Abstract: There is an unmet medical need for anabolic treatments to restore lost bone Human genetic bone disorders provide insight into bone regulatory processes Sclerosteosis is a disease typified by high bone mass due to the loss of SOST expression Sclerostin, the SOST gene protein product, competed with the type I and type II bone morphogenetic protein (BMP) receptors for binding to BMPs, decreased BMP signaling and suppressed mineralization of osteoblastic cells SOST expression was detected in cultured osteoblasts and in mineralizing areas of the skeleton, but not in osteoclasts Strong expression in osteocytes suggested that sclerostin expressed by these central regulatory cells mediates bone homeostasis Transgenic mice overexpressing SOST exhibited low bone mass and decreased bone strength as the result of a significant reduction in osteoblast activity and subsequently, bone formation Modulation of this osteocyte-derived negative signal is therapeutically relevant for disorders associated with bone loss

Abstract: In a large cohort of U.S. women aged 65 and older, we report the relationships of BMD measured at several sites, and subsequent fracture risk at multiple sites over >8 years of follow-up. Although we found almost all fracture types to be related to low BMD, the overall proportion of fractures attributable to low BMD is modest. Introduction: Although several studies have reported the relationship between bone mineral density (BMD) and subsequent fracture risk, most have been limited by short follow-up time, BMD measures at only one or two sites, or availability of data for only select fracture types. Materials and Methods: In the multicenter Study of Osteoporotic Fractures (SOF), we studied the relationship of several different BMD measures to fracture risk of multiple types in 9704 non-black women aged 65 and older. We previously reported on the relationship of peripheral BMD measures to risk of several types of fracture during an average 2.2-year follow-up period. In this expanded analysis, we present results of the relationship of both peripheral and central BMD measures and fractures of multiple types during 10.4 and 8.5 years of follow-up, respectively. We also report population attributable risk (PAR) estimates for osteoporosis and risk of several types of fracture. Results: Our results show that almost all types of fractures have an increased incidence in women with low BMD. However, hip BMD is somewhat more strongly related to most of the fracture types studied than spine or peripheral BMD measures. Nonetheless, the proportion of fractures attributable to osteoporosis (based on a standard definition of osteoporosis) is modest, ranging from <10% to 44% based on the most commonly used definition of osteoporosis (BMD T-score < −2.5). Conclusion: Finding effective prevention strategies for fractures in older women will require additional interventions beside preventions for bone loss, such as prevention of falls and other fracture risk factors.

Abstract: Purpose: To update the 2000 ASCO guidelines on the role of bisphosphonates in women with breast cancer and address the subject of bone health in these women. Results: For patients with plain radiographic evidence of bone destruction, intravenous pamidronate 90 mg delivered over 2 hours or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence supporting the efficacy of one bisphosphonate over the other. Starting bisphosphonates in women who demonstrate bone destruction through imaging but who have normal plain radiographs is considered reasonable treatment. Starting bisphosphonates in women with only an abnormal bone scan but without evidence of bone destruction is not recommended. The presence or absence of bone pain should not be a factor in initiating bisphosphonates. In patients with a serum creatinine less than 3.0 mg/dL (265 μmol/L), no change in dosage, infusion time, or interval is required. Infusion times less than 2 hours with pamidronate or less t...

Abstract: High-frequency mechanical strain seems to stimulate bone strength in animals. In this randomized controlled trial, hip BMD was measured in postmenopausal women after a 24-week whole body vibration (WBV) training program. Vibration training significantly increased BMD of the hip. These findings suggest that WBV training might be useful in the prevention of osteoporosis. Introduction: High-frequency mechanical strain has been shown to stimulate bone strength in different animal models. However, the effects of vibration exercise on the human skeleton have rarely been studied. Particularly in postmenopausal women—who are most at risk of developing osteoporosis—randomized controlled data on the safety and efficacy of vibration loading are lacking. The aim of this randomized controlled trial was to assess the musculoskeletal effects of high-frequency loading by means of whole body vibration (WBV) in postmenopausal women. Materials and Methods: Seventy volunteers (age, 58–74 years) were randomly assigned to a whole body vibration training group (WBV, n = 25), a resistance training group (RES, n = 22), or a control group (CON, n = 23). The WBV group and the RES group trained three times weekly for 24 weeks. The WBV group performed static and dynamic knee-extensor exercises on a vibration platform (35–40 Hz, 2.28–5.09g), which mechanically loaded the bone and evoked reflexive muscle contractions. The RES group trained knee extensors by dynamic leg press and leg extension exercises, increasing from low (20 RM) to high (8 RM) resistance. The CON group did not participate in any training. Hip bone density was measured using DXA at baseline and after the 6-month intervention. Isometric and dynamic strength were measured by means of a motor-driven dynamometer. Data were analyzed by means of repeated measures ANOVA. Results: No vibration-related side effects were observed. Vibration training improved isometric and dynamic muscle strength (+15% and + 16%, respectively; p < 0.01) and also significantly increased BMD of the hip (+0.93%, p < 0.05). No changes in hip BMD were observed in women participating in resistance training or age-matched controls (−0.60% and −0.62%, respectively; not significant). Serum markers of bone turnover did not change in any of the groups. Conclusion: These findings suggest that WBV training may be a feasible and effective way to modify well-recognized risk factors for falls and fractures in older women and support the need for further human studies.

