Showing papers in "Journal of Bone and Mineral Research in 2014"

The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine.

Abstract: The goal of our study was to estimate the prevalence of osteoporosis and low bone mass based on bone mineral density (BMD) at the femoral neck and the lumbar spine in adults 50 years and older in the United States (US). We applied prevalence estimates of osteoporosis or low bone mass at the femoral neck or lumbar spine (adjusted by age, sex, and race/ethnicity to the 2010 Census) for the noninstitutionalized population aged 50 years and older from the National Health and Nutrition Examination Survey 2005-2010 to 2010 US Census population counts to determine the total number of older US residents with osteoporosis and low bone mass. There were more than 99 million adults aged 50 years and older in the US in 2010. Based on an overall 10.3% prevalence of osteoporosis, we estimated that in 2010, 10.2 million older adults had osteoporosis. The overall low bone mass prevalence was 43.9%, from which we estimated that 43.4 million older adults had low bone mass. We estimated that 7.7 million non-Hispanic white, 0.5 million non-Hispanic black, and 0.6 million Mexican American adults had osteoporosis, and another 33.8, 2.9, and 2.0 million had low bone mass, respectively. When combined, osteoporosis and low bone mass at the femoral neck or lumbar spine affected an estimated 53.6 million older US adults in 2010. Although most of the individuals with osteoporosis or low bone mass were non-Hispanic white women, a substantial number of men and women from other racial/ethnic groups also had osteoporotic BMD or low bone mass.

Trabecular bone score: a noninvasive analytical method based upon the DXA image.

Abstract: The trabecular bone score (TBS) is a gray-level textural metric that can be extracted from the two-dimensional lumbar spine dual-energy X-ray absorptiometry (DXA) image. TBS is related to bone microarchitecture and provides skeletal information that is not captured from the standard bone mineral density (BMD) measurement. Based on experimental variograms of the projected DXA image, TBS has the potential to discern differences between DXA scans that show similar BMD measurements. An elevated TBS value correlates with better skeletal microstructure; a low TBS value correlates with weaker skeletal microstructure. Lumbar spine TBS has been evaluated in cross-sectional and longitudinal studies. The following conclusions are based upon publications reviewed in this article: 1) TBS gives lower values in postmenopausal women and in men with previous fragility fractures than their nonfractured counterparts; 2) TBS is complementary to data available by lumbar spine DXA measurements; 3) TBS results are lower in women who have sustained a fragility fracture but in whom DXA does not indicate osteoporosis or even osteopenia; 4) TBS predicts fracture risk as well as lumbar spine BMD measurements in postmenopausal women; 5) efficacious therapies for osteoporosis differ in the extent to which they influence the TBS; 6) TBS is associated with fracture risk in individuals with conditions related to reduced bone mass or bone quality. Based on these data, lumbar spine TBS holds promise as an emerging technology that could well become a valuable clinical tool in the diagnosis of osteoporosis and in fracture risk assessment.

In vivo assessment of bone quality in postmenopausal women with type 2 diabetes.

Abstract: Although patients with type 2 diabetes (T2D) are at significant risk for well-recognized diabetic complications, including macrovascular disease, retinopathy, nephropathy, and neuropathy, it is also clear that T2D patients are at increased risk for fragility fractures. Furthermore, fragility fractures in patients with T2D occur at higher bone mineral density (BMD) values compared to nondiabetic controls, suggesting abnormalities in bone material strength (BMS) and/or bone microarchitecture (bone "quality"). Thus, we performed in vivo microindentation testing of the tibia to directly measure BMS in 60 postmenopausal women (age range, 50-80 years) including 30 patients diagnosed with T2D for >10 years and 30 age-matched, nondiabetic controls. Regional BMD was measured by dual-energy X-ray absorptiometry (DXA); cortical and trabecular bone microarchitecture was assessed from high-resolution peripheral quantitative computed tomography (HRpQCT) images of the distal radius and tibia. Compared to controls, T2D patients had significantly lower BMS: unadjusted (-11.7%; p<0.001); following adjustment for body mass index (BMI) (-10.5%; p<0.001); and following additional adjustment for age, hypertension, nephropathy, neuropathy, retinopathy, and vascular disease (-9.2%; p=0.022). By contrast, after adjustment for confounding by BMI, T2D patients had bone microarchitecture and BMD that were not significantly different than controls; however, radial cortical porosity tended to be higher in the T2D patients. In addition, patients with T2D had significantly reduced serum markers of bone turnover (all p<0.001) compared to controls. Of note, in patients with T2D, the average glycated hemoglobin level over the previous 10 years was negatively correlated with BMS (r=-0.41; p=0.026). In conclusion, these findings represent the first demonstration of compromised BMS in patients with T2D. Furthermore, our results confirm previous studies demonstrating low bone turnover in patients with T2D and highlight the potential detrimental effects of prolonged hyperglycemia on bone quality. Thus, the skeleton needs to be recognized as another important target tissue subject to diabetic complications. © 2014 American Society for Bone and Mineral Research.

