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Purpose: The objective of this study was to examine whether different mechanical modifications and/or impregnation of hyaluronic acid (HA) might enhance aragonite-based scaffold properties for the regeneration of cartilage and bone in an animal model., Methods: Bi-phasic osteochondral scaffolds were prepared using coralline aragonite with different modifications, including 1- to 2-mm-deep drilled channels in the cartilage phase (Group 1, n = 7) or in the bone phase (Group 2, n = 8), and compared with unmodified coral cylinders (Group 3, n = 8) as well as empty control defects (Group 4, n = 4). In each group, four of the implants were impregnated with HA to the cartilage phase. Osteochondral defects (6 mm diameter, 8 mm depth) were made in medial and lateral femoral condyles of 14 goats, and the scaffolds were implanted according to a randomization chart. After 6 months, cartilage and bone regeneration were evaluated macroscopically and histologically by an external laboratory., Results: Group 1 implants were replaced by newly formed hyaline cartilage and subchondral bone (combined histological evaluation according to the ICRS II-2010 and O'Driscoll et al. 34 ± 4 n = 7). In this group, the cartilaginous repair tissue showed a smooth contour and was well integrated into the adjacent native cartilage, with morphological evidence of hyaline cartilage as confirmed by the marked presence of proteoglycans, a marked grade of collagen type II and the absence of collagen type I. The average scores in other groups were significantly lower (Group 2 (n = 8) 28.8 ± 11, Group 3 (n = 8) 23 ± 9 and Group 4 (empty control, n = 4) 19.7 ± 15)., Conclusions: The implants with the mechanical modification and HA impregnation in the cartilage phase outperformed all other types of implant. Although native coral is an excellent material for bone repair, as a stand-alone material implant, it does not regenerate hyaline cartilage. Mechanical modification with drilled channels and impregnation of HA within the coral pores enhanced the scaffold's cartilage regenerative potential. The modified implant shows young hyaline cartilage regeneration. This implant might be useful for the treatment of both chondral and osteochondral defects in humans.

Leptin signaling is required for normal bone homeostasis; however, loss of leptin results in differing effects on cortical and cancellous bone, as well as altered responses between the axial and appendicular regions. Local β-adrenergic actions are responsible for the greater cancellous bone volume in leptin-deficient (ob/ob) mice; however, the mechanism responsible for the opposing reduction in cortical bone in ob/ob mice is not known. Here we show that blocking the leptin-deficient increase in neuropeptide Y (NPY) expression reverses the cortical bone loss in ob/ob mice. Mice null for both NPY and leptin (NPY(-/-) ob/ob), display greater cortical bone mass in both long-bones and vertebra, with NPY(-/-) ob/ob mice exhibiting thicker and denser cortical bone, associated with greater endocortical and periosteal mineral apposition rate (MAR), compared to ob/ob animals. Importantly, these cortical changes occurred without significant increases in body weight, with NPY(-/-) ob/ob mice showing significantly reduced adiposity compared to ob/ob controls, most likely due to the reduced respiratory exchange ratio seen in these animals. Interestingly, cancellous bone volume was not different between NPY(-/-) ob/ob and ob/ob, suggesting that NPY is not influencing the adrenergic axis. Taken together, this work demonstrates the critical role of NPY signaling in the regulation of bone and energy homeostasis, and more importantly, suggests that reduced leptin levels or leptin resistance, which occurs in obesity, could potentially inhibit cortical bone formation via increased central NPY signaling., (Copyright © 2013 American Society for Bone and Mineral Research.)

Bariatric surgery remains the most effective treatment for severely obese patients. However, the potential long-term effects of bariatric surgical procedures on health, including bone health, are only partially understood. The goal of this review was to present data on the impact of bariatric surgery on bone metabolism and to analyse possible reasons for the loss of bone mass that frequently occurs after bariatric surgery. Such factors include nutritional deficiencies, rapid weight loss per se, effects of fat-derived adipokines and gut-derived appetite-regulatory hormones. However, the relative roles of these factors in skeletal regulation and the mechanisms by which they work are not yet fully defined. Our review was focussed on the complex relationship between body weight, fat mass and bone mass, as well as peripheral and central mediators potentially involved in the dual regulation of both energy and bone homeostasis. We also review the data on the inverse relationship between central obesity, bone marrow fat and osteoporosis. As the number of bariatric operations increases, it is imperative to recognize mechanisms responsible for bariatric surgery-induced bone loss, with careful monitoring of bone health including long-term fracture incidence in patients undergoing these procedures., (© 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity.)

