, France: Éditions du Scorpion; 1963.
15. Robinson DH. The Dangerous Sky. A History of Aviation
Medicine. Seattle, Wash: University of Washington; 1973.
16. Hodeir M. L’aviateur Militaire Français de la Première Guerre
Mondiale 1917-1918: Étude du Milieu Social, Approche des Mentalités. Master’s thesis. Paris IV University, 1988.
17. Beyne J. Les examens médicaux spéciaux de l’aéronautique
militaire. Rev Aeronaut Mil. 1924;22:81.
18. Galtier-Boissière. Larousse Médical de Guerre. Paris, France:
Larousse; 1917.
19. Ferry JG. Influence du Vol en Avion sur la Santé de L’aviateur.
Paris, France: Berger-Levrault; 1920.
20. Saint-Exupéry A de. Vol de Nuit. Paris, France: Gallimard;
1931. English translation by Cate C: Southern Mail/Night flight.
London, UK: Penguin Classics; 2000:158.
21. Broca A, Garsaux P. Note préliminaire sur l’étude des effets
de la force centrifuge sur l’organisme. Bull Acad Med. 1919;82:
75-77.
22. Lavernhe J. Les débuts de la médecine de l’aviation en France
(1914-1940). Med Aeronaut Spat. 2003;45:7-15.
MONTAGNES, MONTGOLFIÈRES ET MACHINES VOLANTES
PAUL BERT ET LA NAISSANCE DE LA MÉDECINE AÉRONAUTIQUE EN FRANCE
À
A
la fin du XVIII e siècle, avec l’apparition des montgolfières, l’homme amorçait la conquête des
airs. Il fut alors soumis à des conditions de vie inhabituelles : l’oxygène se raréfie, la pression
et la température atmosphérique baissent. Ce fut le temps des engins volants « plus légers que
l’air ». Dans la seconde moitié du XIX e siècle, les premières recherches sur les conditions d’adaptation et de survie de l’homme dans les airs débutèrent avec les expériences de physiologie humaine sur le « mal des montagnes » identifié depuis des siècles. La naissance de la médecine
aéronautique est contemporaine de l’apparition au début du XXe siècle des premiers aéronefs, les « plus
lourds que l’air ». Il fut rapidement nécessaire, au fur et à mesure de l’évolution technique des aéroplanes,
d’inventer les moyens nécessaires pour repousser les limites physiologiques humaines. On étudiait alors
le « mal des altitudes ». Contemporaine de la Grande Guerre et du développement de l’aviation militaire, la médecine aéronautique n’eut de cesse d’améliorer les performances des pilotes en vol et de compenser les avancées techniques des avions par de nouveaux dispositifs protégeant le navigant. On parlait
alors du « mal des aviateurs ». Terre d’élection de l’aérostat et de l’aviation moderne, la France développa rapidement les recherches sur la physiologie des séjours en altitude. Paul Bert dans la seconde moitié
du XIX e siècle puis Cruchet et Moulinier fondèrent la médecine aéronautique. En France, cette nouvelle
spécialité médicale connut son plein essor dans la période de l’entre-deux-guerres.
408 MEDICOGRAPHIA, VOL 30, No. 4, 2008
The history of aviation medicine in France – Régnier
A
T
O U C H
O F
F
R A N C E
Dominique CAMUS, Journalist
66 rue Henri Violet
76740 Fontaine-le-Dun, FRANCE
(e-mail: [email protected])
Antoine
de Saint Exupéry,
pilgrim of the stars
Pilot, writer, poet
by D. Camus, France
S
aint Exupéry had two passions, writing and flying. Everything
he wrote was inspired by his life, which was action-packed,
whether as a pioneer of airmail, a challenger for long-distance
records on board his Simoun monoplane, or an over-age, careerscarred wartime reconnaissance pilot who, on his final mission,
was to have one mishap too many. Over subsequent decades the
mystery surrounding his death was to prove a powerful motor behind the
Saint Exupéry myth.
Captain Antoine
de Saint Exupéry
at ToulouseFrancazal Air
base, France, in
1939. © Succession Consuelo de
Saint Exupéry. All
rights reserved.
A
ntoine de Saint Exupéry (1900-1944), a pioneer of the airmail adventure who crisscrossed the
skies from Saigon to Patagonia, was in turn station head at Cape Juby in Morocco, director of
the Aeroposta Argentina in Buenos Aires, a press reporter in Moscow and Spain, and a pilot during World War II, during which he was reported missing in action, under unexplained circumstances. His writings drew their inspiration directly from his eventful life. A daredevil pilot, he
repeatedly courted death during long-distance record attempts between Paris and Saigon and
New York and Tierra del Fuego. He flew war missions in 1939-1940 and 1943-1944. Happy memories from
an idealized childhood formed the backdrop to the maelstrom of romantic passions, strong friendships,
solitude, exile, and despair he experienced later in life. His wife, Consuelo, whom he affectionately called
his “little island bird” and immortalized as the rose so lovingly tended by the Little Prince, remained, despite a tumultuous relationship, his lifelong love and literary muse. The death of his nearest and dearest,
as well as of pilot friends like Mermoz and Guillaumet took a heavy toll on Saint Exupéry, precipitating
recurring bouts of melancholy. He was torn between flying and writing and surrendered equally to both.
Several of his novels were awarded literary prizes in France (Vol de Nuit [Night Flight]; Terre des Hommes
[Wind, Sand and Stars]) and received resounding acclaim in America. The Little Prince, which he wrote
to distract himself during the dark years when he suffered bitter criticism from the Gaullist resistance
for his reluctance to join them, became an instant planetary bestseller. Both as a pilot and a writer, Saint
Exupéry, the “pilgrim of the stars” who attempted throughout his life to “tame the human world,” explored
the heavens just as Melville and Conrad before him had explored the high seas. More than fifty years after
the flight that took him to his doom, a fisherman retrieved Saint Exupéry’s silver chain bracelet from the
Mediterranean, and divers subsequently found the remains of his plane. In early 2008, a German pilot confided that he had shot down Saint Exupéry, lifting the last veil of the mystery surrounding the famous
writer-pilot’s death.
www.medicographia.com
Medicographia. 2008;30:409-418.