A meta-analysis of the association of fracture risk and body mass index in women

Abstract: Several recent studies suggest that obesity may be a risk factor for fracture The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20-105) years and follow up of 22 million person-years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred Femoral neck BMD was measured in 108,267 of these women Obesity (BMI ≥ 30 kg/m(2) ) was present in 22% A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non-obese women Compared to a BMI of 25 kg/m(2) , the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m(2) was 087 (95% confidence interval [CI], 085-090) When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 116; 95% CI, 109-123) Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD At a population level, high BMI remains a protective factor for most sites of fragility fracture The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored

Osteoporosis Medication Use After Hip Fracture in U.S. Patients Between 2002 and 2011

Abstract: Hip fractures are common, morbid, costly, and associated with subsequent fractures Historically, postfracture osteoporosis medication use rates have been poor, but have not been recently examined in a large-scale study We conducted a retrospective, observational cohort study based on US administrative insurance claims data for beneficiaries with commercial or Medicare supplemental health insurance Eligible participants were hospitalized for hip fracture between January 1, 2002, and December 31, 2011, and aged 50 years or older at admission The outcome of interest was osteoporosis medication use within 12 months after discharge Patients were censored after 12 months, loss to follow-up, or a medical claim for cancer or Paget's disease, whichever event occurred first During the study period, 96,887 beneficiaries met the inclusion criteria; they had a mean age of 80 years and 70% were female A total of 34,389 (355%) patients were censored before reaching 12 months of follow-up The Kaplan-Meier estimated probability of osteoporosis medication use within 12 months after discharge was 285% The rates declined significantly from 402% in 2002, to 205% in 2011 (p for trend <0001) In multivariable Cox proportional hazards models, a number of patient characteristics were associated with reduced likelihood of osteoporosis medication use, including older age and male gender However, the predictor most strongly and most positively associated with osteoporosis medication use after fracture was osteoporosis medication use before the fracture (hazard ratio = 745; 95% confidence interval [CI], 723–769) Most patients suffering a hip fracture do not use osteoporosis medication in the subsequent year and treatment rates have worsened © 2014 Eli Lilly and Company Journal of Bone and Mineral Research published by Wiley Periodicals, Inc on behalf of the American Society for Bone and Mineral Research

Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures.

Abstract: Osteoporosis as a systemic skeletal disorder is characterized by increased bone fragility and the risk of fractures. According to the World Health Organization, osteoporosis is one of the 10 most common diseases and affects approximately 75 million people in Europe, the United States, and Japan. In this context, the identification of specific microRNA (miRNA) signatures is an important step for new diagnostic and therapeutic approaches. The focus of interest on miRNAs as biomarkers came with new publications identifying free circulating extracellular miRNAs associated with various types of cancer. This study aimed to identify specific miRNAs in patients with osteoporotic fractures compared with nonosteoporotic fractures. For the array analysis, miRNAs were isolated from the serum of 20 patients with hip fractures, transcribed, and the samples were pooled into 10 osteoporotic and 10 nonosteoporotic specimens. With each pool of samples, human serum and plasma miRNA PCR arrays were performed, which are able to identify 83 different miRNAs. Subsequently, a separate validation analysis of each miRNA found to be regulated in the array followed with miRNA samples isolated from the serum of 30 osteoporotic and 30 nonosteoporotic patients and miRNA samples isolated from the bone tissue of 20 osteoporotic and 20 nonosteoporotic patients. With the validation analysis of the regulated miRNAs, we identified 9 miRNAs, namely miR-21, miR-23a, miR-24, miR-93, miR-100, miR-122a, miR-124a, miR-125b, and miR-148a, that were significantly upregulated in the serum of patients with osteoporosis. In the bone tissue of osteoporotic patients, we identified that miR-21, miR-23a, miR-24, miR-25, miR-100, and miR-125b displayed a significantly higher expression. A total of 5 miRNAs display an upregulation both in serum and bone tissue. This study reveals an important role for several miRNAs in osteoporotic patients and suggested that they may be used as biomarkers for diagnostic purposes and may be a target for treating bone loss and optimizing fracture healing in osteoporotic patients.

Trends in Fracture Incidence: A Population‐Based Study Over 20 Years

Abstract: To assess recent trends in fracture incidence from all causes at all skeletal sites, we used the comprehensive (inpatient and outpatient) data resources of the Rochester Epidemiology Project to estimate rates for Olmsted County, MN, USA, residents in 2009 to 2011 compared with similar data from 1989 to 1991. During the 3-year study period, 2009 to 2011, 3549 residents ≥50 years of age experienced 5244 separate fractures. The age- and sex-adjusted (to the 2010 US white population) incidence of any fracture was 2704 per 100,000 person-years (95% confidence interval [CI] 2614 to 2793) and that for all fractures was 4017 per 100,000 (95% CI 3908 to 4127). Fracture incidence increased with age in both sexes, but age-adjusted rates were 49% greater among the women. Overall, comparably adjusted fracture incidence rates increased by 11% (from 3627 to 4017 per 100,000 person-years; p = 0.008) between 1989 to 1991 and 2009 to 2011. This was mainly attributable to a substantial increase in vertebral fractures (+47% for both sexes combined), which was partially offset by a decline in hip fractures (−25%) among the women. There was also a 26% reduction in distal forearm fractures among the women; an increase in distal forearm fractures among men aged 50 years and over was not statistically significant. The dramatic increase in vertebral fractures, seen in both sexes and especially after age 75 years, was attributable in part to incidentally diagnosed vertebral fractures. However, the fall in hip fracture incidence, observed in most age groups, continues the steady decline observed among women in this community since 1950. More generally, these data indicate that the dramatic increases in the incidence of fractures at many skeletal sites that were observed decades ago have now stabilized. © 2014 American Society for Bone and Mineral Research.

Assessment of incident spine and hip fractures in women and men using finite element analysis of CT scans.

