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OBJECTIVE: Radiographic hip osteoarthritis (RHOA) is associated with increased hip areal bone mineral density (aBMD). This study was undertaken to examine whether femoral geometry is associated with RHOA independent of aBMD. METHODS: Participants in the Study of Osteoporotic Fractures in whom pelvic radiographs had been obtained at visits 1 and 5 (mean 8.3 years apart) and hip dual x-ray absorptiometry (DXA) had been performed (2 years after baseline) were included. Prevalent and incident RHOA phenotypes were defined as composite (osteophytes and joint space narrowing [JSN]), atrophic (JSN without osteophytes), or osteophytic (femoral osteophytes without JSN). Analogous definitions of progression were based on minimum joint space and total osteophyte score. Hip DXA scans were assessed using the Hip Structural Analysis program to derive geometric measures, including femoral neck length, width, and centroid position. Relative risks and 95% confidence intervals for prevalent, incident, and progressive RHOA per SD increase in geometric measure were estimated in a hip-based analysis using multinomial logistic regression with adjustment for age, body mass index, knee height, and total hip aBMD. RESULTS: In 5,245 women (mean age 72.6 years), a wider femoral neck with a more medial centroid position was associated with prevalent and incident osteophytic and composite RHOA phenotypes (P < 0.05). Increased neck width and centroid position were associated with osteophyte progression (both P < 0.05). No significant geometric associations with atrophic RHOA were found. CONCLUSION: Differences in proximal femoral bone geometry and spatial distribution of bone mass occur early in hip OA and predict prevalent, incident, and progressive osteophytic and composite phenotypes, but not the atrophic phenotype. These bone differences may reflect responses to loading occurring early in the natural history of RHOA. [ABSTRACT FROM AUTHOR]

Biopsies of muscle and adipose tissue (AT) are useful tools to gain insights into the aging processes in these tissues. However, they are invasive procedures and their risk/benefit profile in older adults can be altered by sarcopenia, frailty, poor healing, and multimorbidity. Their success rates, safety, and tolerability in a geriatric population have not been reported in detail. Investigators in the Study of Muscle, Mobility, and Aging (SOMMA) performed biopsies of muscle and AT in older adults and prospectively collected data on biopsy success rates, safety, and tolerability. We report here the methods and outcomes of these two procedures. In total, 861 participants (aged 70-94) underwent percutaneous biopsies of the Vastus lateralis muscle with a Bergstrom needle. A subset (n = 241) also underwent percutaneous biopsies of the abdominal subcutaneous AT with the tumescent liposuction technique. Success rate was assessed by the percentage of biopsies yielding adequate specimens for analyses; tolerability by pain scores; and safety by frequency of adverse events. All data were prospectively collected. The overall muscle biopsy success rate was 97.1% and was modestly lower in women. The AT biopsy success rate was 95.9% and slightly lower in men. Minimal or no pain was reported in 68% of muscle biopsies and in 83% of AT biopsies. Adverse events occurred in 2.67% of muscle biopsies and 4.15% of AT biopsies. None was serious. In older adults, percutaneous muscle biopsies and abdominal subcutaneous AT biopsies have an excellent safety profile, often achieve adequate tissue yields for analyses, and are well tolerated., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO 2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO 2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (R = 0.48) between a higher oxidation level of eight Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging., (© 2024 Battelle Memorial Institute and The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events "get under the skin" to influence physical well-being. Using data from the Study of Muscle, Mobility, and Aging ( n = 879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (i) maximal adenosine triphosphate production (ATP max ) and (ii) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing one or more adverse childhood events. After adjustment, each additional event was associated with -0.08 SD (95% confidence interval = -0.13, -0.02) lower ATP max . No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism for understanding how early social stress influences health in later life.

