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Some osteoporosis drug trials have suggested that treatment is more effective in those with low BMD measured by DXA. This study used data from a large set of randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We used individual patient data from 25 RCTs (103 086 subjects) of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. Participants were stratified into FN BMD T-score subgroups (≤-2.5, > -2.5). We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes and logistic regression for the radiographic vertebral fracture outcome. We also performed analyses based on BMD quintiles. Overall, 42% had a FN BMD T-score ≤ -2.5. Treatment with anti-osteoporosis drugs led to significant reductions in fractures in both T-score ≤ -2.5 and > -2.5 subgroups. Compared to those with FN BMD T-score > -2.5, the risk reduction for each fracture outcome was greater in those with T-score ≤ -2.5, but only the all-fracture outcome reached statistical significance (interaction P = .001). Results were similar when limited to bisphosphonate trials. In the quintile analysis, there was significant anti-fracture efficacy across all quintiles for vertebral fractures and with greater effects on fracture risk reduction for non-vertebral, all, and all clinical fractures in the lower BMD quintiles (all interaction P ≤ .03). In summary, anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD. Significant fracture risk reduction with treatment for 4 of the 5 fracture endpoints was seen in participants with T-scores above -2.5, though effects tended to be larger and more significant in those with baseline T-scores

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

There is a common belief that antiosteoporosis medications are less effective in older adults. This study used data from randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments and their effects on BMD differ in people ≥70 compared to those

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 (ATPmax) 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 ATPmax. 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.

ObjectiveMost guidelines recommending weight loss for hip osteoarthritis are based on research on knee osteoarthritis. Prior studies found no association between weight loss and hip osteoarthritis, but no previous studies have targeted older adults. Therefore, we aimed to determine whether there is any clear benefit of weight loss for radiographic hip osteoarthritis in older adults because weight loss is associated with health risks in older adults.MethodsWe used data from white female participants aged ≥65 years from the Study of Osteoporotic Fractures. Our exposure of interest was weight change from baseline to follow-up at 8 years. Our outcomes were the development of radiographic hip osteoarthritis (RHOA) and the progression of RHOA over 8 years. Generalized estimating equations (clustering of 2 hips per participant) were used to investigate the association between exposure and outcomes adjusted for major covariates.ResultsThere was a total of 11,018 hips from 5509 participants. There was no associated benefit of weight loss for either of our outcomes. The odds ratios (95% confidence intervals) for the development and progression of RHOA were 0.99 (0.92-1.07) and 0.97 (0.86-1.09) for each 5% weight loss, respectively. The results were consistent in sensitivity analyses where participants were limited to those who reported trying to lose weight and who also had a body mass index in the overweight or obese range.ConclusionOur findings suggest no associated benefit of weight loss in older female adults in the structure of the hip joint as assessed by radiography.

Rationale and objectivesSpinal 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 methodsWe 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).ResultsOur 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%.ConclusionOur 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.

Rationale and objectivesOsteoporosis 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 methodsThe 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.ResultsOur model yielded a sensitivity of 59.8%, a PPV of 91.2%, and an F1 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.ConclusionOur 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.

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).

ContextWhether repeated bone mineral density (BMD) screening improves fracture prediction in men is uncertain.ObjectiveWe evaluated whether a second BMD 7 years after the initial BMD improves fracture prediction in older men.MethodsAmong 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).ResultsDuring 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).ConclusionRepeating BMD after 7 years did not meaningfully improve fracture prediction at the population level in community-dwelling older men.

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).

Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m2 ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m2 ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.