Abstract: Finite element analysis of computed tomography (CT) scans provides non-invasive estimates of bone strength at the spine and hip. To further validate such estimates clinically, we performed a five-year case-control study of 1110 women and men over age 65 from the AGES-Reykjavik cohort (case = incident spine or hip fracture; control = no incident spine or hip fracture, respectively). From the baseline CT scans, we measured femoral and vertebral strength, as well as bone mineral density (BMD) at the hip (areal BMD only) and lumbar spine (trabecular volumetric BMD only). We found that, for incident radiographically-confirmed spine fractures (n=167), the age-adjusted odds ratio for vertebral strength was significant for women (2.8, 95% CI: 1.8–4.3) and men (2.2, 95% CI: 1.5–3.2), and for men, remained significant (p=0.01) independent of vertebral trabecular volumetric BMD. For incident hip fractures (n=171), the age-adjusted odds ratio for femoral strength was significant for women (4.2, 95% CI: 2.6–6.9) and men (3.5, 95% CI: 2.3–5.3) and remained significant after adjusting for femoral neck areal BMD in women and for total hip areal BMD in both sexes; fracture classification improved for women by combining femoral strength with femoral neck areal BMD (p=0.002). For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD-based interventional thresholds for osteoporosis and at corresponding pre-established thresholds for “fragile bone strength” (spine: women ≤ 4,500 N, men ≤ 6,500 N; hip: women ≤ 3,000 N, men ≤ 3,500 N). Since it is well established that individuals over age 65 who have osteoporosis at the hip or spine by BMD criteria should be considered at high risk of fracture, these results indicate that individuals who have “fragile bone strength” at the hip or spine should also be considered at high risk of fracture.

Relationship of weight, height, and body mass index with fracture risk at different sites in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW).

Abstract: Low body mass index (BMI) is a well-established risk factor for fracture in postmenopausal women. Height and obesity have also been associated with increased fracture risk at some sites. We investigated the relationships of weight, BMI, and height with incident clinical fracture in a practice-based cohort of postmenopausal women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). Data were collected at baseline and at 1, 2, and 3 years. For hip, spine, wrist, pelvis, rib, upper arm/shoulder, clavicle, ankle, lower leg, and upper leg fractures, we modeled the time to incident self-reported fracture over a 3-year period using the Cox proportional hazards model and fitted the best linear or nonlinear models containing height, weight, and BMI. Of 52,939 women, 3628 (6.9%) reported an incident clinical fracture during the 3-year follow-up period. Linear BMI showed a significant inverse association with hip, clinical spine, and wrist fractures: adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) per increase of 5 kg/m(2) were 0.80 (0.71-0.90), 0.83 (0.76-0.92), and 0.88 (0.83-0.94), respectively (all p < 0.001). For ankle fractures, linear weight showed a significant positive association: adjusted HR per 5-kg increase 1.05 (1.02-1.07) (p < 0.001). For upper arm/shoulder and clavicle fractures, only linear height was significantly associated: adjusted HRs per 10-cm increase were 0.85 (0.75-0.97) (p = 0.02) and 0.73 (0.57-0.92) (p = 0.009), respectively. For pelvic and rib fractures, the best models were for nonlinear BMI or weight (p = 0.05 and 0.03, respectively), with inverse associations at low BMI/body weight and positive associations at high values. These data demonstrate that the relationships between fracture and weight, BMI, and height are site-specific. The different associations may be mediated, at least in part, by effects on bone mineral density, bone structure and geometry, and patterns of falling.

Influence of physical activity on bone strength in children and adolescents: a systematic review and narrative synthesis.

Abstract: A preponderance of evidence from systematic reviews supports the effectiveness of weight-bearing exercises on bone mass accrual, especially during the growing years. However, only one systematic review (limited to randomized controlled trials) examined the role of physical activity (PA) on bone strength. Thus, our systematic review extended the scope of the previous review by including all PA intervention and observational studies, including organized sports participation studies, with child or adolescent bone strength as the main outcome. We also sought to discern the skeletal elements (eg, mass, structure, density) that accompanied significant bone strength changes. Our electronic-database, forward, and reference searches yielded 14 intervention and 23 observational studies that met our inclusion criteria. We used the Effective Public Health Practice Project (EPHPP) tool to assess the quality of studies. Due to heterogeneity across studies, we adopted a narrative synthesis for our analysis and found that bone strength adaptations to PA were related to maturity level, sex, and study quality. Three (of five) weight-bearing PA intervention studies with a strong rating reported significantly greater gains in bone strength for the intervention group (3% to 4%) compared with only three significant (of nine) moderate intervention studies. Changes in bone structure (eg, bone cross-sectional area, cortical thickness, alone or in combination) rather than bone mass most often accompanied significant bone strength outcomes. Prepuberty and peripuberty may be the most opportune time for boys and girls to enhance bone strength through PA, although this finding is tempered by the few available studies in more mature groups. Despite the central role that muscle plays in bones' response to loading, few studies discerned the specific contribution of muscle function (or surrogates) to bone strength. Although not the focus of the current review, this seems an important consideration for future studies.

Postsurgical hypoparathyroidism--risk of fractures, psychiatric diseases, cancer, cataract, and infections.

Abstract: Data on co-morbidity in patients with postsurgical hypoparathyroidism (HypoPT) are sparse. We aimed to assess risk of fractures, spinal stenosis, cataract, neuropsychiatric diseases, cancer, and infections within the historic cohort of patients with postsurgical HypoPT due to non-malignant causes that we previously have characterized. Patients were identified through the Danish National Patient Registry and regional prescription databases, with subsequent validation of their individual hospital records. Identified cases were matched with three age- (± 2 yr) and gender-matched controls from the general background population. Compared with controls, patients did not have an increased risk of cataract (p = 0.52), spinal stenosis (p = 0.59), or any fracture (p = 0.98). However, the risk of fractures at the upper extremities was significantly decreased in patients (HR 0.69, 95% CI 0.49-0.97). Compared with controls, patients had a significantly increased risk of hospitalization due to infections (HR 1.42, 95% CI 1.20-1.67) and depression/bipolar affective disorders (HR 1.99, 95% CI 1.14-3.46). The risk of malignant diseases did not differ between groups although the risk of gastrointestinal cancers was significantly lower in patients compared with controls (HR 0.63, 95% CI 0.44-0.93). In conclusion, HypoPT is associated with an increased risk of depression and other types of neuropsychiatric diseases as well as infections, whereas patients seem to be protected against fractures at the upper extremities and gastrointestinal malignancies.