Chronic opiate usage, whether prescribed or illicit, has been associated with changes in bone mass and is a recognized risk factor for the development of osteoporosis; however, the mechanism behind this effect is unknown. Here we show that lack of dynorphin, an endogenous opioid, in mice (Dyn-/-), resulted in a significantly elevated cancellous bone volume associated with greater mineral apposition rate and increased resorption indices. A similar anabolic phenotype was evident in bone of mice lacking dynorphin's cognate receptor, the kappa opioid receptor. Lack of opioid receptor expression in primary osteoblastic cultures and no change in bone cell function after dynorphin agonist treatment in vitro indicates an indirect mode of action. Consistent with a hypothalamic action, central dynorphin signaling induces extracellular signal-regulated kinase (ERK) phosphorylation and c-fos activation of neurons in the arcuate nucleus of the hypothalamus (Arc). Importantly, this signaling also leads to an increase in Arc NPY mRNA expression, a change known to decrease bone formation. Further implicating NPY in the skeletal effects of dynorphin, Dyn-/-/NPY-/- double mutant mice showed comparable increases in bone formation to single mutant mice, suggesting that dynorphin acts upstream of NPY signaling to control bone formation. Thus the dynorphin system, acting via NPY, may represent a pathway by which higher processes including stress, reward/addiction and depression influence skeletal metabolism. Moreover, understanding of these unique interactions may enable modulation of the adverse effects of exogenous opioid treatment without directly affecting analgesic responses., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Bone mineral density (BMD) is a complex trait that is the single best predictor of the risk of osteoporotic fractures. Candidate gene and genome-wide association studies have identified genetic variations in approximately 30 genetic loci associated with BMD variation in humans. α-Actinin-3 (ACTN3) is highly expressed in fast skeletal muscle fibres. There is a common null-polymorphism R577X in human ACTN3 that results in complete deficiency of the α-actinin-3 protein in approximately 20% of Eurasians. Absence of α-actinin-3 does not cause any disease phenotypes in muscle because of compensation by α-actinin-2. However, α-actinin-3 deficiency has been shown to be detrimental to athletic sprint/power performance. In this report we reveal additional functions for α-actinin-3 in bone. α-Actinin-3 but not α-actinin-2 is expressed in osteoblasts. The Actn3(-/-) mouse displays significantly reduced bone mass, with reduced cortical bone volume (-14%) and trabecular number (-61%) seen by microCT. Dynamic histomorphometry indicated this was due to a reduction in bone formation. In a cohort of postmenopausal Australian women, ACTN3 577XX genotype was associated with lower BMD in an additive genetic model, with the R577X genotype contributing 1.1% of the variance in BMD. Microarray analysis of cultured osteoprogenitors from Actn3(-/-) mice showed alterations in expression of several genes regulating bone mass and osteoblast/osteoclast activity, including Enpp1, Opg and Wnt7b. Our studies suggest that ACTN3 likely contributes to the regulation of bone mass through alterations in bone turnover. Given the high frequency of R577X in the general population, the potential role of ACTN3 R577X as a factor influencing variations in BMD in elderly humans warrants further study., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Changes in whole body energy levels are closely linked to alterations in body weight and bone mass. Here, we show that hypothalamic signals contribute to the regulation of bone mass in a manner consistent with the central perception of energy status. Mice lacking neuropeptide Y (NPY), a well-known orexigenic factor whose hypothalamic expression is increased in fasting, have significantly increased bone mass in association with enhanced osteoblast activity and elevated expression of bone osteogenic transcription factors, Runx2 and Osterix. In contrast, wild type and NPY knockout (NPY (-/-)) mice in which NPY is specifically over expressed in the hypothalamus (AAV-NPY+) show a significant reduction in bone mass despite developing an obese phenotype. The AAV-NPY+ induced loss of bone mass is consistent with models known to mimic the central effects of fasting, which also show increased hypothalamic NPY levels. Thus these data indicate that, in addition to well characterized responses to body mass, skeletal tissue also responds to the perception of nutritional status by the hypothalamus independently of body weight. In addition, the reduction in bone mass by AAV NPY+ administration does not completely correct the high bone mass phenotype of NPY (-/-) mice, indicating the possibility that peripheral NPY may also be an important regulator of bone mass. Indeed, we demonstrate the expression of NPY specifically in osteoblasts. In conclusion, these data identifies NPY as a critical integrator of bone homeostatic signals; increasing bone mass during times of obesity when hypothalamic NPY expression levels are low and reducing bone formation to conserve energy under 'starving' conditions, when hypothalamic NPY expression levels are high.

