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Context: Declining muscle strength and performance in older adults are associated with falls, fractures, and premature death., Objective: To determine whether supplementation with vitamin D3 or omega-3 fatty acids vs. placebo for 2 years improves physical performance measures., Design: VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled randomized trial of supplemental vitamin D3 and/or omega-3 fatty acids vs. placebo in the prevention of cancer and cardiovascular disease in 25,871 U.S. adults. This ancillary study was completed in a New England sub-cohort that had in-person evaluations at baseline and 2-year follow-up., Setting: Center for Clinical Investigations in Boston., Participants: 1,054 participants (men ≥50 and women ≥55 years)., Interventions: 2x2 factorial design of supplemental vitamin D3 (cholecalciferol, 2000 IU/day) and/or marine omega-3 fatty acids (1 g/day)., Main Outcome Measures: 2-year changes in physical performance measures of grip strength, walking speed, standing balance, repeated chair stands, and Timed-up and Go (TUG)., Results: At 2 years, all randomized groups showed worsening walking speeds and TUG. There were no differences in changes in grip strength, walking speeds, Short Physical Performance Battery (composite of walking speed, balance, and chair stands), and TUG between the vitamin D3-treated and the placebo-treated groups and between the omega-3-treated and the placebo-treated groups. Effects overall did not vary by sex, age, body mass index, or baseline measures of total or free 25-hydroxyvitamin D (25[OH]D) or plasma n-3 index; TUG slightly worsened with vitamin D supplementation, compared to placebo, in participants with baseline total 25(OH)D levels above the median (p=0.01, p for interaction=0.04)., Conclusions: Neither supplemental vitamin D3 nor marine omega-3 fatty acids for 2 years improved physical performance in this generally healthy adult population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: Serum 25-hydroxyvitamin D (25(OH)D) is the current marker of vitamin D adequacy, but its relationship with bone health has been inconsistent. The ratio of 24,25-dihydroxyvitamin D3 to 25(OH)D3 (vitamin D metabolite ratio or VMR) is a marker of vitamin D that has been associated with longitudinal changes in bone mineral density (BMD) and fracture risk., Objective: High-resolution peripheral quantitative computed tomography (HR-pQCT) provides information on bone health beyond standard dual-energy x-ray absorptiometry, in that it measures volumetric BMD (vBMD) as well bone strength. The relationship of the VMR with vBMD and bone strength remains unknown., Methods: We evaluated the associations of the VMR and 25(OH)D3 with vBMD and bone strength in the distal radius and tibia, assessed by HR-pQCT in 545 older men participating in the Osteoporotic Fractures in Men (MrOS) Study. Primary outcomes were vBMD and estimated failure load (EFL, a marker of bone strength) at the distal radius and tibia., Results: The mean age was 84 ± 4 years, 88.3% were White, and 32% had an estimated glomerular filtration rate <60 mL/min/1.73 m2. In adjusted models, each twofold higher VMR was associated with a 9% (3%, 16%) higher total vBMD and a 13% (5%, 21%) higher EFL at the distal radius. Results were similar at the distal tibia. 25(OH)D3 concentrations were not associated with any of the studied outcomes., Conclusion: Among older men, a higher VMR was associated with greater vBMD and bone strength while 25(OH)D3 was not. The VMR may serve as a valuable marker of skeletal health in older men., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.)

Context: Bariatric surgery results in reduced muscle mass as weight is lost, but postoperative changes in muscle strength and performance are incompletely understood., Objective: To examine changes in body composition, strength, physical activity, and physical performance following Roux-en-Y gastric bypass (RYGB)., Design, Participants, Outcomes: In a prospective cohort of 47 adults (37 women, 10 men) aged 45 ± 12 years (mean ± SD) with body mass index (BMI) 44 ± 8 kg/m2, we measured body composition by dual-energy X-ray absorptiometry, handgrip strength, physical activity, and physical performance (chair stand time, gait speed, 400-m walk time) before and 6 and 12 months after RYGB. Relative strength was calculated as absolute handgrip strength/BMI and as absolute strength/appendicular lean mass (ALM)., Results: Participants experienced substantial 12-month decreases in weight (-37 ± 10 kg or 30% ± 7%), fat mass (-48% ± 12%), and total lean mass (-13% ± 6%). Mean absolute strength declined by 9% ± 17% (P < 0.01). In contrast, relative strength increased by 32% ± 25% (strength/BMI) and 9% ± 20% (strength/ALM) (P < 0.01 for both). There were clinically significant postoperative improvements in all physical performance measures, including mean improvement in gait speed of >0.1 m/s (P < 0.01) and decrease in 400-m walk time of nearly a full minute., Conclusions: In the setting of dramatic weight loss, lean mass and absolute grip strength declined after RYGB. However, relative muscle strength and physical function improved meaningfully and are thus noteworthy positive outcomes of gastric bypass.

