0021-972X/00/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 6
Printed in U.S.A.
CLINICAL CASE SEMINAR
Osteoporosis: An Unusual Presentation of Childhood
Crohn’s Disease*
M. THEARLE, M. HORLICK, J. P. BILEZIKIAN, J. LEVY, J. M. GERTNER,
L. S. LEVINE, M. HARBISON, W. BERDON, AND S. E. OBERFIELD
Divisions of Pediatric Endocrinology (M.T., M.Ho., L.S.L., S.E.O.), Medicine and Pharmacology
(J.P.B.), Pediatric Gastroenterology and Nutrition (J.L.), and Pediatric Radiology (W.B.), Columbia
University College of Physicians and Surgeons, New York, New York 10032; and The Division of
Pediatric Endocrinology (J.M.G., M.Ha.), Weill-Cornell University Medical College, New York,
New York 10021
ABSTRACT
Osteoporosis is known to be associated with Crohn’s disease. We
report a 12-yr-old boy without a history of steroid use, in whom severe
osteoporosis and multiple collapsed vertebrae were the presenting
manifestations of Crohn’s disease. After treatment of the Crohn’s
disease, he resumed normal growth and progressed through puberty.
O
STEOPOROSIS is a known extraintestinal complication of Crohn’s disease, both in children (1–5) and
adults (6 –12). The pathogenesis of decreased bone mass in
Crohn’s disease is multifactorial, and the relative contribution of the primary disease process, as compared with
secondary factors, has not been well defined. Corticosteroid use is often implicated as the major factor in the
pathogenesis of osteopenia associated with Crohn’s disease (1–3, 5, 7, 8, 11, 13, 14). We report a pediatric patient
whose extensive osteoporosis occurred before the diagnosis and treatment of Crohn’s disease, demonstrating
that substantial bone loss in Crohn’s disease can occur in
the absence of corticosteroid use.
Recovery from osteoporosis, in terms of increases in bone
mineral density (BMD), does occur in adults (15, 16); but
reconstitution of collapsed vertebrae and improvement in
kyphosis, when it occurs in association with vertebral collapse, is not described. However, in children, substantial
recovery of BMD, along with reconstitution of vertebral compression fractures, has been reported (17–19). The patient
presented herein exhibited dramatic recovery of bone mass,
restoration of vertebral height, and partial correction of kyphosis, once his underlying Crohn’s disease was treated.
Potential mechanisms of bone loss and bone healing during
the course of his illness are discussed in this report.
Received November 9, 1999. Revision received February 9, 2000.
Accepted February 29, 2000.
Address correspondence and requests for reprints to: Sharon E. Oberfield, M.D., Babies and Children’s Hospital of New York, Columbia
University, 3959 Broadway, Box 50, New York, New York 10032. E-mail:
[email protected].
* Supported in part by NIH Grant NIH-DK-37352.
Concomitantly, he demonstrated a substantial recovery of vertebral
bone mineral density and structure. Possible pathophysiological
mechanisms underlying the osteoporosis and the subsequent improvement in bone density are discussed. (J Clin Endocrinol Metab
85: 2122–2126, 2000)
Case Report
The patient, a 12-yr-old male of Sephardic Jewish descent,
presented with 2 yr of severely decreased growth velocity
and 5 months of progressive nontraumatic back pain associated with 2 months of daily fevers, nausea, vomiting, and
anorexia. His dietary intake was estimated to be less than
1000 calories per day. He had no abdominal pain, constipation, diarrhea, melena, or hematochezia. He was not receiving any medications, including oral or inhaled corticosteroids. There was no family history of inflammatory bowel
disease (IBD) or osteoporosis. Physical examination revealed
marked kyphosis, clubbing, and prepubertal genitalia. His
height was 129 cm (51 in) (⬍⬍5 percentile), and his weight
was 28.7 kg (63.1 lb.) (⬍5 percentile).