MiR-503 regulates osteoclastogenesis via targeting RANK.

Abstract: MicroRNAs (miRNAs) play important roles in osteoclastogenesis and bone resorption. However, no study has investigated the role of miRNA in postmenopausal osteoporosis. Here, we report that miR-503 was markedly reduced in circulating progenitors of osteoclasts-CD14(+) peripheral blood mononuclear cells (PBMCs) from postmenopausal osteoporosis patients compared with those from postmenopausal healthy women. Overexpression of miR-503 in CD14(+) PBMCs inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Conversely, silencing of miR-503 in CD14(+) PBMCs promoted osteoclastogenesis. RANK, which is activated by the binding of RANKL and inducing osteoclast differentiation, was confirmed to be a target of miR-503. In vivo, silencing of miR-503 using a specific antagomir in ovariectomy (OVX) mice increased RANK protein expression, promoted bone resorption, and decreased bone mass, whereas overexpression of miR-503 with agomir inhibited bone resorption and prevented bone loss in OVX mice. Thus, our study revealed that miR-503 plays an important role in the pathogenesis of postmenopausal osteoporosis and contributes to a new therapeutic way for osteoporosis.

Bone metabolism after bariatric surgery.

Abstract: Bariatric surgery is a popular and effective treatment for severe obesity but may have negative effects on the skeleton. This review summarizes changes in bone density and bone metabolism from animal and clinical studies of bariatric surgery, with specific attention to Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB), and sleeve gastrectomy (SG). Skeletal imaging artifacts from obesity and weight loss are also considered. Despite challenges in bone density imaging, the preponderance of evidence suggests that bariatric surgery procedures have negative skeletal effects that persist beyond the first year of surgery, and that these effects vary by surgical type. The long-term clinical implications and current clinical recommendations are presented. Further study is required to determine mechanisms of bone loss after bariatric surgery. Although early studies focused on calcium/vitamin D metabolism and mechanical unloading of the skeleton, it seems likely that surgically induced changes in the hormonal and metabolic profile may be responsible for the skeletal phenotypes observed after bariatric surgery.

Standardizing vitamin D assays: the way forward

Abstract: For a number of years it has been widely assumed that measurement of serum 25-hydroxyvitamin D [25(OH)D] concentration is the best approach to assessing an individual's vitamin D status. However, it has also been recognized that there is substantial within-assay variation in 25(OH)D measurement and even greater between-assay variability. Such assay variation clearly confounds attempts to define what constitutes the diagnosis of hypovitaminosis D. Importantly, assay variability makes pooling of 25(OH)D results from different studies in systematic reviews for the specific purpose of determining dose-response and/or clinical cut points at best problematic. Therefore, to develop and implement evidence-based clinical guidelines, it is essential that 25(OH)D measurement be standardized in both clinical and research laboratories. In this Perspective we outline a way forward toward achieving this goal-the Vitamin D Standardization Program (VDSP).

Cortical porosity identifies women with osteopenia at increased risk for forearm fractures.

Abstract: Most fragility fractures arise among the many women with osteopenia, not the smaller number with osteoporosis at high risk for fracture. Thus, most women at risk for fracture assessed only by measuring areal bone mineral density (aBMD) will remain untreated. We measured cortical porosity and trabecular bone volume/total volume (BV/TV) of the ultradistal radius (UDR) using high-resolution peripheral quantitative computed tomography, aBMD using densitometry, and 10-year fracture probability using the country-specific fracture risk assessment tool (FRAX) in 68 postmenopausal women with forearm fractures and 70 age-matched community controls in Olmsted County, MN, USA. Women with forearm fractures had 0.4 standard deviations (SD) higher cortical porosity and 0.6 SD lower trabecular BV/TV. Compact-appearing cortical porosity predicted fracture independent of aBMD; odds ratio (OR) = 1.92 (95% confidence interval [CI] 1.10–3.33). In women with osteoporosis at the UDR, cortical porosity did not distinguish those with fractures from those without because high porosity was present in 92% and 86% of each group, respectively. By contrast, in women with osteopenia at the UDR, high porosity of the compact-appearing cortex conferred an OR for fracture of 4.00 (95% CI 1.15–13.90). In women with osteoporosis, porosity is captured by aBMD, so measuring UDR cortical porosity does not improve diagnostic sensitivity. However, in women with osteopenia, cortical porosity was associated with forearm fractures.

Stem Cell–Derived Endochondral Cartilage Stimulates Bone Healing by Tissue Transformation

Abstract: Although bone has great capacity for repair, there are a number of clinical situations (fracture non-unions, spinal fusions, revision arthroplasty, segmental defects) in which auto- or allografts attempt to augment bone regeneration by promoting osteogenesis. Critical failures associated with current grafting therapies include osteonecrosis and limited integration between graft and host tissue. We speculated that the underlying problem with current bone grafting techniques is that they promote bone regeneration through direct osteogenesis. Here we hypothesized that using cartilage to promote endochondral bone regeneration would leverage normal developmental and repair sequences to produce a well-vascularized regenerate that integrates with the host tissue. In this study, we use a translational murine model of a segmental tibia defect to test the clinical utility of bone regeneration from a cartilage graft. We further test the mechanism by which cartilage promotes bone regeneration using in vivo lineage tracing and in vitro culture experiments. Our data show that cartilage grafts support regeneration of a vascularized and integrated bone tissue in vivo, and subsequently propose a translational tissue engineering platform using chondrogenesis of mesenchymal stem cells (MSCs). Interestingly, lineage tracing experiments show the regenerate was graft derived, suggesting transformation of the chondrocytes into bone. In vitro culture data show that cartilage explants mineralize with the addition of bone morphogenetic protein (BMP) or by exposure to human vascular endothelial cell (HUVEC)-conditioned medium, indicating that endothelial cells directly promote ossification. This study provides preclinical data for endochondral bone repair that has potential to significantly improve patient outcomes in a variety of musculoskeletal diseases and injuries. Further, in contrast to the dogmatic view that hypertrophic chondrocytes undergo apoptosis before bone formation, our data suggest cartilage can transform into bone by activating the pluripotent transcription factor Oct4A. Together these data represent a paradigm shift describing the mechanism of endochondral bone repair and open the door for novel regenerative strategies based on improved biology.