Abstract: Teriparatide [rhPTH(1-34)] increases bone mineral density and reduces the risk of vertebral fracture in women. We randomized 437 men with spine or hip bone mineral density more than 2 SD below the young adult male mean to daily injections of placebo, teriparatide 20 microg, or teriparatide 40 microg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine bone mineral density was greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 microg) and 9.0% (40 microg) above baseline (p < 0.001 vs. placebo for both comparisons). Femoral neck bone mineral density increased 1.5% (20 microg; p = 0.029) and 2.9% (40 microg; p < 0.001), and whole body bone mineral content increased 0.6% (20 microg; p = 0.021) and 0.9% (40 microg;p = 0.005) above baseline in the teriparatide subjects. There was no change in radial bone mineral density in the teriparatide groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline bone mineral density, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-microg groups, but more frequent in the 40-microg group. This study shows that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men.

Abstract: A 1-year prospective, randomized, double-blind, and placebo-controlled trial of 70 postmenopausal women demonstrated that brief periods (<20 minutes) of a low-level (0.2g, 30 Hz) vibration applied during quiet standing can effectively inhibit bone loss in the spine and femur, with efficacy increasing significantly with greater compliance, particularly in those subjects with lower body mass. Introduction: Indicative of the anabolic potential of mechanical stimuli, animal models have demonstrated that short periods (<30 minutes) of low-magnitude vibration (<0.3g), applied at a relatively high frequency (20–90 Hz), will increase the number and width of trabeculae, as well as enhance stiffness and strength of cancellous bone. Here, a 1-year prospective, randomized, double-blind, and placebo-controlled clinical trial in 70 women, 3–8 years past the menopause, examined the ability of such high-frequency, low-magnitude mechanical signals to inhibit bone loss in the human. Materials and Methods: Each day, one-half of the subjects were exposed to short-duration (two 10-minute treatments/day), low-magnitude (2.0 m/s2 peak to peak), 30-Hz vertical accelerations (vibration), whereas the other half stood for the same duration on placebo devices. DXA was used to measure BMD at the spine, hip, and distal radius at baseline, and 3, 6, and 12 months. Fifty-six women completed the 1-year treatment. Results and Conclusions: The detection threshold of the study design failed to show any changes in bone density using an intention-to-treat analysis for either the placebo or treatment group. Regression analysis on the a priori study group demonstrated a significant effect of compliance on efficacy of the intervention, particularly at the lumbar spine (p = 0.004). Posthoc testing was used to assist in identifying various subgroups that may have benefited from this treatment modality. Evaluating those in the highest quartile of compliance (86% compliant), placebo subjects lost 2.13% in the femoral neck over 1 year, whereas treatment was associated with a gain of 0.04%, reflecting a 2.17% relative benefit of treatment (p = 0.06). In the spine, the 1.6% decrease observed over 1 year in the placebo group was reduced to a 0.10% loss in the active group, indicating a 1.5% relative benefit of treatment (p = 0.09). Considering the interdependence of weight, the spine of lighter women (<65 kg), who were in the highest quartile of compliance, exhibited a relative benefit of active treatment of 3.35% greater BMD over 1 year (p = 0.009); for the mean compliance group, a 2.73% relative benefit in BMD was found (p = 0.02). These preliminary results indicate the potential for a noninvasive, mechanically mediated intervention for osteoporosis. This non-pharmacologic approach represents a physiologically based means of inhibiting the decline in BMD that follows menopause, perhaps most effectively in the spine of lighter women who are in the greatest need of intervention.