Important and novel roles for neuropeptide Y (NPY) signaling in the control of bone homeostasis have recently been identified, with deletion of either the Y1 or Y2 receptors resulting in a generalized increase in bone formation. Whereas the Y2 receptor-mediated anabolic response is mediated by a hypothalamic relay, the Y1-mediated response is likely mediated by osteoblastic Y1 receptors. The presence of Y1 receptors on osteoblasts and various other peripheral tissues suggests that, in addition to neuronal input, circulating factors may also interact with the Y1-mediated pathways. The skeletal and adipose tissue (peripheral and marrow) responses to Y1 receptor deficiency were examined after (1) leptin deficiency, (2) gonadectomy, and (3) hypothalamic NPY overexpression. Bone formation was consistently increased in intact Y1(-/-) mice. However, the hypogonadism of gonadectomy or leptin deficiency blocked this anabolism in male Y1(-/-) mice, whereas females remained unchanged. The Y1-mediated bone anabolic pathway thus seems to be dependent on the presence of intact androgen signaling. Y1 deficiency also led to increased body weight and/or adiposity in all experimental models, with the exception of male ob/ob, showing a general adipogenic effect of Y1 deficiency that is not dependent on androgens. Interestingly, marrow adipocytes were regulated differently than general adipose depots in these models. Taken together, this interaction represents a novel mechanism for the integration of endocrine and neural signals initiated in the hypothalamus and provides further insight into the coordination of bone and energy homeostasis.

The importance of neuropeptide Y (NPY) and Y2 receptors in the regulation of bone and energy homeostasis has recently been demonstrated. However, the contributions of the other Y receptors are less clear. Here we show that Y1 receptors are expressed on osteoblastic cells. Moreover, bone and adipose tissue mass are elevated in Y1(-/-) mice with a generalized increase in bone formation on cortical and cancellous surfaces. Importantly, the inhibitory effects of NPY on bone marrow stromal cells in vitro are absent in cells derived from Y1(-/-) mice, indicating a direct action of NPY on bone cells via this Y receptor. Interestingly, in contrast to Y2 receptor or germ line Y1 receptor deletion, conditional deletion of hypothalamic Y1 receptors in adult mice did not alter bone homeostasis, food intake, or adiposity. Furthermore, deletion of both Y1 and Y2 receptors did not produce additive effects in bone or adiposity. Thus Y1 receptor pathways act powerfully to inhibit bone production and adiposity by nonhypothalamic pathways, with potentially direct effects on bone tissue through a single pathway with Y2 receptors.

Background: It is not clear whether bone turnover markers can be used to make inference regarding changes in bone mineral density (BMD) in untreated healthy elderly men. The present study was designed to address three specific questions: (i) is there a relationship between bone turnover markers and femoral neck BMD within an individual; (ii) is there a relationship between baseline measurements of bone turnover markers and subsequent change in BMD; and (iii) is there a relationship between changes in bone turnover markers and changes in femoral neck BMD?, Methods: The present study was part of the on-going Dubbo Osteoporosis Epidemiology Study, which was designed as a prospective investigation. Men who had had at least 3 sequential visits with serum samples available during follow-up were selected from the study population. Serum C-terminal telopeptide of type I collagen (sICTP), N-terminal propeptide of type I collagen (sPINP) and femoral neck BMD were measured by competitive radioimmunoassays. Femoral neck bone mineral density (BMD) was measured by a densitometer (GE Lunar Corp, Madison, WI). Various mixed-effects models were used to assess the association between the markers and changes in BMD., Results: One hundred and one men aged 70 +/- 4.1 years (mean +/- SD) met the criteria of selection for analysis. On average, sPINP decreased by 0.7% per year (p = 0.026), sICTP increased by 1.7% per year (p = 0.0002), and femoral neck BMD decreased by 0.4% per year (p < 0.01). Within-subject analysis indicated that changes in BMD were significantly associated with changes in sPINP (p = 0.022), but not with changes in sICTP (p = 0.84). However, neither baseline sPINP (p = 0.50) nor baseline sICTP (p = 0.63) was associated with subsequent changes in BMD. Moreover, changes in BMD were not significantly associated with previous changes in sPINP (p = 0.13) or sICTP (p = 0.95)., Conclusion: These results suggest that in elderly men of Caucasian background, changes in sPINP were inversely related to changes in BMD within an individual. However, neither sPINP nor sICTP was sufficiently sensitive to predict the rate of change in BMD for a group of individuals or for an individual.