Single- and Multiple-Dose Randomized Studies of Blosozumab, a Monoclonal Antibody Against Sclerostin, in Healthy Postmenopausal Women

Abstract: Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses (intravenous [iv] and subcutaneous [sc]) of blosozumab in postmenopausal women, including prior/current bisphosphonate (BP) users. In these phase 1, randomized, subject- and investigator-blind, placebo-controlled studies, subjects received escalating doses of blosozumab: single iv doses up to 750 mg, single sc doses of 150 mg, multiple iv doses up to 750 mg every 2 weeks (Q2W) for 8 weeks, multiple sc doses up to 270 mg Q2W for 8 weeks, or placebo. Six subjects were randomized to each dose in the single-dose study (12 to placebo) and up to 12 subjects to each arm in the multiple-dose study. Blosozumab was well tolerated with no safety concerns identified after single or multiple administrations up to 750 mg. Dose-dependent responses were observed in sclerostin, N-terminal propeptide of procollagen type 1, bone-specific alkaline phosphatase, osteocalcin, C-terminal fragment of type 1 collagen, and bone mineral density (BMD) after single and multiple (up to 5) administrations of blosozumab. There was up to a 3.41% (p = 0.002) and up to a 7.71% (p < 0.001) change from baseline in lumbar spine BMD at day 85 after single or multiple administrations of blosozumab, respectively. Prior BP use did not appear to have a clear impact on the effects of single doses of blosozumab when considering bone biomarker and BMD responses. Antibodies to blosozumab were detected by a screening assay, but no patterns with regard to dose or route of administration and no clear impact on blosozumab exposure or PD responses were identified. In summary, blosozumab was well tolerated and exhibited anabolic effects on bone. These findings support further investigation of blosozumab as a potential anabolic therapy for osteoporosis. © 2014 American Society for Bone and Mineral Research.

Effects of Weight-Bearing Activities on Bone Mineral Content and Density in Children and Adolescents: A Meta-Analysis

Abstract: Osteoporosis and associated fractures are a major health concern in Western industrialized nations. Exercise during growth is suggested to oppose the involutional bone loss later in life by increasing peak bone mass. The primary aim of the present meta-analysis was to provide a robust estimate of the effect of weight-bearing activities (WBAs) on bone mineral content (BMC) and areal bone mineral density (aBMD), during childhood and adolescence. To locate relevant studies up to June 2012, computerized searches of multiple bibliographic databases and hand searches of key journals and reference lists were performed. Results were extracted by two independent reviewers. The quality of the included trials was assessed via the Physiotherapy Evidence Database (PEDro) score. The study group effect was defined as the difference between the standardized mean change for the treatment and control groups divided by the pooled pretest SD. From 109 potentially relevant studies, only 27 met the inclusion criteria. The analyzed training programs were capable of significantly increasing BMC and aBMD during growth. However, the weighted overall effect sizes (ESs) for changes in BMC (ES 0.17; 95% confidence interval [CI], 0.05–0.29; p < 0.05) and aBMD (ES 0.26; 95% CI, 0.02–0.49) were small. Stepwise backward regression revealed that more than one-third of the observed variance (r2 = 0.35) between subgroups of the BMC dataset could be explained by differences in the amount of habitual calcium intake per day (beta 0.54, p < 0.01) and the maturational stage (beta −0.28, p < 0.01) at baseline. No significant moderators were identified for aBMD, possibly due to the small number of trials investigating WBAs on aBMD. The results of this meta-analysis conclude that WBAs alongside high calcium intake provide a practical, relevant method to significantly improve BMC in prepubertal children, justifying the application of this exercise form as an osteoporosis prophylaxis in this stage of maturity. © 2014 American Society for Bone and Mineral Research.

Trabecular Bone Score (TBS) Predicts Vertebral Fractures in Japanese Women Over 10 Years Independently of Bone Density and Prevalent Vertebral Deformity: The Japanese Population-Based Osteoporosis (JPOS) Cohort Study

Abstract: Bone strength is predominantly determined by bone density, but bone microarchitecture also plays an important role. We examined whether trabecular bone score (TBS) predicts the risk of vertebral fractures in a Japanese female cohort. Of 1950 randomly selected women aged 15 to 79 years, we analyzed data from 665 women aged 50 years and older, who completed the baseline study and at least one follow-up survey over 10 years, and who had no conditions affecting bone metabolism. Each survey included spinal imaging by dual-energy X-ray absorptiometry (DXA) for vertebral fracture assessment and spine areal bone mineral density (aBMD) measurement. TBS was obtained from spine DXA scans archived in the baseline study. Incident vertebral fracture was determined when vertebral height was reduced by 20% or more and satisfied McCloskey-Kanis criteria or Genant's grade 2 fracture at follow-up. Among eligible women (mean age 64.1 ± 8.1 years), 92 suffered incident vertebral fractures (16.7/103 person-years). These women were older with lower aBMD and TBS values relative to those without fractures. The unadjusted odds ratio of vertebral fractures for one standard deviation decrease in TBS was 1.98 (95% confidence interval [CI] 1.56, 2.51) and remained significant (1.64, 95% CI 1.25, 2.15) after adjusting for aBMD. The area under the receiver operating characteristic curve of TBS and aBMD combined was 0.700 for vertebral fracture prediction and was not significantly greater than that of aBMD alone (0.673). However, reclassification improvement measures indicated that TBS and aBMD combined significantly improved risk prediction accuracy compared with aBMD alone. Further inclusion of age and prevalent vertebral deformity in the model improved vertebral fracture prediction, and TBS remained significant in the model. Thus, lower TBS was associated with higher risk of vertebral fracture over 10 years independently of aBMD and clinical risk factors including prevalent vertebral deformity. TBS could effectively improve fracture risk assessment in clinical settings. © 2014 American Society for Bone and Mineral Research.

