Associations of components of sarcopenia with risk of fracture in the Osteoporotic Fractures in Men (MrOS) study.

Our aim was to evaluate the associations between the individual components of sarcopenia and fracture types. In this cohort, the risk of experiencing any clinical, hip, or major osteoporotic fracture is greater in men with slow walking speed in comparison to normal walking speed. INTRODUCTION: The association between the components of sarcopenia and fractures has not been clearly elucidated and has hindered the development of appropriate therapeutic interventions. Our aim was to evaluate the associations between the individual components of sarcopenia, specifically lean mass, strength, and physical performance and fracture (any fracture, hip fracture, major osteoporotic fracture) in the Osteoporotic Fractures in Men (MrOS) study. METHODS: The Osteoporotic Fractures in Men study (MrOS) recruited 5995 men ≥ 65 years of age. We measured appendicular lean mass (ALM) by dual-energy X-ray absorptiometry (low as residual value < 20th percentile for the cohort), walking speed (fastest trial of usual pace, values < 0.8 m/s were low), and grip strength (max score of 2 trials, values < 30 kg were low). Information on fractures was assessed tri-annually over an average follow-up of 12 years and centrally adjudicated. Cox proportional hazard models estimated the hazard ratio (HR) (95% confidence intervals) for slow walking speed, low grip strength, and low lean mass. RESULTS: Overall, 1413 men had a fracture during follow-up. Slow walking speed was associated with an increased risk for any HR = 1.39, 1.05-1.84; hip HR = 2.37, 1.54-3.63; and major osteoporotic, HR = 1.89, 1.34-2.67 in multi-variate-adjusted models. Low lean mass and low grip strength were not significantly associated with fracture. CONCLUSIONS: In this cohort of older adult men, the risk of experiencing any, hip, or major osteoporotic fracture is greater in men with slow walking speed in comparison to men with normal walking speed, but low grip strength and low lean mass were not associated with fracture.

High dairy protein intake is associated with greater bone strength parameters at the distal radius and tibia in older men: a cross-sectional study.

Dairy protein but not plant protein was associated with bone strength of the radius and tibia in older men. These results are consistent with previous results in women and support similar findings related to fracture outcomes. Bone strength differences were largely due to thickness and area of the bone cortex. INTRODUCTION: Our objective was to determine the association of protein intake by source (dairy, non-dairy animal, plant) with bone strength and bone microarchitecture among older men. METHODS: We used data from 1016 men (mean 84.3 years) who attended the Year 14 exam of the Osteoporotic Fractures in Men (MrOS) study, completed a food frequency questionnaire (500-5000 kcal/day), were not taking androgen or androgen agonists, and had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal or diaphyseal tibia. Protein was expressed as percentage of total energy intake (TEI); mean ± SD for TEI = 1548 ± 607 kcal/day and for total protein = 16.2 ± 2.9%TEI. We used linear regression with standardized HR-pQCT parameters as dependent variables and adjusted for age, limb length, center, education, race/ethnicity, marital status, smoking, alcohol intake, physical activity level, corticosteroids use, supplement use (calcium and vitamin D), and osteoporosis medications. RESULTS: Higher dairy protein intake was associated with higher estimated failure load at the distal radius and distal tibia [radius effect size = 0.17 (95% CI 0.07, 0.27), tibia effect size = 0.13 (95% CI 0.03, 0.23)], while higher non-dairy animal protein was associated with higher failure load at only the distal radius. Plant protein intake was not associated with failure load at any site. CONCLUSION: The association between protein intake and bone strength varied by source of protein. These results support a link between dairy protein intake and skeletal health, but an intervention study is needed to evaluate causality.

Associations of total and free 25OHD and 1,25(OH)2D with serum markers of inflammation in older men.