Unlabelled: Among the potential risk factors for fragility fractures, bone turnover is considered an important determinant. In a case-cohort control study of 151 elderly men followed prospectively over 6.3 years, high bone resorption as assessed by S-ICTP was associated with increased risk of osteoporotic fracture, independent of BMD. Combining measurements of BMD and bone turnover may improve fracture prediction in elderly men., Introduction: Approximately one-third of osteoporotic fractures occur in men. Among the potential risk factors for fragility fractures, bone turnover is considered an important determinant. The association between fracture risk and rates of bone turnover has not been well established in men. We examined this relationship in elderly community-dwelling men., Materials and Methods: This case-cohort control study included 50 men with incident low-trauma fractures (cases; age, 72.3 +/- 6.7 years) and 101 men without fracture (controls; age, 70.4 +/- 4.1 years), who have been prospectively followed in the Dubbo Osteoporosis Epidemiology Study for a median of 6.3 years (range, 2-13 years). BMD at the lumbar spine (LSBMD) and at the femoral neck (FNBMD) and markers of bone turnover were measured at baseline. Bone resorption was assessed by measuring nonfasting serum concentrations of the carboxyterminal cross-linked telopeptide of type I collagen (S-ICTP) and of a linear octapeptide derived from the carboxyterminal type I collagen telopeptide (S-CTX). Bone formation was assessed by measuring the serum levels of the aminoterminal propeptide of type I procollagen (S-PINP)., Results: Men with subsequent fractures had lower BMD at baseline, both at the femoral neck and the spine, lower dietary calcium intake, and higher S-ICTP levels than age-and weight-matched controls. Smoking habits, S-CTX, and S-PINP did not differ between groups. Based on univariate regression analyses, S-ICTP (relative risk [RR] for 1 SD change: 1.8; 95% CI, 1.4-2.3) and serum creatinine levels (RR, 1.4; 95% CI, 1.1-1.7) were associated with increased risk of fracture. In multivariate regression analyses, S-ICTP (RR, 1.4; 95% CI, 1.0-1.9) and FNBMD (RR, 1.8; 95% CI, 1.4-2.3) remained independent predictors of fracture risk. Men within the highest quartile of S-ICTP had a 2.8-fold (95% CI 1.4-5.4) increased risk of fracture compared with those in the lowest quartile. The incidence of osteoporotic fractures was 10 times higher in men with high S-ICTP and low FNBMD compared with men with low S-ICTP and high FNBMD. Of the fracture risk in the population, 20% was attributable to high S-ICTP and low FNBMD, and S-ICTP contributed 17% to this increased risk., Conclusion: High bone resorption is associated with an increased risk of osteoporotic fracture in elderly men, independent of BMD. Combining measurements of BMD and bone turnover, which correlated with fracture in this cohort, could improve fracture risk prediction in elderly men.

Osteoporotic fracture is considered to result from reduced bone strength and to be related to decreased bone mass and impaired bone architecture. Quantitative ultrasound measurements (QUS) of bone, that may reflect certain architectural aspects of bone, have been shown to be associated with fracture, but it is not clear whether the association is independent of bone mineral density (BMD). This study was designed to examine the contributions of cortical QUS and BMD measurements to the prediction of fracture risk in postmenopausal Caucasian women. Speed of sound (SOS) at the distal radius, tibia, and phalanx (Sunlight Omnisense) and BMD at the lumbar spine and femoral neck (GE Lunar) were measured in 549 women, aged 63.2 +/- 12.3 years (mean +/- SD; range, 49-88 years), including 77 fracture cases. Lower SOS at the distal radius, tibia, and phalanx, which were correlated with each other, were associated with increased risk of fracture. Independent predictors of fracture risk (in multivariate analysis) were distal radius SOS (OR per SD = 1.8; 95% CI, 1.3-2.4), femoral neck BMD (OR per SD = 1.9; 95% CI, 1.4-2.4), and age (OR per 5 years = 1.2; 95% CI, 1.0-1.5). Approximately 30% of the women had distal radius SOS T-scores <-2.5; however, only 6.6% of women had both BMD and SOS T-scores <-2.5. Among the 77 fracture cases, only 14 (18.2%) had both BMD and QUS T-scores below -2.5. These data in postmenopausal women suggest that speed of sound at the distal radius was associated with fracture risk, independent of BMD and age. The combination of QUS and BMD measurements may improve the accuracy of identification of women who will sustain a fracture.