Cadmium (Cd) is a heavy metal and natural element found in soil and crops with increasing concentrations linked to phosphate fertilizers and sewage sludge applied to crop lands. A large fraction of older US men and woman have documented Cd exposure. Cd exposure has proven health concerns such as risk of lung cancer from inhalation and impaired renal function; however, growing evidence suggests it also influences bone and muscle health. Given that low levels of Cd could affect bone and muscle, we have designed prospective studies using the two largest and most detailed US studies of bone health in older men and women: the Osteoporotic Fractures in Men Study and the Study of Osteoporotic Fractures. We are investigating the association of urinary cadmium (U-Cd), as a surrogate for long-term Cd exposure, with bone and muscle health. Building off suggestive evidence from mechanistic and cross-sectional studies, this will be the first well-powered prospective study of incident fracture outcomes, bone loss, and muscle loss in relation to U-Cd, an established biomarker of long-term Cd exposure. The following is a proposed protocol for the intended study; if successful, the proposed studies could be influential in directing future US policy to decrease Cd exposure in the US population similar to recent policies adopted by the European Union to limit Cd in fertilizers., Competing Interests: The authors state that they have no known conflicts of interest to declare that could appear to influence or alter the work put forth in this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Rationale and Objectives: Spinal osteoporotic compression fractures (OCFs) can be an early biomarker for osteoporosis but are often subtle, incidental, and underreported. To ensure early diagnosis and treatment of osteoporosis, we aimed to build a deep learning vertebral body classifier for OCFs as a critical component of our future automated opportunistic screening tool., Materials and Methods: We retrospectively assembled a local dataset, including 1790 subjects and 15,050 vertebral bodies (thoracic and lumbar). Each vertebral body was annotated using an adaption of the modified-2 algorithm-based qualitative criteria. The Osteoporotic Fractures in Men (MrOS) Study dataset provided thoracic and lumbar spine radiographs of 5994 men from six clinical centers. Using both datasets, five deep learning algorithms were trained to classify each individual vertebral body of the spine radiographs. Classification performance was compared for these models using multiple metrics, including the area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, and positive predictive value (PPV)., Results: Our best model, built with ensemble averaging, achieved an AUC-ROC of 0.948 and 0.936 on the local dataset's test set and the MrOS dataset's test set, respectively. After setting the cutoff threshold to prioritize PPV, this model achieved a sensitivity of 54.5% and 47.8%, a specificity of 99.7% and 99.6%, and a PPV of 89.8% and 94.8%., Conclusion: Our model achieved an AUC-ROC>0.90 on both datasets. This testing shows some generalizability to real-world clinical datasets and a suitable performance for a future opportunistic osteoporosis screening tool., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nathan Cross, Qifei Dong, Sandra Johnston, Jessica Perry, and David Haynor report financial support was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Gang Luo reports financial support was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Heart Lung and Blood Institute. Jeffrey Jarvik reports financial support was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and reports a relationship with the General Electric-Association of University Radiologists Radiology Research Academic Fellowship (GERRAF) that includes travel reimbursement. Nathan Cross reports financial support was provided by the General Electric-Association of University Radiologists Radiology Research Academic Fellowship (GERRAF). Nathan M. Cross, Jeffrey Jarvik, David R. Haynor, Gang Luo, Sandra Johnston, Qifei Dong, Jonathan Renslo, Brian Chang, and Jessica Perry have patent #63/463823 pending to the University of Washington., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: Osteoporosis affects 9% of individuals over 50 in the United States and 200 million women globally. Spinal osteoporotic compression fractures (OCFs), an osteoporosis biomarker, are often incidental and under-reported. Accurate automated opportunistic OCF screening can increase the diagnosis rate and ensure adequate treatment. We aimed to develop a deep learning classifier for OCFs, a critical component of our future automated opportunistic screening tool., Materials and Methods: The dataset from the Osteoporotic Fractures in Men Study comprised 4461 subjects and 15,524 spine radiographs. This dataset was split by subject: 76.5% training, 8.5% validation, and 15% testing. From the radiographs, 100,409 vertebral bodies were extracted, each assigned one of two labels adapted from the Genant semiquantitative system: moderate to severe fracture vs. normal/trace/mild fracture. GoogLeNet, a deep learning model, was trained to classify the vertebral bodies. The classification threshold on the predicted probability of OCF outputted by GoogLeNet was set to prioritize the positive predictive value (PPV) while balancing it with the sensitivity. Vertebral bodies with the top 0.75% predicted probabilities were classified as moderate to severe fracture., Results: Our model yielded a sensitivity of 59.8%, a PPV of 91.2%, and an F 1 score of 0.72. The areas under the receiver operating characteristic curve (AUC-ROC) and the precision-recall curve were 0.99 and 0.82, respectively., Conclusion: Our model classified vertebral bodies with an AUC-ROC of 0.99, providing a critical component for our future automated opportunistic screening tool. This could lead to earlier detection and treatment of OCFs., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Type 2 diabetes (T2D) is associated with increased risk of fractures. However, it is unclear whether current osteoporosis treatments reduce fractures in individuals with diabetes. The aim of the study was to determine whether presence of T2D influences the efficacy of antiresorptive treatment for osteoporosis using the Foundation for the National Institutes of Health (FNIH)-American Society for Bone and Mineral Research (ASBMR)-Study to Advance Bone Mineral Density (BMD) as a Regulatory Endpoint (SABRE) cohort, which includes individual patient data from randomized trials of osteoporosis therapies. In this study we included 96,385 subjects, 6.8% of whom had T2D, from nine bisphosphonate trials, two selective estrogen receptor modulator (SERM) trials, two trials of menopausal hormone therapy, one denosumab trial, and one odanacatib trial. We used Cox regression to obtain the treatment hazard ratio (HR) for incident nonvertebral, hip, and all fractures and logistic regression to obtain the treatment odds ratio (OR) for incident morphometric vertebral fractures, separately for T2D and non-DM. We used linear regression to estimate the effect of treatment on 2-year change in BMD (n = 49,099) and 3-month to 12-month change in bone turnover markers (n = 12,701) by diabetes status. In all analyses, we assessed the interaction between treatment and diabetes status. In pooled analyses of all 15 trials, we found that diabetes did not impact treatment efficacy, with similar reductions in vertebral, nonvertebral, all, and hip fractures, increases in total hip and femoral neck BMD, and reductions in serum C-terminal cross-linking telopeptide (CTX), urinary N-telopeptide of type I collagen/creatinine (NTX/Cr) and procollagen type 1 N propeptide (P1NP) (all interactions p > 0.05). We found similar results for the pooled analysis of bisphosphonate trials. However, when we considered trials individually, we found a few interactions within individual studies between diabetes status and the effects of denosumab and odanacatib on fracture risk, change in BMD or bone turnover markers (BTMs). In sum, these results provide strong evidence that bisphosphonates and most licensed antiresorptive drugs are effective at reducing fracture risk and increasing BMD irrespective of diabetes status. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Context: Whether repeated bone mineral density (BMD) screening improves fracture prediction in men is uncertain., Objective: We evaluated whether a second BMD 7 years after the initial BMD improves fracture prediction in older men., Methods: Among 3651 community-dwelling men (mean age 79.1 years) with total hip BMD at baseline and Year 7 (Y7), self-reported fractures after Y7 were confirmed by radiographic reports. Fracture prediction assessed using Cox proportional hazards regression and logistic regression with receiver operating characteristic curves for models based on initial BMD, BMD change, and the combination of initial BMD and BMD change (combination model)., Results: During an average follow-up of 8.2 years after Y7, 793 men experienced ≥ 1 clinical fractures, including 426 men with major osteoporotic fractures (MOF) and 193 men with hip fractures. Both initial BMD and BMD change were associated with risk of fracture outcomes independent of each other, but the association was stronger for initial BMD. For example, the multivariable hazard ratio of MOF in the combination model per 1 SD decrement in BMD was 1.76 (95% CI 1.57-1.98) for initial BMD and 1.19 (95% CI 1.08-1.32) for BMD change. Discrimination of fracture outcomes with initial BMD models was somewhat better than with BMD change models and similar to combination models (AUC value for MOF 0.68 [95% CI 0.66-0.71] for initial BMD model, 0.63 [95% CI 0.61-0.66] for BMD change model, and 0.69 [95% CI 0.66-0.71] for combination model)., Conclusion: Repeating BMD after 7 years did not meaningfully improve fracture prediction at the population level in community-dwelling older men., (Published by Oxford University Press on behalf of the Endocrine Society 2022.)