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
(see French abstract on page 418)
MEDICOGRAPHIA, VOL 30, No. 4, 2008 409
A T
OUCH
OF
FRANCE
Youth
Antoine de Saint Exupéry was born in 1900 in Lyon, and had a happy childhood. Like many of his friends
at that time, he became fascinated by flying. In those early years of the century, pilots were boys’ heroes.
Their strange bat-winged flying machines were the stuff of children’s dreams. At 12, Antoine captured his
maiden flight in a poem: The wings flutter in the evening breeze
The soul sleeps to the engine’s hum
Touched by the caress of the fading sun.
Britannia may have ruled the waves, but the French predominated in their belief in flying as the future’s
means of transport: “by 1912, the French Flying Club had issued around a thousand pilot licenses, almost
three times more than in Great Britain or Germany. The American tally was barely two hundred.” Antoine
was keen on writing from a very early age and enjoyed reading his compositions to family and friends. All
remembered being woken in the middle of the night to listen to him reading his latest inspiration. After
passing his baccalaureate Antoine attended the Lycée Saint-Louis in Paris to study for the entrance examination to Navy school. But he failed and instead enrolled in the architectural section of the Paris art school.
But his great dream was to fly, and he had no scruples in playing the social rank card as the Count of Saint
Exupéry in trying to enter the air force: in 1921 he began his military service as ground crew in Strasbourg.
First flying lessons
In Strasbourg he saved on his meager grant to pay for flying lessons from a civilian instructor. He had his
first, non-serious, accident. After getting his pilot’s license, he entered officer school and finished his military service at the Le Bourget base outside Paris where he had a second accident, this time sustaining a
fractured skull. At 23, he became engaged to Louise de Vilmorin (1902-1969), from a similar if much wealthier background, who from the mid-1930s onwards was to become a celebrated writer and socialite. Given
her family’s opposition to flying as a career choice, Saint Exupéry gave up the idea of joining the air force,
took an office job, and later sold trucks. Having been captivated by the reckless, if broke, young aristocrat,
Louise gradually distanced herself from Antoine’s transformation into a gray office worker. His response to
depression was to write and fly. He was already maintaining a voluminous correspondence with his mother and sisters. In Paris he met two famous women bookshop owners: the American Sylvia Beach (18871962) at Shakespeare & Company, frequented by Fitzgerald, Hemingway, and Joyce; and Adrienne Monnier
(1892-1955) at La Maison des Amis des Livres, frequented by the likes of Gide, Breton, and Apollinaire. In
April 1926, Antoine published a short story, L’Aviateur, which was a preliminary version of Courrier Sud
(published in English as Southern Mail).
Airline pilot: the great airmail adventure
In 1926 Antoine arrived in Toulouse to begin a new phase in his life, dedicated to his continuing twin passions of writing and flying, It lasted until 1931. He was taken on by the legendary First World War ace
Didier Daurat (1891-1969), the hard-nosed operations director of the airmail wing of the Latécoère airline,
serving Africa from Toulouse. For a trial period Antoine was a grease monkey, servicing planes after their
return to base.
Saint Exupéry entered aviation in the way that others enter the Church. His five years in Toulouse proved
essential to his inspiration. Daurat was to become the model for Rivière in Night flight. “Before 1919 […]
pilots flew free in the air and had to keep checking the ground for landmarks or emergency landing strips
[…]. Dare-devil dedication was their only defense against mechanical breakdown […] Over 120 pilots died
launching Latécoère’s routes to North and West Africa, and later to South America.”
In 1927 Antoine’s job as a regular airline pilot was to fly mail from Toulouse to Casablanca, and then
from Casablanca to Dakar. He was part of the celebrated team of pioneers that included Paul Vachet, Jean
Mermoz (1901-1936), Estienne, Henri Guillaumet (1902-1940), and Lescrivain. Their common bond was
the priority of the mail, elevated to near-mythological significance: it had to get through, no matter what.
This was still an era of colonial expansion. Both France and Spain were seeking control of the Western
Sahara. In North Africa, France was fighting rebel tribes. Toulouse to Casablanca required two pilots and
four stops: the first pilot flew the first two legs, to Barcelona and then Alicante, where the second pilot took
over for the two-leg flight to Morocco. Once, when flying back from Alicante to Toulouse, Saint Exupéry
encountered fog and crash-landed in a field. On another flight back from Rabat, he rode out a 9-hour storm
that tossed him around “like a tennis ball.”
Station head at Cape Juby
Saint Exupéry was appointed station head at Cape Juby, on the southwestern coast of Morocco (modern
Tarfaya), a stopover on the Casablanca-Dakar route that crossed the Rio de Oro, a region within the ex-Spanish Western Sahara inhabited by rebel tribes. Pilots making forced landings were fair game for slaughter
410 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
A TOUCH
OF
FRANCE
Reconnaissance
flight in the Andes
in a Potez 25 Aeropostale airplane.
© Roger-Viollet.
or ransom. Six months earlier, some French pilots, including Mermoz, and some Uruguayans, had been
captured and released on payment of a ransom. Others had been massacred. Saint Exupéry’s brief on taking up his appointment was: “to assist any pilot in danger, no matter the time, or the place in the desert.”
Saint Exupéry was fascinated by the desert, describing it, in almost religious language, as an “essential
initiation.” He wrote Louise de Vilmorin: “I spent days of bleak depression bogged down in a rotten shack,
but what I remember now is a life full of poetry.” He felt he was living “a magical adventure. I feel ready to
gain a better understanding of this sand, this mirage, and this astonishing silence.”
Saint Ex knew how to tame people, paying frequent visits to the Spanish in their fort, and staying late
to play chess or belote, a trick-taking card game. He got on well with the Arab tribes, treating them with
respect and earning their respect in return by learning Arabic. During his watch, six crews were taken captive and he went to pilots’ assistance 14 times. “Taming is my job here,” he wrote his mother. He also knew
how to tame animals: a chameleon that he watched for hours, a gazelle that fed from his hand, and a sand
fox (fennec). It’s just such a fox, with long pointed ears, that features in The Little Prince: “If you tame me,
we’ll need each other,” says the fox to the Little Prince. “There’ll be no one else like you for me in the world.”
