Risk factors for vertebral and nonvertebral fracture over 10 years: a population-based study in women.

UNLABELLED: Risk factors may vary for different types of fracture, in particular for vertebral fractures. We followed 367 women >50 yr of age from a population-based cohort for up to 10 yr. Factors that predicted vertebral rather than nonvertebral fractures related to physical weakness, poor health, and weight loss. Similar factors were also associated with greater bone loss at the hip. INTRODUCTION: Many risk factors predict fractures overall, but it is less clear whether certain factors relate to vertebral fractures in particular. The aim of this study was to compare the risk factors for vertebral and nonvertebral fractures. MATERIALS AND METHODS: We carried out a 10-yr prospective population-based study of 375 women who were 50-85 yr of age initially. At baseline, we measured BMD, blood and urine biochemistry, and anthropometric measurements. Medical and lifestyle data were obtained by questionnaire. Incident vertebral fractures were determined for 311 subjects from spinal radiographs at 0, 2, 5, 7, and 10 yr using an algorithm-based qualitative method, and nonvertebral fractures were confirmed radiographically. Relative risks were calculated by Cox regression analysis. RESULTS: During follow-up, 70 subjects sustained one or more nonvertebral fractures and 29 sustained one or more vertebral fractures. Risk factors that predicted both types of fracture included increasing age, decreasing BMD at all sites, prevalent vertebral fracture, and shorter estrogen exposure. For nonvertebral fractures only, the risk factors included low urinary creatinine and less frequent use of stairs. The factors for vertebral fractures included lighter weight, reduced body fat, heavy smoking, lower serum calcium, albumin, and thyroid T(3), weak grip strength, and poor physical capability. In a multivariate model, weight, fat mass, serum calcium and T(3), prevalent vertebral fracture, and physical capability remained significant. Furthermore, grip strength, serum albumin, weight loss, and physical capability were associated with rate of bone loss at the femoral neck, and a fast rate of bone loss was also associated with vertebral fractures. CONCLUSIONS: We conclude that overall frailty, which may consist of general poor health, small or thin body size, and lack of strength and physical capability, predicts vertebral fractures but is not a significant predictor of nonvertebral fractures. Bone loss rates are associated with similar risk factors and also with the incidence of vertebral fractures.

Effect of chemotherapy on skeletal health in male survivors from testicular cancer and lymphoma.

PURPOSE: There are concerns over the late effects of cancer therapy, including accelerated bone loss leading to increased risk of osteoporosis. Treatment-related bone loss is well recognized in breast and prostate cancer, due to overt hypogonadism, but there has been little evaluation of the skeletal effects of chemotherapy alone in adults. This study assesses the extent of bone loss due to previous chemotherapy in men. EXPERIMENTAL DESIGN: The bone mineral density (BMD) of men who had received previously chemotherapy with curative intent for lymphoma or testicular cancers was compared with that of an age-matched population of men from a cancer control population that had not received chemotherapy. BMD was measured by dual-energy X-ray scanning. Additionally, measurement of sex hormones and the bone turnover markers N-telopeptide fragment of type I collagen and bone-specific alkaline phosphatase were done. All statistical tests were two sided. RESULTS: One hundred fifteen chemotherapy-treated patients and 102 cancer controls were recruited. There was no statistical difference in BMD between the chemotherapy and control groups at either spine or hip and the mean BMD values in both groups were no lower than that of a reference population. There were no significant differences in estradiol, luteinizing hormone, and testosterone, but follicle-stimulating hormone values were significantly higher in the chemotherapy group (P=0.011). The mean values of NH2-terminal telopeptide fragment of type I collagen and bone-specific alkaline phosphatase were within the reference ranges. CONCLUSIONS: The absence of accelerated bone loss following chemotherapy is reassuring and suggests that standard dose cytotoxic chemotherapy has no lasting clinically important direct effects on bone metabolism.

Use of an in vitro model of tissue-engineered skin to investigate the mechanism of skin graft contraction.