BackgroundCardiac fat is emerging as an important parameter for cardiovascular risk stratification. Accurate and reproducible volumetric measurements can facilitate in the serial assessment of cardiac fat by computed tomography (CT). We assessed the intra- and inter-observer variability of cardiac fat volumetric measurements using a semi-automated CT software.MethodsWe used non-contrast coronary calcium CT scans to quantify epicardial and intra-thoracic fat volumes. Two expert readers analyzed baseline and follow up CT scans of 45 subjects by using a semi-automated CT software (QFAT 2.0, Cedars Sinai-Medical Center). Correlation and Bland-Altman analysis was performed for both intra- and inter-observer comparisons for each cardiac fat type.ResultsThe intra-observer correlation coefficients ranged between 0.86 to 0.99 and 0.87 to 0.99 for epicardial (median fat per reader (cm3) 20.9 to 25.7) and intra-thoracic (median fat per reader (cm3) 27.1 to 31.6) fat volumes respectively, with no significant differences between individual data points (all p > 0.38). The inter-observer correlation coefficient was 0.99 (p

ObjectivesThere is growing evidence that urine cadmium is a temporally stable biomarker indicative of long-term cadmium exposure; however questions remain with regard to generalizability to older persons, the impact of changes in smoking behavior, and the degree of temporal stability when repeat sample collection spans years instead of weeks or months.MethodsUsing archived samples from cohorts of older men (Osteoporotic Fractures in Men (MrOS-US)) and women (Study of Osteoporotic Fractures (SOF)) (mean age = 80 at study visit 2), we analyzed two morning urine samples each from 39 men and 18 women with a diverse self-reported smoking history. For MrOS, samples were collected approximately 6 years apart, and 4 years apart for SOF. Intra-class correlations were computed to assess temporal stability, and adjusted for age and body mass index.ResultsThe median creatinine-adjusted urinary cadmium levels (0.39 μg/g for men, 0.89 μg/g for women) were similar to levels expected for these age/sex groups in the US according to the National Health and Nutrition Examination Survey. The overall intra-class correlation was high (ICC = 0.85; 95% CI: 0.76-0.91) and similar between cohorts (MrOS: ICC = 0.74; 95% CI: 0.58-0.86; SOF: ICC = 0.81; 95% CI: 0.59-0.93), but slightly lower among those who stopped smoking between visits of sample collection (ICC = 0.64; 95% CI: 0.31-0.87) or among former smokers who quit prior to the first sample collection (ICC = 0.68; 95% CI: 0.25-0.93).ConclusionsWe report good-to-excellent reproducibility of urine cadmium using morning urine samples collected 4-6 years apart from older men and women, but slightly lower correlations among those with a history of smoking. Single measures of urine cadmium are a reliable biomarker in older men and women.

ObjectivesTo determine the association between cumulative burden of depressive symptoms and risk of nursing home (NH) placement over 2 decades.DesignProspective cohort study with data linked to Medicare claims files.SettingClinic sites in Baltimore, Maryland; Minneapolis, Minnesota; and the Monongahela Valley near Pittsburgh, Pennsylvania.ParticipantsInitially community-dwelling women aged 65 and older (N=3,646).MeasurementsDepressive symptom burden was determined using the Geriatric Depression Scale measured over 18 years to calculate accumulation of burden. NH placement was determined using Medicare claims data.ResultsIn Fine-Gray proportional hazards analyses including demographic characteristics, medical comorbidities, functional impairment, and recent depression exposure and accounting for competing risk of death, women with low depressive symptom burden were twice as likely to experience NH placement as those with minimal burden (hazard ratio (HR) = 1.92, 95% confidence interval (CI) = 1.16-3.20), women with moderate burden were more than twice as likely (HR = 2.62, 95% CI = 1.59-4.31), and women with high burden (HR = 3.08, 95% CI = 1.87-5.08) were three times as likely. The addition of antidepressant use to this model attenuated the risk only slightly.ConclusionIn older women, cumulative burden of depressive symptoms over nearly 2 decades is associated with greater risk of transitioning from community-living to a NH irrespective of recent depression exposure, medical comorbidities, functional impairment, and the competing risk of death. This work supports the need for improving recognition, monitoring, and treatment of depressive symptoms early, which may reduce or delay NH placement.

