L. Mosekilde

Diagnosis of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop

BACKGROUND At the Third International Workshop on Asymptomatic Primary Hyperparathyroidism (PHPT) in May 2008, recent data on the disease were reviewed. We present the results of a literature review on issues arising from the clinical presentation and natural history of PHPT. METHODS Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was reviewed, and the questions of the International Task Force were addressed by the Consensus Panel. CONCLUSIONS 1) Data on the extent and nature of cardiovascular involvement in those with mild disease are too limited to provide a complete picture. 2) Patients with mild PHPT have neuropsychological complaints. Although some symptoms may improve with surgery, available data remain inconsistent on their precise nature and reversibility. 3) Surgery leads to long-term gains in spine, hip, and radius bone mineral density (BMD). Because some patients have early disease progression and others lose BMD after 8-10 yr, regular monitoring (serum calcium and three-site BMD) is essential in those followed without surgery. Patients may present with normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism). Data on the incidence and natural history of this phenotype are limited. 4) In the absence of kidney stones, data do not support the use of marked hypercalciuria (>10 mmol/d or 400 mg/d) as an indication for surgery for patients. 5) Patients with bone density T-score -2.5 or less at the lumbar spine, hip, or distal one third radius should have surgery.

Sex differences in age-related loss of vertebral trabecular bone mass and structure—biomechanical consequences

Density, structure, and biomechanical competence of trabecular bone were analyzed on cylinders from the central part of the third lumbar vertebral body (L3) from 91 normal individuals aged 15-91 years (48 males and 43 females). A significant and identical age-related decrease (p less than 0.001) in bone density (apparent ash-density and trabecular bone volume) was found for both males and females. The structural analyses revealed a marked, age-related increase (p less than 0.001) in the distance between the horizontal trabeculae in both sexes. In individuals older than 75 years, this increase was significantly higher for females than for males (p less than 0.05). No other significant sex-related differences could be demonstrated in the age-related changes in the trabecular network. The biomechanical compression tests showed a significant and identical age-related decrease (p less than 0.001) in stress-values in the vertical direction for both males and females. When horizontal cylinders were compressed, a steady decrease of bone strength was seen in males, while in females there was a tendency to a pronounced loss of bone strength around the age of 40-50 years. The present study demonstrated clearly a sex-related difference in the changes in vertebral trabecular architecture with age, with a higher tendency to perforation of the horizontal supporting struts in females than in males. The biomechanical consequences of this in these normal individuals were minor--but might be very marked in osteoporotic patients.

Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in US and Europe

Objectives To identify participants’ characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium. Design Individual patient data analysis using pooled data from randomised trials. Data sources Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). Study selection Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. Data synthesis Logistic regression analysis was used to identify significant interaction terms, followed by Cox’s proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use. Results Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 μg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 μg or 20 μg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy. Conclusion This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 μg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.

Sex differences in age-related changes in vertebral body size, density and biomechanical competence in normal individuals

Size, ash-density and biomechanical competence were investigated on whole vertebral bodies (L2) from 90 normal individuals (47 males and 43 females), aged 15-91 years. At all ages, cross-sectional area was significantly greater in males than in females. Furthermore, in males a significant increase of 25-30% in cross-sectional area was demonstrated with aging (r = 0.33, p less than 0.05). Conversely, no age-related change in cross-sectional area was detected in females (r = 0.03, n.s.). A significant and identical age-related decrease (p less than 0.001) in apparent ash-density was found for both males and females. Biomechanical compression tests revealed significant and identical decreases (p less than 0.001) in vertebral body load and stress with age in both males and females. However, because of their greater cross-sectional area and an increase in this with age, the level for the load-values was higher in men than in women up to the age of 75 years (p less than 0.05). The present study has demonstrated that in men there is a significantly greater cross-sectional area and a significant increase in vertebral body size, due to continuous periosteal growth. This could, to some extent, compensate for the unavoidable loss of vertebral bone density and stress with age. No age-related compensatory mechanism could be demonstrated in women.

Normal vertebral body size and compressive strength relations to age and to vertebral and iliac trabecular bone compressive strength