Radiographs of the spine showed diffuse osteopenia with
multiple collapsed thoracic and lumbar vertebrae (T8-T11,
L1-L5) (Fig. 1A). The kyphosis angle was 71 degrees. An
upper gastrointestinal series was diagnostic of Crohn’s jejunitis with extensive nodularity, mucosal ulceration, and
thickening of the jejunum; esophagoduodenogastroscopy
and colonoscopy were grossly normal. Biopsies demonstrated duodenitis and gastritis; there was no active inflammation of the colon. An abdominal CT scan showed thickening of jejunal loops with enlargement of the draining
mesenteric lymph nodes consistent with Crohn’s disease.
Bone age was 10.5 yr. Pertinent laboratory values included
an elevated erythrocyte sedimentation rate of 68 mm/h [normal (nl), ⬍15 mm/h]; hemoglobin, 11.3 g/dL (nl, 12.3–15
g/dL) with a mean corpuscular volume of 74.8 fl (nl, 78 –99
fl); calcium, 9.5 mg/dL (nl, 8.5–10.5 mg/dL); phosphorus, 5.1
(nl, 3.2– 6.3 mg/dL); albumin, 3.6 g/dL (nl, 3– 4.5 g/dL); and
an alkaline phosphatase activity of 149 U/L (nl, 100 –390
2122
CLINICAL CASE SEMINAR
2123
FIG. 1. A, Spinal radiograph at presentation. Note the thoracic and lumbar collapsed vertebrae (T8 –T11, L1–L5). B, Spinal radiograph after
30 months of treatment. There is a striking reconstitution of the shape of the dorsolumbar vertebrae.
U/L). The urinary calcium-to-creatinine ratio was 0.14. The
intact PTH level was 3.66 pmol/L (15 pg/mL) (nl, 2.44 –15.86
pmol/L), and the urinary N-telopeptide (NTx) was 258
nmol/mmol creatinine [reference lab normal range for age,
429 –902 nmol/mmol creatinine (Cr) (20)]. 1,25 dihydroxycholecalciferol was 93.6 pmol/L (39 pg/mL) (nl, 57.6 –156.0
pmol/L), and 25 hydroxycholecalciferol D was 64.9 nmol/L
(26 ng/mL) (nl, 42.4 –134.8 nmol/L). Thyroid function tests
were normal.
Treatment was begun with a semielemental diet (Peptamen, Clintec Nutrition Company, Deerfield, IL) containing
hydrolyzed protein, maltodextrin, and a medium chain triglyceride/corn oil fat mixture plus 800 mg/L calcium and
700 mg/L phosphorus. Initial treatment also included Asacol
(mesalamine 5-ASA) 800-mg bid and a multivitamin with 200
mg of calcium. During the first year of treatment, urinary
calcium-to-creatinine levels were highly variable, secondary
to dietary intake, but ranged from 0.07– 0.43. Bone pain resolved within 3 months of initiation of therapy. 6-Mercaptopurine was added 6 months later with a maximum daily
dose of 50 mg. Fifteen months after diagnosis, a therapeutic
trial of 15-mg pamidronate infusions were given monthly for
4 months. Twenty four and a half months after diagnosis,
three additional infusions of 30 mg of pamidronate were
given at 2-week intervals (Fig. 2). Pamidronate was discontinued thereafter because of resulting severe abdominal pain.
An abdominal CT scan, after 17 months of treatment, showed
residual thickening of only a single loop of jejunum. Because
of the jejunal involvement, after 17 months of treatment,
Pentasa (mesalamine 5-ASA) 500-mg qid, which may be released earlier in the gastrointestinal tract, was substituted for
FIG. 2. NTx and serum alkaline phosphatase activity levels over
time. The boxes indicate the times of pamidronate treatment. The age
at diagnosis was 12 yr. Normal NTx values were from Bollen and Eyre
(20); 12-yr-old boy, 429 –902 nmol/mmol Cr; 13-yr-old boy, 326 – 628
nmol/mmol Cr; 14-yr-old boy, 292–528 nmol/mmol Cr; 15-yr-old boy,
230 – 481 nmol/mmol Cr.
Asacol. Budesonide (6 mg daily; Astra Zeneca, Wilmington,
DE) was added 20 months after diagnosis.