BackgroundThis study examines effects of mobility and multimorbidity on hospitalization and inpatient and postacute care (PAC) facility days among older men.MethodsProspective study of 1,701 men (mean age 79.3 years) participating in Osteoporotic Fractures in Men (MrOS) Study Year 7 (Y7) examination (2007-2008) linked with their Medicare claims. At Y7, mobility ascertained by usual gait speed and categorized as poor, intermediate, or good. Multimorbidity quantified by applying Elixhauser algorithm to inpatient and outpatient claims and categorized as none, mild-moderate, or high. Hospitalizations and PAC facility stays ascertained during 12 months following Y7.ResultsReduced mobility and greater multimorbidity burden were independently associated with a higher risk of inpatient and PAC facility utilization, after accounting for each other and traditional indicators. Adjusted mean total facility days per year were 1.13 (95% confidence interval [CI] = 0.74-1.40) among men with good mobility increasing to 2.43 (95% CI = 1.17-3.84) among men with poor mobility, and 0.67 (95% CI = 0.38-0.91) among men without multimorbidity increasing to 2.70 (95% CI = 1.58-3.77) among men with high multimorbidity. Men with poor mobility and high multimorbidity had a ninefold increase in mean total facility days per year (5.50, 95% CI = 2.78-10.87) compared with men with good mobility without multimorbidity (0.59, 95% CI = 0.37-0.95).ConclusionsAmong older men, mobility limitations and multimorbidity were independent predictors of higher inpatient and PAC utilization after considering each other and conventional predictors. Marked combined effects of reduced mobility and multimorbidity burden may be important to consider in clinical decision-making and planning health care delivery strategies for the growing aged population.

ObjectiveSeveral cross-sectional studies have reported an association between visual contrast sensitivity (a functional measure of low contrast vision) and poor cognitive performance or dementia, but no studies have investigated this association prospectively in a population-based cohort with final adjudication of mild cognitive impairment (MCI)/dementia.MethodsIn a prospective, community-based study of aging women (Study of Osteoporotic Fractures), we analyzed whether visual contrast sensitivity was associated with increased risk of MCI or dementia and/or worse performance on various cognitive tests assessed 10 years later. Contrast sensitivity was assessed at baseline in each eye using a VISTECH VCTS 6500 wall chart. MCI/dementia was adjudicated by an expert panel. Multivariate logistic and linear regression models were analyzed.ResultsOf 1,352 white (88.2%) and African American (11.8%) women with a mean age of 77.7 years (standard deviation = 3.3), 536 (39.6%) went on to develop MCI/dementia over 10 years. MCI/dementia risk was more than doubled (odds ratio = 2.16, 95% confidence interval = 1.58-2.96) in women with the lowest quartile of contrast sensitivity compared to the highest (p

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 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.

Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12 , B6 , 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 Womens 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 B6 (50 mg/day), and vitamin B12 (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 B12 or B6 , 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.

Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12 , B6 , 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 B6 (50 mg/day), and vitamin B12 (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 B12 or B6 , 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.

BackgroundThe association between various definitions of sarcopenia and hospitalization has not been evaluated in community-dwelling older men.MethodsWe used data from 1,516 participants at Visit 3 of the Osteoporotic Fractures in Men (MrOS) study who also had linked Medicare Fee-For-Service Claims data available. We examined the association between several sarcopenia definitions (International Working Group, European Working Group for Sarcopenia in Older Persons, Foundation for the NIH Sarcopenia Project, Baumgartner, and Newman) and hospitalization, using two-part ("hurdle") models, adjusted for age, clinical center, functional limitations, self-reported health, comorbidity, and cognitive function. Predictors included sarcopenia status (the summary definitions and the components of slowness, weakness, and/or lean mass); outcomes included hospitalization and cumulative inpatient days/year in the 3 years following the Visit 3 exam.ResultsAfter accounting for confounding factors, none of the summary definitions or the definition components (slowness, weakness, or low lean mass) were associated with likelihood of hospitalization, the rate ratio of inpatient days among those hospitalized, or the mean rate of inpatient days amongst all participants.ConclusionsSarcopenia was not associated hospitalization in community-dwelling older men. These results provide further evidence that current sarcopenia definitions are unlikely to identify those who are most likely to have greater hospitalization.