Background: Mortality research has identified biomarkers predictive of all-cause mortality risk. Most of these markers, such as body mass index, are predictive cross-sectionally, while for others the longitudinal change has been shown to be predictive, for instance greater-than-average muscle and weight loss in older adults. And while sometimes markers are derived from imaging modalities such as DXA, full scans are rarely used. This study builds on that knowledge and tests two hypotheses to improve all-cause mortality prediction. The first hypothesis is that features derived from raw total-body DXA imaging using deep learning are predictive of all-cause mortality with and without clinical risk factors, meanwhile, the second hypothesis states that sequential total-body DXA scans and recurrent neural network models outperform comparable models using only one observation with and without clinical risk factors., Methods: Multiple deep neural network architectures were designed to test theses hypotheses. The models were trained and evaluated on data from the 16-year-long Health, Aging, and Body Composition Study including over 15,000 scans from over 3000 older, multi-race male and female adults. This study further used explainable AI techniques to interpret the predictions and evaluate the contribution of different inputs., Results: The results demonstrate that longitudinal total-body DXA scans are predictive of all-cause mortality and improve performance of traditional mortality prediction models. On a held-out test set, the strongest model achieves an area under the receiver operator characteristic curve of 0.79., Conclusion: This study demonstrates the efficacy of deep learning for the analysis of DXA medical imaging in a cross-sectional and longitudinal setting. By analyzing the trained deep learning models, this work also sheds light on what constitutes healthy aging in a diverse cohort., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Background: despite fall history being a well-known risk factor for falls and fractures, the association between very recent falls and imminent fracture risk is not clearly elucidated., Objective: to study the very recent (<4 months) fall-related absolute risk of fractures in the following year., Methods: two large prospective cohort studies of women (Study of Osteoporotic Fractures [SOF]) and men (Osteoporotic Fractures in Men Study [MrOS]) aged 65 years or older were included. Data on falls were collected every 4 months, and the primary outcomes were any non-spine and hip fractures in the next 12 months., Results: a total of 9,704 women contributed 419,149, and 5,994 men contributed 223,885 four-monthly periods of observations during the 14.8-year SOF and 12.6-year MrOS follow-up. Falls within 4 months indicated a high risk of non-spine and hip fractures in the following year for both sexes; in women, a recent fall indicated an 8.1% absolute risk of a non-spine fracture within 1 year, a 2.5-fold higher risk than that in women without falls, a 2.5% absolute risk of hip fracture, and a 3.1-fold increased risk. Falls increased the risk of fractures regardless of whether a fracture occurred or not. Men had similar risk patterns, albeit with a lower absolute risk of fracture., Conclusions: in older people, a fall within 4 months indicates a high risk of fracture in the next year, regardless of fracture occurrence. A recent fall warrants urgent evaluation and consideration of treatments to reduce the imminent risk of fractures., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The surrogate threshold effect (STE) is defined as the minimum treatment effect on a surrogate that is reliably predictive of a treatment effect on the clinical outcome. It provides a framework for implementing a clinical trial with a surrogate endpoint. The aim of this study was to update our previous analysis by validating the STE for change in total hip (TH) BMD as a surrogate for fracture risk reduction; the novelty of this study was this validation. To do so, we used individual patient data from 61,415 participants in 16 RCTs that evaluated bisphosphonates (nine trials), selective estrogen receptor modulators (four trials), denosumab (one trial), odanacatib (one trial), and teriparatide (one trial) to estimate trial-specific treatment effects on TH BMD and all, vertebral, hip, and nonvertebral fractures. We then conducted a random effects meta-regression of the log relative fracture risk reduction against 24-month change in TH BMD, and computed the STE as the intersection of the upper 95% prediction limit of this regression with the line of no fracture reduction. We validated the STE by checking whether the number of fractures in each trial provided 80% power and determining what proportion of trials with BMD changes ≥ STE reported significant reductions in fracture risk. We applied this analysis to (i) the trials on which we estimated the STE; and (ii) trials on which we did not estimate the STE. We found that the STEs for all, vertebral, hip, and nonvertebral fractures were 1.83%, 1.42%, 3.18%, and 2.13%, respectively. Among trials used to estimate STE, 27 of 28 were adequately powered, showed BMD effects exceeding the STE, and showed significant reductions in fracture risk. Among the validation set of 11 trials, 10 met these criteria. Thus STE differs by fracture type and has been validated in trials not used to develop the approach. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Few analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction seeking to estimate the proportion of treatment effect explained (PTE) by BTMs. Pooling such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from up to 62,000 participants enrolled in 12 bisphosphonate (BP) and four selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and one bone resorption marker (C-terminal telopeptide of type I collagen [CTX]) and incident fracture outcome data, we estimated the PTE using two different models. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 5 years of follow-up. For vertebral fracture, the results showed that changes in all three BTMs at 6 months explained a large proportion of the treatment effect of ARs (57 to >100%), but not for and non-vertebral or hip fracture. We conclude that short-term AR treatment-related changes in bone ALP, PINP, and CTX account for a large proportion of the treatment effect for vertebral fracture. Change in BTMs is a useful surrogate marker to study the anti-fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research., (© 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.)

Red cell distribution width (RDW), routinely assessed as a component of a complete blood count (CBC), quantifies the variation in the size of red blood cells. It increases with age, and increased RDW predicts many aging-related diseases and mortality. However, whether it also predicts hip fracture is unknown. We prospectively evaluated the association between RDW and hip fracture using data from the Osteoporotic Fracture in Men (MrOS) study. RDW was measured in 3635 men (aged 71 to 99 years) along with bone mineral density (BMD) in MrOS. RDW ranged from 11.3% to 32.9% (median 14.0%; interquartile range 13.5% to 14.8%) and was categorized into four groups (≤13.0%, 13.1% to 14.0%, 14.1% to 15.0%, ≥15.1%). Study participants with a hemoglobin level <13.0 g/dL were classified as having anemia. During an average 8.1 years, 164 men suffered hip fractures. The risks of hip fractures increased with increase of RDW category. Furthermore, there was a significant interaction between anemia and RDW: An association between RDW and hip fractures was only observed in participants without anemia. In those without anemia, the relative hazard of hip fractures increased with increases in RDW category: Men in the highest RDW category had a 2.8 times higher risk of hip fractures than men in the lowest group (95% confidence interval 1.1 to 7.1). The risks of all-clinical fractures were also increased along with higher RDW values. Additionally, RDW was significantly associated with the risk of having a fall but not with femoral neck or total hip BMD. In conclusion, RDW and anemia defined by hemoglobin are widely available routine laboratory measurements that together could indicate increased risk of hip fracture, reflecting the neuromuscular effects of aging rather than lower hip BMD. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)