Context: Both subclinical thyroid dysfunction and frailty are common among older individuals, but data on the relationship between these 2 conditions are conflicting., Objective: The purpose of this study was to assess the cross-sectional and prospective associations between subclinical thyroid dysfunction and frailty and the 5 frailty subdomains (sarcopenia, weakness, slowness, exhaustion, and low activity)., Setting and Design: The Osteoporotic Fractures in Men Study is a prospective cohort study., Participants: Men older than 65 years (n = 1455) were classified into 3 groups of thyroid status: subclinical hyperthyroidism (n = 26, 1.8%), subclinical hypothyroidism (n = 102, 7.0%), and euthyroidism (n = 1327, 91.2%)., Main Outcome Measures: Frailty was defined using a slightly modified Cardiovascular Health Study Index: men with 3 or more criteria were considered frail, men with 1 to 2 criteria were considered intermediately frail, and men with no criteria were considered robust. We assessed the cross-sectional relationship between baseline thyroid function and the 3 categories of frailty status (robust/intermediate/frail) as well as the prospective association between baseline thyroid function and subsequent frailty status and mortality after a 5-year follow-up., Results: At baseline, compared with euthyroid participants, men with subclinical hyperthyroidism had an increased likelihood of greater frailty status (adjusted odds ratio, 2.48; 95% confidence interval, 1.15-5.34), particularly among men aged <74 years at baseline (odds ratio for frailty, 3.63; 95% confidence interval, 1.21-10.88). After 5 years of follow-up, baseline subclinical hypothyroidism and hyperthyroidism were not consistently associated with overall frailty status or frailty components., Conclusion: Among community-dwelling older men, subclinical hyperthyroidism, but not subclinical hypothyroidism, is associated with increased odds of prevalent but not incident frailty.

Context: Evidence suggests an inverse association between circulating 25(OH) vitamin D and cardiovascular disease (CVD)., Objective: To determine the association between serum 25(OH) vitamin D and risk for CVD events., Setting and Design: From March 2000 to April 2002, participants were recruited for the Osteoporotic Fractures in Men (MrOS) study. Between December 2003 and March 2005, members of the MrOS cohort were invited to participate in the MrOS Sleep Study. Participants were recruited from 6 clinical centers across the United States and followed for a mean of 5.9 years. Three-thousand-one-hundred-thirty-five men ages 65 and older were included from the MrOS cohort, of whom 116 were excluded for missing vitamin D or CVD data. Participants were divided into two groups based on serum 25(OH) vitamin D levels, <20 ng/mL and ≥20 ng/mL. Participants were followed for CVD endpoints including coronary heart disease (CHD) and cerebrovascular events. Age- and multivariable-adjusted hazard ratios were calculated and stratified by use of vitamin D containing supplements., Results: We observed no significant association between circulating 25(OH) vitamin D and risk of CVD event (HR, 0.91; 95% confidence interval (CI), 0.73-1.13) and CHD event (HR, 0.81; 95% CI, 0.61-1.07). For cerebrovascular events, men with vitamin D deficiency exhibited a higher risk (HR, 1.44; 95% CI, 1.00-2.08) using the minimally adjusted model and after excluding supplement users (HR, 1.70; 95% CI, 1.02-2.83)., Conclusions: 25(OH) vitamin D was not associated with risk of CVD and CHD events. However, vitamin D deficiency may be associated with an increased risk of cerebrovascular events.