This charmed relationship with an animal was to recur in Terre des Hommes (1939, published in English
as Wind, Sand and Stars): when his plane tips over in the Libyan desert, and he faces death by thirst, the
pilot finds reserves of strength thanks to a fennec fox that inspires him with the will to survive. At the end
of his Cape Juby posting, Antoine had become a respected leader of men, and he was made a chevalier of
the civil aviation Legion of Honor in recognition of his services.
On returning to France on leave, in 1928, he took a course in advanced air navigation in Brest. At night,
instead of revising his lecture notes, he corrected the proofs of Southern Mail.
Director of Aeroposta Argentina
In 1929, Saint Exupéry was appointed operations director of Aeroposta Argentina, a subsidiary of the Compagnie Générale Aéropostale, previously Latécoère. His Buenos Aires posting gave him many more opportunities to fly than at Cape Juby, and often in appalling weather conditions. His brief was to organize
and extend the air network established by Mermoz and Guillaumet to all of Latin America while awaiting
the transatlantic link with Dakar. He was also expected to set up a regular service to Patagonia and Tierra
del Fuego 2500 km to the south. With the Argentine pilot Luro Cambacérès (1895->1958), Saint Exupéry
pioneered the Patagonia line.
Night flying
To speed the airline’s expansion, the decision was taken to fly at night. In April 1928, Mermoz was the first
to fly the Rio de Janeiro to Buenos Aires route. Saint Exupéry enjoyed flying over “a landscape of moonlight
and stones.” But the flight was about as dangerous as it could be. The pilots had to find upflowing air currents to lift them over mountains more than 7000 meters high. On June 13, 1930 Guillaumet crossed the
Andes for the 22nd time but in weather so bad that he crash-landed. It took him over five days to cross a
pass at 4200 meters on foot without the proper equipment. He eventually reached civilization. His miraculous escape made a profound impression on Saint Exupéry and was the inspiration behind Night Flight.
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
MEDICOGRAPHIA, VOL 30, No. 4, 2008 411
A T
OUCH
OF
FRANCE
Henris Guillaumet’s
crashed Potez 25
airplane in June 1930
in the Andes.
© Roger-Viollet.
Consuelo: “little island bird”
The pilots were stars in Buenos Aires. Their courage attracted women in droves. In 1930, at a reception
at the Alliance Française, Saint Exupéry met the beautiful Consuelo (1901-1979) from El Salvador, the
young widow of Enrique Gomez Carillo, a Guatemalan writer who had been the Argentine consul in France
for several years. Since breaking off his engagement with Louise de Vilmorin, Antoine had had no serious
affairs, finding solace in the nightclubs of Buenos Aires instead. But Consuelo was pretty, bubbly, artistic,
and a little unconventional. Not only was she captivated by the pilot writer, but he
was very soon spellbound himself. Antoine showed her passages from his manuscript of Night flight.
Consuelo had a house in Cimiez, near Nice, where the couple stayed together.
It was a setting that enchanted Antoine, and it was there that he completed Night
flight. Consuelo was to remember this period as “the most exalting and beautiful
of our lives.” They married in 1932, against the wishes of the Saint Exupéry family
who had hoped that Antoine would marry an aristocrat.
Antoine and Consuelo, shortly after
their wedding. © Succession Consuelo
de Saint Exupéry. All rights reserved.
The Aéropostale goes bankrupt
A combination of political intrigue and internal dissension drove the Société
Aéropostale into compulsory liquidation. Chief executive officer Beppo de Massini
(1875-1960) resigned, as did Daurat. Saint Exupéry and his fellow pilots followed
suit. Antoine moved to Casablanca to fly the France-South America route. He took
the mail from Casablanca to Port Étienne (now Nouadhibou) in Mauritania. Consuelo, far from the artistic Parisian setting in which she thrived, was reduced to
the same role as that of other pilots’ wives, sharing their anxiety over the long and
usually dangerous missions. After Saint Exupéry won the Prix Femina in 1931 for
Night flight, Consuelo hoped that he would devote himself solely to literature from
then on. It was not to be.
Test piloting, long-distance record attempts, and accidents
1932 was a painful year, on several counts. The situation at the Société Aéropostale forced Saint Exupéry
to work for Latécoère as a seaplane test pilot. It brought him his third accident, a failed landing and neardrowning in Saint-Raphaël bay. The company cancelled his contract. Antoine and Consuelo were both
lavish spenders and mired in financial problems as a result. Antoine had a Bugatti and his own plane, but
it never occurred to him to divest himself of either. Consuelo sold her house in Cimiez. In 1933 Saint
Exupéry worked on the scenario of a feature film, Anne-Marie, then flew some poorly paid missions for a
new company, Air France. In 1934 he finished the shooting script of the film Southern Mail in which he
stood in for the star in the flying sequences. He was a reporter in Moscow for the declining right-wing
daily L’Intransigeant. Also, under the aegis of Air France, he undertook a lecture tour of the Mediterranean
on board a Simoun monoplane, designed by Maurice Riffard for the Caudron company in Paris.
412 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
A TOUCH
OF
FRANCE
Long-distance record attempt: Paris-Saigon
On December 29, 1935, Saint Exupéry and his navigator André Prévot set out from Paris to Saigon in the
Simoun, aiming to beat the record of 98 hours 52 minutes set by André Japy only 2 weeks previously.
Inevitably their preparations were rushed, and 20 hours into their flight, they crash-landed in the desert
around 200 km from Cairo. It was Antoine’s fourth accident. After walking for 5 days, they were rescued
by a caravan. Antoine returned to Consuelo in Paris where money troubles hounded them from apartment
to cheap hotel. Neither was able to make the concessions that would have been needed for them to live in
harmony, and Antoine’s hectic life only compounded the chaos within their marriage.