Meta-analyses conducted >15 years ago reported that improvements in bone mineral density (BMD) were associated with reduction in vertebral and nonvertebral fractures in osteoporosis trials. Numerous studies have been conducted since then, incorporating new therapies with different mechanisms of action and enrolling many more subjects. To extend these prior analyses, we conducted a meta-regression of 38 placebo-controlled trials of 19 therapeutic agents to determine the association between improvements in BMD and reductions in fracture risk. We used a linear model to examine the relationship between mean percent difference in BMD change between treatment and placebo groups and the logarithm of the relative risk. We found that greater improvements in BMD were strongly associated with greater reductions in vertebral and hip fractures but not nonvertebral fractures. For vertebral fracture, the r 2 values for total hip, femoral neck, and lumbar spine BMD change were 0.56, 0.54, and 0.63, respectively (p ≤ 0.0002). For a 2% or 6% improvement in total hip BMD, we might expect a 28% or 66% reduction, respectively, in vertebral fracture risk. For hip fracture, the r 2 values for total hip, femoral neck, and lumbar spine BMD change were 0.48 (p = 0.01), 0.42 (p = 0.02), and 0.22 (ns), respectively. For a 2% or 6% improvement in total hip BMD, we might expect a 16% or 40% reduction in hip fracture risk. In conclusion, our results extend prior observations that larger improvements in dual-energy X-ray absorptiometry (DXA)-based BMD are associated with greater reductions in fracture risk, particularly for vertebral and hip fractures. Although these results cannot be directly applied to predict the treatment benefit in an individual patient, they provide compelling evidence that improvements in BMD with osteoporosis therapies may be useful surrogate endpoints for fracture in trials of new therapeutic agents. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. Such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from 28,000 participants enrolled in 11 bisphosphonate (BP) and three selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r 2  = 0.82 [p < 0.001] and r 2  = 0.75 [p = 0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r 2  = 0.33 [p = 0.053] and r 2  = 0.53 [p = 0.065], respectively) and hip fracture (r 2  = 0.17 [p = 0.24] and r 2  = 0.43 [p = 0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

The ability of bone mineral density (BMD) and other risk factors to predict fracture risk is well-established for as long as 5 to 10 years. However, their value to predict risk over a longer term has not been directly studied. We investigated whether a single assessment of femoral neck BMD and fracture history can predict fracture risk over 20 to 25 years. We used data from the Study of Osteoporotic Fractures (SOF) that assessed BMD and risk factors in 7959 women age ≥67 (mean = 73.4) in 1988-1990. Follow-up for fractures continued for 25 years for hip fracture, and for 20 years for any nonvertebral fracture. Using age-adjusted proportional hazards models, we analyzed the relationships between a single baseline assessment of femoral neck BMD, fracture history and age, and 20-25-year fracture incidence. The 25-year cumulative incidence of hip fracture was 17.9%; 20-year incidence of any nonvertebral fracture was 46.2%. The 25-year hip fracture incidence was highest in those ≥80 years old (22.6%) compared to 13.9% in women aged <70 years. A single femoral neck BMD measurement strongly predicted long-term hip fracture risk to 25 years: 29.6% risk in the lowest BMD quartile versus 7.6% with the highest relative hazard (RH) = 4.9 (95% CI, 4.1 to 6.0). Femoral neck BMD predicted hip fracture with little degradation over time from RH/SD = 2.6 (2.2 to 3.0) for 0 to 5 years to RH/SD = 1.8 (1.4 to 2.4) for 20 to 25 years. Lifetime hip fracture risk was similar (∼30%) regardless of age from 67 to >80 years. History of hip fracture predicted hip fractures only slightly better than history of nonvertebral fracture (RH = 1.6 [95% CI, 1.1 to 2.2] versus RH = 1.4 [95% CI, 1.2 to 1.5], respectively). Fracture history remained strongly predictive up to 25 years. We conclude that a single BMD and fracture history assessment can predict fracture risk over 20 to 25 years. Long-term risk of hip fracture remains extremely high in the oldest age groups, supporting risk assessment and consideration of treatment even in the oldest, highest-risk women.© 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B 12 , B 6 , and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5 mg/day), vitamin B 6 (50 mg/day), and vitamin B 12 (1 mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard = 1.08; 95% confidence interval, 0.88 to 1.34). In a nested case-cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B 12 or B 6 , or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Low bone mineral density (BMD) is associated with increased mortality risk, yet the impact of BMD loss on mortality is relatively unknown. We hypothesized that greater BMD loss is associated with increased mortality risk in older men. Change in femoral neck BMD was assessed in 4400 Osteoporotic Fractures in Men (MrOS) study participants with two to three repeat dual-energy X-ray absorptiometry scans over an average of 4.6 ± 0.4 (mean ± SD) years. Change in femoral neck BMD was estimated using mixed effects models; men were grouped into three categories of BMD change: maintenance ( n = 1087; change ≥ 0 g/cm 2 ); expected loss ( n = 2768; change between 0 g/cm 2 and <1 SD below mean change [>-0.034 g/cm 2 ]); and accelerated loss ( n = 545; change 1 SD below mean change or worse [≤-0.034 g/cm 2 ]). Multivariate proportional hazards models adjusted for potential confounders estimated the risk of all-cause mortality over 8.1 ± 2.8 years following visit 2. Mortality was centrally adjudicated by physician review of death certificates. At visit 1, mean age was 72.9 ± 5.5 years. Men who maintained BMD were less likely to die during the subsequent follow-up period (33.7%) than men who had accelerated BMD loss (60.6%) ( p < 0.001). Compared to men who had maintained BMD, those who had accelerated BMD loss had a 44% greater risk of mortality in multivariate-adjusted models (HR, 1.44; 95% CI, 1.23 to 1.68). Compared to men who had maintained BMD, there was no significant difference in mortality risk for men with expected loss of BMD (36.9% died) (multivariate HR, 1.00; 95% CI, 0.89 to 1.13). Further adjustment for visit 1 or visit 2 BMD measurement did not substantially alter these associations. Results for total hip BMD were similar. In conclusion, accelerated loss of BMD at the hip is a risk factor for mortality in men that is not explained by comorbidity burden, concurrent change in weight, or physical activity., Competing Interests: Disclosures All authors state that they have no conflicts of interest.