Context: Previous 25-hydroxyvitamin D [25(OH)D] and mortality studies have included mostly individuals of European descent. Whether the relationship is similar in Blacks and to what extent differences in 25(OH)D explain racial disparities in mortality is unclear., Objective: The objective of the study was to examine the relationship between 25(OH)D, PTH, and mortality in Black and white community-dwelling older adults over 8.5 yr of follow-up., Design and Setting: Health ABC is a prospective cohort study conducted in Memphis, TN, and Pittsburgh, PA., Participants: Well-functioning Blacks and whites aged 71-80 yr with measured 25(OH)D and PTH (n = 2638; 49% male, 39% Black) were included in the study., Main Outcome Measure: Multivariate-adjusted proportional hazards models estimated the hazard ratios (HR) for all-cause, cardiovascular, cancer, and noncancer, noncardiovascular mortality (n = 691 deaths)., Results: Mean 25(OH)D concentrations were higher in whites than in Blacks [mean (sd): 29.0 (9.9) and 20.8 (8.7) ng/ml, respectively; P < 0.001]. Serum 25(OH)D by race interactions were not significant, however. Lower 25(OH)D concentrations were associated with higher mortality in Blacks and whites combined [HR (95% confidence interval [CI] 2.27 (1.59-3.24), 1.48 (1.20-1.84), and 1.25 (1.02-1.52) for < 10, 10 to < 20, and 20 to < 30 vs. ≥30 ng/ml]. In the multivariate model without 25(OH)D, Blacks had 22% higher mortality than whites [HR (95% CI) 1.22 (1.01, 1.48)]; after including 25(OH)D in the model, the association was attenuated [1.09 (0.90-1.33)]. The mortality population attributable risks (95% CI) for 25(OH)D concentrations less than 20 ng/ml and less than 30 ng/ml in Blacks were 16.4% (3.1-26.6%) and 37.7% (11.6-55.1%) and in whites were 8.9% (3.9-12.7%) and 11.1% (-2.7 to 22.0%), respectively. PTH was also associated with mortality [HR (95% CI) 1.80 (1.33-2.43) for ≥70 vs. <23 pg/ml]., Conclusions: Low 25(OH)D and high PTH concentrations were associated with increased mortality in Black and white community-dwelling older adults. Because 25(OH)D concentrations were much lower in Blacks, the potential impact of remediating low 25(OH)D concentrations was greater in Blacks than whites.

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.

Introduction: There is little information on the association between intact PTH (iPTH) and longitudinal changes in bone mineral density (BMD) in older men. This association was evaluated in relation to conditions related to higher iPTH [e.g. decreased renal function, low serum 25-hydroxyvitamin D (25[OH]D)]., Methods: Eligible men were part of a random sample of 1593 community-dwelling individuals aged 65 yr or older participating in the Osteoporotic Fractures in Men study with baseline iPTH data. Of these, 1227 had at least two BMD measurements at the total hip and femoral neck over a mean follow-up of 4.5 yr. Annualized BMD change across iPTH quartiles was estimated using mixed-effects regression models, adjusting for age, serum calcium, serum 25(OH)D, estimated glomerular filtration rate, and other factors. Splines were used to identify more optimal iPTH thresholds associated with less BMD loss., Results: Among the cohort of 1138 eligible men, men in the highest quartile of iPTH (≥38 pg/ml) lost 0.46% per year at the total hip compared with men in the lowest iPTH quartile who lost 0.22% per year (P = 0.0004). Results were similar at the femoral neck. The association between iPTH and BMD loss was not modified by baseline estimated glomerular filtration rate or 25(OH)D status. Spline results suggested that iPTH levels below 30 pg/ml were more physiologically optimal than higher iPTH values in reducing BMD loss, although an exact threshold for optimal iPTH was not identified., Conclusion: Older men with higher iPTH levels had approximately a 2-fold greater rate of BMD loss compared with men with lower iPTH levels, irrespective of estimated glomerular filtration rate and 25(OH)D.

