Vol. 81, No 1
Prmtd
in US A.
Journal of Clinical Endocrinology
and Metabolism
Copyright 0 1996 by The Endocrine Society
CLINICAL
REVIEW
The Nature
of Osteoporosis
ROBERT
76
MARCUS
Aging Study Unit, VA Medical Center Palo Alto, and Division of Endocrinology,
Gerontology,
Metabolism, Stanford University School of Medicine, Palo Alto, California 94304
0
STEOPOROSIS is a condition of generalized skeletal
fragility in which bone is sufficiently weak that fractures occur with minimal trauma, often no more than is
applied by routine daily activity. Inquiries into its nature and
causes have traditionally
embraced a disease model,
whereby specific abnormalities are attributed to the skeleton
and specific pathophysiological mechanisms have been
sought. Thus, Albright and Reifenstein (1) proposed in 1948
that primary osteoporosis comprises two separate entities,
one related to menopausal estrogen loss and the other to
aging, a concept that has been elaborated upon by Riggs et al.
(2), who suggested the terms Type I osteoporosis, to signify a
loss of trabecular bone after menopause, and Type II
osteoporosis, to represent a loss of cortical and trabecular bone
in men and women as the end result of age-related bone loss.
Whereas the Type I disorder directly results from lack of
endogenous estrogen, Type II osteoporosis reflects the composite influences of long-term remodeling efficiency, calcium
and vitamin D nutriture, intestinal and renal mineral handling, and parathyroid hormone (PTH) secretion. In addition, the traditional model allows for secondary forms of
osteoporosis, which include skeletal fragility seen with systemic illness, intestinal malabsorption, or medication
exposure.
Despite the obvious heuristic value in defining subsets of
patients in this manner, compelling validation of the disease
model has not been offered. When osteoporosis is caused by
some disorders, such as myeloma or mastocytosis, iliac crest
biopsies are diagnostic, but no characteristic histological profile adequately distinguishes patients whose clinical status
suggests type I osteoporosis from those who are more likely
to have the type II disorder. In part, this diagnostic nonspecificity reflects the fact that the bone field has, until very
recently, adhered to a paradigm of bone loss. Post-menopausal women with low bone mass have been assumed to
have experienced a drastic menopausal loss of bone. This
view is now frequently and speciously expressed when
young women who have undergone a bone mass assessment
are informed that they have already lost 15% of their bone
and
mass because their bone mineral density (BMD) lies 1 SD
below age-predicted means.
Bone mass in an adult equals its maximum level at skeletal
maturity (peak bone mass) minus that which has been subsequently lost. A woman who experienced prolonged amenorrhea, bed-rest, anorexia nervosa, or systemic illness during adolescence would likely enter adult life with a lower
bone mass than would be predicted from her genetic or
constitutional profile. If she then lost bone at a normal rate,
her skeleton would still be in jeopardy simply because of the
deficit in peak bone mass. Furthermore, two recently menopausal women could have the identical low BMD, in the first
case caused by assorted insults during adolescence, and in
the second because of menopausal bone loss. Thus, the mechanisms by which osteopenia developed cannot be predicted
from a simple bone mass measurement. For the present,
therefore, it is more appropriate to consider osteoporosis the
product of multiple genetic, physical, hormonal, and nutritional factors acting alone or in concert.
Defining
Osteoporosis
Until recently, diagnosis of osteoporosis was by necessity
clinical, requiring a history of one or more low-trauma fractures. Although highly specific, such a grossly insensitive
diagnostic criterion offers no assistance to physicians who
hope to identify and treat affected individuals before fracture
occurs. With accurate noninvasive bone mass measurements
came the opportunity for early diagnosis. BMD of patients
with osteoporotic fractures is generally lower than that of
age-matched nonfractured controls, but substantial overlap
in this measurement has proven it incapable of predicting
accurately the presence of osteoporotic fractures (2-5).
A different conclusion is reached when bone mass is used
to predict an individual’s long-term fracture risk. Prospective studies show that a 1 standard deviation (SD) reduction
in BMD from the age-specific mean population value confers
a 2 to 3-fold increase in fracture risk (6-9). In a manner
similar to that by which serum cholesterol concentration
predicts risk for heart attack, or blood pressure predicts risk
for stroke, BMD measurements can help physicians identify
patients at greatest risk of fracture and who stand to benefit
most from therapy.
Recently, a definition of osteoporosis has been proposed
that is based exclusively on bone mass (10). This proposal
Received July 25, 1995. Revised September 15, 1995. Accepted September 21, 1995.