Skin graft contraction leading to loss of joint mobility and cosmetic deformity remains a major clinical problem. In this study we used a tissue-engineered model of human skin, based on sterilized human adult dermis seeded with keratinocytes and fibroblasts, which contracts by up to 60% over 28 days in vitro, as a model to investigate the mechanism of skin contraction. Pharmacologic agents modifying collagen synthesis, degradation, and cross-linking were examined for their effect on contraction. Collagen synthesis and degradation were determined using immunoassay techniques. The results show that skin contraction was not dependent on inhibition of collagen synthesis or stimulation of collagen degradation, but was related to collagen remodelling. Thus, reducing dermal pliability with glutaraldehyde inhibited the ability of cells to contract the dermis. So did inhibition of matrix metalloproteinases and inhibition of lysyl oxidase-mediated collagen cross-linking, but not transglutaminase-mediated cross-linking. In summary, this in vitro model of human skin has allowed us to identify specific cross-linking pathways as possible pharmacologic targets for prevention of graft contracture in vivo.

Effect of temperature on the longitudinal variability of quantitative ultrasound variables.

It is unclear whether longitudinal change in phantom measurements bears any relation to the long-term in vivo instrument performance of quantitative ultrasound devices. Longitudinal quantitative ultrasound phantom data were obtained by measuring the manufacturer-provided phantom at ambient temperature and two different sets of Leeds phantoms at either ambient temperature or following a phantom temperature-control protocol. Measurements were performed using the Achilles Plus bone densitometer. Changes in longitudinal phantom data were compared to in vivo quantitative ultrasound data obtained from seven healthy, young volunteers. A cosinor model with linear trend and Hotelling's T2-test were used to quantify seasonal rhythms and long-term drift in quantitative ultrasound variables. Temperature effects and marked seasonal rhythms on quantitative ultrasound phantom measurements were evident but were far less apparent in vivo. Longitudinal precision of quantitative ultrasound variables was poorer for the manufacturer-provided phantom than for phantoms that were subjected to a temperature-control protocol or for healthy volunteers. This study has shown that longitudinal precision and longitudinal change differs between in vivo and phantom data. Longitudinal quantitative ultrasound measurements for monitoring change in skeletal status cannot, as yet, be properly controlled.

Serum retinoids and beta-carotene as predictors of hip and other fractures in elderly women.

UNLABELLED: There is debate about the possible deleterious effect of excessive vitamin A exposure on fracture risk. In this nested case control study in older women (312 cases and 934 controls), serum retinol, retinyl palmitate, and beta-carotene were not associated with fracture risk, and there was no evidence of excess risk with multivitamin or cod liver oil supplementation. INTRODUCTION: Recent studies have suggested that higher vitamin A intake may account for a component of fracture risk within the general population and that supplemental vitamin A may be harmful even within recommended limits. No studies have examined the relationship between biochemical retinol status and fracture in older women. MATERIALS AND METHODS: We examined serum retinol, retinyl palmitate, and beta-carotene as predictors of incident hip and other fractures in a large prospective study of British women over the age of 75 years (n = 2606, 312 incident osteoporotic fractures, 92 incident hip fractures; mean follow-up duration, 3.7 years). Fasting blood samples (9:00-11:00 a.m.) were collected at baseline. Using a case-control design (three controls per case), serum retinol, retinyl palmitate, and beta-carotene were assessed as univariate predictors of incident osteoporotic fracture or hip fracture. Baseline BMD at the total hip, age, 25(OH)D, serum beta Crosslaps, bone-specific alkaline phosphatase, weight, height, and smoking were considered as covariates in a multivariate model. RESULTS: Serum retinol, retinyl palmitate, and beta-carotene were not significant univariate predictors of either hip fracture or any fracture (all p > 0.05; Cox proportional hazards regression). For all osteoporotic fractures, the hazard ratio (HR) was 0.92 (95% CI, 0.81-1.05) per 1 SD increase in serum retinol. Risk of any osteoporotic fracture was slightly less in the highest quartile of serum retinol compared with the lowest quartile (HR, 0.85; 95% CI, 0.69-1.05; p = 0.132) There was a tendency for increased serum retinol to predict benefit rather than harm in terms of BMD (r = 0.09, p = 0.002). Multivitamin or cod liver oil supplementation was associated with a significantly lower risk of any fracture (HR, 0.76; 95% CI, 0.60-0.96; p = 0.021). In multivariate analysis, only age, total hip BMD, and weight were associated with fracture risk (p < 0.05). CONCLUSIONS: We found no evidence to support any skeletal harm associated with increased serum indices of retinol exposure or modest retinol supplementation in this population.

What have we learnt about the regulation of phosphate metabolism?