Secular Trends in Hip Fractures Worldwide: Opposing Trends East Versus West

Abstract: Despite wide variations in hip rates fractures worldwide, reasons for such differences are not clear. Furthermore, secular trends in the age-specific hip fracture rates are changing the world map of this devastating disease, with the highest rise projected to occur in developing countries. The aim of our investigation is to systematically characterize secular trends in hip fractures worldwide, examine new data for various ethnic groups in the United States, evidence for divergent temporal patterns, and investigate potential contributing factors for the observed change in their epidemiology. All studies retrieved through a complex Medline Ovid search between 1966 and 2013 were examined. For each selected study, we calculated the percent annual change in age-standardized hip fracture rates de-novo. Although occurring at different time points, trend breaks in hip fracture incidence occurred in most Western countries and Oceania. After a steep rise in age-adjusted rates in these regions, a decrease became evident sometimes between the mid-seventies and nineties, depending on the country. Conversely, the data is scarce in Asia and South America, with evidence for a continuous rise in hip fracture rates, with the exception of Hong-Kong and Taiwan that seem to follow Western trends. The etiologies of these secular patterns in both the developed and the developing countries have not been fully elucidated, but the impact of urbanization is at least one plausible explanation. Data presented here show close parallels between rising rates of urbanization and hip fractures across disparate geographic locations and cultures. Once the proportion of the urban population stabilized, hip fracture rates also stabilize or begin to decrease perhaps due to the influence of other factors such as birth cohort effects, changes in bone mineral density and BMI, osteoporosis medication use and/or lifestyle interventions such as smoking cessation, improvement in nutritional status and fall prevention.

Osteoclast‐Derived Complement Component 3a Stimulates Osteoblast Differentiation

Abstract: Bone remodeling is regulated by a coupling of resorption to subsequent formation; however, the "coupling factor" and underlying mechanism are not fully understood. Here, we found that the condition medium (CM) of mature osteoclasts contains a humoral factor that stimulates the differentiation of primary osteoblasts, as determined by alkaline phosphatase (ALP) activity. We purified osteoblastogenesis-stimulating activity from 3 L of osteoclast CM through successive ion exchange chromatographies by monitoring the ALP activity of osteoblasts and identified complement component 3 (C3). Expression of the C3 gene increased during osteoclastogenesis, and the cleavage product C3a was detected by ELISA in the CM of osteoclasts but not in that of bone marrow macrophages. The osteoblastogenesis-stimulating activity present in osteoclast CM was inhibited by a specific antagonist of the C3a receptor (C3aR), SB290157. Conversely, the retroviral expression of C3a as well as treatment with the C3aR agonist, benzeneacetamide, stimulated osteoblast differentiation. C3 gene expression in bone was increased in the high bone turnover states of ovariectomy (OVX) or a receptor activator of NF-κB ligand (RANKL) injection, and blocking the action of C3a with the daily administration of SB290157 resulted in the attenuation of bone formation elevated by OVX and the exacerbation of bone loss. These results suggest that osteoclast-derived C3a functions in the relay from bone resorption to formation and may be a candidate for a coupling factor.

mTORC2 regulates mechanically induced cytoskeletal reorganization and lineage selection in marrow-derived mesenchymal stem cells.

Abstract: The cell cytoskeleton interprets and responds to physical cues from the microenvironment. Applying mechanical force to mesenchymal stem cells induces formation of a stiffer cytoskeleton, which biases against adipogenic differentiation and toward osteoblastogenesis. mTORC2, the mTOR complex defined by its binding partner rictor, is implicated in resting cytoskeletal architecture and is activated by mechanical force. We asked if mTORC2 played a role in mechanical adaptation of the cytoskeleton. We found that during bi-axial strain-induced cytoskeletal restructuring, mTORC2 and Akt colocalize with newly assembled focal adhesions (FA). Disrupting the function of mTORC2, or that of its downstream substrate Akt, prevented mechanically induced F-actin stress fiber development. mTORC2 becomes associated with vinculin during strain, and knockdown of vinculin prevents mTORC2 activation. In contrast, mTORC2 is not recruited to the FA complex during its activation by insulin, nor does insulin alter cytoskeletal structure. Further, when rictor was knocked down, the ability of mesenchymal stem cells (MSC) to enter the osteoblastic lineage was reduced, and when cultured in adipogenic medium, rictor-deficient MSC showed accelerated adipogenesis. This indicated that cytoskeletal remodeling promotes osteogenesis over adipogenesis. In sum, our data show that mTORC2 is involved in stem cell responses to biophysical stimuli, regulating both signaling and cytoskeletal reorganization. As such, mechanical activation of mTORC2 signaling participates in mesenchymal stem cell lineage selection, preventing adipogenesis by preserving β-catenin and stimulating osteogenesis by generating a stiffer cytoskeleton.