Address correspondence and reprint requests to: Robert Marcus,
M.D., Director, Aging Study Unit, VA Medical Center, GRECC 182-B,
3801 Miranda Ave, Palo Alto, California 94304.
1
.JCE & M . 1996
Vol81 l No 1
MARCUS
2
was based on the rationale that the clinical significance of
osteoporosis lies exclusively in the fractures that occur and
that BMD predicts long-term fracture risk. The authors reasoned that if a diagnostic BMD criterion is chosen with sufficient rigor, the great majority of affected individuals can be
identified while minimizing the number of individuals who
are incorrectly diagnosed. They suggested that a BMD value
of 2.5 SD below the average for healthy young adult women
satisfies this condition. Using this value, approximately 30%
of postmenopausal women would be diagnosed with osteoporosis, which gives a realistic projection of lifetime fracture
rates. In addition, the authors proposed that BMD values of
l-2 SD below the young adult mean designate individuals at
increased relative risk for fracture, but for whom a diagnosis
of osteoporosis would not be justified since the rate of false
positive diagnoses would be unacceptably high.
Although this diagnostic criterion may prove extremely
useful for clinical management, it has limitations. Its applicability to men and to non-Caucasian women is not established, and it does not apply to children. Its predictive capacity may be confounded by bone size and geometry.
Because BMD correlations among skeletal sites are not
strong, designating a person as normal based on a single site,
(e.g.the lumbar spine) necessarily overlooks individuals with
low BMD elsewhere (e.g. the hip). It is reasonable to suppose
that adjustment of bone density readings for such factors as
body size, bone geometry, and ethnic background might
improve the accuracy of this technique. However, it should
also be evident that it will offer limited utility to investigators
whose interest is the nature and causes of osteoporosis.
Knowledge of a low BMD at one point in time offers no
information regarding the adequacy of peak bone mass, the
amount of bone that may have been lost, or the quality of
bone that remains.
The Nature
of Osteoporotic
Bone
At a recent consensus development conference, osteoporosis was defined as “a disease characterized by low bone
mass and microarchitectural deterioration of bone tissue,
leading to enhanced bone fragility and a consequent increase
in fracture risk”(l1). Implicit in this definition is the view that
the residual bone is defective in amount and distribution, but
not in matrix composition or mineralization. However, BMD
overlap between individuals with and without fracture suggests that other aspects of bone quality may contribute to
skeletal fragility. If this is so, one might rightly challenge an
exclusively mass-based diagnostic approach.
Considerable evidence supports such a view. For any
given BMD, older people have a substantially higher risk for
fracture than young people (12) (Fig. 1). The study of bone
quality, as distinguished from bone mass, remains fairly
rudimentary, but a number of laboratories have explored the
response of bone to the application of sound waves as an
index of its material and microarchitectural properties. Several age-related changes in the response of bone to sound
waves have been demonstrated (13-15), and these appear to
identify fracture patients and predict incident fractures independently of the effect of bone mass (16-18). The National
Institute on Aging recently sponsored a multidisciplinary
conference to address the problem of bone quality in osteoporosis (191, from which one may safely conclude that very
little information yet exists in this area. The varieties of qualititative abnormality that have been described are listed in
Table 1 and discussed below.
TABLE
1 Aspects of bone quality
Undermineralized
matrix
Trabecular thinning, perforation,
Cortical porosity
Cement line accumulation
Fatigue accumulation
Alterations
in osteoporosis
and disruption
in bone composition
The traditional view that no systematic differences distinguish osteoporotic from normal bone tissue may be true
when bone specimens are grossly compared, but careful
examination of biopsy material reveals mineralization to be
spatially heterogeneous and variable with age and demonstrates subtle, but clinically meaningful alterations in bone
composition for at least some osteoporotic patients. Burnell
et al. (20) reported a reduced fraction of mineral per gram of
bone tissue in iliac crest biopsies from about 25% of women
with vertebral osteoporosis, even though there was no hint
of osteomalacia. What is the mechanical consequence of this
degree of undermineralization to an already porotic bone?
Mineralization contributes importantly to bone structural
strength, at least in part by affecting such fundamental bone
material properties as Young’s modulus of elasticity. Currey
(21) found that only a modest increase of 7% in bone mineral
content was associated with a 3-fold increase in bone stiffness
and a doubling in breaking strength. Thus, it seems inescapable that undermineralization
would promote bone
fragility.
Heterogeneous mineralization within individual osteons
may affect bone material properties and strength. Crofts et al.
(22) described age and locational differences in osteonal mineralization among different regions of femoral cortex. They
noted a 12% decrease in ash content of bones from an older
group compared with those from young adults, and they also
found a decrease in mineralization with distance from the
central Haversian canal. These results have major, although
imperfectly understood, implications regarding the site
within bone where fractures are likely to be initiated (23).