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/cm2); expected loss (n = 2768; change between 0 g/cm2 and -0.034 g/cm2]); and accelerated loss (n = 545; change 1 SD below mean change or worse [≤-0.034 g/cm2]). 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.

BackgroundAutonomic dysfunction contributes to atrial fibrillation (AF).ObjectiveWe 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).Methods2350 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.ResultsLower 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).ConclusionsSleep-related reduced sympathovagal balance (LF/HF) and increased atrial ectopy are independently associated with future AF; a relationship modified by obstructive apnea.

Determine the associations of sleep disturbances with hospitalization risk among older women. One thousand eight hundred and twenty-seven women (mean age 83.6 years) participating in Study of Osteoporotic Fractures Year 16 (Y16) examination (2002-2004) linked with Medicare and/or HMO claims. At Y16 examination, sleep/wake parameters were measured by actigraphy (total sleep time [TST], sleep efficiency [SE], sleep latency [SL], and wake after sleep onset [WASO]) and subjective sleep measures (sleep quality [Pittsburgh Sleep Quality Index] and daytime sleepiness [Epworth Sleepiness Scale]) were assessed by questionnaire. Measures except TST were dichotomized based on clinical thresholds. Incident hospitalizations were determined from claims data. Nine hundred and seventy-six women (53%) had ≥1 hospitalization in the 3 years after the Year 16 examination. Reduced SE (odds ratio [OR] = 2.39, 95% confidence interval [CI] 1.69-3.39), prolonged SL (OR = 1.41, 95% CI 1.11-1.78), greater WASO (OR = 1.57, 95% CI 1.28-1.93), shorter TST (OR = 1.98, 95% CI 1.42-2.77) and poorer sleep quality (OR = 1.33, 95% CI 1.07-1.65) were each associated with a higher age and site-adjusted odds of hospitalization; associations were attenuated after multivariable adjustment for traditional prognostic factors with the OR for reduced SE (OR = 1.60, 95% CI 1.08-2.38) and shorter TST (OR = 1.63, 95% CI 1.12-2.37) remaining significant. Among women who were hospitalized, greater WASO (rate ratio [RR] = 1.20, 95% CI 1.04-1.37) and poorer sleep quality (RR = 1.18, 95% CI 1.02-1.35) were each associated with a greater age and site-adjusted RR of inpatient days, but associations did not persist after multivariate adjustment. Older women with sleep disturbances have an increased risk of hospitalization partially attributable to demographics, poorer health status, and comorbidities.

BackgroundThis study examines effects of mobility and cognition on hospitalization and inpatient days among women late in life.MethodsProspective study of 663 women (mean age 87.7 years) participating in the Study of Osteoporotic Fractures Year 20 examination (2006-2008) linked with their inpatient claims data. At Year 20, mobility ascertained by Short Physical Performance Battery categorized as poor, intermediate, or good. Cognitive status adjudicated based on neuropsychological tests and classified as normal, mild cognitive impairment, or dementia. Hospitalizations (n = 182) during 12 months following Year 20.ResultsReduced mobility and poorer cognition were each associated in a graded manner with higher inpatient health care utilization, even after accounting for each other and traditional prognostic indicators. For example, adjusted mean inpatient days per year were 0.94 (95% confidence interval [CI] 0.52-1.45) among women with good mobility increasing to 2.80 (95% CI 1.64-3.89) among women with poor mobility and 1.59 (95% CI 1.08-2.03) among women with normal cognition increasing to 2.53 (95% CI 1.55-3.40) among women with dementia. Women with poor mobility/dementia had a nearly sixfold increase in mean inpatient days per year (4.83, 95% CI 2.73-8.54) compared with women with good mobility/normal cognition (0.84, 95% CI 0.49-1.44).ConclusionsAmong women late in life, mobility limitations and cognitive deficits were each independent predictors of higher inpatient health care utilization even after considering each other and conventional predictors. Additive effects of reduced mobility and poorer cognition may be important to consider in medical decision making and health care policy planning for the growing population of adults aged ≥85 years.