Bone Loss After Bariatric Surgery: Discordant Results Between DXA and QCT Bone Density

Abstract: Several studies, using dual-energy x-ray absorptiometry (DXA), have reported substantial bone loss after bariatric surgery. However, profound weight loss may cause artifactual changes in DXA areal bone mineral density (aBMD) results. Assessment of volumetric bone mineral density (vBMD) by quantitative computed tomography (QCT) may be less susceptible to such artifacts. We assessed changes in BMD of the lumbar spine and proximal femur prospectively for 1 year using DXA and QCT in 30 morbidly obese adults undergoing Roux-en-Y gastric bypass surgery and 20 obese non-surgical controls. At one year, subjects who underwent gastric bypass surgery lost 37 ± 2 kg compared with 3 ± 2 kg lost in the non-surgical controls (p<0.0001). Spine BMD declined more in the surgical group than in the non-surgical group whether assessed by DXA (−3.3 vs. −1.1%, p=0.034) or by QCT (−3.4 vs. 0.2%, p=0.010). Total hip and femoral neck aBMD declined significantly in the surgical group when assessed by DXA (−8.9 vs. −1.1%, p<0.0001 for the total hip and −6.1 vs. −2.0%, p=0.002 for the femoral neck), but no changes in hip vBMD were noted using QCT. Within the surgical group, serum P1NP and CTX levels increased by 82 ± 10% and by 220 ± 22%, respectively, by 6 months and remained elevated over 12 months (p<0.0001 for all). Serum calcium, vitamin D, and PTH levels remained stable in both groups. We conclude that moderate vertebral bone loss occurs in the first year after gastric bypass surgery. However, striking declines in DXA aBMD at the proximal femur were not confirmed with QCT vBMD measurements. These discordant results suggest that artifacts induced by large changes in body weight after bariatric surgery affect DXA and/or QCT measurements of bone, particularly at the hip.

Effects of a Targeted Multimodal Exercise Program Incorporating High-Speed Power Training on Falls and Fracture Risk Factors in Older Adults: A Community-Based Randomized Controlled Trial

Abstract: Multi-modal exercise programs incorporating traditional progressive resistance training (PRT), weight-bearing impact and/or balance training are recommended to reduce risk factors for falls and fracture. However, muscle power, or the ability to produce force rapidly, has emerged as a more crucial variable to functional decline than muscle strength or mass. The aim of this 12-month community-based randomised controlled trial, termed Osteo-cise: Strong Bones for Life, was to evaluate the effectiveness and feasibility of a multi-modal exercise program incorporating high-velocity (HV)-PRT, combined with an osteoporosis education and behavioural change program, on bone mineral density (BMD), body composition, muscle strength and functional muscle performance in older adults. Falls incidence was evaluated as a secondary outcome. 162 older adults (mean ± SD; 67 ± 6 years) with risk factors for falls and/or low BMD were randomised to the Osteo-cise program (n = 81) or a control group (n = 81). Exercise consisted of fitness centre-based HV-PRT, weight-bearing impact and challenging balance/mobility activities performed three times weekly. After 12 months, the Osteo-cise program led to modest but significant net gains in femoral neck and lumbar spine BMD (1.0-1.1%, P Language: en

Tissue‐Level Mechanisms Responsible for the Increase in Bone Formation and Bone Volume by Sclerostin Antibody

Abstract: Bone formation can be remodeling-based (RBF) or modeling-based (MBF), the former coupled to bone resorption and the latter occurring directly on quiescent surfaces. Unlike osteoanabolic therapies such as parathyroid hormone (PTH) 1-34 that increase bone remodeling and thus both formation and resorption, sclerostin antibody (Scl-Ab) increases bone formation while decreasing bone resorption. With this unique profile, we tested our hypothesis that Scl-Ab primarily elicited MBF by examining bones from Scl-Ab–treated ovariectomized (OVX) rats and male cynomolgus monkeys (cynos). Histomorphometry was performed to quantify and characterize bone surfaces in OVX rats administered vehicle or Scl-Ab (25 mg/kg) subcutaneously (sc) twice/week for 5 weeks and in adolescent cynos administered vehicle or Scl-Ab (30 mg/kg) sc every 2 weeks for 10 weeks. Fluorochrome-labeled surfaces in L2 vertebra and femur endocortex (cynos only) were considered to be MBF or RBF based on characteristics of their associated cement lines. In OVX rats, Scl-Ab increased MBF by eightfold (from 7% to 63% of bone surface, compared to vehicle). In cynos, Scl-Ab markedly increased MBF on trabecular (from 0.6% to 34%) and endocortical surfaces (from 7% to 77%) relative to vehicle. Scl-Ab did not significantly affect RBF in rats or cynos despite decreased resorption surface in both species. In cynos, Scl-Ab resulted in a greater proportion of RBF and MBF containing sequential labels from week 2, indicating an increase in the lifespan of the formative site. This extended formation period was associated with robust increases in the percent of new bone volume formed. These results demonstrate that Scl-Ab increased bone volume by increasing MBF and prolonged the formation period at both modeling and remodeling sites while reducing bone resorption. Through these unique effects on bone formation and resorption, Scl-Ab may prove to be an effective therapeutic to rapidly increase bone mass in diseases such as osteoporosis. © 2014 American Society for Bone and Mineral Research.

Maternal vitamin D status during pregnancy and bone mass in offspring at 20 years of age: a prospective cohort study.