Abstract: Background Bone loss increases after menopause. However, bone strength also depends on structural characteristics such as bone size. Whether bone size increases as a result of periosteal apposition and whether a strength index accounting for both bone density and bone size might predict the risk of fracture better than bone density alone are unclear. Methods Bone mass and the skeletal structure of the distal radius were evaluated by single-photon absorptiometry every other year in 108 women, all of whom were followed from the time of menopause for a mean period of 15 years. Postmenopausal serum estradiol levels and fractures of the distal radius were noted. Results The mean (±SD) annual decrease in bone mineral density was 1.9±0.7 percent. The medullary bone diameter increased annually by 1.1±0.9 percent, and the periosteal diameter by 0.7±0.3 percent; the strength index decreased by 0.7±0.7 percent. The expansion of the medullary diameter and the expansion of the periosteal diameter were correlated with ...

Abstract: Bone is a dynamic tissue that is subject to the balanced processes of bone formation and bone resorption. Imbalance can give rise to skeletal pathologies with increased bone density. In recent years, several genes underlying such sclerosing bone disorders have been identified. The LDL receptor-related protein 5 (LRP5) gene has been shown to be involved in both osteoporosis-pseudoglioma syndrome and the high–bone-mass phenotype and turned out to be an important regulator of peak bone mass in vertebrates. We performed mutation analysis of the LRP5 gene in 10 families or isolated patients with different conditions with an increased bone density, including endosteal hyperostosis, Van Buchem disease, autosomal dominant osteosclerosis, and osteopetrosis type I. Direct sequencing of the LRP5 gene revealed 19 sequence variants. Thirteen of these were confirmed as polymorphisms, but six novel missense mutations (D111Y, G171R, A214T, A214V, A242T, and T253I) are most likely disease causing. Like the previously reported mutation (G171V) that causes the high–bone-mass phenotype, all mutations are located in the aminoterminal part of the gene, before the first epidermal growth factor–like domain. These results indicate that, despite the different diagnoses that can be made, conditions with an increased bone density affecting mainly the cortices of the long bones and the skull are often caused by mutations in the LRP5 gene. Functional analysis of the effects of the various mutations will be of interest, to evaluate whether all the mutations give rise to the same pathogenic mechanism.

Abstract: OBJECTIVE: To evaluate predictors of vertebral fractures, including a threshold for bone mineral density (BMD), in patients receiving oral glucocorticoids (GCs). METHODS: Data were obtained from 2 randomized clinical trials (prevention and treatment trials of risedronate) using similar methods, but different inclusion criteria were applied with regard to prior exposure to GCs. Predictors of vertebral fracture in the placebo group were identified using Cox regression with forward selection. The BMD threshold analysis involved a comparison of the 1-year fracture risk in postmenopausal women receiving placebo in the GC trials with that in postmenopausal women not taking GCs in 3 other trials. RESULTS: The study population comprised 306 patients with baseline and 1-year followup data on vertebral fractures (111 receiving placebo and 195 receiving risedronate). In the placebo group, the statistically significant predictors of incident fracture were the baseline lumbar spine BMD (for each 1-point decrease in T score, relative risk [RR] 1.85, 95% confidence interval [95% CI] 1.06-3.21) and the daily GC dose (for each 10-mg dose increase, RR 1.62, 95% CI 1.11-2.36). In the BMD threshold analysis, compared with nonusers of GCs, patients receiving GCs were younger, had a higher BMD at baseline, and had fewer prevalent fractures; nevertheless, the risk of fracture was higher in the GC users compared with nonusers (adjusted RR 5.67, 95% CI 2.57-12.54). The increased risk of fracture was observed in GC users regardless of whether osteoporosis was present. CONCLUSION: The daily, but not cumulative, GC dose was found to be a strong predictor of vertebral fracture in patients receiving GCs. At similar levels of BMD, postmenopausal women taking GCs, as compared with nonusers of GCs, had considerably higher risks of fracture.

Abstract: Factors that determine a post-menopausal woman's bone mineral density (BMD) include her mass at the time of skeletal maturity (peak BMD), menopause and the rate of loss she experiences as she ages. Understanding the relative influence of each of these factors may help identify important preventive treatments and provide new ways to identify women at risk for osteoporosis. In this analysis we utilize a computer model of the bone remodeling process to predict the relative influences of peak BMD, menopause and age-related bone loss on the development of osteoporosis. The delay in the onset of osteoporosis (defined as BMD <2.5 SD from the young adult mean) caused by modifying peak BMD, age-related bone loss or the age at menopause is quantified. A 10% increase in peak BMD is predicted to delay the development of osteoporosis by 13 years, while a 10% change in the age at menopause or the rate of non-menopausal bone loss is predicted to delay osteoporosis by approximately 2 years, suggesting that peak BMD may be the single most important factor in the development of osteoporosis.