Hélène (Nelly) de Voguë
Saint Exupéry about to
leave on his Paris-Saigon
raid, on 29 December
1935. © Albert Harlingue/Roger-Viollet.
It was the cue for the entry of a new woman in Antoine’s life: Nelly de Voguë. Consuelo may have had the
temperament and artistic flair associated with her Latin-American roots, but Antoine had more intellectual affinities with Nelly. She played an important role both in his literary career and for long after his death,
since it was she who inherited his manuscript of Citadelle (1948, published in English as The Wisdom
of the Sands). “A novelist herself, […] she had money, contacts, and the management skills to get Saint
Exupéry out of difficulty.” Observing
him as he wrote, she described the
almost physical fever that completely overcame him: “sweating, cutting,
striking through, and attacking certain phrases with ferocity, he rewrote
the first sentence of Wind, Sand and
Stars 30 times.” In 1936, Saint Exupéry, who had always been interested
in the manufacturing side of aviation
and had already filed 14 patents, designed a jet plane. He also began his
first notes for The Wisdom of the
Sands. On December 7, Mermoz was
lost over the Atlantic in a seaplane.
Simoun pilot
In 1937, Antoine, who had “old scores to settle with the desert,” went to the Air Ministry with the idea of
opening up a Casablanca-Timbuktu route in his brand-new red Simoun. The Ministry accepted the plan,
and bankrolled it jointly with Air France. Unlike the Paris-Saigon flight, this mission was perfectly prepared and organized, hence a striking success. Antoine regained confidence in himself, as did his employers. He then traveled to the front to cover the Spanish Civil War for the evening daily Paris-Soir.
Long-distance record attempt: New York-Tierra del Fuego
In 1938 Saint Exupéry went back to the Air Ministry with the idea of flying from New York to Tierra del
Fuego (14 000 km), and secured backing for his plan. Several biographers have interpreted these record
attempts as escapes from financial and personal problems.
On February 15, Saint Exupéry and Prévot took off from New York and arrived safely in Guatemala
(5500 km) after flying for 32 hours. On landing, Saint Exupéry left Prévot to carry out the checks and
maintenance, and to fill the tanks. A few minutes after take-off, Antoine found the plane overloaded. To
avoid a low hill, he tried to regain altitude but the plane plunged downwards and crashed. Dragged out
half-conscious, Prévot had a broken leg and multiple bruises while Saint Exupéry had concussion and
several skull and limb fractures. Consuelo hurried to his bedside. He never properly recovered from this
terrible accident. For example, he could never fully raise his left arm again, meaning that he could not use
a parachute. He bore severe pain for the next 5 years. During his forced convalescence, he lived in an apartment lent by Colonel William “Wild Bill” Donovan (1883-1959), who in World War II was to found, and then
lead, the Office of Strategic Services (predecessor of the Central Intelligence Agency). Finally Antoine began to write again, returned to France, and worked on Wind, Sand and Stars.
Writer-pilot or pilot-writer?
When Antoine flew, his imagination was wont to wander. It could make him absent-minded, even careless.
Some of his accidents were ascribed to lack of concentration. There were aviators who admired both the
pilot and writer, whereas others considered him more as a writer and did not take him seriously as a pilot.
It was the same in the literary world: some idolized him, whereas others considered him as a pilot first and
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
MEDICOGRAPHIA, VOL 30, No. 4, 2008 413
A T
OUCH
OF
FRANCE
foremost, and on that score an unworthy citizen in the
republic of letters. In 1939, he published Wind, Sand and
Stars, a collection of pieces on aviation and the desert,
modeled on The Mirror of the Sea by Joseph Conrad, as
suggested by André Gide. In June he received the French
Academy’s Grand Prix and from then until the end of the
year lived one of the most stressful periods of his life. He
went to the United States twice: in a seaplane with Guillaumet, who was trying to better his record for crossing the North Atlantic; and then to meet his American
publishers: Wind, Sand and Stars was chosen as book of
the month and became a bestseller. Success on both sides
of the Atlantic finally gave him financial stability.
The author
at his desk in
Paris in 1939.
© LIDO/SIPA.
The dark years
In August 1939, sensing that war was imminent, he hurried back to France. On September 4, he was mobilized
in Toulouse, where he was reminded of his arrival in the
glorious airmail age. Times had changed. The planes that in his youth had so magnificently symbolized
adventure, exoticism, and travel had become transformed into machines of destruction, never more so
than for a witness of the bombing of civilians by the Luftwaffe in Spain.
Fighter pilot
Saint Exupéry made repeated applications to get back in harness. On November 3, despite being declared
unfit by the medical board, he managed to join a combat unit and have himself assigned to the Grand
Reconnaissance 2/33 high-altitude photography squadron. It flew a new plane, the Bloch 174, a twin-engine
fighter-bomber that was to become famous in literature thanks to Antoine.
First air reconnaissance missions, the French collapse, and the move to the United States
The German offensive started on May 10, 1940. On May 23, Saint Exupéry undertook a reconnaissance flight
over Arras. It was considered one of the most dangerous of the squadron’s missions. A key to its success was
the plane’s superb performance. For a pilot brought up on just two or three basic instruments, it was a
shock to encounter a plane with 103 dials, gauges and indicators. This mission was the inspiration behind
Pilote de Guerre (published in English as Flight to Arras). On June 17, France collapsed. The officers of 2/33
squadron retreated to Algiers where Saint Exupéry waited to be demobbed.
While the Vichy government was being put in place, the British navy destroyed the French fleet at Mers
el-Kebir in Algeria to stop it falling into German hands. Almost 1300 sailors perished. Saint Exupéry was
outraged to find that De Gaulle had failed to condemn the attack. As a result he was very probably influenced not to join De Gaulle and to remain faithful to Pétain instead. He went to Vichy intending to offer
his services to the new government and met Marshal Pétain. But then he hesitated, finding that he had
little if any confidence in the Vichy administration, and absolutely no enthusiasm for the anti-Jewish legislation it had just introduced. For a while he stayed with his sister Gabrielle d’Agay in the Var (Provence)
where he worked on The Wisdom of the Sands. In late 1940 he decided to leave for the United States.