Three thoracic (T5-T7) and three lumbar (L1-L3) vertebral bodies and the anterior parts of both iliac crests were removed from 44 normal individuals aged 15-87 years who had died suddenly. Small, cylindrical samples of trabecular bone (length 5 mm, diameter 7 mm) from T6, L1, and L3 and from the standard site for iliac crest biopsies were compressed in an Alwetron-250 materials testing machine. Whole vertebral bodies from T5, T7, and L2 with cut planoparallel end-plates were compressed in an Instron materials testing machine. The maximum compressive stress value sigma max of the whole vertebral bodies and of the vertical vertebral trabecular bone decreased with age with almost parallel linear regression lines. At any age the sigma max for whole vertebral bodies was about 1.6 MPa (1 MPa = 100 N/cm2) higher than for the trabecular bone. The average cross-sectional area of the vertebral bodies increased by 25-30% from the age of 20 to 80 years. The anisotropic properties of the vertebral trabecular bone (expressed as the ratio between the vertical and horizontal sigma max) increased markedly with age. A highly significant positive correlation was observed between the vertical vertebral trabecular bone sigma max (X) and the total vertebral body sigma max (y = 0.90x + 1.75, r = 0.88, P less than 0.01). The slope was not significantly different from 1, whereas the intercept was positive (P less than 0.01). The average total vertebral body sigma max (range 1.5-7.8 MPa) could be predicted from mechanical tests on horizontal iliac crest bone biopsies with standard error of estimate (SEE) of 0.92 MPa.(ABSTRACT TRUNCATED AT 250 WORDS)

Fracture rates and risk factors for fractures in patients with spinal cord injury

Aim: To study fracture rates and risk factors for fractures in patients with spinal cord injuries. Material and methods: A self-administered questionnaire was mailed to 646 members of the Danish Paraplegic Association and 1000 randomly selected normal controls. 438 patients (309 males, 129 females, 67.8%) and 654 controls (332 males, 322 females, 65.4%) returned the questionnaire. Median age in patients was 42, range 10–80 years, and in controls 43, range 19–93 years (2p=0.25). Results: The crude fracture rate was 2% per year in patients and 1% per year in controls (RR=2.0, P<0.001). Low-energy fractures were much more prominent in patients (19.0% of all fractures) than in controls (1.4%, P<0.001). The fracture rate did not differ before the injury but increased after the injury to a constant level from the third year and forward. Fractures of the lower extremities were more prominent in patients than controls (femurs: RR=23.4, P<0.001, lower legs: RR=5.2, P<0.001, feet/toes: RR=2.4, P=0.006) while fractures of the forearms (P<0.001) and clavicles (P=0.03) were absent among patients. Fractures were more frequent in female patients (RR=1.6, P=0.008) and in male patients with a family history of fractures (RR=2.0, P=0.004). Conclusions: Low-energy fractures especially of the lower extremities are frequent in spinal cord injury patients and especially among female patients. The forearms seem protected from fractures.

A randomized study on the effects of estrogen/gestagen or high dose oral calcium on trabecular bone remodeling in postmenopausal osteoporosis.

Thirty-seven patients with postmenopausal crush fracture osteoporosis were randomized to oral cyclic estrogen/gestagen (n = 20) or oral calcium (2000 mg elemental calcium per day) (n = 17). Fourteen in each group completed 1 year of treatment. Iliac crest bone biopsies were obtained after intravital double labeling with tetracycline before and after treatment in 10 patients on estrogen/gestagen and 11 patients on calcium. In the estrogen/gestagen group the activation frequency in trabecular bone decreased from 0.52 + 0.11 (SEM) year−1 to 0.27 + 0.08 year−1 (p < 0.01). No significant changes were found in resorption or formation periods. The osteoid surfaces and the mineralizing surfaces decreased (p < 0.05), whereas the decrease in eroded surfaces was insignificant. Furthermore, no significant changes were observed in final resorption depth, wall thickness or bone balance per remodeling cycle. Serum alkaline phosphatase and renal hydroxyproline excretion decreased during treatment (p < 0.002), whereas the lumbar bone mineral content (BMC) increased {ifp < 0.01}. In the calcium group the extent and thickness of osteoid surfaces decreased (p < 0.05) without significant changes in activation frequency. Serum alkaline phosphatase and renal hydroxyproline excretion decreased during treatment (p < 0.02). No significant changes were observed in lumbar BMC or the other histomorphometric parameters. The study supports that the positive effect of estrogen/gestagen on BMC can be explained by a reduction in the activation frequency of new remodeling cycles leading to a decreased remodeling space and an increase in mean bone age. There is no evidence of a positive balance per remodeling cycle. High dose calcium may improve osteoid mineralization, but there is no histomorphometric evidence of a significant reduction in activation frequency or a more positive balance per remodeling cycle.