Context: Vitamin D deficiency and frailty are common with aging, but the association between these conditions is uncertain., Objective: To determine the association between 25-hydroxyvitamin D (25(OH)D) levels and prevalent and incident frailty status among older women., Design: Cross-sectional and longitudinal analyses of a prospective cohort study., Setting: Four U.S. centers., Participants: 6307 women aged≥69 years., Main Outcome Measures: Frailty status classified as robust, intermediate stage, or frail at baseline; and robust, intermediate stage, frail, or dead (all-cause mortality) at follow-up an average of 4.5 years later., Results: At baseline, there was a U-shaped association between 25(OH)D level and odds of frailty with the lowest risk among women with levels 20.0-29.9 ng/ml (referent group). Compared with this group, the odds of frailty were higher among those with levels<15.0 ng/ml [multivariable odds ratio (MOR) 1.47, 95% confidence interval (CI), 1.19-1.82], those with levels 15.0-19.9 ng/ml (MOR 1.24, 95% CI 0.99-1.54), and those with levels≥30 ng/ml (MOR 1.32, 95% CI 1.06-1.63). Among 4551 nonfrail women at baseline, the odds of frailty/death (vs. robust/intermediate) at follow-up appeared higher among those with levels 15.0-19.9 ng/ml (MOR 1.21, 95% CI 0.99-1.49), but the CI overlapped 1.0. The odds of death (vs. robust/intermediate/frail at follow-up) was higher among those with levels<15.0 ng/ml (MOR 1.40, 95% CI 1.04-1.88) and those with levels 15.0-19.9 ng/ml (MOR 1.30, 95% CI 0.97-1.75), although the latter association did not quite reach significance., Conclusion: Lower (<20 ng/ml) and higher (≥30 ng/ml) levels of 25(OH)D among older women were moderately associated with a higher odds of frailty at baseline. Among nonfrail women at baseline, lower levels (<20 ng/ml) were modestly associated with an increased risk of incident frailty or death at follow-up.

Context: Older adults with type 2 diabetes are at higher risk for fracture compared with nondiabetic adults after adjustment for their higher bone mineral density. Infiltration of muscle by fat predicts increased risk of hip fracture., Objective: We investigated whether fat infiltration of muscle, which is greater in diabetic adults, is associated with all clinical fracture and whether it accounts for the increased fracture risk in those with diabetes., Design, Setting, and Participants: Data were analyzed from the Health, Aging, and Body Composition Study, a cohort of community-dwelling adults aged 70-79 yr. Glucose metabolism status and x-ray attenuation of thigh muscle were determined at baseline for 2762 participants., Main Outcome Measures: During a mean 8.2 ± 2.3 yr follow-up, 331 participants reported at least one clinical fracture., Results: Fat infiltration of muscle was higher in those with diabetes or impaired glucose metabolism than in those with normal glucose metabolism (P < 0.001). Fat infiltration of muscle was independently associated with a 19% increased risk of incident clinical fracture (multivariate hazard ratio = 1.19; 95% confidence interval = 1.04-1.36); this association did not differ across glucose metabolism groups (P for interaction = 0.65). As previously reported, diabetes was associated with a greater fracture risk compared with normal glucose metabolism (hazard ratio = 1.42; 95% confidence interval = 1.07-1.89) after adjustment for bone mineral density, but further adjustment for fat infiltration of muscle did not attenuate this association., Conclusions: Fat infiltration of muscle predicts clinical fracture in older adults. Although fat infiltration of muscle is higher among those with diabetes, it does not account for their increased fracture risk.

Context: Low 25-hydroxyvitamin D [25(OH)D] and high PTH may contribute to increased mortality risk in older adults., Objective: The aim of the study was to test the association between 25(OH)D, PTH, and mortality in older men., Design and Setting: The prospective Osteoporotic Fractures in Men (MrOS) study was conducted at six U.S. clinical centers., Participants: We studied community-dwelling men at least 65 yr old (n = 1490)., Main Outcome Measure: Multivariate-adjusted proportional hazards models estimated the hazard ratio (HR) for mortality; cause of death was classified as cancer, cardiovascular, and other by central review of death certificates., Results: During 7.3 yr of follow-up, 330 (22.2%) participants died: 97 from cancer, 110 from cardiovascular disease, and 106 from other causes. The adjusted HR per sd decrease in 25(OH)D for all-cause mortality was 1.01 (95% CI, 0.89, 1.14); no association between 25(OH)D and cardiovascular or other-cause mortality was seen. Unexpectedly, lower 25(OH)D levels were modestly associated with a decreased risk of cancer mortality (adjusted HR per sd decrease, 0.80; 95% CI, 0.64, 0.99). Analyzing 25(OH)D as a categorical variable did not alter these results. Higher PTH levels (log-transformed) were associated with an increased risk of all-cause mortality (adjusted HR per sd increase, 1.15; 95% CI, 1.03, 1.29) and cardiovascular mortality (adjusted HR per sd increase in PTH, 1.21; 95% CI, 1.00, 1.45)., Conclusions: In contrast to previous studies, lower 25(OH)D levels were not associated with an increased risk of all-cause or cause-specific mortality in older men. Higher PTH levels were associated with a modest increase in mortality risk.