A cohort of 15 immigrant females to Australia and 7 native Australian controls were monitored on a monthly basis with high-precision lead isotopic methods during gestation and for 6 months after pregnancy to determine the extent of lead mobilization from the maternal skeleton. Quarterly environmental samples of house dust, drinking water, urban air, gasoline, and a 6-day duplicate diet were also measured. The geometric mean blood lead concentration for the immigrant females on arrival in Australia was 3.0 microg/dl (range: 1.9 to 20 microg/dl), and for the Australian controls was 3.1 gm/dl (range: 1.9 to 4.3 microg/dl). During gestation and after pregnancy, blood lead concentrations varied, with mean individual changes of -14% to 83%. For the immigrant subjects, the percentage change in blood lead concentration was significantly greater during the postpregnancy period than during the 2nd and 3rd trimesters (p < 0.001). Skeletal contribution to blood lead, based on the isotopic composition for the immigrant subjects, increased in an approximately linear manner during pregnancy. The mean increases for each individual during pregnancy varied from 26% to 99%. Skeletal lead contribution to blood lead was significantly greater (p < 0.001) during the postpregnancy period than during the 2nd and 3rd trimesters. The contribution of skeletal lead to blood lead during the postpregnancy period remained essentially constant at the increased level of lead mobilization, although the duration of breastfeeding varied from 1 week to more than 6 months. The increased contribution of skeletal lead to blood lead during the postpregnancy period is attributed to increased mobilization of lead from maternal skeletal stores during lactation. The increased contribution of skeletal lead both during pregnancy and in the postpregnancy period is consistent with increased bone resorption, and may be associated with an inadequate calcium intake observed in quarterly 6-day duplicate diets. Mobilization of skeletal lead stores represents a potentially important source of perinatal lead intake and accumulation in the developing fetus. Only two subjects consumed dietary supplements for calcium, and their mobilization of lead from the skeleton to the blood was the lowest of all the subjects. These two subjects' use of calcium supplements may have reduced mobilization of skeletal mineral stores to supply the calcium needs of pregnancy and lactation. Calcium supplementation may be an important means of limiting fetal exposure to lead.

Bone mineral density (BMD) and bone turnover are both heritable. Although bone turnover affects bone mass, it is not clear whether these parameters are under common genetic or environmental control. The relative contribution of genetic and environmental factors to the determination of an index of bone turnover, bone specific alkaline phosphatase (BSAP), and the extent of common genetic regulation with BMD, were examined in 97 female twin pairs, aged 50 +/- 15 years (mean +/- SD), consisting of 48 monozygotic (MZ) and 49 dizygotic (DZ) pairs. BSAP was analyzed by radioimmunometric assay. Bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) was measured by dual-energy X-ray absorptiometry. Twin resemblance for variable traits was assessed by intraclass correlation coefficients. Estimates of genetic and environmental components of variance were based on univariate and multivariate genetic models. As expected, BSAP in premenopausal women (9.8 +/- 4.3 microg/L) was significantly lower than in postmenopausal women (13.3 +/- 6.6 microg/L, p < 0.001), but similar to the subgroup of postmenopausal women on hormone replacement therapy (10.8 +/- 2.6 microg/L, p = 0.15). Although BSAP and BMD were correlated in a cross-sectional analysis (r = -0.35, p < 0.001 for LS-BMD; r = -0.16, p = 0.03 for FN-BMD), the intrapair difference in BSAP was not significantly correlated with the intrapair difference in BMD for MZ twin pairs. After adjustment for menopausal status, the intraclass correlation for BSAP was significantly higher in MZ than DZ twins (0.60 +/- 0.09 vs. 0.27 +/- 0.13, p = 0.03). Univariate model-fitting analyses indicated a heritability of 63% for BSAP, and 77% and 72% for lumbar spine and femoral neck BMD, respectively. By multivariate analyses, genes specifically influencing BSAP accounted for 16% of the total genetic variance in LS-BMD and 4% of the total genetic variance in FN-BMD. There was no evidence for shared environmental factors affecting BSAP and BMD. These findings indicate that BSAP and BMD are heritable and negatively correlated. However, the genetic loci influencing BSAP and BMD appear to be largely independent as are any environmental factors.