Fracture risk is increased in Crohn's disease, but not in ulcerative colitis

AIMS To study fracture rates and risk factors for fractures in patients with Crohns disease and ulcerative colitis. METHODS 998 self administered questionnaires were issued to members of the Danish Colitis/Crohn Association, and 1000 questionnaires were issued to randomly selected control subjects. 845 patients (84.5%) and 645 controls (65.4%) returned the questionnaire (p<0.01). 817 patients and 635 controls could be analysed. RESULTS Analysis was performed on 383 patients with Crohns disease (median age 39, range 8–82 years; median age at diagnosis 26, range 1–75 years), 434 patients with ulcerative colitis (median age 39, range 11–86 years; median age at diagnosis 29, range 10–78 years), and 635 controls (median age 43, range 19–93 years, p<0.01). The fracture risk was increased in female patients with Crohns disease (relative risk (RR) = 2.5, 95% confidence interval (CI) 1.7–3.6), but not in male patients with Crohns disease (RR = 0.6, 95% CI 0.3–1.3) or in patients with ulcerative colitis (RR = 1.1, 95% CI 0.8–1.6). An increased proportion of low energy fractures was observed in patients with Crohns disease (15.7% versus 1.4 % in controls, 2p<0.01), but not in patients with ulcerative colitis (5.4%, 2p=0.30). The increased fracture frequency in Crohns disease was present for fractures of the spine, feet, and toes and fractures of the ribs and pelvis. Fracture risk increased with increasing duration of systemic corticosteroid use in Crohns disease (2p=0.028), but not in ulcerative colitis (2p=0.50). CONCLUSIONS An increased risk of low energy fractures was observed in female patients with Crohns disease, but not in male patients with Crohns disease or in patients with ulcerative colitis.

Growth hormone stimulates proliferation and differentiation of normal human osteoblast-like cells in vitro

SummaryIn this study we investigated the direct, shortterm effects of human growth hormone (hGH) on the biology of normal adult human osteoblast-like (hOB) cells cultured from trabecular bone explants. In Subconfluent cultures, hGH stimulated hOB proliferation in a dose-dependent fashion (P<0.001, n=15) with half-maximal effects at a concentration of 10 ng/ml. These mitogenic effects were detectable within 24 hours as shown by bromodeoxyuridine labeling. In confluent cultures containing mainly quiescent cells, hGH increased levels of alkaline phosphatase (P<0.05, n=10) and to a lesser degree levels of procollagen type I carboxyterminal propeptide (PICP) (P=0.07, n=9). Effects on osteocalcin (bone GLa protein, BGP) levels were highly variable among different cell strains and only 7 of 10 cell strains showed a stimulatory response (P=0.16). We also studied the effects of hGH on osteoblastic production of insulin-like growth factor I (IGF-I) and IGF-II as well as the production of GH-dependent, insulin-like growth factor binding protein 3 (IGFBP-3). Under basal conditions, human osteoblasts produced IGF-II and IGFBP-3 in the conditioned medium. When stimulated with hGH, minor insignificant increase in both IGF-II and IGFBP-3 (125% and 126% of control, respectively) were detectable. No IGF-I was detectable in the conditioned medium under basal conditions or after stimulation with hGH. In conclusion, the results obtained in this study suggest that GH exerts direct anabolic effects on human osteoblasts.

Age- and sex-related changes in iliac cortical bone mass and remodeling

Iliac crest bone biopsies were obtained from 64 normal individuals (41 women and 23 men) aged 19-90 (mean 48.2) years. Thirty-four were double-labeled with tetracycline before biopsy. The following variables were measured in all biopsies: biopsy core width (C.Wi), absolute (A.Ct.Wi) and fractional (F.Ct.Wi) cortical width, absolute (A.Cn.Wi) and fractional (F.Cn.Wi) cancellous width, cortical porosity (Ct.Po), osteon diameter (On.Dm), Haversian canal diameter (Ha.Ca.Dm), and wall thickness (W.Th). In the tetracycline-labeled biopsies the typical cortical remodeling cycle was reconstructed and the activation frequency was estimated. A negative cortical bone balance with aging was found in both sexes. In females F.Ct.Wi decreased (p < 0.02) with aging because of marrow expansion (p < 0.05). Furthermore, Ct.Po increased (p < 0.001) because of a decrease in W.Th (p < 0.01) and an increase in H.Ca.Dm (p < 0.001). In males the negative cortical bone balance with aging was exclusively caused by an increase in Ct.Po (p < 0.001) partially explained by an expanding H.Ca.Dm (p < 0.01). The On.Dm increased with aging (p < 0.01), but surprisingly, no fall in W.Th was observed. Reconstruction of the remodeling cycle did not reveal any significant difference between younger women and men. However, the activation frequency rose from 0.5 per year in premenopausal to 1.0 per year in postmenopausal women (p < 0.001), giving rise to a high turnover state, an increase in the remodeling space, and thereby the porosity in the cortical bone immediately after menopause. The present study has shown a reduction in cortical bone mass in elderly people, compared with younger, which may be explained by an age-related remodeling imbalance. This reduction is further increased in women in the postmenopausal state because of a postmenopausal accelerated bone turnover.