Context: Extremely low hemoglobin (Hgb) values have been linked to increased fracture risk at different sites. However, careful assessment of clinically defined anemia and fracture risk is lacking., Objective: To determine whether men with anemia were at increased risk of fracture after accounting for bone mineral density (BMD) and bone loss., Design: Cross-sectional analysis (at visit 3) and prospective analysis (from baseline to visit 3) in the Osteoporotic Fractures in Men (MrOS), a multisite, longitudinal cohort study., Setting: Six communities in the United States., Participants: A total of 3632 community-dwelling men (age ≥65 years) in MrOS at baseline (2000 through 2002) who were able to walk unassisted, did not have hip replacement or fracture, and had complete blood cell counts at visit 3 (2007 through 2009)., Outcomes: Adjudicated spine and nonspine fractures during a median 7.2 years of follow-up., Results: Analytic baseline characteristics associated with fractures or anemia (defined as Hgb <12 g/dL) were included in multivariable models. Anemia was associated with increased risk of any fracture [hazard ratio (HR), 1.67; 95% confidence interval (CI), 1.26 to 2.21] and nonspine fracture (HR, 1.70; 95% CI, 1.25 to 2.31). A model including change in BMD slightly attenuated the association with any (HR, 1.60; 95% CI, 1.20 to 2.13) and nonspine fractures (HR, 1.57; 95% CI, 1.14 to 2.15). Including absolute BMD did not significantly alter the anemia-fracture association. Anemia was not associated with spine fracture., Conclusions: Community-dwelling older men with anemia had a 57% to 72% increase in nonspine fracture risk independent of BMD and bone loss., (Copyright © 2017 Endocrine Society)

Background: Autonomic dysfunction contributes to atrial fibrillation (AF)., Objective: We hypothesized that polysomnogram (PSG)-based heart rate variability (HRV) autonomic function biomarkers are associated with incident AF and these associations are modified by measures of sleep disordered breathing (SDB)., Methods: 2350 participants of a multi-center prospective study (Outcomes of Sleep Disorders in Older Men Study) without baseline AF underwent sleep studies with incident adjudicated AF follow up (8.0 ± 2.6 years). Cox proportional hazard models were used to analyze sleep study-ECG spectral HRV indices [low and high frequency power (LF, HF), LF/HF] and time domain indices [mean of normal to normal beats (MNN), short and long term variability (STV, LTV) and STV/LTV] and premature atrial contractions (PACs) and incident AF (HR and 95% CI). Statistical interactions between HRV and SDB were examined. Models were adjusted for age, race, body mass index, waist circumference, cardiac medications, co-morbid diseases, alcohol use and study site., Results: Lower LF/HF and lower LF were associated with higher AF incidence (LF/HF Q1 vs. Q4: 1.46, 1.02-2.08, LF Q1 vs. Q4: 1.46, 1.02-2.10). Higher STV/LTV was associated with an increased risk of AF (p-trend= 0.028). The highest PAC quartile had a 3-fold increased AF risk (2.99, 1.94-4.62) compared to the lowest quartile. A significant interaction of obstructive apnea was observed in the LF-AF relationship (0.045)., Conclusions: Sleep-related reduced sympathovagal balance (LF/HF) and increased atrial ectopy are independently associated with future AF; a relationship modified by obstructive apnea.

Hematopoiesis depends on a supportive microenvironment. Preclinical studies in mice have demonstrated that osteoblasts influence the development of blood cells, particularly erythrocytes, B lymphocytes, and neutrophils. However, it is unknown whether osteoblast numbers or function impact blood cell counts in humans. We tested the hypothesis that men with low BMD or greater BMD loss have decreased circulating erythrocytes and lymphocytes and increased myeloid cells. We performed a cross-sectional analysis and prospective analysis in the Osteoporotic Fractures in Men (MrOS) study, a multisite longitudinal cohort study. A total of 2571 community-dwelling men (≥65 years) who were able to walk without assistance, did not have a hip replacement or fracture, and had complete blood counts (CBCs) at the third study visit were analyzed. Multivariable (MV)-adjusted logistic regression estimated odds of white blood cell (WBC) subtypes (highest and lowest quintile versus middle), and anemia (clinically defined) associated with BMD by DXA scan (at visit 3), annualized percent BMD change (baseline to visit 3), and high BMD loss (>0.5%/year, from baseline to visit 3) at the femoral neck (FN) and total hip (TH). MV-adjusted models included age, BMI, cancer history, smoking status, alcohol intake, corticosteroid use, self-reported health, thiazide use, and physical activity. At visit 3 greater TH BMD loss (per 1 SD) was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Annualized BMD loss of >0.5% was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Similar results were observed for FN BMD regarding anemia and lymphocytes. We conclude that community-dwelling older men with declining hip BMD over about 7 years had increased risks of anemia, lower lymphocyte count, and higher neutrophil count, consistent with preclinical studies. Bone health and hematopoiesis may have greater interdependency than previously recognized. © 2016 American Society for Bone and Mineral Research., Competing Interests: Disclosures: The authors have no conflicts to report., (© 2016 American Society for Bone and Mineral Research.)

Objective: To determine the risk of all-cause and disease-specific mortality among older women with hip osteoarthritis (OA) and to identify mediators in the causal pathway., Methods: Data were from the Study of Osteoporotic Fractures, a US population-based cohort study of 9,704 white women age ≥65 years. The analytic sample included women with hip radiographs at baseline (n = 7,889) and year 8 (n = 5,749). Mortality was confirmed through October 2013 by death certificates and hospital discharge summaries. Radiographic hip OA (RHOA) was defined as a Croft grade of ≥2 in at least 1 hip (definite joint space narrowing or osteophytes plus 1 other radiographic feature)., Results: The mean ± SD followup time was 16.1 ± 6.2 years. The baseline and year 8 prevalence of RHOA were 8.0% and 11.0%, respectively. The cumulative incidence (proportion of deaths during the study period) was 67.7% for all-cause mortality, 26.3% for cardiovascular disease (CVD) mortality, 11.7% for cancer mortality, 1.9% for gastrointestinal disease mortality, and 27.8% for all other mortality causes. RHOA was associated with an increased risk of all-cause mortality (hazard ratio 1.14 [95% confidence interval 1.05-1.24]) and CVD mortality (hazard ratio 1.24 [95% confidence interval 1.09-1.41]) adjusted for age, body mass index, education, smoking, health status, diabetes, and stroke. These associations were partially explained by the mediating variable of physical function., Conclusion: RHOA was associated with an increased risk of all-cause and CVD mortality among older white women followed up for 16 years. Dissemination of evidence-based physical activity and self-management interventions for hip OA in community and clinical settings can improve physical function and might also contribute to lower mortality., (© 2015, American College of Rheumatology.)