Human and murine osteocalcin genes demonstrate similar cell-specific expression patterns despite significant differences in gene locus organization and sequence variations in cis-acting regulatory elements. To investigate whether differences in these regulatory regions result in an altered response to 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in vivo, we compared the response of the endogenous mouse osteocalcin gene to a bacterial reporter gene directed by flanking regions of the human osteocalcin gene in transgenic mice. Transgene expression colocalized with endogenous osteocalcin expression in serial sections, being detected in osteoblasts, osteocytes and hypertrophic chondrocytes. In calvarial cell culture lysates from transgenic and nontransgenic mice, the endogenous mouse osteocalcin gene did not respond to 1,25-(OH)2D3 treatment. Despite this, transgene activity was significantly increased in the same cells. Similarly, Northern blots of total cellular RNA and in situ hybridization studies of transgenic animals demonstrated a maximal increase in transgene expression at 6 h after 1,25-(OH)2D3 injection (23.6+/-3.6-fold) with a return to levels equivalent to uninjected animals by 24 h (1.2+/-0.1-fold). This increase in transgene expression was also observed at 6 h after 1,25-(OH)2D3 treatment in animals on a low calcium diet (25.2+/-7.7-fold) as well as in transgenic mice fed a vitamin D-deficient diet containing strontium chloride to block endogenous 1,25-(OH)2D3 production (7.5+/-0.9-fold). In contrast to the increased transgene expression levels, neither endogenous mouse osteocalcin mRNA levels nor serum osteocalcin levels were significantly altered after 1,25-(OH)2D3 injection in transgenic or nontransgenic mice, regardless of dietary manipulations, supporting evidence for different mechanisms regulating the response of human and mouse osteocalcin genes to 1,25-(OH)2D3. Although the cis- and trans-acting mechanisms directing cell-specific gene expression appear to be conserved in the mouse and human osteocalcin genes, responsiveness to 1,25-(OH)2D3 is not. The mouse osteocalcin genes do not respond to 1,25-(OH)2D3 treatment, but the human osteocalcin-directed transgene is markedly upregulated under the same conditions and in the same cells. The divergent responses of these homologous genes to 1,25-(OH)2D3 are therefore likely to be due to differences in mouse and human osteocalcin-regulatory sequences rather than to variation in the complement of trans-acting factors present in mouse osteoblastic cells. Increased understanding of these murine-human differences in osteocalcin regulation may shed light on the function of osteocalcin and its regulation by vitamin D in bone physiology.

Recent studies have shown that genetic effects on bone mineral density (BMD) and bone turnover are related to allelic variation in the vitamin D receptor (VDR) gene. We examined allelic influences of the VDR gene on bone turnover and density in 202 normal healthy premenopausal Japanese women (age 30.1 +/- 1.2, mean +/- SEM). The VDR effect on BMD and turnover is similar to that observed in Caucasian women; however, there are major differences in allele frequency. The B allele by BsmI restriction fragment length polymorphisms (RFLPs), associated with low BMD and high bone turnover, is found in only 12% of Japanese women (1.4% homozygote BB), compared with 41% of Caucasians (16.7% homozygote BB). In comparing the two most frequent genotypes, Bb heterozygotes (21.5%) and bb homozygotes (77.1%), BMD is 5.3% lower in Bb heterozygotes, and levels of bone formation markers including osteocalcin and bone-specific alkaline phosphatase are 20-32% higher with lower serum calcium (2.30 +/- 0.02 vs 2.35 +/- 0.01 mmol/l) and higher 1,25-dihydroxyvitamin D (95 +/- 4.8 vs. 76 +/- 3.8 pmol/l). Further discrimination of the genotype was achieved using two additional RFLPs (ApaI, A and TaqI, T); the lumbar spine BMD of the common genotype BbAATt was 9.3% (0.94 SD) lower than in the bbaaTT genotype in premenopausal Japanese women. These data confirm that VDR RFLPs affect bone mineral metabolism regardless of racial differences. Moreover, the VDR genotypes based on haplotype analysis should yield useful insights into the potential prevention of osteoporosis.

The vitamin D endocrine system is central to the control of bone and calcium homeostasis. The active hormonal form of vitamin D, 1,25 dihydroxyvitamin D (calcitriol), the circulating level of which is tightly regulated, acts through a specific receptor to mediate its genomic actions on almost every aspect of calcium homeostasis. Because of its transactivation function, it is possible that a small difference in vitamin D receptor level could be amplified into a biologically significant alteration in physiological setpoint. The recent finding that polymorphisms in the vitamin D receptor gene are predictive of bone density (Morrison et al., Nature 367:284-287, 1994) is the first example of an allelic effect in such a homeostatically controlled system. This raises the possibility that such central operators may exist in other regulatory pathways, and could explain a large part of the observed "normal" population distribution that exists for all physiological parameters.