Context: As men age, the prevalence of frailty increases whereas levels of androgens decline. Little is known about the relation between these factors., Objective: The aim of this study was to assess cross-sectional and longitudinal associations of estradiol, bioavailable estradiol, testosterone, bioavailable testosterone (bioT), and SHBG with frailty status., Design and Setting: The Osteoporotic Fractures in Men (MrOS) study was conducted at six U.S. clinical centers., Participants: A total of 1469 community-dwelling men at least 65 yr old with baseline data participated; 1245 men had frailty status reassessed 4.1 yr later., Main Outcome Measure: Proportional odds models estimated the likelihood of greater frailty status. Frail men had at least three of the following: weakness, slowness, low activity, exhaustion, and shrinking/sarcopenia; intermediate men had one or two criteria; and robust men had none. At follow-up, death was included as an additional ordinal outcome. Sex hormones were assayed by spectrometry/chromatographic methods., Results: In cross-sectional analyses, men in the lowest quartile of bioT had 1.39-fold (95% confidence interval, 1.02, 1.91) increased odds of greater frailty status compared to men in the highest quartile after adjustment for covariates including age, body size, health status, and medical conditions. In age-adjusted longitudinal analyses, men in the lowest quartile of bioT had 1.51-fold (95% confidence interval, 1.10, 2.07) increased odds of greater frailty status 4.1 yr later. This association was largely attenuated by adjustment for covariates. No other hormones were associated in a cross-sectional or longitudinal manner with frailty status after adjustment., Conclusions: Low levels of bioT were independently associated with worse baseline frailty status. Frailty status should be considered as an outcome in trials of testosterone supplementation.

Context: Vitamin D deficiency is common among older adults, but the association between 25-hydroxyvitamin D [25(OH)D] levels and rates of bone loss is uncertain., Objective: Our aim was to test the hypothesis that lower 25(OH)D levels are associated with higher rates of hip bone loss in older men., Design and Setting: We conducted a prospective cohort study in six U.S. centers., Participants: A total of 1279 community-dwelling men aged 65 yr or older with 25(OH)D levels (liquid chromatography-tandem mass spectroscopy) and hip bone mineral density (BMD) (dual-energy x-ray absorptiometry) at baseline and repeat hip BMD an average of 4.4 yr later participated in the study., Main Outcome Measure(s): We measured the annualized percentage rate of change in hip BMD., Results: After adjustment for multiple potential confounders, the average rate of decline in total hip BMD was -0.59%/yr among men with 25(OH)D levels below 15.0 ng/ml, -0.54%/yr among men with 25(OH)D levels 15.0-19.9 ng/ml, -0.35%/yr among men with 25(OH)D levels 20.0-29.9 ng/ml, and -0.37%/yr among men with 25(OH)D levels of at least 30 ng/ml (P trend = 0.008 for multivariable model). Evidence was strong to support an association among men aged 75 yr and older (P trend <0.001), but not among younger men (P trend = 0.55). Findings were similar when 25(OH)D level was expressed in quintiles and when BMD at hip subregions was substituted for total hip BMD., Conclusions: In this cohort of community-dwelling older men, men with 25(OH)D levels below 20 ng/ml had greater subsequent rates of hip bone loss, but rates of loss were similar among men with higher levels. These results lend support to the view that low 25(OH)D levels are detrimental to BMD in older men.