Fourteen months after treatment of his Crohn’s disease
was initiated, the patient had progressed from prepubertal to
pubertal status (Tanner Stage IV, genitalia and pubic hair).
Both growth velocity (averaging 10.3 cm/yr) and weight
increased significantly. After 2.5 yr of treatment, he had
grown 22.9 cm (9 in) (5th–10th percentile for height) and
gained 17.3 kg (38 lb.) (10th–25th percentile for weight). At
age 14.3 yr, his bone age was 14 yr, yielding a predicted adult
height of 163.8 cm (64.5 inches), within his target range of
2124
JCE & M • 2000
Vol 85 • No 6
THEARLE ET AL.
158.8 cm (62.5 in) to 168.9 cm (66.5 in) [as calculated by the
Roche-Wainer-Thissen method (21)].
Before treatment, initial dual-energy x-ray absorptiometry scans (DXA; Lunar Corp. DPX) demonstrated a total
body BMD of 0.753 g/cm2 (Z score, ⫺2.97), a lumbar spine
BMD of 0.314 g/cm2 (Z score, ⫺6.65) and a total leg BMD
of 0.581 g/cm2. Z scores for total body and lumbar spine
BMD were derived by comparing BMD measurements
with age-specific reference values, as proposed by Boot et
al. (22). Because BMD in a growing child does not account
for changes in bone size attributable to puberty or body
size (23), we also report lumbar spine bone mineral content
(BMC) with Z scores that were corrected for bone area,
height, weight, and pubertal level, as recommended by
Warner et al. (23) for children and adolescents (Fig. 3).
Initial lumbar spine BMC was 8.88 g (Z score, ⫺5.22).
Fifteen months after treatment for Crohn’s disease, repeat
DXA studies revealed a total body BMD of 0.735 g/cm2 (Z
score, ⫺2.63), lumbar spine BMD of 0.409 g/cm2 (Z score,
⫺3.53), lumbar spine BMC of 12.79 g (Z score, ⫺4.49), and
a total leg BMD of 0.649 g/cm2. Whole-body DXA, 30
months after the initial test, demonstrated a 5.4% increase
in total body BMD, to 0.794 g/cm2 (Z score, ⫺2.62), and a
30.8% increase in total leg BMD to 0.760 g/cm2. After 3 yr
of treatment, the lumbar spine BMD had increased 69.1%
over the initial value to 0.531 g/cm2 (Z score, ⫺2.62), the
lumbar spine BMC had increased 137.4%, to 21.08 g (Z
score, ⫺3.68) (Fig. 3); and the combined lumbar (L1–L4)
vertebral height had increased from 8.88 cm to 11.40 cm.
Additionally, 30 months after treatment, a lumbar spine
radiograph showed a decrease in kyphosis, to 56 degrees,
and a striking reconstitution of the height of the thoracic and
lumbar vertebrae, although diffuse osteopenia of the lumbar
spine and pelvis persisted (Fig. 1B). Current treatment for the
bone disease is 400 U vitamin D and 1000 mg calcium carbonate daily.
After 15 months, as BMD and growth velocity increased,
both the serum alkaline phosphatase activity and urinary
NTx rose to maximum levels of 410 (2.8-fold) and 1135 (4.4fold), respectively; but then, by 30 months, they decreased to
103 and 151, respectively (Fig. 2). Calcium, phosphorus, PTH,
1,25 dihydroxycholecalciferol, and 25 hydroxycholecalciferol
remained normal throughout his course.
FIG. 3. Bar graph of absolute BMD at the lumbar spine and Z scores
for BMC corrected as per Warner et al. (23) over 3 yr of treatment.