Osteoporosis is a major health problem in Australia, as it is in most Western societies. Bone mineral density in the spine and femoral neck are accurate indicators of osteopenia and thus useful indicators of the risk of a fracture. Dual-photon absorptiometry is a non-invasive technique that allows the accurate quantitation of bone mineral density in the lumbar vertebrae and proximal femur with a low radiation exposure. The increasing availability of this technique dictates the requirement for "normal" ranges and quality control. We report here lumbar vertebral and proximal femur bone mineral density as measured by dual-photon absorptiometry in 179 normal Australian women. Forearm bone mineral content in these subjects, as measured by single-photon absorptiometry, is also presented. There was a relative stability of lumbar bone mineral density and forearm bone mineral content before the menopause, after which there was an age-related decline. On the other hand, bone mineral density at all three sites in the proximal femur showed an age-related decline throughout adult life. Intraoperator variability in calculated bone mineral density did not exceed 2.3%. The requirement for correct positioning of the patient is illustrated. The data allow statistical analysis and the development of normal ranges. They provide an Australian base against which individual patient values can now be compared.

Osteoporosis, a major health problem in all Western countries, is a condition in which many dietary factors have been implicated. To determine the influence of diet on bone mass in the proximal femur, the intake of 14 nutrients was measured in 159 Caucasian women, aged 23-75 years and bone mineral density (BMD) quantitated in the hip by dual photon absorptiometry. BMD was also measured in the spine and bone mineral content (BMC) in the forearm by single photon absorptiometry. No significant correlation was found between current calcium intake and bone mass at any site. Iron was a positive predictor of BMD in the femoral neck and alcohol intake a positive predictor of BMD in the trochanteric region of the proximal femur in premenopausal women by multiple regression analysis. Iron, zinc and magnesium intake were positively correlated with forearm BMC in premenopausal women. Iron and magnesium were significant predictors of forearm BMC in premenopausal and postmenopausal women respectively by multiple regression analysis. These results suggest that bone mass is influenced by dietary factors other than calcium.

Low dose corticosteroids are effective in suppressing synovitis in rheumatoid arthritis (RA), but there remains concern about their side effects, particularly osteoporosis. To examine the effects of low dose corticosteroids on bone loss in RA bone mineral density (BMD) was measured in the lumbar spine and hip for up to two years in 15 patients treated with these agents (mean dose prednis(ol)one 6.6 mg/day). 15 patients not receiving them, and 15 age matched controls. The initial BMD at both skeletal sites was significantly reduced in both patient groups compared with controls. The mean change in bone density was 0.2, 0.1, and -0.1% a year in the spine and -2.0, -1.9, and -1.0% a year in the hip respectively for the three groups. These rates of bone loss were not significantly different between groups at either site. These findings suggest that low dose corticosteroid treatment in RA is not associated with an increased risk of osteoporosis.

Controversy exists about rates of bone mineral loss from the lumbar spine at the menopause. Cross-sectional studies of lumbar bone mineral against age have been interpreted as evidence for or against a menopause-related change in lumbar bone loss, depending on their goodness of fit to either linear or nonlinear equations. To investigate the ability of cross-sectional studies to detect accelerated lumbar bone loss at the menopause, we constructed models of different patterns of loss and evaluated the findings in cross-sectional analyses of computer-simulated populations of normal women. A sample size of greater than 300 was needed to distinguish between linear and nonlinear patterns of bone loss with a power of 90% when the data was analyzed throughout life. Examining for differences between the slopes of the regressions of pre- and postmenopausal women was more useful for detecting nonlinear bone loss under some circumstances. A difference between slopes was apparent in studies containing 100 subjects if lumbar bone density (BMD) was assumed to be unchanged prior to the menopause, but a larger study size was needed (greater than 1000) if BMD was assumed to fall before the menopause. We also measured lumbar BMD by dual photon absorptiometry in 141 normal females. When the data was analyzed against age throughout life, a nonlinear pattern of bone loss was found, and comparison of pre- and postmenopausal subjects showed a significant difference in the slopes of the linear regressions. Our patient data support the concept of a relatively stable lumbar BMD prior to the menopause with a rapid but transient decline postmenopausally.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between physical fitness and bone mass in the femoral neck, lumbar spine, and forearm was studied in 84 normal women. Femoral neck and lumbar spine bone mineral density and forearm bone mineral content were estimated by absorptiometry. Fitness was quantitated from predicted maximal oxygen uptake. Femoral neck and lumbar bone mineral density were significantly correlated with fitness as well as age and weight. In the 46 postmenopausal subjects, fitness was the only significant predictor of femoral neck bone mineral density, and both weight and fitness predicted the lumbar bone mineral density. These data represent the first demonstration of a correlation between physical fitness, and, by implication, habitual physical activity, and bone mass in the femoral neck; they also support the previous reported correlation between lumbar bone mass and physical activity. The data suggest that increased physical fitness may increase bone mass at the sites of clinically important fractures in osteoporosis.