Abstract: A unique mutation in LRP5 is associated with high bone mass in man. Transgenic mice expressing this LRP5 mutation have a similar phenotype with high bone mass and enhanced strength. These results underscore the importance of LRP5 in skeletal regulation and suggest targets for therapies for bone disease. A mutation (G171V) in the low-density lipoprotein receptor related protein 5 (LRP5) has been associated with high bone mass (HBM) in two independent human kindreds. To validate the role of the mutation, several lines of transgenic mice were created expressing either the human LRP5 G171V substitution or the wildtype LRP5 gene in bone. Volumetric bone mineral density (vBMD) analysis by pQCT showed dramatic increases in both total vBMD (30-55%) and trabecular vBMD (103-250%) of the distal femoral metaphysis and increased cortical size of the femoral diaphysis in mutant G171V transgenics at 5, 9, 17, 26, and 52 weeks of age (p < 0.01 for all). In addition, high-resolution microcomputed tomography (microCT) analysis of the distal femorae and lumbar vertebrae revealed an increase (110-232%) in trabecular bone volume fraction caused by both increased trabecular number (41-74%) and increased trabecular thickness (34-46%; p < 0.01 for all) in the mutant G171V mice. The increased bone mass was associated with significant increases in vertebral compressive strength (80-140%) and the increased cortical size with significant increases in femoral bending strength (50-130%). There were no differences in osteoclast number at 17 weeks of age. However, compared with littermate controls, the mutant G171V transgenic mice showed an increase in actively mineralizing bone surface, enhanced alkaline phosphatase staining in osteoblasts, and a significant reduction in the number of TUNEL-positive osteoblasts and osteocytes. These results suggest that the increased bone mineral density in mutant G171V mice was caused by increased numbers of active osteoblasts, which could in part be because of their increased functional lifespan. While slight bone anabolic activity was observed from overexpression of the wildtype LRP5 gene, it is clear that the G171V mutation, rather than overexpression of the receptor itself, is primarily responsible for the dramatic HBM bone effects. Together, these findings establish the importance of this novel and unexpected role of a lipoprotein receptor in regulating bone mass and afford a new model to explore LRP5 and its recent association with Wnt signaling in bone biology.

Abstract: Objectives: To test the hypothesis that unintentional weight loss increases the rate of bone loss and risk of hip fracture more than intentional weight loss. Design: Prospective cohort study. Setting: Four communities within the United States. Participants: Six thousand seven hundred eighty-five elderly white women with measurement of weight change and assessment of intention to lose weight. Measurements: Weight change between baseline and fourth examinations (average 5.7 years between examinations) and assessment of intention to lose weight. Weight loss was defined as a decrease of 5% or more from baseline weight, stable weight was defined as less than a 5% change from baseline weight, and weight gain was defined as an increase of 5% or more from baseline weight. Rate of change in bone mineral density at the hip between fourth and sixth examinations (average 4.4 years between examinations) was measured using dual-energy x-ray absorptiometry. Incident hip fractures occurring after the fourth examination until June 1, 2001 (average follow-up 6.6 years) was confirmed using radiographic reports. Results: The adjusted average rate of decline in total hipbone density steadily increased from −0.52% per year in women with weight gain to −0.68% per year in women with stable weight to −0.92% per year in women with weight loss (P-value for trend <.001). Higher rates of hip-bone loss were observed in women with weight loss irrespective of body mass index (BMI) or intention to lose weight. During follow-up of an average 6.6 years after the fourth examination, 400 (6%) of the cohort suffered a first hip fracture. Women with weight loss had 1.8 times the risk (95% confidence interval (CI)=1.43–2.24) of subsequent hip fracture as those with stable or increasing weight. The association between weight loss and increased risk of hip fracture was consistent across categories of BMI and intention to lose weight. Even voluntary weight loss in overweight women with a BMI of 25.9 kg/m2 (median) or greater increased the risk of hip fracture (multivariate hazard ratio=2.48, 95% CI=1.33–4.62). Conclusion: Older women who experience weight loss in later years have increased rates of hip-bone loss and a two-fold greater risk of subsequent hip fracture, irrespective of current weight or intention to lose weight. These findings indicate that even voluntary weight loss in overweight elderly women increases hip fracture risk.