Abstract: It is uncertain whether the vitamin D status of pregnant women influences bone mass of their children. Cohort studies have yielded conflicting results; none have examined offspring at skeletal maturity. This longitudinal, prospective study investigated the association between maternal vitamin D status and peak bone mass of offspring in 341 mother and offspring pairs in the Western Australian Pregnancy Cohort (Raine) Study. Maternal serum samples collected at 18 weeks gestation were assayed for 25-hydroxyvitamin D (25OHD). Outcomes were total body bone mineral content (BMC) and bone mineral density (BMD) measured by dual-energy X-ray absorptiometry in offspring at 20 years of age. The mean (± SD) maternal serum 25OHD concentration was 57.2 ± 19.2 nmol/L; 132 women (38.7%) were vitamin D-deficient (25OHD <50 nmol/L). After adjustment for season of sample collection, maternal factors, and offspring factors (sex, birth weight, and age, height, lean mass, and fat mass at 20 years), maternal 25OHD concentration was positively associated with total body BMC and BMD in offspring, with a mean difference of 19.2 (95% confidence interval [CI], 5.6–32.7) g for BMC and 4.6 (95% CI, 0.1–9.1) mg/cm2 for BMD per 10.0 nmol/L of maternal 25OHD. Maternal vitamin D deficiency was associated with 2.7% lower total body BMC (mean ± SE) (2846 ± 20 versus 2924 ± 16 g, p = 0.004) and 1.7% lower total body BMD (1053 ± 7 versus 1071 ± 5 mg/cm2, p = 0.043) in the offspring. We conclude that vitamin D deficiency in pregnant women is associated with lower peak bone mass in their children. This may increase fracture risk in the offspring in later life. © 2014 American Society for Bone and Mineral Research.

Analysis of αSMA-labeled progenitor cell commitment identifies notch signaling as an important pathway in fracture healing

Abstract: Fracture healing is a regenerative process that involves coordinated responses of many cell types, but characterization of the roles of specific cell populations in this process has been limited. We have identified alpha smooth muscle actin (αSMA) as a marker of a population of mesenchymal progenitor cells in the periosteum that contributes to osteochondral elements during fracture healing. Using a lineage tracing approach, we labeled αSMA-expressing cells, and characterized changes in the periosteal population during the early stages of fracture healing by histology, flow cytometry, and gene expression profiling. In response to fracture, the αSMA-labeled population expanded and began to differentiate toward the osteogenic and chondrogenic lineages. The frequency of mesenchymal progenitor cell markers such as Sca1 and PDGFRα increased after fracture. By 6 days after fracture, genes involved in matrix production and remodeling were elevated. In contrast, genes associated with muscle contraction and Notch signaling were downregulated after fracture. We confirmed that activating Notch signaling in αSMA-labeled cells inhibited differentiation into osteogenic and adipogenic lineages in vitro and ectopic bone formation in vivo. By characterizing changes in a selected αSMA-labeled progenitor cell population during fracture callus formation, we have shown that modulation of Notch signaling may determine osteogenic potential of αSMA-expressing progenitor cells during bone healing.

Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation.

Abstract: Synthesis of cartilage by chondrocytes is an obligatory step for endochondral ossification. Global deletion of the Runx2 gene results in complete failure of the ossification process, but the underlying cellular and molecular mechanisms are not fully known. Here, we elucidated Runx2 regulatory control distinctive to chondrocyte and cartilage tissue by generating Runx2 exon 8 floxed mice. Deletion of Runx2 gene in chondrocytes caused failure of endochondral ossification and lethality at birth. The limbs of Runx2(ΔE8/ΔE8) mice were devoid of mature chondrocytes, vasculature, and marrow. We demonstrate that the C-terminus of Runx2 drives its biological activity. Importantly, nuclear import and DNA binding functions of Runx2 are insufficient for chondrogenesis. Molecular studies revealed that despite normal levels of Sox9 and PTHrP, chondrocyte differentiation and cartilage growth are disrupted in Runx2(ΔE8/ΔE8) mice. Loss of Runx2 in chondrocytes also impaired osteoprotegerin-receptor activator of NF-κB ligand (OPG-RANKL) signaling and chondroclast development. Dwarfism observed in Runx2 mutants was associated with the near absence of proliferative zone in the growth plates. Finally, we show Runx2 directly regulates a unique set of cell cycle genes, Gpr132, Sfn, c-Myb, and Cyclin A1, to control proliferative capacity of chondrocyte. Thus, Runx2 is obligatory for both proliferation and differentiation of chondrocytes.

Osteoporosis: A Lifecourse Approach

Abstract: It is becoming increasingly apparent that the risk of developing osteoporosis is accrued throughout the entire lifecourse, even from as early as conception. Thus early growth is associated with bone mass at peak and in older age, and risk of hip fracture. Novel findings from mother-offspring cohorts have yielded greater understanding of relationships between patterns of intrauterine and postnatal growth in the context of later bone development. Study of biological samples from these populations has helped characterize potential mechanistic underpinnings, such as epigenetic processes. Global policy has recognized the importance of early growth and nutrition to the risk of developing adult chronic noncommunicable diseases such as osteoporosis; testing of pregnancy interventions aimed at optimizing offspring bone health is now underway. It is hoped that through such programs, novel public health strategies may be established with the ultimate goal of reducing the burden of osteoporotic fracture in older age.

A Review of Rodent Models of Type 2 Diabetic Skeletal Fragility

Abstract: Evidence indicating that adult type 2 diabetes (T2D) is associated with increased fracture risk continues to mount Unlike osteoporosis, diabetic fractures are associated with obesity and normal to high bone mineral density, two factors that are typically associated with reduced fracture risk Animal models will likely play a critical role in efforts to identify the underlying mechanisms of skeletal fragility in T2D and to develop preventative treatments In this review we critically examine the ability of current rodent models of T2D to mimic the skeletal characteristics of human T2D We report that although there are numerous rodent models of T2D, few have undergone thorough assessments of bone metabolism and strength Further, we find that many of the available rodent models of T2D have limitations for studies of skeletal fragility in T2D because the onset of diabetes is often prior to skeletal maturation and bone mass is low, in contrast to what is seen in adult humans There is an urgent need to characterize the skeletal phenotype of existing models of T2D, and to develop new models that more closely mimic the skeletal effects seen in adult-onset T2D in humans