Discussion
Osteopenia is associated with Crohn’s disease in childhood, with a reported prevalence as high as 41% (3). Though
osteopenia has been detected at presentation of Crohn’s disease (4, 6, 9), we found no reports of the symptoms of bone
loss (severe bone pain, vertebral collapse, kyphosis) as the
initial presentation of Crohn’s disease. The etiology of osteoporosis in Crohn’s disease is often attributed, in large part,
to corticosteroids (1–3, 5, 7, 8, 11, 13, 14); however, this patient
makes it clear that substantial bone loss can occur in Crohn’s
disease in the absence of corticosteroid use. His course also
demonstrates the remarkable capacity of the growing skeleton to reconstitute itself, with major gains in bone mass and
vertebral height. Such increases are rarely seen in the fully
formed adult skeleton.
Cowan et al. (4) described a 16-yr-old boy with osteopenia
when the diagnosis of Crohn’s disease was made but who
did not develop symptomatic osteoporosis with vertebral
compression fractures until he was treated with high-dose
steroids for 3 months. In contrast, our patient’s exposure to
steroids occurred 20 months after diagnosis. The severity of
our patient’s osteoporosis before any steroid use suggests
that primary disease factors are important in the pathophysiology of osteoporosis in Crohn’s disease.
This suggestion is supported by in vitro data demonstrating decreased dry weight and calcium content, as well as
disorganized histology of fetal rat parietal bone cultured in
serum from children with Crohn’s disease who had not received steroids for at least 12 months (24). These findings
were attributed to an imbalance of inflammatory cytokines,
which are elevated in patients with active IBD (12, 25) and
are known to inhibit bone formation and enhance bone resorption (26, 27).
Other possible contributing factors to reduced bone mass
in Crohn’s disease are deficiencies of calories (2, 8) or specific
nutrients related to particular areas of intestinal involvement. Although, in our patient, it was difficult to assess what
role, if any, specific nutrient deficiencies had in the development of osteoporosis, there has been no uniform correlation between intestinal site of Crohn’s disease and low BMD
(3, 9, 11, 28). Patients with chronic IBD and caloric deficiency
secondary to decreased oral intake, decreased absorption,
and increased loss of nutrients (29) often have associated
pubertal and growth delay (29 –32) with decreased insulinlike growth factor 1 (IGF1) that improves with increased
caloric intake (33). IGF1 is anabolic, with respect to bone.
Estrogen and testosterone are also important for normal bone
mineral accumulation, as shown by the osteopenia found in
estrogen (34) and androgen (35, 36) -resistant syndromes and
by the late pubertal peak bone mineral accumulation that
follows peak statural growth (37– 40). Boot et al. (2) found that
decreased BMD in IBD is associated with nutritional status.
Therefore, decreased caloric intake may contribute to reduced bone acquisition by causing relative growth-factor
and sex-steroid deficiencies.
NTx, a measure of bone resorption, was initially low in this
patient, compared with reported pediatric reference values
(20), suggesting decreased age-appropriate new bone formation rather than increased bone resorption. Growth and
CLINICAL CASE SEMINAR
pubertal delay alone cannot explain his severe osteoporosis,
because this is not seen with either GH deficiency or constitutional delay of puberty (41). As suggested by the work
of Hyams et al. (24), a process unique to Crohn’s disease may
be the driving force for such osteoporosis as that seen in our
patient.
The mainstay of his treatment was the semielemental diet.
Improved nutrition was associated with rapid growth and
progression through puberty (Tanner stage I to IV within 14
months). At the same time, he had a 2.8-fold increase of
serum alkaline phosphatase followed by a 4.4-fold increase
in urinary NTx (Fig. 2), reaching levels above published
normal reference values (20). The concomitant rise of these
two bone markers indicated not only rapid new bone modeling seen in a growing child but also remodeling of impoverished bone. As expected, during Pamidronate treatment,
markers of bone resorption and bone formation decreased
(Fig. 2). After Pamidronate, these markers did not return to
the previous elevated levels, suggesting normalized bone
dynamics with reduction of the accelerated phase of bone
deposition.
The result of his rapid bone formation was a dramatic
recovery in vertebral height and in bone mass (Figs. 1B and
3). We recognize the limitations of areal bone density measurement (DXA technology) in growing children and adolescents. However, this is a widely available, noninvasive,
low-radiation technique that, when used in one patient over
time, may be informative (42). His second DXA study demonstrated a small decrease in total body BMD, although the
age-matched Z score and the other measures of BMD improved. This is likely attributable to a more rapid initial
increase in bone area during his growth spurt, relative to
bone mineral accretion, which occurred later (37, 43, 44).