Abstract: The role of dietary silicon in bone health in humans is not known. In a cross-sectional, population-based study (2847 participants), associations between dietary silicon intake and BMD were investigated. Dietary silicon correlated positively and significantly with BMD at all hip sites in men and premenopausal women, but not in postmenopausal women, suggesting that increased silicon intake is associated with increased cortical BMD in these populations. Introduction: Osteoporosis is a burgeoning health and economic issue. Agents that promote bone formation are widely sought. Animal and cellular data suggest that the orthosilicate anion (i.e., dietary silicon) is involved in bone formation. The intake of silicon (Si, ∼30 mg/day) is among the highest for trace elements in humans, but its contribution to bone health is not known. Materials and Methods: In a cross-sectional, population-based study, we examined the association between silicon intake and bone mineral density (BMD) in 1251 men and 1596 pre- and postmenopausal women in the Framingham Offspring cohort (age, 30–87 years) at four hip sites and lumbar spine, adjusting for all potential confounding factors known to influence BMD and nutrient intake. Results: Silicon intake correlated positively with adjusted BMD at four hip sites in men and premenopausal women, but not in postmenopausal women. No significant association was observed at the lumbar spine in any group. Categorical analysis by Si intake, or energy-adjusted Si intake, supported these findings, and showed large differences in BMD (up to 10%) between the highest (>40 mg Si/day) and lowest (<14 mg Si/day) quintiles of silicon intake. A significant association at the lumbar spine in men was also observed. Further analyses indicated that some of the effects seen for moderate consumption of alcoholic beverages on BMD might be attributed to Si intake. Conclusions: These findings suggest that higher dietary silicon intake in men and younger women may have salutary effects on skeletal health, especially cortical bone health, that has not been previously recognized. Confirmation of these results is being sought in a longitudinal study and by assessment of the influence of silicon intake on bone markers in this cohort.

Abstract: Anorexia nervosa (AN) is a disorder that is increasing in frequency in adolescents, and the age of onset is often in the prepubertal years, potentially affecting the development of peak bone mass and linear growth. The GH-IGF-I axis plays an important role in bone formation, and alterations in GH secretory patterns have been described in adult women with AN. However, GH secretory dynamics in adolescents with AN have not been described, and the effects of alterations in GH secretory patterns and GH concentration on bone metabolism in AN are not known. We examined patterns of GH secretion by deconvolutional analysis, and GH concentration by Cluster analysis, in adolescent girls with AN (n = 22) and controls (n = 20) of comparable bone age and pubertal stage. We also examined the roles of cortisol, leptin, and estradiol in the regulation of GH secretion and concentration, and the relationship of GH secretory patterns and concentration to bone metabolism. Basal GH secretion and secretory pulse number in adolescent girls with AN were increased compared with control values (P = 0.03 and 0.007, respectively), and increased disorderliness of GH secretion (approximate entropy) was found in AN (P = 0.004). Mean and nadir GH concentrations and total area under the concentration curve were increased (P = 0.03, 0.002, and 0.03, respectively), and IGF-I levels were decreased (P = 0.0002) in girls with AN compared with healthy adolescent girls. IGF-I levels correlated negatively with nadir GH concentrations (r = -0.35; P = 0.02). Serum cortisol levels were higher in girls with AN than in controls (P < 0.0001) and correlated inversely with IGF-I (r = -0.58; P = 0.0001) and weakly with GH concentration (area under the concentration curve; r = -0.43; P = 0.05). A strong inverse relationship between markers of nutritional status (body mass index, fat mass, and leptin) and basal and pulsatile GH secretion, and mean and nadir GH concentrations was observed. GH concentration predicted levels of all markers of bone formation and a marker of bone resorption (N-telopeptide) in healthy controls, but not in AN. We demonstrate increases in basal GH secretion, number of secretory bursts, and GH concentration in adolescents with AN compared with controls, accompanied by low IGF-I levels. These data are consistent with the hypothesis that an acquired GH resistance occurs in this undernourished group. We also demonstrate that GH secretion and concentration are nutritionally regulated, and that the effects of nutrition exceed the effects of cortisol on GH concentration. Acquired GH resistance may play a role in the osteopenia and decreased peak bone mass frequently associated with AN.

Abstract: The underlying mechanisms of several bone disorders in human immunodeficiency virus (HIV)-infected persons and any relation to antiretroviral therapy have yet to be defined. A longitudinal study was conducted to estimate the prevalence of osteopenia or osteoporosis in HIV-infected persons; to assess bone mineralization, metabolism, and histomorphometry over time; and to evaluate predisposing factors. A total of 128 patients enrolled the study, and 93 were observed for 72 weeks. "Classic" risk factors (low body mass index, history of weight loss, steroid use, and smoking) for low bone mineral density (BMD) and duration of HIV infection were strongly associated with osteopenia. There was a weak association between low BMD and receipt of treatment with protease inhibitors; this association disappeared after controlling for the above factors. Markers of bone turnover tended to be elevated in the whole cohort but were not associated with low BMD. BMD increased slightly during follow-up. Traditional risk factors and advanced HIV infection play a more significant pathogenic role in the development of osteopenia and osteoporosis associated with HIV infection than do treatment-associated factors.