In the months between the Armistice and his departure for New York, events confirmed Saint Exupéry in
his views about the Nazi victory: “France is not equipped to resist the Germans. The most sensible option
is therefore to withdraw from the war and wait for help from the United States.” After De Gaulle launched
his appeal of June 18 in London, France was torn apart between those rallying to the Free French forces
and those who accepted the Pétain government in Vichy. Saint Exupéry saw this divide as a rehearsal for
future fratricidal battles and wondered whether France was not about to plunge into a civil war like Spain.
New York exile: December 1940 to April 1943
In New York, Saint Exupéry finished the manuscript that was published in February 1942 under the title
Flight to Arras. It headed the best-seller list for 6 months. Published in France the same year, the praise it
heaped on the Jewish pilot Israel caused a scandal, and in 1943 the book was banned by the German Occupation authorities.
In an interview with the New York Times, Antoine kept to his self-imposed rule of avoiding questions on
Pétain, who immediately interpreted his silence as a form of support. A month later, Antoine found himself appointed, without forewarning, to the Vichy National Council. He refused the appointment and told
the American press that “he was not a politician and that he had no intention of promoting the interests
414 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
A TOUCH
OF
FRANCE
of France other than by his writings.” Despite him taking this position, the Gaullists launched into him,
describing him as a traitor, coward or both, and wounding him deeply. In 1941, his refusal to submit to
the authority of De Gaulle meant that he could not be posted to the Royal Air Force. At the same time,
he was tormented by the prospect of civil war in France and spoke of little else. In American eyes, Saint
Exupéry was the most famous refugee writer in the United States. Living on South Central Park, he was
neighbor to the elderly Belgian writer Maurice Maeterlinck. In Hollywood he met the film director Jean
Renoir who planned a film version of Wind, sand and stars. But severe fever spikes led to a diagnosis of an
old abscess resulting from his first accident at Le Bourget, causing him to be admitted to a Los Angeles
hospital. He then returned to New York where two events encouraged him to hurry and finish his manuscript: the arrival of Consuelo, and the attack on Pearl Harbor (December 7, 1941), bringing the Americans into the war. To concentrate on his writing, he set up Consuelo in a neighboring apartment where she
could entertain her friends, André Breton, Joan Miro, Salvador Dali, etc. Their final phase of married life
ran from Christmas 1942 to April 1943 in Beekman Place.
THE LITTLE PRINCE, A UNIVERSAL MASTERPIECE
Saint Exupéry tried in vain to tame the
Around 1930 Consuelo, with her own touplanet of men. He’d always drawn human
sled hair, had drawn: “a small child, with a
figures, animals, and planets. This particuscarf around his neck, against a starlit backlar “little chap,” who looked so vulnerable,
ground.” Her strikingly similar portrait sughad long haunted him. One day, when lunchgests that there were various influences on
ing in New York at the Café Arnold with his
Antoine before he finally shaped his characpublisher Eugène Reynal, he drew a little boy
ter. His illustrations offer an extraordinary
with tousled hair on the paper tablecloth.
echo to the poetry and profundity of his fable.
Reynal, so the legend goes, said: “Why don’t
That The Little Prince should have been
you write a children’s story?” Antoine anpublished for Christmas 1942 was itself magswered with a surprised laugh, in half-defiical. Antoine himself recognized that Conance: “And why not!” Thus was The Little
suelo had done everything to encourage him
Prince born.
to finish it, telling her: “The Little Prince was
Maybe it was this little boy who was Anborn of your own bright fire.”
toine’s confidant during the lonely starlight
At that very moment he was applying to
nights at Cape Juby, the walk across the
fly with his old squadron. The fable has auCover of Le Petit Prince.
Libyan desert, and the exile in New York. We
tobiographical elements.
© Bridgeman Art Library.
will never know when he had the idea of
The pilot in the desert, the character of
making the little boy the hero of a book. He knew that to write
Consuelo evoked by her country’s volcanoes, her asthmatic
the book, he would have to “restore within himself the heavy
cough… and the “rose” that she’d always represented in his
tangle of memories” and feel what it was like to be a child again.
eyes, with thorns that called for caution, but beauty and vulHe idealized childhood, having had the good fortune to be
nerability that called for celebration. He complained of her
brought up in a close-knit family: “What’s marvelous about a
vanity, her chatter, and her superficiality. The little prince had
house is not that it shelters you or keeps you warm, or that it’s
“difficulties with a flower,” so he went off to conquer a unique
your own piece of real estate. It’s the reserves of happiness that
rose and the stars.
it gradually builds up within us.”
Isn’t The Little Prince simply Antoine as a little boy? PerSaint Exupéry sketched his little boy everywhere. Was he a
haps over the years we can imagine him becoming the child that
frustrated father? Perhaps. He often wrote as much. He sketched
Antoine never had, a make-believe child living on another planthe little boy with wings. “There was the idea early on of a little
et. As a universal masterpiece, translated and published in virchap who flies midway between heavtually every country in the world, The
en and earth.” He then thought of a
Little Prince is not only required readwell-heeled fat-bellied bourgeois, a
ing for every child but required reking, a businessman, a geographer, a
reading for every adult: The Little
boa, a sheep, an elephant, and a fenPrince is alive in the child’s heart that
nec fox. His final thought was of rosbeats somewhere within each of us.
es: “go back and look at the roses,”
Bevin House, as painted by Consuelo
said the fox to the little prince, “you’ll
in 1943. In this 22-room Victorian
see that yours is unique in the world.”
mansion located on the north shore
of Long Island, New York, The Little
And he added: “You only see well with
Prince came into being. © Succesyour heart.” The tale became philosion Consuelo de Saint Exupéry.
sophical.
All rights reserved.
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
MEDICOGRAPHIA, VOL 30, No. 4, 2008 415
A T
OUCH
OF
FRANCE
To his American publisher who asked “When do you find the time to write?” Antoine replied: “I rarely
begin to write before 11 pm and I always have a tray close at hand with large glasses of black coffee. I’m free,
and I can concentrate for hours […]. Once I start a book, I feel possessed. While I’m writing, I’m convinced
that what I’m doing is good. When I’ve finished, I’m convinced that it’s worthless.”