PURPOSE OF REVIEW: The search for hormones which specifically regulate phosphate metabolism has fuelled recent tantalizing studies. These studies have been motivated by diseases involving renal phosphate wasting, including tumor-induced osteomalacia, X-linked hypophosphatemic rickets, and autosomal dominant hypophosphatemia. This review focuses on likely candidate 'phosphatonins' and their possible physiological significance. RECENT FINDINGS: Candidate phosphatonins include fibroblast growth factor 23, matrix extracellular phosphoglycoprotein, stanniocalcin, and Frizzled-related protein 4. Fibroblast growth factor 23 has emerged as the prime candidate explaining pathophysiology of these diseases. FGF-23 is expressed in most tumors in tumor-induced osteomalacia. Serum fibroblast growth factor 23 is increased in most patients with X-linked hypophosphatemic rickets and tumor-induced osteomalacia. Injection of recombinant fibroblast growth factor 23 induces phosphaturia, hypophosphatemia, and suppression of 1,25-dihydroxyvitamin D in animals. Many unanswered questions remain, including the relationship between PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) mutations and elevated fibroblast growth factor 23. It is also not clear whether these candidate phosphatonins play a role in phosphate or vitamin D metabolism in healthy humans, or that this role is endocrine. The most compelling evidence derives from the fibroblast growth factor 23-knockout mouse which shows hyperphosphatemia and increased serum 1,25-dihydroxyvitamin D. A physiologically relevant phosphatonin should explain renal adaptation to variable dietary phosphate intake. The tissue source and determinants of serum fibroblast growth factor 23 are unknown. SUMMARY: Pathophysiological and animal studies serve as a logical foundation on which to base further questions of human physiology. The definition of what is or is not a phosphatonin may need to be refined. There is a need to return to 'old-fashioned' human physiology studies to place recent findings in perspective.

Clinical performance of immunoreactive tartrate-resistant acid phosphatase isoform 5b as a marker of bone resorption.

Previous immunoassays developed for the measurement of serum tartrate-resistant acid phosphatase (TRACP) have lacked specificity for osteoclastic TRACP, TRACP 5b, or have not shown satisfactory clinical performance. The aim of this study was to evaluate the clinical performance of a novel immunocapture activity assay for TRACP 5b, in comparison to telopeptide fragments of type I collagen. Within-subject variability and the effect of feeding on TRACP 5b and telopeptides of type I collagen were assessed in 20 healthy premenopausal women. Diurnal variation of TRACP 5b and serum beta C-terminal cross-linked telopeptide of type I collagen (sbetaCTX) was assessed in 12 healthy postmenopausal women. Renal clearance was assessed in 19 end stage renal failure patients undergoing routine haemodialysis. Response to antiresorptive treatment and calcium supplementation was assessed in osteoporotic postmenopausal women treated with alendronate and calcium (n = 16) or with calcium alone (n = 7) for 24 weeks.Within-subject variability (CVi) of TRACP 5b was 6.6%, lower than CVi of urinary and serum telopeptides. TRACP 5b decreased by 2.4 +/- 0.8%, in response to feeding (P < 0.05) compared to 7.0 +/- 2.6% to 7.9 +/- 3.7% for urinary telopeptides (P < 0.05 to < 0.01) and 8.5 +/- 1.7% to 17.8 +/- 2.6% for serum telopeptides (P < 0.0001). The amplitude of the diurnal rhythm for TRACP 5b was small compared to that of sbetaCTX, 14 +/- 4% vs. 137 +/- 14%. Haemodialysis did not have a significant effect on TRACP 5b but reduced sbetaCTX by 46 +/- 4% (P < 0.0001). In response to alendronate, TRACP 5b decreased by 39 +/- 4% compared to 49 +/- 4% to 69 +/- 5% for urinary telopeptides and 75 +/- 8% for sbetaCTX. We conclude that TRACP 5b shows an attenuated response to antiresorptive therapy in comparison with other markers of bone resorption, but that this may be offset by lower biological variability. TRACP 5b may provide useful additional information about bone resorption.

Octreotide abolishes the acute decrease in bone turnover in response to oral glucose.