BackgroundAlthough there are several consensus definitions of sarcopenia, their association with health care utilization has not been studied.MethodsWe included women from the prospective Study of Osteoporotic Fractures with complete assessment of sarcopenia by several definitions at the Study of Osteoporotic Fractures Year 10 (Y10) exam (1997-1998) who also had available data from Medicare Fee- For-Service Claims (N = 566) or Kaiser Encounter data (N = 194). Sarcopenia definitions evaluated were: International Working Group, European Working Group for Sarcopenia in Older Persons, Foundation for the NIH Sarcopenia Project, Baumgartner, and Newman. Hurdle models and logistic regression were used to assess the relation between sarcopenia status (the summary definition and the components of slowness, weakness and/or lean mass) and outcomes that included hospitalizations, cumulative inpatient days/year, short-term (part A paid) skilled nursing facility stay in the 3 years following the Y10 visit.ResultsNone of the consensus definitions, nor the definition components of weakness or low lean mass, was associated with increased risk of hospitalization or greater likelihood of short-term skilled nursing facility stay. Women with slowness by any criterion definition were about 50% more likely to be hospitalized; had a greater rate of hospitalization days amongst those hospitalized; and had 1.8 to 2.1 times greater likelihood of a short-term skilled nursing facility stay than women without slowness. There was the suggestion of a protective association of low lean mass by the various criterion definitions on short-term skilled nursing facility stay.ConclusionEstimated effects of sarcopenia on health care utilization were negligible. However, slowness was associated with greater health care utilization.

BackgroundPrior studies have only considered one measurement of physical performance in its relationship to fractures and mortality. A single measurement is susceptible to large within-person changes over time, and thus, may not capture the true association between physical performance and the outcomes of interest.MethodsUsing data from the Study of Osteoporotic Fractures, we followed 7,015 women enrolled prior to age 80 years who had outcome information beyond this age. Trajectories of walking speed (m/s) and chair stand speed (stands/s) were estimated up to the last visit prior to age 80 years using mixed-effects linear regression. Physical performance at age 80 (PF_age80) was assessed at the last visit prior to age 80 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression and multivariate models adjusted for all other covariates.ResultsGreatest walking speed decline and chair stand speed decline were both associated with higher risk of hip fracture (HR: 1.28; 95% CI: 1.03, 1.58 and HR: 1.26; 95% CI: 1.03, 1.54, respectively), but not nonspine fractures. Greatest walking speed decline and chair stand speed decline were both associated with a significant 29% (95% CI: 17-42%) and 27% (95% CI: 15-39%) increased risk of mortality, respectively.ConclusionsGreatest declines in walking speed and chair stand speed were both associated with an increased risk of hip fracture and mortality independent of PF_age80 and other important confounders. Both physical performance change and the single physical performance measurement should be considered in the etiology of hip fracture and mortality.

ObjectivesTo evaluate the relationship between life-space mobility (extent, frequency, independence of movement) and mortality in older women.DesignProspective cohort study.SettingFour U.S. clinical sites.ParticipantsWomen (N = 1,498) aged 75 to 102 (mean 87.6) followed from 2006 to 2015.MeasurementsLife-space during the past 4 weeks was assessed in an interview, scored from 0 (daily restriction to bedroom) to 120 (daily trips outside town without assistance), and categorized (0-20, 21-40, 41-60, 61-80, 81-120). All-cause mortality was the primary outcome; noncancer, cardiovascular, cancer, and noncardiovascular noncancer mortality were secondary outcomes.ResultsOver a mean 5.2 years, 842 (56.2%) women died. Unadjusted risk of all-cause mortality was 82.6% in women with the lowest level of life-space (0-20 points) and 36.2% in those with the highest level (81-120 points). In multivariable proportional hazards models, there was a strong relationship between less life-space and greater risk of all-cause mortality (Ptrend < .001). Women with the lowest level of life-space (0-20 points) had a risk of all-cause mortality that was 2.4 times as high (95% confidence interval (CI) = 1.5-4.0) as that of women with the highest level (81-120 points); women with life-space scores between 21 and 60 had a risk of all-cause mortality that was 1.5 times as high as that of women with the highest level. Each standard deviation decrease in life-space was associated with a 1.2 times greater (95% CI = 1.1-1.4) risk of all-cause mortality. Women unable to travel beyond their neighborhood without assistance had a risk of all-cause mortality that was 1.4 times (95% CI = 1.1-1.7) as high as that of women who could travel beyond their neighborhood without assistance. Results were similar for noncancer, cardiovascular, and other mortality and did not change after controlling for underlying disease or living arrangement.ConclusionLife-space scores of 60 or less were associated with mortality in older women independent of other strong risk factors.