Loss of trabecular
connectivity
Normal trabecular bone is a honeycomb of highly connected vertical and horizontal trabecular plates. By contrast,
osteoporotic trabecular bone shows replacement of plates by
rods, obvious trabecular disruption, and particular loss of
horizontal trabeculae, giving rise to the view that loss of
connectivity contributes importantly to skeletal fragility in
osteoporosis (Fig. 2). Although horizontal trabeculae are
shorter and thinner than vertical trabeculae, they make an
important contribution to trabecular strength. A single horizontal connecting element may confer a 4-fold increase in
load-bearing capacity.
Multiple techniques have been used to characterize the
CLINICAL REVIEW
:
160
1
120
-
AGE (years)
75 -
79
a
70- 74
65 - 69
60 - 64
55 - 59
0
’
I
>l.O
I
I
0.90
0.80
-0.99
-0.89
I
0.70
-0.79
BONE MASS
I
0.60
-0.69
I
<0.60
(g/cm)
FIG. 1. Effect of bone mass on fracture risk as a function of age. It can
be seen that, at any given bone mass value, there is a progressive
increase in incident fractures as subjects age, beginning about age 50.
(Reproduced from Hui et al. (12) with permission).
changes in trabecular architecture with age and osteoporosis.
These changes include thinning and loss of contiguity. Parfitt
et al. (24) concluded that loss of trabecular connections was
most important. Subsequent work from Weinstein and
Hutson (25) indicated that thinning and disruption are both
important aspects of bone loss, whereas that from other
laboratories (26, 27) suggested that trabecular thinning occurs with age in men, but not in women. The weight of
evidence, therefore, indicates the primary feature in women
to be loss of entire trabecular elements.
Kleerekoper et al. (28) observed a 20% decrease in trabecular plate density and equivalent increases in the separation
and thickness of trabecular plates on iliac crest biopsy specimens from patients with osteoporotic fracture compared
with those from nonfracture controls who had approximately the same trabecular and cortical bone mass. Similarly,
Reeker (29) showed an 11% decrease in trabecular number,
a 37% decrease in trabecular connecting nodes, and a 37%
increase in trabecular free ends in osteoporotic bone compared with that of controls with similar BMD.
Stereologic assessment of trabecular connectivity is not a
trivial undertaking and involves assumptions regarding isotropy and section obliquity. Different tools that have been
applied to this problem, including the Star volume (30), strut
analysis (31), and fractal geometry (32), suffer from the fundamental weakness that they require extrapolating two-dimensional information into three dimensions. Vogel et al. (33)
introduced an ingenious approach to measure both 2-D and
3-D architecture in the same biopsy samples. The results of
a small number of samples indicate that age-related de-
creases in trabecular bone volume are caused primarily by
transformation of trabecular plates into rods by multiple
perforations.
The use of microcomputed tomography of biopsy samples
is a promising approach to assess 3-dimensional structure.
Goldstein et nl. (34) prepared 8 mm cubic trabecular specimens of bone from several cadavers for microcomputed tomography scanning followed by mechanical testing. Results
showed highly significant relationships of both the trabecular plate number and connectivity with the trabecular bone
volume. They also indicated that the bone volume explained
90% of the variance in bone strength. Consequently, although
connectivity is an important feature of skeletal integrity, its
contribution to bone strength is contained within the information provided by bone volume itself.
It remains premature to offer a firm conclusion regarding
an independent role for trabecular connectivity in osteoporotic fracture. The reason for this uncertainty lies primarily
in the inadequacy of stereological methods that have been
applied to this question. Extrapolation from 2-dimensional
images seems highly flawed, and ultimate resolution of this
question will await more extensive application of such techniques as microcomputed tomography.
Cement line accumulation
Cement lines, the visible residua of previous bone remodeling events, are observed as thin ribbons of loosely-woven
collagen fibers, distinguished easily under light microscopy
from the surrounding lamellar bone. They denote the area of
deepest bone resorption and form the scaffold upon which
new bone is deposited. Following completion of a remodeling cycle, the new, apparently pristine lamellar bone is
interrupted by an area of structurally weaker woven bone.
Carter and Hayes (35) demonstrated debonding and disruption of bone at the cement line as a consequence of fatigue
microdamage, indicating that cement lines represent loci of
structural least resistance. After many years of bone remodeling, both cortical and trabecular bone show a plethora of
cement lines (Fig. 3). For any given bone density, such highly
remodeled bone is structurally weaker than primary lamellar
bone of younger adults.