In 1942, the Ministry of Defense in Washington asked for his help in interpreting aerial photographs.
In February 1943, Letter to a Hostage was published in New York, followed in April by an allegorical, philosophical, and poetical tale, The Little Prince. This timeless and universal work occupies a unique and unclassifiable place in the history of literature. Consisting of barely more than 100 pages of generously spaced
text illustrated by the author’s own watercolors, this invitation to return to the magic of childhood was to
prove immensely, and lastingly, successful. The Little Prince has been translated into over 180 languages
and dialects, and has been published in virtually every country in the world. New editions and translations
continue to appear.
SAINT EXUPÉRY: THE FINAL SECRET
Parts of the wreckage of Saint Exupéry’s P38, recovered off the
coast of Marseilles, in 2004. Also shown is a model of the plane.
© TSCHAEN/SIPA.
For years, whenever each new piece of wreckage was discovered, the ghost of the author of The Little Prince would reappear. The Lockheed Lightnings lost over sea had over time become “pilots’ tombs,” and were subject to very strict regulations.
In 1998 Jean-Louis Bianco, a Marseille fisherman, brought
up a silver bracelet in his net. It was engraved with the aviator’s name, followed by that of his wife, and the address of his
American publishers: Saint Exupéry-Consuelo. C/O Reynal and
Hitchcock Inc. 386 4th Ave. N.Y.C. U.S.A. Bianco told the head
of the offshore exploration company, Comex, and they decide
to keep the find secret, initially at least. But rumors began to
circulate and Saint Exupéry’s beneficiaries laid claim to the bracelet. It was passed to the Ministry of Defense and examined by
experts: “There is no evidence that it is authentic, but none that
it might be a fake.” Photographs sent from the United States
showed Saint Exupéry, in May 1944, with a silver bracelet on
his left wrist.
Luc Vanrell, a diver and archeologist, discovered debris from
the wreckage of a P 38 near the uninhabited island of Riou, between Marseille and Cassis. He sent photographs of his find to
an American ex-pilot, Jack Curtis, who interpreted them as
showing “two planes: one German and one American.” Luc Vanrell learned that Saint Exupéry was flying one of the 110 Lightning P-38s, converted into an aerial reconnaissance version
known as the F-5B. After Vanrell managed to free a conclusive
item element from the wreck, namely a turbocompressor,
416 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Saint Exupéry’s family argued that further disturbance of the
wreckage would be sacrilege: the site was closed and further investigations stalled. Marseille asked for the identification number of the plane found by Vanrell. With difficulty the Comex
divers deciphered the numbers 2734L. Lockheed confirmed that
this was the F 5B flown by Saint Ex. The press relayed the news
to the world immediately.
But this was not the end of the Saint Exupéry affair for JeanLouis Bianco, who was embroiled in legal proceedings with the
Saint Exupéry family, nor for Luc Vanrell who started on a second investigation. Seeking to understand exactly what had happened on July 31, 1944, he worked closely with a German, Lino
von Gartzen. The wreck of the Messerschmitt was transported
to Germany and identified. The pilot was Alexis von Bentheim,
who had disappeared on January 21, 1944. Gartzen met up with
fighter squadron veterans. One of them advised him to speak
to Horst Rippert: “he’s still very sharp, he’ll have information
for you.” True enough, with no hesitation, Rippert told him:
“You can call off your search. It was me who shot down Exupéry.
One July 31 […] I fired […] nobody jumped clear […] I could
never have known it was Exupéry […] If I’d known, I’d never
have fired, not on him!”
Why was Saint Exupéry flying so low? General Gavoille, his
commanding officer in Bastia, and the last person to see him
alive on the morning he took off, gave a convincing explanation: “He was very tall, and he couldn’t move in the narrow
cockpit. All his fractures and injuries caused him terrible pain
at altitude […] That’s why I think he’d given up on surveillance
at high altitude, it would have involved movements that were
too exhausting.”
Saint Exupéry’s
silver chain
bracelet, brought
up in a fishing net
near Marseilles,
in 1998. © Alexis
Rosenfeld.
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
A TOUCH
Saint Exupéry on NBC calling for support of General
Giraud following the Allied
landing in North Africa on 8
November, 1942. © Succession Consuelo de Saint Exupéry. All rights reserved.
OF
FRANCE
Piloting lightnings under United States command
While Saint Exupéry’s fame as an author continued to increase
in the United States, his political stance remained misunderstood in France. After the Allied landing in North Africa on
November 6, 1942, his Gaullist critics became increasingly vociferous. Explanations were no longer sufficient. He could restore his honor only by returning to duty. Saint Exupéry applied to rejoin his 2/33 squadron in Algeria. On November 29,
by radio from New York, he launched an appeal for the French
people to unite. On April 10, 1943 he left for North Africa where
he was ready to accept the most dangerous missions, and throw
down the gauntlet to death.
Thanks to the intervention of Roosevelt’s son, Saint Exupéry,
aged 44, was able to defy the age limit and return to his 2/33
squadron in Algeria, where it was now under United States
command. Lockheed Lightnings were extremely complex aircraft. Saint Exupéry had to retrain and recondition to improve
his stamina and skill. Flying at 10 000 meters was physically
challenging for the pilots who had to scan the skies for enemy
while flying in a poorly heated unpressurized cockpit with a
permanent requirement for oxygen. Such missions were grueling enough for the younger pilots, let alone for Antoine,
whose fractures and rheumatic pains were revived by the fall
in barometric pressure. Despite this handicap “you could see in his eyes the spiritual exaltation experienced by someone who had finally returned to his rightful position in the fray, and was once again able to
pursue, in action, the ideal that had inspired his life as a writer.”
On July 21, he was flying over the Rhone valley on a photographic assignment when engine failure caused
him to crash-land, with his plane ending upside down at the end of the runway. The American commander reminded him that he was over the age limit and grounded him. In August, Antoine returned to Algiers.