Over 3 yr, the BMD of his lumbar spine increased by 69.1%,
and the BMD of his lower extremities increased by 30%.
Moreover, recovery of normal vertebral shape was associated with a gain of 2.52 cm of lumbar vertebral height (L1–
L4). Even more striking, his kyphosis decreased from a debilitating 71 degrees to 56 degrees. The greater involvement
and improvement of his lumbar spine, as compared with his
total body, suggests that trabecular bone was affected more
than cortical bone.
Such dramatic reversal is rare in adults, but almost complete spinal recovery has been described after disease treatment in children with acute lymphoblastic lymphoma (17),
Cushing’s syndrome (18), and idiopathic juvenile osteoporosis (19). In adults, bone density improvements have been
reported in hypercalciuric, osteoporotic men treated with
hydrochlorothiazide (15) and in osteitis fibrosa cystica after
parathyroidectomy (16). However, in the latter study, the
most marked improvements occurred in a 17-yr-old girl who
probably still had potential for bone mineral acquisition (16).
The ability of children, but not adults, to evince dramatic
improvement of osteoporosis, vertebral collapse, and kyphosis indicates that, while bone is still in the acquisition stage,
there is tremendous capacity for reconstitution.
Although deficiencies of sex steroids and growth factors
may not have been the major cause of our patient’s low BMD,
the surge of anabolic factors, once the Crohn’s disease was
controlled, probably contributed significantly to bone recov-
2125
ery. A report of adult men with idiopathic osteoporosis
treated with GH or IGF1 demonstrated increased rates of
bone formation and resorption, although this study was not
long enough to document increased BMD (45). Men with
decreased bone density secondary to hypogonadotropic hypogonadism have shown increased BMD with androgen
therapy (36). These increases were most pronounced in men
with immature skeletons (36). In addition, PTH, an anabolic
agent for cancellous bone, led to an increase in BMD in men
with idiopathic osteoporosis (46). Therefore, anabolic agents
can improve BMD, even in adults. However, as our patient
demonstrates, the growth potential of children, combined
with the high concentration of anabolic factors, allows for
accelerated bone acquisition and more significant recovery
after diffuse bone injury.
References
1. Semeao EJ, Stallings VA, Peck SN, Piccoli DA. 1997 Vertebral compression
fractures in pediatric patients with Crohn’s disease. Gastroenterology.
112:1710 –1713.
2. Boot AM, Bouquet J, Krenning EP, de Muinck Keizer-Schrama SMPF. 1998
Bone mineral density and nutritional status in children with chronic inflammatory bowel disease. Gut. 42:188 –194.
3. Cowan FJ, Warner JT, Dunstan FDJ, Evans WD, Gregory JW, Jenkins HR.
1997 Inflammatory bowel disease and predisposition to osteopenia. Arch Dis
Child. 76:325–329.
4. Cowan FJ, Parker DR, Jenkins HR. 1995 Osteopenia in Crohn’s disease. Arch
Dis Child. 73:255–256.
5. Gokhale R, Favus MJ, Karrison T, Sutton MM, Rich B, Kirschner BS. 1998
Bone mineral density assessment in children with inflammatory bowel disease.
Gastroenterology. 114:902–911.
6. Abitbol V, Roux C, Chaussade S, et al. 1995 Metabolic bone assessment in
patients with inflammatory bowel disease. Gastroenterology. 108:417– 422.
7. Bischoff SC, Herrmann A, Göke M, Manns MP, von zur Mühlen A, Brabant
G. 1997 Altered bone metabolism in inflammatory bowel disease. Am J Gastroenterol. 92:1157–1163.
8. Compston JE, Judd D, Crawley EO, et al. 1987 Osteoporosis in patients with
inflammatory bowel disease. Gut. 28:410 – 415.