While accentuated kyphosis is associated with osteoporosis, it is unknown whether it increases risk of future fractures, independent of bone mineral density (BMD) and vertebral fractures. We examined the associations of baseline Cobb angle kyphosis and 15 year change in kyphosis with incident non-spine fractures using data from the Study of Osteoporotic Fractures. A total of 994 predominantly white women, aged 65 or older, were randomly sampled from 9704 original participants to have repeated Cobb angle measurements of kyphosis measured from lateral spine radiographs at baseline and an average of 15 years later. Non-spine fractures, confirmed by radiographic report, were assessed every 4 months for up to 21.3 years. Compared with women in the lower three quartiles of kyphosis, women with kyphosis greater than 53° (top quartile) had a 50% increased risk of non-spine fracture (95% CI, 1.10-2.06 after adjusting for BMD, prevalent vertebral fractures, prior history of fractures, and other fracture risk factors. Cobb angle kyphosis progressed an average of 7° (SD = 6.8) over 15 years. Per 1 SD increase in kyphosis change, there was a multivariable adjusted 28% increased risk of fracture (95% CI, 1.06-1.55) that was attenuated by further adjustment for baseline BMD (HR per SD increase in kyphosis change, 1.19; 95% CI 0.99-1.44). Greater kyphosis is associated with an elevated non-spine fracture risk independent of traditional fracture risk factors in older women. Furthermore, worsening kyphosis is also associated with increased fracture risk that is partially mediated by low baseline BMD that itself is a risk factor for kyphosis progression. These results suggest that randomized controlled fracture intervention trials should consider implementing kyphosis measures to the following: (1) further study kyphosis and kyphosis change as an additional fracture risk factor; and (2) test whether therapies may improve or delay its progression., (© 2014 American Society for Bone and Mineral Research.)

Hip fractures are the most devastating consequence of osteoporosis and impact 1 in 6 white women leading to a two- to threefold increased mortality risk in the first year. Despite evidence of inflammatory markers in the pathogenesis of osteoporosis, few studies have examined their effect on hip fracture. To determine if high levels of inflammation increase hip fracture risk and to explore mediation pathways, a case-cohort design nested in a cohort of 4709 white women from the Study of Osteoporotic Fractures was used. A random sample of 1171 women was selected as the subcohort (mean age 80.1 ± 4.2 years) plus the first 300 women with incident hip fracture. Inflammatory markers interleukin-6 (IL-6) and soluble receptors (SR) for IL-6 (IL-6 SR) and tumor necrosis factor (TNF SR1 and TNF SR2) were measured, and participants were followed for a median (interquartile range) of 6.3 (3.7, 6.9) years. In multivariable models, the hazard ratio (HR) of hip fracture for women in the highest inflammatory marker level (quartile 4) was 1.64 (95% confidence interval [CI], 1.09-2.48, p trend = 0.03) for IL-6 and 2.05 (95% CI, 1.35-3.12, p trend <0.01) for TNF SR1 when compared with women in the lowest level (quartile 1). Among women with 2 and 3-4 inflammatory markers in the highest quartile, the HR of hip fracture was 1.51 (95% CI, 1.07-2.14) and 1.42 (95% CI, 0.87-2.31) compared with women with zero to one marker(s) in the highest quartile (p trend = 0.03). After individually adjusting for seven potential mediators, cystatin-C (a biomarker of renal function) and bone mineral density (BMD) attenuated HRs among women with the highest inflammatory burden by 64% and 50%, respectively, suggesting a potential mediating role. Older white women with high inflammatory burden are at increased risk of hip fracture in part due to poor renal function and low BMD., (© 2014 American Society for Bone and Mineral Research.)

Uric acid (UA) is produced from purines by the enzyme xanthine oxidase, and elevated levels may cause arthritis and kidney stones. Conversely, UA also appears to function as an antioxidant and may protect against the oxidative stress associated with aging and disease. We performed a prospective fracture case-cohort study to understand the relation of UA and fracture risk in older men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men aged 65 years and older attending the baseline MrOS examination, we evaluated a subgroup 1680 men in a case-cohort study design. The analytic group included 387 men with incident nonspine fractures (73 hip) and a random sample of 1383. Serum UA was measured in baseline serum samples. Modified proportional hazards models that account for case-cohort study design were used to estimate the relative hazards (RH) of hip and nonspine fracture in men for serum UA. Models were adjusted for age, race, clinic site, body mass index, vitamin D, parathyroid hormone, walking speed, Physical Activity Scale for the Elderly (PASE) score, frailty, and total. Subjects with incident nonspine fractures were older, had lower total hip bone mineral density (BMD), and higher serum phosphorus. There was an 18% decreased risk of nonspine fractures (95% confidence interval [CI] 0.71-0.93; p = 0.003) per 1 SD increase of baseline serum and 34% decreased risk of nonspine fractures in quartile 4 of UA versus quartiles 1, 2, and 3 (95% CI 0.49-0.89; p = 0.028) compared with nonfracture cases after multivariate adjustment. Hip fractures were not significantly associated with UA. Total hip BMD was significantly higher in the group of men with high UA levels compared with lower UA levels and increased linearly across quartiles of UA after multivariate adjustment (p for trend = 0.002). In summary, higher serum UA levels were associated with a reduction in risk of incident nonspine fractures but not hip fractures and higher hip BMD., (© 2014 American Society for Bone and Mineral Research.)

In rodent models, undercarboxylated osteocalcin (ucOC) acts as a hormone that promotes insulin sensitivity and secretion. If ucOC plays a similar role in humans, then antiresorptive therapies, which reduce ucOC levels, may increase the risk of insulin resistance and diabetes. We tested whether antiresorptive therapies result in higher fasting glucose, increased weight, or greater diabetes incidence in post hoc analyses of three randomized, placebo-controlled trials in postmenopausal women: Fracture Intervention Trial (FIT) (N = 6151) of alendronate (4 years), Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N = 7113) of zoledronic acid (3 years), and Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (N = 7076) of denosumab (3 years). Fasting glucose was measured annually in FIT and HORIZON in a subset of women, and every 6 months in FREEDOM in all participants. Weight was measured annually in all trials. Incident diabetes was identified from adverse event reports, initiation of diabetes medication, or elevated fasting glucose. Differences in fasting glucose changes from randomization to trial conclusion between treatment and placebo groups were not statistically significant: -0.47 mg/dL in FIT, 0.20 mg/dL in HORIZON-PFT, and 0.09 mg/dL in FREEDOM, all p > 0.6. Weight change differed between treatment and placebo groups in FIT (0.32 kg, p = 0.003) and FREEDOM (0.31 kg, p = 0.023) but not in HORIZON-PFT (0.15 kg, p = 0.132). In the three trials combined, diabetes occurred in 203 and 225 women assigned to treatment or placebo, respectively. Diabetes incidence was not increased in any of the treatment groups or in the pooled estimate (pooled relative risk [RR] = 0.90; 95% confidence interval [CI] 0.74-1.10). Antiresorptive therapy does not have a clinically important effect on fasting glucose, weight, or diabetes risk in postmenopausal women. Contrary to predictions from mouse models, reduced bone turnover does not appear to play a significant role in glucose metabolism in humans., (Copyright © 2013 American Society for Bone and Mineral Research.)