On September 7, a Free French captain, Léon Wencelius (1900-1971), a professor at Swarthmore College
in Pennsylvania and an authority on the esthetics of John Calvin, arrived from New York bearing a suitcase
for Antoine. It contained 700 typed pages of his philosophical work as a present from Consuelo, together
with some love letters. At Christmas 1943, Consuelo wrote to him. In his reply, he asked her to prepare for
his return from the war, and to welcome him “dressed in flowers.” She was still his muse. After all, she had
been at his side when he’d written his two masterpieces, Night Flight and The Little Prince. After she’d appeared to him in one of his dreams, he told her: “Consuelo, that’s when I understood that I loved you for
ever.” Antoine was frustrated at being deprived of a front-line role. He defied the age ban and continued
to fight for his honor. His determination won him three Croix de Guerre. He made multiple applications,
even going to Naples to meet General Ira Eaker (1896-1987), Air Commander-in-Chief of the Mediterranean
theater. Promoted major, he was permitted to return to 2/33
squadron provided he flew no more than five missions.
In July 1944 the squadron was in Corsica. He wrote to Consuelo asking her to protect him: “Darling Consuelo, be my
protection […] Cloak me in your love. Your husband, Antoine.”
He had already flown eight missions, and was insisting on being granted more.
On July 31, bending regulations a final time, he left on his
last mission. The target was Grenoble and Annecy. He took off
at 8 am; by 1.30 pm he had still failed to return to base, and he
had fuel for only one hour’s more flying. At 2.30 pm, he could
be in the air no longer: there could be no further doubt, Saint
Exupéry had flown for the last time. The announcement of his
death was followed by an explosion of theorizing: suicide, pilot error, failure of navigation instruments, engine failure etc;
he had crash-landed in Switzerland, he was hiding out in the
Savoyard maquis, he’d been captured. In Algiers, they thought
he’d probably landed in Vichy. However, the most plausible hy- Consuelo with one of the busts of Saint
Exupéry that she sculpted in the 1950s.
pothesis was that he had been shot down by the enemy. His © Succession Consuelo de Saint Exupéry.
All rights reserved.
death made headlines in the press.
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
MEDICOGRAPHIA, VOL 30, No. 4, 2008 417
A T
OUCH
OF
FRANCE
French 50-franc
banknote depicting
Antoine de Saint
Exupéry and his
Little Prince (first
issued in 1992).
© Roger-Viollet.
In 1948, a German captain, Hermann Korth, wrote to Saint Exupéry’s publisher Gallimard that he had
recorded downing a plane in his log on July 31, 1944: “a spy plane, burning on the sea, after battle.” Did
that finally solve the Saint Exupéry mystery? Investigation suggested that the captain had mistaken the
date. There were no clues in the German archives. In 1972, the German regular soldier magazine Der
Landser published a letter that senior officer cadet Robert Heichele had written to a friend on August 1,
1944: “Yesterday, even though I have no fighter qualifications, I shot down a Lightning in a dogfight, and
came out without a scratch.” But he said that the enemy plane had attacked him, whereas the spy planes
were unarmed. Even so, these two testimonies concentrated search operations offshore, beyond the SaintRaphaël bay (see Box). Saint Exupéry’s mother, who died in 1972, was never reconciled to the idea that
her son had no grave. By way of a tomb she wrote a poem, which ended as follows:
Pilgrim of the stars,
Pilgrim of the sky, did he reach
Heaven’s landing strip? Ah! If only I knew
I’d need no veil to hide my scars. Acknowledgement: The Editor of Medicographia wishes to express his grateful thanks to Mr and Mrs Martinez-Fructuoso for providing photos from their personal archives (Succession Consuelo de Saint Exupéry) at a moment’s notice, as well as to Mr P. Bottura, Publisher (Les Arènes) for his kind and patient help.
FURTHER READING
– Pradel J, Vanrell L. Saint Exupéry, l’Ultime Secret. Paris,
France: Editions du Rocher; 2008.
– Radio France dossier: http://www.radiofrance.fr/reportage/
dossiers/stexupery/enigme.php.
– Vircondelet A. La Véritable Histoire du Petit Prince. Paris,
France: Flammarion; 2008.
ANTOINE
DE
– Vircondelet A. Antoine et Consuelo de Saint Exupéry, un Amour
de Légende. Paris, France: Les Arènes, 2005.
– Webster P. Antoine de Saint Exupéry: The Life and Death of
The Little Prince. London, UK: Macmillan; 1993.
– Werth L, Delange R. La Vie de Saint Exupéry, Suivi de “Tel que
Je L’Ai Connu...”. Paris, France: Le Seuil; 1948.
SAINT EXUPÉRY, PÈLERIN DES
PILOTE, ÉCRIVAIN, POÈTE
ÉTOILES
A
ntoine de Saint Exupéry (1900-1944), pionnier de l’aéropostale ayant parcouru les cieux de Saigon à la Patagonie, fut tour à tour chef de poste à Cap Juby au Maroc, directeur de l’Aeroposta
Argentina à Buenos Aires, journaliste à Moscou, reporter en Espagne et pilote durant la seconde
guerre mondiale où il laissera la vie dans des circonstances inexpliquées. Tous ses écrits sont
inspirés par l’homme d’action qu’il a été. Esprit aventureux il a frôlé la mort plusieurs fois, notamment au cours des raids Paris-Saigon et New York-Terre de Feu. Saint Exupéry a eu une
vie trépidante et un parcours hors du commun. De son enfance heureuse, dont il sublimera les souvenirs,
à sa vie d’adulte, s’entremêlent passions amoureuses, amitiés fortes, solitude, exil et désespoir. Sa femme
Consuelo – « son petit oiseau des îles », la rose qu’aime le petit prince – restera, malgré leur relation tumultueuse, son grand amour et sa muse littéraire. La mort de ses proches ainsi que celles de ses amis pilotes, tels que Mermoz et Guillaumet, lui déclencheront toute sa vie des crises de mélancolie. Aucune de
ses deux passions, l’aviation et l’écriture, ne l’emportera sur l’autre. Plusieurs de ses livres (Vol de Nuit,
Terre des Hommes), couronnés par un prix littéraire, connaissent un succès retentissant aux États-Unis.