Increased
cortical porosity
Porosity is a measure of the prevalence and size of holes
within bony cortex. Such holes represent Haversian canals,
osteocyte lacunae, and cutting cones that have been produced by alterations in systemic or local factors favoring
resorption over bone formation. Cortical porosity is difficult
to assess, because most cortical holes are too small for the
resolution capability of the measuring instruments. Even
with biopsy, this has been a difficult problem, since much of
the process appears as trabecularization of the endocortex.
When bone is acquired during growth, primary Haversian
canals constitute the major, if not exclusive, source of cortical
porosity. Later, as a consequence of continuous remodeling,
secondary Haversian systems gradually accumulate. Progressive cortical porosity after age 40 largely reflects an expanded remodeling space resulting from an increased re-
MARCUS
JCE & M . 1996
Vol81.
No 1
FIG. 2. Scanning electron micrograph of normal (left) and osteoporotic (right) vertebral trabecular bone. Note transformation of trabecular plates to rods and trabecular perforations (photograph by
Dr. Jon Kosek, reproduced with permission).
modeling activation rate (36). Thus, increased cortical
porosity is a feature of normal skeletal aging. Increased porosity is also characteristic of MI-I-dependent bone resorption. Therefore, to the extent that hypersecretion of PTH in
older individuals promotes increased remodeling activity,
increased cortical porosity caused by expanded remodeling
space will occur. In theory, interventions designed to suppress PTH secretion and constrict the remodeling space
should constrain the accumulation of cortical porosity with
age.
Bone fatigue
Accumulation of fatigue with sustained use is a fundamental property of all materials. Although many investigators treat the terms fatigue damage and microscopic damage
interchangeably, this is a simplistic construction, since cyclic
loading produces functional yet invisible changes over time.
Repetitive loading of compact bone leads to progressive deterioration in the modulus of elasticity, and ultimately to
structural failure. Fatigue accumulates over time. The relatively high frequency of clinical stress or fatigue fractures
with overuse, particularly when habitual loading has been
precipitously increased, argues for the clinical relevance of
fatigue accumulation. The contribution of fatigue to osteoporotic fracture is likely complex. Certainly, it is important
to the extent that, by stimulating bone remodeling, fatigue
promotes the visible deterioration in cortical and trabecular
microarchitecture described above. Beyond that, however,
even before the emergence of visible damage, changes in
fundamental bone material properties accumulate as a result
of repetetive loading over time, and these subtle changes
may contribute to overall bone fragility.
Conclusions
I argued earlier that a BMD-based diagnostic criterion for
osteoporosis may be limited by failing to acount for a group
of factors collectively referred to as bone quality. It is somewhat reassurring to note that some of these factors are, in fact,
FIG. 3. Cortical bone from iliac crest. Note high density of Haversion
systems. Dark lines indicated by arrows are cement lines (photograph
by Dr. Robert Reeker, reproduced with permission).
reflected in the BMD measurement. Since clinical densitometry depends on the attenuation of photon transmission by
bone mineral, it should be sensitive to both reduced matrix
mineralization and increased cortical porosity. Similarly, it is
difficult to imagine a serious degree of trabecular thinning
and loss of connectivity without measureable loss of total
bone mass. Indeed, the preliminary data of Goldstein et al.
(34) suggest that trabecular disruption of sufficient magnitude to be mechanically important does register as a bone
mineral deficit, and therefore as a lower BMD. For the
present, these considerations should prove helpful to clinicians whose only recourse currently is to use bone mass
assessment to predict fracture risk. However, the inability of
BMD to account for cement line and fatigue accumulation, its
insensitivity to variations in bone size and geometry as contributors to bone strength, and the gross disparity in fracture
incidence that is observed between young and old people at
any given BMD value clearly indicate that neither BMD nor
perhaps any estimate of bone mass, can be used as a defining
criterion for the presence of a porotic skeleton. Whether
ultrasound attenuation or other so-called measures of bone
quality will prove to have sufficient accuracy for this purpose
remains to be established, and it will be important to assess
these methodologies against histological, mechanical, and
CLINICAL
other bone structural properties before their diagnostic value
can be determined.
There is nothing specific about any aspect of bone quality
that I have discussed, so these abnormalities do not support
paradigms for osteoporosis that are based on disease processes.All emerge during the course of normal human aging,
arising as a consequence of bone remodeling, the final common pathway through which the skeleton responds to mechanical, dietary, and hormonal stress. As with any biological process, remodeling is not completely efficient, and
resorbed bone is not entirely replaced. Thus, bone remodeling itself underlies age-related loss of bone mass and quality, reinforcing the view that minimizing the rate of bone
turnover through dietary, hormonal, and other interventions
offers an effective strategy for maintaining long-term skeletal
integrity.
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