Recent studies indicate that obesity is not protective against fracture in postmenopausal women and increases the risk of fracture at some sites. Risk factors for fracture in obese women may differ from those in the nonobese. We aimed to compare the ability of FRAX with and without bone mineral density (BMD) to predict fractures in obese and nonobese older postmenopausal women who were participants in the Study of Osteoporotic Fractures. Data for FRAX clinical risk factors and femoral neck BMD were available in 6049 women, of whom 18.5% were obese. Hip fractures, major osteoporotic fractures, and any clinical fractures were ascertained during a mean follow-up period of 9.03 years. Receiving operator curve (ROC) analysis, model calibration, and decision curve analysis were used to compare fracture prediction in obese and nonobese women. ROC analysis revealed no significant differences between obese and nonobese women in fracture prediction by FRAX, with or without BMD. Predicted hip fracture risk was lower than observed risk in both groups of women, particularly when FRAX + BMD was used, but there was good calibration for FRAX + BMD in prediction of major osteoporotic fracture in both groups. Decision curve analysis demonstrated that both FRAX models were useful for hip fracture prediction in obese and nonobese women for threshold 10-year fracture probabilities in the range of 4% to 10%, although in obese women FRAX + BMD was superior to FRAX alone. For major osteoporotic fracture, both FRAX models were useful in both groups of women for threshold probabilities in the range of 10% to 30%. For all clinical fractures, the FRAX models were not useful at threshold probabilities below 30%. We conclude that FRAX is of value in predicting hip and major osteoporotic fractures in obese postmenopausal women, particularly when used with BMD., (Copyright © 2013 American Society for Bone and Mineral Research.)

Objective: To evaluate sleep quality in women with hip pain due to daily activities involving the lower extremity joints., Methods: We evaluated the association of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) hip pain severity score with objective sleep measures obtained by wrist actigraphy in 2,225 white women ≥ 65 years of age enrolled in the Study of Osteoporotic Fractures., Results: Women had an increased odds of spending ≥ 90 minutes awake after sleep onset (odds ratio [OR] 1.28, 95% confidence interval [95% CI] 1.11-1.50) for every 5-point increase in hip pain score after adjustment for all covariates. Hip pain when sitting or lying was the strongest predictor of sleep fragmentation (OR 2.0, 95% CI 1.47-2.73); however, standing pain was associated with a higher number of awake minutes in bed scored from sleep onset to the end of the last sleep episode, independent of pain while in bed (OR 1.41, 95% CI 1.07-2.01). Sleep disturbances increased significantly after the first 2 hours of sleep in women with severe hip pain compared to those without hip pain (mean ± SD 1.4 ± 0.47 minutes per hour of sleep; P < 0.003). Similar associations were observed for long wake episodes >5 minutes. There were no associations between daytime napping, sleep latency, sleep efficiency, and total sleep minutes and WOMAC hip pain., Conclusion: Fragmented sleep was greater in women with hip pain compared to those without hip pain; however, fragmented sleep in women with severe hip pain compared to those without hip pain was unchanged until after the first 2 hours of sleep. Further investigations into pain medications wearing off over time or the prolonged periods of inactivity decreasing the pain threshold are warranted., (Copyright © 2012 by the American College of Rheumatology.)

Context: Sclerostin, a protein secreted by osteocytes, inhibits bone formation. Individuals with genetic mutations that decrease the availability of sclerostin have very high bone mass., Objective: The aim of this study was to examine the hypothesis that elevated serum sclerostin levels are associated with increased risk of hip fracture in older women., Design, Setting, and Participants: This was a case-cohort study of a prospective, community-based cohort of 9704 women aged 65 yr or older. Sclerostin levels were measured in serum collected in 1989-1990 in 228 women with incident hip fractures and 227 women in a randomly selected sample; average follow-up time was 9.8 yr., Results: Serum sclerostin levels were correlated with total hip bone mineral density (BMD; r = 0.27, P < 0.001). The risk of hip fracture increased across quartiles of serum sclerostin (test for trend, P < 0.001) and was significantly elevated among those in the fourth quartile (hazard risk 3.4, 95% confidence interval 1.7-7.0) compared with women in the lowest quartile, after adjusting for age, body mass index, estrogen use, history of fracture since age 50 yr, and total hip BMD. When dividing the cohort into eight groups by sclerostin quartile and median hip BMD, women with lower total hip BMD in the highest sclerostin quartile had a 22.3-fold (95% confidence interval 5.8-86.3) increased risk of fracture compared with women with higher total hip BMD in the lowest sclerostin quartile., Conclusions: We conclude that higher serum sclerostin levels are associated with a greater risk of hip fractures in older women. In addition, the risk of hip fracture is amplified when high sclerostin levels are combined with lower BMD.

We examined if height loss in older women predicts risk of hip fractures, other nonspine fractures, and mortality, and whether this risk is independent of both vertebral fractures (VFx) and bone mineral density (BMD) by dual-energy X-ray absorptiometry. Among 3124 women age 65 and older in the Study of Osteoporotic Fractures, we assessed the association with measured height change between year 0 (1986-1988) and year 15 (2002-2004) and subsequent risk of radiologically confirmed hip fractures, other nonspine fractures, and mortality assessed via death certificates. Follow-up occurred every 4 months for fractures and vital status (>95% contacts complete). Cox proportional hazards models assessed risk of hip fracture, nonspine fracture, and mortality over a mean of 5 years after height change was assessed (ie, after final height measurement). After adjustment for VFx, BMD, and other potential covariates, height loss >5 cm was associated with a marked increased risk of hip fracture [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.06, 2.12], nonspine fracture (HR 1.48; 95% CI 1.20, 1.83), and mortality (1.45; 95% CI 1.21, 1.73). Although primary analyses were a subset of 3124 survivors healthy enough to return for a year 15 height measurement, a sensitivity analysis in the entire cohort (n = 9677) using initial height in earlier adulthood [self-reported height at age 25 (-40 years) to measured height age >65 years (Year 0)] demonstrated consistent results. Height loss >5 cm (2″) in older women was associated with a nearly 50% increased risk of hip fracture, nonspine fracture, and mortality-independent of incident VFx and BMD., (Copyright © 2012 American Society for Bone and Mineral Research.)