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 (VO2 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 VO2 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. [ABSTRACT FROM AUTHOR]

The association between vitamin D status and diabetes risk is inconsistent among observational studies, and most of the available studies have been with women. In the present study we investigated the association between serum 25-hydroxyvitamin D (25(OH)D) levels and incident type 2 diabetes (T2D) in older men (≥65years old) who participated in the multisite Osteoporotic Fractures in Men (MrOS) study enrolled from March 2000 to April 2002. Baseline 25(OH)D levels were available in 1939 subjects without prevalent T2D. Clinical information, body mass index (BMI) and other factors related to T2D were assessed at the baseline visit. Incident diabetes, defined by self-report and medication use, was determined over an average follow-up of 6.4years. At baseline, participants were, on average, 73.3 (±5.7) years old, had a mean BMI in the overweight range (27.2kg/m(2)±3.6) and had total serum 25(OH)D of 26.1ng/ml (±8.3). Incident diabetes was diagnosed in 139 subjects. Cox regression analysis showed a trend toward a protective effect of higher 25(OH)D levels with a lower risk of T2D (HR 0.87, 95% CI: 0.73-1.04 per 1 SD increase of 25(OH)D). After adjusted for BMI and other potential confounders, the relationship between 25(OH)D levels and incident diabetes was further attenuated (HR 1.03, 95% CI 0.85-1.25). No significant difference in the incidence of diabetes emerged after analyzing study subjects according to baseline 25(OH)D quartiles. In conclusion, 25(OH)D levels were not associated with incident T2D in older men.

BackgroundVertebral fractures (VFx) are the most common osteoporotic fracture and are associated with higher risk of impaired function, additional fractures and death. The purpose of this analysis was to test the hypotheses that VFx are also associated with greater inpatient healthcare utilization.MethodsWe studied 4709 Caucasian women enrolled in the Study of Osteoporotic Fractures (SOF) and merged SOF cohort data with Medicare claims or Kaiser encounter data. To be included in this analysis, women had to be enrolled in Medicare Fee for Service or Kaiser as of 1/1/1991 and have radiographic information on VFx status at SOF Visit 3 (1991-92). VFx status was assessed using quantitative morphometry on lateral thoracic and lumbar spine radiographs. Prevalent VFx were defined as any height ratio>3 standard deviations below normal. Women were considered to have a clinical VFx if they reported a new diagnosis of VFx and a clinical radiographic report that confirmed that a VFx was present. Any hospitalization and the number of annualized days of hospitalization were identified through inpatient claims or encounter data. Specific hospitalizations for 5 major common reasons for hospitalizations were also examined.ResultsOver 5-years, 2632 (55.9%) women were hospitalized. In multivariate adjusted models, women with a prevalent radiographic VFx were 21% (95% CI, 2-44%) more likely to be hospitalized for any reason. This association was independent of a number of risk factors including smoking. The annualized rate of inpatient day was, however, similar, 1.67 and 1.48 among women with and without a VFx, respectively, p=0.49. Women with an incident clinical VFx were more likely to be hospitalized including women without evidence of a prevalent radiographic VFx (odds ratio (OR)=5.33; 95% confidence interval (CI)=1.81-15.71) and women with a prevalent radiographic VFx (OR=2.13; 95% CI, 1.05-4.33). Women with a VFx were more likely to be hospitalized specifically for hip fracture or chronic obstructive pulmonary disease (COPD) but not stroke, myocardial infarction or congestive heart failure. The association with COPD was attenuated to non-significance after adjusting for smoking.ConclusionOur results extend the potential public health impact of radiographic and clinical VFx to include an increased risk of any hospitalization.