Abstract: This study examined changes in bone mineral and fracture risk after treatment for hyperthyroidism in a meta-analysis. The PubMed and EMBASE were searched using the MESH terms "hyperthyroidism," "bone mineral density" (BMD), and "fracture," resulting in retrieval of 289 references. Twenty references describing BMD and five describing fracture risk were included in the meta-analysis. BMD was significantly decreased in patients with untreated hyperthyroidism. Upon treatment BMD increased significantly and reversed to normal levels with a temporary increase above normal levels 1-4 years after diagnosis. The risk of hip fractures increased significantly with age at diagnosis of hyperthyroidism. The hip fracture risk after diagnosis predicted from studies on BMD was close to that observed in clinical studies comparing fracture risk in hyperthyroid patients with normal controls. Thus BMD is significantly decreased and fracture risk increased in untreated hyperthyroidism. Upon normalization of the hyperthyroid state BMD return to normal even though no specific antiosteoporotic measures are taken other than normalizing the hyperthyroid state.

Abstract: The human spine is composed of highly specific tissues and structures, which together provide the extensive range of motion and considerable load carrying capacity required for the physical activities of daily life. Alterations to the form and composition of the individual structures of the spine with increasing age can increase the risk of injury and can have a profound influence on the quality of life. Cancellous bone forms the structural framework of the vertebral body. Individual trabeculae are oriented along the paths of principal forces and play a crucial role in the transfer of the predominantly compressive forces along the spine. Age-related changes to the cancellous core of the vertebra includes a loss of bone mineral density, as well as morphological changes including trabecular thinning, increased intratrabecular spacing, and loss of connectivity between trabeculae. Material and morphological changes may lead to an increased risk of vertebral fracture. The vertebral endplate serves the dual role of containing the adjacent disc and evenly distributing applied loads to the underlying cancellous bone and the cortex of the vertebra. With aging, thinning of the endplate, and loss of bone mineral density increases the risk of endplate fracture. Ossification of the endplate may have consequences for the nutritional supply and hydration of the intervertebral disc. The healthy intervertebral disc provides mobility to the spine and transfers load via hydrostatic pressurization of the hydrated nucleus pulposus. Changes to the tissue properties of the disc, including dehydration and reorganization of the nucleus and stiffening of the annulus fibrosus, markedly alter the mechanics of load transfer in the spine. There is no direct correlation between degenerative changes to the disc and to the adjacent vertebral bodies. Furthermore, advancing age is not the sole factor in the degeneration of the spine. Further study is crucial for understanding the unique biomechanical function of the aging spine.

Abstract: The operative treatment of fractures of the proximal humerus can be complicated by poor bone quality. Our aim was to evaluate a new method which allows prediction of the bone quality of the proximal humerus from radiographs. Anteroposterior radiographs were taken of 19 human cadaver humeri. The cortical thickness was measured at two levels of the proximal humeral diaphysis. The bone mineral density (BMD) was determined for the humeral head (HH), the surgical neck (SN), the greater tuberosity (GT) and lesser tuberosity (LT) using dual-energy x-ray absorptiometry. The mean cortical thickness was 4.4 +/- 1.0 mm. Specimens aged 70 years or less had a significantly higher cortical thickness than those aged over 70 years. A significant positive correlation was found between cortical thickness and the BMD for each region of interest. The cortical thickness of the proximal diaphysis is a reliable predictor of the bone quality of the proximal humerus.

Abstract: Osteoporotic fractures are a major cause of morbidity and mortality in ageing populations. Osteoporosis, defined as low bone mineral density (BMD) and associated fractures, have significant genetic components that are largely unknown. Linkage analysis in a large number of extended osteoporosis families in Iceland, using a phenotype that combines osteoporotic fractures and BMD measurements, showed linkage to Chromosome 20p12.3 (multipoint allele-sharing LOD, 5.10; p value, 6.3 × 10−7), results that are statistically significant after adjusting for the number of phenotypes tested and the genome-wide search. A follow-up association analysis using closely spaced polymorphic markers was performed. Three variants in the bone morphogenetic protein 2 (BMP2) gene, a missense polymorphism and two anonymous single nucleotide polymorphism haplotypes, were determined to be associated with osteoporosis in the Icelandic patients. The association is seen with many definitions of an osteoporotic phenotype, including osteoporotic fractures as well as low BMD, both before and after menopause. A replication study with a Danish cohort of postmenopausal women was conducted to confirm the contribution of the three identified variants. In conclusion, we find that a region on the short arm of Chromosome 20 contains a gene or genes that appear to be a major risk factor for osteoporosis and osteoporotic fractures, and our evidence supports the view that BMP2 is at least one of these genes.