Background: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood., Methods: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies., Results: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer., Conclusion: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Bone mineral density (BMD) is a strong predictor of fracture, yet most fractures occur in women without osteoporosis by BMD criteria. To improve fracture risk prediction, the World Health Organization recently developed a country-specific fracture risk index of clinical risk factors (FRAX) that estimates 10-year probabilities of hip and major osteoporotic fracture. Within differing baseline BMD categories, we evaluated 6252 women aged 65 or older in the Study of Osteoporotic Fractures using FRAX 10-year probabilities of hip and major osteoporotic fracture (ie, hip, clinical spine, wrist, and humerus) compared with incidence of fractures over 10 years of follow-up. Overall ability of FRAX to predict fracture risk based on initial BMD T-score categories (normal, low bone mass, and osteoporosis) was evaluated with receiver-operating-characteristic (ROC) analyses using area under the curve (AUC). Over 10 years of follow-up, 368 women incurred a hip fracture, and 1011 a major osteoporotic fracture. Women with low bone mass represented the majority (n = 3791, 61%); they developed many hip (n = 176, 48%) and major osteoporotic fractures (n = 569, 56%). Among women with normal and low bone mass, FRAX (including BMD) was an overall better predictor of hip fracture risk (AUC = 0.78 and 0.70, respectively) than major osteoporotic fractures (AUC = 0.64 and 0.62). Simpler models (eg, age + prior fracture) had similar AUCs to FRAX, including among women for whom primary prevention is sought (no prior fracture or osteoporosis by BMD). The FRAX and simpler models predict 10-year risk of incident hip and major osteoporotic fractures in older US women with normal or low bone mass., (Copyright © 2011 American Society for Bone and Mineral Research.)

The mechanism whereby poor intrauterine growth increases risk of adult hip fracture is unclear. We report the association between birth weight and proximal femoral geometry and density in community-dwelling elderly men. We used self-reported birth weight, measured adult height and weight and proximal femoral quantitative computed tomography (QCT) measurements of femoral neck axis length, cross-sectional area, and volumetric BMD (vBMD) among the participants in the Osteoporotic Fractures in Men (MrOS), a cohort study of community-dwelling US men aged 65 and older. We compared men with birth weight <7 pounds (lower birth weight [LBW]; n = 501) and ≥ 9 pounds (higher birth weight [HBW]; n = 262) with those weighing 7-8.9 pounds (medium birth weight [MBW], referent group; n = 1068) using linear regression adjusting for current age, height, and BMI. The mean age of the 1831 men who had both birth weight and QCT measurements was 73 years (SD 5.9). Compared with the referent MBW, HBW men had concordantly longer femoral neck (+0.16 SD; p = .028) and cross-sectional area (+0.24 SD, p = .001). LBW men had a smaller cross-sectional (-0.26 SD, p < .001) but longer femoral neck for their height (+0.11 SD, p = .05). Neither cortical nor trabecular vBMD at the femoral neck was associated with birth weight. These findings support the hypothesis that the skeletal envelope, but not density, is set, in part, at birth. Further research exploring the association between early developmental factors and lifetime fracture risk is needed and may inform primary preventative strategies for fracture prevention., (Copyright © 2011 American Society for Bone and Mineral Research.)

Fracture prediction models help to identify individuals at high risk who may benefit from treatment. Area under the curve (AUC) is used to compare prediction models. However, the AUC has limitations and may miss important differences between models. Novel reclassification methods quantify how accurately models classify patients who benefit from treatment and the proportion of patients above/below treatment thresholds. We applied two reclassification methods, using the National Osteoporosis Foundation (NOF) treatment thresholds, to compare two risk models: femoral neck bone mineral density (BMD) and age (simple model) and FRAX (FRAX model). The Pepe method classifies based on case/noncase status and examines the proportion of each above and below thresholds. The Cook method examines fracture rates above and below thresholds. We applied these to the Study of Osteoporotic Fractures (SOF). There were 6036 (1037 fractures) and 6232 (389 fractures) participants with complete data for major osteoporotic and hip fracture, respectively. Both models for major osteoporotic fracture (0.68 versus 0.69) and hip fracture (0.75 versus 0.76) had similar AUCs. In contrast, using reclassification methods, each model classified a substantial number of women differently. Using the Pepe method, the FRAX model (versus the simple model) missed treating 70 (7%) cases of major osteoporotic fracture but avoided treating 285 (6%) noncases. For hip fracture, the FRAX model missed treating 31 (8%) cases but avoided treating 1026 (18%) noncases. The Cook method (both models, both fracture outcomes) had similar fracture rates above/below the treatment thresholds. Compared with the AUC, new methods provide more detailed information about how models classify patients., (Copyright © 2011 American Society for Bone and Mineral Research.)

The new US National Osteoporosis Foundation's (NOF's) Clinician's Guide to Prevention and Treatment of Osteoporosis includes criteria for recommending pharmacologic treatment based on history of hip or vertebral fracture, femoral neck or spine bone mineral density (BMD) T-scores of -2.5 or less, and presence of low bone mass at the femoral neck or spine plus a 10-year risk of hip fracture of 3% or greater or of major osteoporotic fracture of 20% or greater. The proportion of men who would be recommended for treatment by these guidelines is not known. We applied the NOF criteria for treatment to men participating in the Osteoporotic Fractures in Men Study (MrOS). To determine how the MrOS population differs from the general US population of Caucasian men aged 65 years and older, we compared men in MrOS with men who participated in the National Health and Nutrition Examination Survey (NHANES) III on criteria included in the NOF treatment guidelines that were common to both cohorts. Compared with NHANES III, men in MrOS had higher femoral neck BMD values. Application of NOF guidelines to MrOS data estimated that at least 34% of US white men aged 65 years and older and 49% of those aged 75 years and older would be recommended for drug treatment. Application of the new NOF guidelines would result in recommending a very large proportion of white men in the United States for pharmacologic treatment of osteoporosis, for many of whom the efficacy of treatment is unknown., (2010 American Society for Bone and Mineral Research.)