Bone density measurements are currently being performed throughout the world in the diagnosis and management of osteoporosis as well as in research into this major health problem. However, it is not clear to what extent bone mineral density (BMD) values determined by dual-photon absorptiometry at one center can be applied to another. This is particularly relevant for the quantitative comparison of results from studies carried out in different laboratories. Furthermore, many centers now acquiring densitometers may not have the resources to determine their own normal range, relying instead on a "normal" range provided by the manufacturer. The question of the comparability of BMD data obtained in different centers was examined by comparing the normal range for the lumbar spine and proximal femur in 203 normal white Australian women and 892 normal white U.S. women, obtained using the same model densitometer. The two populations were compared according to decade. From superimposition of the Australian individual values on the North American normal ranges, only minor differences between the two populations were seen at any of the sites measured at any decade. None of these minor differences were statistically significant. This study shows a close similarity between BMD values in both the proximal femur and lumbar spine in normal white women in Australia and North America, provided the same model densitometer is used. Thus data obtained from different centers in populations with similar ethnic composition may be compared directly. These findings provide for the first time a sound basis for the quantitative comparison of the at times conflicting studies carried out in widely differing settings around the world.

A relationship between circulating insulin and bone mass has been postulated. To test this hypothesis we measured fasting serum insulin and quantitated bone density in the forearm, spine and femoral neck by single and dual photon absorptiometry of 70 normal women. There was no statistically significant relationship between insulin and bone density at any site by correlation or regression analysis. Although the relationship between a single measurement of a hormone (at one point in time) and bone density (the result of lifelong factors) should be interpreted with caution, our findings do not support the hypothesis that there is an association between serum insulin and bone mass.

Age-related bone loss has been attributed to a decline in bone formation due to decreased osteoblast function. However, studies examining the relationship between age or menopausal status and indices of bone formation such as serum osteocalcin have yielded conflicting results. To examine these relationships we studied indices of bone formation and resorption and bone mineral density in 247 normal women, including 96 postmenopausal women ranging in age from 20-75 yr. A cubic polynomial regression best fit the relationship between age and serum osteocalcin (r = 0.32; n = 228; P = 0.0001) and urinary hydroxyproline/creatinine excretion (r = 0.40; n = 228; P = 0.0001), with both indices declining before the menopause, rising at the menopause, and subsequently falling through the seventh and eighth decades. While a significant decline in osteocalcin levels was observed in the postmenopausal group older than 60 yr, levels in subjects older than 60 yr remained higher (+31%) than those in late premenopausal subjects. Urinary calcium to creatinine excretion rose in the premenopausal years, increased markedly after the menopause, and remained at this level subsequently. Urinary hydroxyproline/creatinine, but not serum osteocalcin or urinary calcium/creatinine excretion, was a significant predictor of bone mineral density at the lumbar spine and the femoral neck independent of age. These data are consistent with the hypothesis that age-related bone loss after the menopause occurs in the presence of initially increased but subsequently decreasing bone turnover with maintenance of a relative excess of bone resorption.

The relative importance of genetic factors in determining bone mass in different parts of the skeleton is poorly understood. Lumbar spine and proximal femur bone mineral density and forearm bone mineral content were measured by photon absorptiometry in 38 monozygotic and 27 dizygotic twin pairs. Bone mineral density was significantly more highly correlated in monozygotic than in dizygotic twins for the spine and proximal femur and in the forearm of premenopausal twin pairs, which is consistent with significant genetic contributions to bone mass at all these sites. The lesser genetic contribution to proximal femur and distal forearm bone mass compared with the spine suggests that environmental factors are of greater importance in the aetiology of osteopenia of the hip and wrist. This is the first demonstration of a genetic contribution to bone mass of the spine and proximal femur in adults and confirms similar findings of the forearm. Furthermore, bivariate analysis suggested that a single gene or set of genes determines bone mass at all sites.