Feeding or oral intake of glucose results in an acute suppression of bone turnover. This does not appear to be mediated by insulin. Several gastrointestinal hormones modulate bone turnover in vitro and may mediate this response. We examined whether inhibiting the production of gastrointestinal hormones using octreotide could block glucose-mediated suppression of bone turnover. Fifteen subjects were each studied on four occasions in a randomized, single-blind, crossover study after receiving 1) oral placebo, iv saline; 2) oral glucose, iv saline; 3) oral glucose, iv octreotide; or 4) iv octreotide alone. We measured serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen, osteocalcin, procollagen type I N-terminal propeptide, PTH, insulin, ionized calcium, and glucose over 4 h. All bone turnover markers decreased significantly after oral glucose (P < 0.001). At 120 min serum C-terminal telopeptide decreased by 45 +/- 2%, urinary N-terminal telopeptide by 31 +/- 7%, osteocalcin by 16 +/- 1%, and procollagen type I N-terminal propeptide by 8 +/- 1%. There was no significant decrease in bone turnover in response to oral glucose during octreotide infusion. Octreotide alone resulted in a significant increase in all bone turnover markers (P < 0.05) and PTH (P < 0.01). We conclude that octreotide completely abolishes the bone turnover response to glucose intake and increases PTH secretion. The apparent bone turnover response to feeding is probably mediated by an octreotide-inhibitable endocrine factor.

11beta-hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone.

Individual susceptibility to glucocorticoid-induced osteoporosis is difficult to predict clinically. We recently characterized expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in human osteoblasts. This enzyme generates active cortisol (or prednisolone) from inactive cortisone (or prednisone) and regulates glucocorticoid action in vitro. We, thus, hypothesized that osteoblastic 11beta-HSD1 mediates susceptibility to glucocorticoid-induced osteoporosis. Twenty healthy males ingested 5 mg prednisolone twice daily for 7 d, and relationships between changes in bone turnover markers and urinary measures of corticosteroid metabolism were examined. The bone formation markers osteocalcin and N-terminal propeptide of type I collagen decreased in all subjects (P < 0.001), but resorption markers were unchanged. The extent of fall in formation markers correlated with baseline 11beta-HSD1 activity with high activity predicting the greatest fall [for osteocalcin d 4 and 7, r = -0.58 and -0.56 (P < 0.01); for N-terminal propeptide of type I collagen d 4, r = -0.51 (P < 0.05)]. There was no correlation with measures of glucocorticoid inactivation or total corticosteroid metabolite production. Urinary measures of 11beta-HSD1 activity predict the response of bone formation markers to glucocorticoids, and this appears to reflect increased generation of active glucocorticoids within osteoblasts. Measures of 11beta-HSD1 activity may predict individual susceptibility to glucocorticoid-induced osteoporosis, and these data should facilitate the development of bone-sparing glucocorticoids.

Absence of marked seasonal change in bone turnover: a longitudinal and multicenter cross-sectional study.

UNLABELLED: The effect of season on bone turnover is controversial. No information is available on seasonality of new serum markers of bone resorption. In this study, we have been unable to confirm findings of a marked wintertime increase in bone formation and resorption within the general population. Seasonality was assessed by cosinor analysis. INTRODUCTION: We investigated the effect of season on seven markers of bone turnover in a longitudinal study (six men and six premenopausal women; age, 24-44 years) and a separate large population-based multicenter European study (n = 2780 women, Osteoporosis and Ultrasound Study [OPUS]). MATERIALS AND METHODS: Measurements included serum Crosslaps, procollagen type I N-terminal propeptide (PINP), osteocalcin (OC), and the N-telopeptide fragment of type I collagen in urine (NTX). Seasonality was assessed by cosinor analysis with Hotelling's T2 test. RESULTS: Serum 25(OH) vitamin D showed a marked seasonal rhythm. There was no significant seasonal component for any marker of bone turnover in the longitudinal analysis (cosinor analysis, p > 0.05). The percentage of within subject variance accounted for by any seasonal trend was very small for all markers (less than 2.5%). Less than 1% of the between-person variance was accounted for by seasonality in the cross-sectional analysis for all markers (n = 2780). There was a small but statistically significant summertime increase in OC and PINP in the healthy postmenopausal population after exclusions based on disease or medication use (remaining n = 1226, amplitudes 5.6% and 5.4%, respectively, p < 0.001). CONCLUSIONS: We have been unable to confirm findings of a marked wintertime increase in bone formation and resorption within the general population. The absence of marked seasonality was irrespective of age, menopausal status, reported supplemental Vitamin D intake, age or geographical location. The small but statistically significant summertime increase in bone formation in this and other studies is unlikely to confound clinical interpretation of these measurements.