Quant au Petit Prince, son succès est planétaire. Sa rédaction, durant les années sombres où il doit affronter la critique des gaullistes, représente un instant de grâce. Saint Exupéry a cherché à « apprivoiser l’homme ». Pèlerin des étoiles il a exploré le ciel, comme Melville et Conrad ont exploré la mer. Plus de
cinquante ans après le vol au cours duquel il disparut, un pêcheur ramena sa gourmette dans ses filets
en Méditerranée ; peu de temps après des plongeurs retrouvèrent l’épave de son avion. Début 2008, un pilote allemand admit qu’il avait abattu Saint Exupéry, levant l’ultime coin du voile sur la mort du célèbre
pilote-écrivain.
418 MEDICOGRAPHIA, VOL 30, No. 4, 2008
Antoine de Saint Exupéry, pilgrim of the stars: pilot, writer, poet – Camus
Medicographia
A
Ser vier
publication
I nstructions
for authors
General instructions
N Manuscripts should be provided by e-mail ([email protected].
com) or by CD double-spaced, with 2.5-cm margins. Pages must
be numbered. Standard typed page = 25 lines of 90 characters
(including spaces) double-spaced, 2.5-cm margins = a total of
about 320 words per page.
N All texts should be submitted in English.
N Provide 1 color photograph of main author.
N On the title page, provide: a title (concise and informative); full
names of authors (first name, middle name initial, and last name);
highest academic degrees (in country-of-origin language); affiliations (names of department[s] and institution[s] at the time the work
was done); a short running title (no more than 50 letters and spaces),
keywords (5-10); corresponding author’s complete mailing address
and telephone No., fax No., and e-mail address; acknowledgments
(on title page, or at end of main text).
N Include an Abstract of 200-230 words for all texts except Editorials and replies to the Controversial Question.
N Figures and Tables. Figures should be of good quality or professionally prepared, numbered according to their order, with proper
orientation indicated (eg, "top," or "left"). Figures may be provided
as pdf files (printing resolution = 300 dpi scans, on CDrom, or via
e-mail; screen resolution = 72 dpi scans acceptable only if largesized format [A4]). Provide fully explicit legends, not repetitive of
text. All abbreviations used should be explained in the legends. As
figures and graphs may need to be reduced or enlarged, all absolute
values and statistics should be provided. Illustrations will be reproduced in full color only when clearly necessary, eg, images from nuclear medicine or histology. Provide each table on a separate sheet,
with title above and description below. All figures and tables should
be cited in the text, with distinct numbering for figures and tables.
N Note that Editorials and Abstracts will be published in English
and French. Translations into French will be provided by the Publisher’s Editorial Department.
N Include Headings using a consistent style for the various levels
of headings, to highlight key points and facilitate comprehension of
the text. The Editorial Department reserves the right to add or delete
headings when necessary.
N Abbreviations should be used sparingly and expanded at first
mention. A list of selected abbreviations and acronyms should be
provided (or will be prepared by the Editorial Department) where
necessary.
N Use Système International (SI) units.
N Use generic names of drugs.
N All references should be cited in the text and numbered consecutively using superscript arabic numerals. Presentation of the
references should be based on the Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Ann Intern Med. 1997;
126:36-47 (“Vancouver style”). The author-date system of citation
is NOT acceptable. In press references are to be avoided. In the
bibliography, titles of journals should be abbreviated according to
the Index Medicus. All authors should be listed up to six; if there
are more, only the first three should be listed, followed by “et al.”
Where necessary, references will be styled by the Editorial Department to Medicographia copyediting requirements. Authors bear
total responsibility for the accuracy and completeness of all references and for correct text citation. Example of style for references:
1. Ouriel K, Geary K, Green RM, Geary JE, DeWeese JA. Factors
determining survival after ruptured abdominal aneurysm. J Vasc Surg.
1990;11:493-496.
2. Darling RC, Brewster DC, Ottinger LW. Autopsy study of unoperated abdominal aortic aneurysms: the case for early resection.
Circulation. 1977;56(suppl II):II161-II164.
3. Schulman JL. Immunology of influenza. In: Kilbourne ED, Alfade
RT, eds. The Influenza Viruses and Influenza. Orlando, Fla: Academic
Press Inc; 1975:373-393.
Specific formats
N Editorial: 1500 words. No abstract or illustrations should be includ-
ed. A French translation of the Editorial will be provided by the Editorial Department and submitted to the author.
N Theme - Focus - Update - Therapeutic outlook article - Touch
of France: Abstract: 200-230 words. Main text: 2800-3200 words.
References: their number should not exceed 50. Illustrations (figures and tables): their number should not exceed 5 unless clearly
necessary.
N Interview: Abstract: 200-230 words. Main text: 2000-2500 words.
Headings are the questions posed at the interview. References, if
cited, should in no case exceed 10. No illustrations.
N Replies to the Controversial Question: 400-600 words. No abstract or illustrations should be included. References, if cited, should
in no case exceed 6.
Editorial processing
N Editorial style: All contributions to Medicographia will be styled
by the Editorial Department according to the specifications of the current edition of the American Medical Association Manual of Style,
Williams & Wilkins.
N Page proofs and editorial queries will be sent to the corresponding author for approval. Corrections should be returned within 48
hours by e-mail, and fax or express mail. If this deadline is not met,
changes made by the Editorial Department will be assumed to be
accepted by the author. Authors are responsible for all statements
made in their work, including changes made by the Editorial Department and authorized by the author. Articles and abstracts will be edited to required length or returned to the author if specific requirements
are not complied with.
Copyright
N Copyright of articles will be transferred to the Publisher of Medicographia. The Copyright Transfer Agreement must be signed by the
main author and all coauthors and returned to the Publisher.
N For reproduction of copyrighted work, it is the author’s responsibility to obtain authorizations from the author(s) (including self) and
the publisher(s) and provide copies of these authorizations with the
manuscript.