Abstract: Quantitative information about bone tissue-level loading is essential for understanding bone mechanical behavior. We made microfinite element models of a healthy and osteoporotic human femur and found that tissue-level strains in the osteoporotic femoral head were 70% higher on average and less uniformly distributed than those in the healthy one. INTRODUCTION: Bone tissue stresses and strains in healthy load-adapted trabecular architectures should be distributed rather evenly, because no bone tissue is expected to be overloaded or unused. In this study, we evaluate this paradigm with the use of microfinite element (microFE) analyses to calculate tissue-level stresses and strains for the human femur. Our objectives were to quantify the strain distribution in the healthy femur, to investigate to what extent this distribution is affected by osteoporosis, to determine if osteoporotic bone is simply bone adapted to lower load levels, and to determine the "safety factor" for trabecular bone. MATERIALS AND METHODS: microFE models of a healthy and osteoporotic proximal femur were made from microcomputed tomography images. The models consisted of over 96 and 71 million elements for the healthy and osteoporotic femur, respectively, and represented their internal and external morphology in detail. Stresses and strains were calculated for each element and their distributions were calculated for a volume of interest (VOI) of trabecular bone in the femoral head. RESULTS: The average tissue-level principal strain magnitude in the healthy VOI was 304 +/- 185 microstrains and that in the osteoporotic VOI was 520 +/- 355 microstrains. Calculated safety factors were 8.6 for the healthy and 4.9 for the osteoporotic femurs. After reducing the force applied to the osteoporotic model to 59%, the average strain compared with that of the healthy femur, but the SD was larger (208 microstrains). CONCLUSIONS: Strain magnitudes in the osteoporotic bone were much higher and less uniformly distributed than those in the healthy one. After simulated joint-load reduction, strain magnitudes in the osteoporotic femur were very similar to those in the healthy one, but their distribution is still wider and thus less favorable.

Abstract: In a recent study of women with postmenopausal osteoporosis, treatment with teriparatide for a median of 19 months increased bone mineral density and decreased the risk of vertebral and nonvertebral fractures. Using the same cohort, the current study evaluated the relationship between these therapeutic effects and the patient's baseline age, vertebral bone mineral density, and prevalent vertebral fractures. In women over 65 years of age, treatment resulted in a greater increase in vertebral bone mineral density than in younger women (treatment-by-age interaction, p = 0.037), but baseline age had no effect on the relative risk reduction for vertebral fractures (treatment-by-age interaction, p = 0.558). In women receiving placebo (with calcium and vitamin D), there was an inverse relationship between baseline vertebral bone mineral density and vertebral fracture risk. When compared across bone mineral density tertiles, the effects of teriparatide on the relative risk for developing new vertebral fractures and increase in vertebral bone mineral density did not differ significantly (p = 0.817 and p = 0.615, respectively). Teriparatide treatment significantly decreased vertebral fracture risk in patients with a vertebral bone mineral density T score of less than -33 or a score between -2.1 and -3.3 (p < 0.001 and p = 0.027, respectively) and showed a trend toward reduced fracture risk in the group with a T score greater than -2.1 (p = 0.115). Placebo-treated women with two or more prevalent vertebral fractures had a significantly greater risk of developing new vertebral fractures than women with zero or one prevalent vertebral fracture (p < 0.001). When compared within prevalent vertebral fracture subgroups, the effects of teriparatide on the relative risk for developing new vertebral fractures were similar. The results of this study indicate that teriparatide offers clinical benefit to patients across a broad range of age and disease severity.