BackgroundThis study examines the effects of mobility and cognition on mortality risk in women late in life.MethodsA prospective study was conducted among 1,495 women (mean age 87.6 years) participating in the Study of Osteoporotic Fractures Year 20 examination (2006-2008). Mobility (ascertained by Short Physical Performance Battery [SPPB]) was categorized as poor (SPPB 0-3, n = 312), intermediate (SPPB 4-9, n = 799), or good (SPPB 10-12, n = 384). Cognitive status (adjudicated based on neuropsychological tests) was classified as normal (n = 873), mild cognitive impairment (n = 354), or dementia (n = 268). Deaths (n = 749) were identified from Year 20 through July 31, 2014 (average follow-up 4.9 years).ResultsThere was not strong evidence of an interaction between mobility and cognition for prediction of mortality risk (p interaction term .16). Compared to women with good mobility, mortality risks were increased among women with intermediate mobility (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.02-1.57) and those with poor mobility (HR 1.64, 95% CI 1.24-2.16) after consideration of cognition and other mortality risk factors. Similarly, mortality risks were higher among women with mild cognitive impairment (HR 1.46, 95% CI 1.21-1.76) and those with dementia (HR 1.88, 95% CI 1.54-2.31) compared to women with normal cognition after consideration of mobility and other mortality risk factors.ConclusionsAmong women late in life, 5-year mortality risk was substantially increased among women with deficits in mobility even after accounting for cognition and traditional prognostic indicators. Similarly, deficits in cognition were associated with increased 5-year mortality despite consideration of mobility and conventional risk factors.

ObjectiveTo 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.MethodsData 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).ResultsThe 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.ConclusionRHOA 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.

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.

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.

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.

CONTEXT: Despite the frequent occurrence of depressive symptoms among older adults, especially women, little is known about the long-term course of late-life depressive symptoms. OBJECTIVE: To characterize the natural course of depressive symptoms among older women (from the young old to the oldest old) followed up for almost 20 years. DESIGN: Using latent-class growth-curve analysis, we analyzed women enrolled in an ongoing prospective cohort study (1988 through 2009). SETTING: Clinic sites in Baltimore, Maryland; Minneapolis, Minnesota; the Monongahela Valley near Pittsburgh, Pennsylvania; and Portland, Oregon. PARTICIPANTS: We studied 7240 community-dwelling women 65 years or older. MAIN OUTCOME MEASURE: The Geriatric Depression Scale short form (score range, 0-15) was used to routinely assess depressive symptoms during the follow-up period. RESULTS: Among older women, we identified 4 latent classes during 20 years, with the predicted probabilities of group membership totaling 27.8% with minimal depressive symptoms, 54.0% with persistently low depressive symptoms, 14.8% with increasing depressive symptoms, and 3.4% with persistently high depressive symptoms. In an adjusted model for latent class membership, odds ratios (ORs) for belonging in the increasing depressive symptoms and persistently high depressive symptoms classes, respectively, compared with a group having minimal depressive symptoms were substantially and significantly (P < .05) elevated for the following variables: baseline smoking (ORs, 4.69 and 7.97), physical inactivity (ORs, 2.11 and 2.78), small social network (ORs, 3.24 and 6.75), physical impairment (ORs, 8.11 and 16.43), myocardial infarction (ORs, 2.09 and 2.41), diabetes mellitus (ORs, 2.98 and 3.03), and obesity (ORs, 1.86 and 2.90). CONCLUSIONS: During 20 years, almost 20% of older women experienced persistently high depressive symptoms or increasing depressive symptoms. In addition, these women had more comorbidities, physical impairment, and negative lifestyle factors at baseline. These associations support the need for intervention and prevention strategies to reduce depressive symptoms into the oldest-old years.