9. Ghosh S, Cowen S, Hannan WJ, Ferguson A. 1994 Low bone mineral density
in Crohn’s disease, but not in ulcerative colitis, at diagnosis. Gastroenterology.
107:1031–1039.
10. Scharla SH, Minne HW, Lempert UG, et al. 1994 Bone mineral density and
calcium regulating hormones in patients with inflammatory bowel disease
(Crohn’s disease and ulcerative colitis). Exp Clin Endocrinol. 102:44 – 49.
11. Jahnsen J, Falch JA, Aadland E, Mowinckel P. 1997 Bone mineral density is
reduced in patients with Crohn’s disease but not in patients with ulcerative
colitis: a population based study. Gut. 40:313–319.
12. Pollak RD, Karmeli F, Eliakim R, Ackerman Z, Tabb K, Rachmilewitz D.
1998 Femoral neck osteopenia in patients with inflammatory bowel disease.
Am J Gastroenterol. 93:1483–1490.
13. Silvennoinen JA, Karttunen TJ, Niemelä SE, Manelius JJ, Lehtola JK. 1995
A controlled study of bone mineral density in patients with inflammatory
bowel disease. Gut. 37:71–76.
14. Bernstein CN, Seeger LL, Sayre JW, Anton PA, Artinian L, Shanahan F. 1995
Decreased bone density in inflammatory bowel disease is related to corticosteroid use and not disease diagnosis. J Bone Miner Res. 10:250 –256.
15. Adams JS, Song CF, Kantorovich V. 1999 Rapid recovery of bone mass in
hypercalciuric, osteoporotic men treated with hydrochlorothiazide. Ann Intern Med. 130:658 – 660.
16. Kulak CAM, Bandeira C, Voss D, et al. 1998 Marked improvement in bone
mass after parathyroidectomy in osteitis fibrosa cystica. J Clin Endocrinol
Metab. 83:732–735.
17. D’Angelo P, Conter V, Chiara GD, Rizzari C, Memeo A, Barigozzi P. 1993
Severe osteoporosis and multiple vertebral collapses in a child during treatment for B-ALL. Acta Haematol. 89:38 – 42.
18. Goswami R, Shah P, Ammini AC, Berry M. 1995 Healing of osteoporotic
vertebral compression fractures following cure of Cushing’s syndrome. Australas Radiol. 39:195–197.
19. Smith R. 1995 Idiopathic juvenile osteoporosis: experience of twenty-one
patients. Br J Rheumatol. 34:68 –77.
20. Bollen AM, Eyre DR. 1994 Bone resorption rates in children monitored by the
urinary assay of collagen type I cross-linked peptides. Bone. 15:31–34.
21. Roche AF, Wainer H, Thissen D. 1975 The RWT method for the prediction of
adult stature. Pediatrics. 56:1027–1033.
22. Boot AM, de Ridder MAJ, Pols HAP, Krenning EP, de Muinck Keizer-
2126
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
THEARLE ET AL.
Schrama SMPF. 1997 Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity. J Clin Endocrinol
Metab. 82:57– 62.
Warner JT, Cowan FJ, Dunstan FDJ, Evans WD, Webb DKH, Gregory JW.
1998 Measured and predicted bone mineral content in healthy boys and girls
aged 6 –18 years: adjustment for body size and puberty. Acta Paediatr.
87:244 –249.
Hyams JS, Wyzga N, Kreutzer DL, Justinich CJ, Gronowicz GA. 1997 Alterations in bone metabolism in children with inflammatory bowel disease: an
in vitro study. J Pediatr Gastroenterol Nutr. 24:289 –295.
Reinecker HC, Steffen M, Witthoeft T, et al. 1993 Enhanced secretion of
tumour necrosis factor-alpha, IL-6, and IL-1␤ by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp
Immunol. 94:174 –181.
Roodman GD. 1993 Roles of cytokines in the regulation of bone resorption.
Calcif Tissue Int. 53(Suppl 1):S94 –S98.
Bellido T, Jilka RL, Boyce BF, et al. 1995 Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens: the role of the androgen receptor.
J Clin Invest. 95:2886 –2895.