Abstract: Although several observational studies have demonstrated an association between vitamin K status and bone mineral density (BMD) in postmenopausal women, no placebo-controlled intervention trials of the effect of vitamin K1 supplementation on bone loss have been reported thus far. In the trial presented here we have investigated the potential complementary effect of vitamin K1 (1 mg/day) and a mineral + vitamin D supplement (8 µg/day) on postmenopausal bone loss. The design of our study was a randomized, double-blind, placebo-controlled intervention study; 181 healthy postmenopausal women between 50 and 60 years old were recruited, 155 of whom completed the study. During the 3-year treatment period, participants received a daily supplement containing either placebo, or calcium, magnesium, zinc, and vitamin D (MD group), or the same formulation with additional vitamin K1 (MDK group). The main outcome was the change in BMD of the femoral neck and lumbar spine after 3 years, as measured by DXA. The group receiving the supplement containing additional vitamin K1 showed reduced bone loss of the femoral neck: after 3 years the difference between the MDK and the placebo group was 1.7% (95% Cl: 0.35–3.44) and that between the MDK and MD group was 1.3% (95% Cl: 0.10–3.41). No significant differences were observed among the three groups with respect to change of BMD at the site of the lumbar spine. If co-administered with minerals and vitamin D, vitamin K1 may substantially contribute to reducing postmenopausal bone loss at the site of the femoral neck.

Abstract: The net amount of bone lost during aging is determined by the difference between the amount of bone removed from the endocortical, trabecular and intracortical components of its endosteal (inner) envelope and formed beneath its periosteal (outer) envelope. Endosteal bone loss is determined by the remodeling rate (number of basic multicellular units, BMUs) and the negative balance (the difference between the volumes of bone resorbed and formed in each BMU). Bone loss already occurs in young adult women and men and is probably due to a decline in the volume of bone formed in each BMU. The rate of loss is slow because the remodeling rate is low in young adulthood. Bone loss accelerates in women at menopause because remodeling intensity increases and BMU balance becomes more negative as estrogen deficiency reduces osteoblast lifespan and increases osteoclast lifespan. The high remodeling rate also reduces the mineral content of bone tissue. The negative BMU balance results in trabecular thinning, disappearance and loss of connectivity, cortical thinning and increased intracortical porosity. These changes compromise the material and structural properties of bone while concurrent age-related subperiosteal bone formation increases the cross-sectional area (CSA) of bone partly offsetting endosteal bone loss and the loss of structural and material strength. Thus, treatments aimed at reducing the progression of bone fragility, and reversing it, should reduce activation frequency and so reduce the number of remodeling sites, reduce osteoclastic resorption in the BMU, and so reduce the volume of bone resorbed on each of the three components of the endosteal surface thereby reducing the progression of trabecular thinning, loss of connectivity, cortical thinning and porosity. If treatment also increases periosteal bone formation, the CSA of the whole bone and its cortical area will increase. If treatment also increases endosteal bone formation in the BMU, bone balance will be less negative, especially if resorption depth is reduced. This may produce thickening of trabeculae provided activation frequency is not too low. If treatment can increase de novo bone formation at quiescent endosteal surfaces, this will increase cortical and trabecular thickness, and reduce intracortical porosity. In this way, drugs directed at both the resorptive and formative aspects of remodeling, and bone modeling may (i) increase compressive and bending strength of cortical bone by increasing the diameter of the whole bone, its CSA and the distance the cortical mass is placed from the neutral long bone axis; (ii) maintain or increase peak compressive stress and peak strain in trabecular bone, preventing microcracks and buckling; and (iii) increase the material density of bone tissue, an effect that probably should not be permitted to reach a level which reduces resistance to microdamage accumulation and progression (toughness).

Abstract: Previous studies indicate that low bone mineral density (BMD) in the hip is a useful predictor of cardiovascular mortality among the elderly. The objective of this study was to investigate whether low hip BMD is directly associated with the severity of atherosclerosis. The per-protocol population consisted of 963 women aged 60-85 years. Study variables were aortic calcification (AC) graded on lateral lumbar radiographs, BMD at various anatomic sites (distal radius, lumbar spine, proximal femur) measured by DXA, information on various risk factors, and medical history. After adjustment for age, BMD at the proximal femur, but not at the radius or spine BMD, showed statistically significant association with the severity of AC (r = −0.12−17, P < 0.001). Age, years since menopause, BMI, level of education, current and previous smoking, and weekly fitness activity were significant common risk factors (all P < 0.05) with contrasting influence on AC and hip BMD. In a multiple regression model, AC contributed significantly and independently to the variation in hip BMD (β = −0.10, P = 0.004). Impaired blood flow represented by 40 women with documented history of intermittent claudication was not an independent contributor and did not alter the association between AC and hip BMD. However, AC and demineralization in the hip was particularly severe in women with intermittent claudication accompanied by a higher prevalence of coronary heart disease compared with age-matched controls (all P < 0.001). In conclusion, severe osteoporosis in the hip may indicate advanced atherosclerosis and thereby an increased risk for not only hip fractures but also for coronary heart disease. The results further emphasize that osteoporosis in the hip and peripheral vascular disease are linked by common risk factors and pathomechanisms.