Bjarnason I, MacPherson A, Mackintosh C, Buxton-Thomas M, Forgacs I,
Moniz C. 1997 Reduced bone density in patients with inflammatory bowel
disease. Gut. 40:228 –233.
Kelly DG, Fleming CR. 1995 Nutritional considerations in inflammatory
bowel diseases. Gastroenterol Clin North Am. 24:597– 611.
McCaffery TD, Nasr K, Lawrence AM, Kirsner JB. 1970 Severe growth retardation in children with inflammatory bowel disease. Pediatrics. 45:386 –393.
Griffiths AM, Nguyen P, Smith C, MacMillan JH, Sherman PM. 1993 Growth
and clinical course of children with Crohn’s disease. Gut. 34:939 –943.
Markowitz J, Grancher K, Rosa J, Aiges H, Daum F. 1993 Growth failure in
pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr.
16:373–380.
Kirschner BS, Sutton MM. 1986 Somatomedin-C levels in growth-impaired
children and adolescents with chronic inflammatory bowel disease. Gastroenterology. 91:830 – 836.
Smith EP, Boyd J, Frank GR, et al. 1994 Estrogen resistance caused by a
mutation in the estrogen-receptor gene in a man. N Engl J Med. 331:1056 –1061.
JCE & M • 2000
Vol 85 • No 6
35. Bertelloni S, Cappa M, Lala R, Sorrentino MC, Saggese G. 1997 Altered bone
mineralization in complete androgen insensitivity syndrome (Abstract). Horm
Res. 48(Suppl 2):811A.
36. Finkelstein JS, Klibanski A, Neer RM, et al. 1989 Increases in bone density
during treatment of men with idiopathic hypogonadotropic hypogonadism.
J Clin Endocrinol Metab. 69:776 –783.
37. Martin AD, Bailey DA, McKay HA, Whiting S. 1997 Bone mineral and
calcium accretion during puberty. Am J Clin Nutr. 66:611– 615.
38. Mølgaard C, Thomsen BL, Michaelsen KF. 1998 Influence of weight, age and
puberty on bone size and bone mineral content in healthy children and adolescents. Acta Paediatr. 87:494 – 499.
39. Magarey AM, Boulton TJC, Chatterton BE, Schultz C, Nordin BEC, Cockington RA. 1999 Bone growth from 11 to 17 years: relationship to growth,
gender and changes with pubertal status including timing of menarche. Acta
Paediatr. 88:139 –146.
40. Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R. 1991 Critical years and
stages of puberty for spinal and femoral bone mass accumulation during
adolescence. J Clin Endocrinol Metab. 73:555–563.
41. Finkelstein JS, Neer RM, Biller BMK, Crawford JD, Klibanski A. 1992
Osteopenia in men with a history of delayed puberty. N Engl J Med.
326:600 – 604.
42. Seeman E. 1998 Growth in bone mass and size – are racial and gender differences in bone mineral density more apparent than real? J Clin Endocrinol
Metab. 83:1414 –1419.
43. Bass S, Delmas PD, Pearce G, Hendrick E, Tabensky A, Seeman E. 1999 The
differing tempo of growth in bone size, mass and density in girls is region
specific. J Clin Invest. 104:795– 804.
44. Bachrach LK, Hastie T, Wang MC, Narasimhan B, Marcus R. 1999 Bone
mineral acquisition in healthy Asian, Hispanic, Black and Caucasian youth: a
longitudinal study. J Clin Endocrinol Metab. 84:4702– 4712.
45. Johansson AG, Lindh E, Blum WF, Kollerup G, Sørensen OH, Ljunghall S.
1996 Effects of growth hormone and Insulin-like growth factor I in men with
idiopathic osteoporosis. J Clin Endocrinol Metab. 81:44 – 48.
46. Kurland ES, Cosman F, McMahon DJ, Rosen CJ, Lindsay R, Bilezikian JP.
1998 Parathyroid hormone (PTH1–34) increases cancellous bone mass markedly in men with idiopathic osteoporosis (Abstract). Bone. 23(Suppl 5):1039A.