UNLABELLED: Vitamin D is hypothesized to suppress inflammation. We tested total and free vitamin D metabolites and their association with inflammatory markers. Interleukin-6 levels were lower with higher 25-hydroxyvitamin D. 1,25-dihydroxyvitamin D and free 25OHD associations mirrored those of 25OHD. However, associations for the two metabolites diverged for tumor necrosis factor alpha (TNF-α) soluble receptors. INTRODUCTION: Vitamin D is hypothesized to suppress inflammation, and circulating 25-hydroxyvitamin D (25OHD) and inflammatory markers are inversely correlated. However, total serum 25OHD may not be the best indicator of biologically active vitamin D. METHODS: We tested serum total 25OHD, total 1,25(OH)2D, vitamin D binding protein (DBP), and estimated free 25OHD and free 1,25(OH)2D associations with inflammatory markers serum interleukin-6 (IL-6), TNF-α and their soluble receptors, interleukin-10 (IL-10), and C-reactive protein (CRP) as continuous outcomes and the presence of ≥2 inflammatory markers in the highest quartile as a dichotomous outcome, in a random subcohort of 679 men in the Osteoporotic Fractures in Men (MrOS) study. RESULTS: IL-6 was lower in men with higher 25OHD (-0.23 µg/mL per standard deviation (SD) increase in 25OHD, 95 % confidence intervals (CI) -0.07 to -0.38 µg/mL) and with higher 1,25(OH)2D (-0.20 µg/mL, 95 % CI -0.0004 to -0.39 µg/mL); free D associations were slightly stronger. 25OHD and DBP, but not 1,25(OH)2D, were independently associated with IL-6. TNF-α soluble receptors were inversely associated with 1,25(OH)2D but positively associated with 25OHD, and each had independent effects. The strongest association with ≥2 inflammatory markers in the highest quartile was for free 1,25(OH)2D (odds ratios (OR) 0.70, 95 % CI 0.54 to 0.89 per SD increase in free 1,25(OH)2D). CONCLUSIONS: Associations of 1,25(OH)2D and free 25OHD with IL-6 mirrored those of 25OHD, suggesting that 1,25(OH)2D and free D do not improve upon 25OHD in population-based IL-6 studies. However, associations for the two metabolites diverged for TNF-α soluble receptor, warranting examination of both metabolites in studies of TNF-α and its antagonists.

Association of stressful life events with accelerated bone loss in older men: the osteoporotic fractures in men (MrOS) study.

UNLABELLED: Prior studies suggest an association between stressful life events and fractures that may be mediated by BMD. In the current study, risk of accelerated hip BMD loss was higher in older men with any type of stressful life event and increased with the number of types of stressful life events. INTRODUCTION: Prior studies suggest that stressful life events may increase adverse health outcomes, including falls and possibly fractures. The current study builds on these findings and examines whether stressful life events are associated with increased bone loss. METHODS: Four thousand three hundred eighty-eight men aged ≥65 years in the Osteoporotic Fractures in Men study completed total hip bone mineral density (BMD) measures at baseline and visit 2, approximately 4.6 years later, and self-reported stressful life events data mid-way between baseline and visit 2, and at visit 2. We used linear regression to model the association of stressful life events with concurrent annualized total hip BMD loss, and log binomial regression or Poisson regression to model risk of concurrent accelerated BMD loss (>1 SD more than mean annualized change). RESULTS: Men (75.3 %) reported ≥1 type of stressful life event, including 43.3 % with ≥2 types of stressful life events. Mean annualized BMD loss was -0.36 % (SD 0.88), and 13.9 % of men were categorized with accelerated BMD loss (about 5.7 % or more total loss). Rate of annualized BMD loss increased with the number of types of stressful life events after adjustment for age (p < 0.001), but not after multivariable adjustment (p = 0.07). Multivariable-adjusted risk of accelerated BMD loss increased with the number of types of stressful life events (RR, 1.10 [95 % confidence interval (CI), 1.04-1.16]) per increase of one type of stressful life event). Fracture risk was not significantly different between stressful life event-accelerated bone loss subgroups (p = 0.08). CONCLUSIONS: In these older men, stressful life events were associated with a small, dose-related increase in risk of concurrent accelerated hip bone loss. Low frequency of fractures limited assessment of whether rapid bone loss mediates any association of stressful life events with incident fractures. Future studies are needed to confirm these findings and to investigate the mechanism that may underlie this association.

Bone-muscle indices as risk factors for fractures in men: the Osteoporotic Fractures in Men (MrOS) Study.

OBJECTIVE: To assess bone-muscle (B-M) indices as risk factors for incident fractures in men. METHODS: Participants of the Osteoporotic Fractures in Men (MrOS) Study completed a peripheral quantitative computed tomography scan at 66% of their tibial length. Bone macrostructure, estimates of bone strength, and muscle area were computed. Areal bone mineral density (aBMD) and body composition were assessed with dual-energy X-ray absorptiometry. Four year incident non-spine and clinical vertebral fractures were ascertained. B-M indices were expressed as bone-to-muscle ratios for: strength, mass and area. Discriminative power and hazards ratios (HR) for fractures were reported. RESULTS: In 1163 men (age: 77.2±5.2 years, body mass index (BMI): 28.0±4.0 kg/m(2), 4.1±0.9 follow-up years, 7.7% of men ⋝1 fracture), B-M indices were smaller in fractured men except for bending and areal indices. Smaller B-M indices were associated with increased fracture risk (HR: 1.30 to 1.74) independent of age and BMI. Strength and mass indices remained significant after accounting for lumbar spine but not total hip aBMD. However, aBMD correlated significantly with B-M indices. CONCLUSION: Mass and bending B-M indices are risk factors for fractures in men, but may not improve fracture risk prediction beyond that provided by total hip aBMD.

Abdominal body composition measured by quantitative computed tomography and risk of non-spine fractures: the Osteoporotic Fractures in Men (MrOS) Study.

UNLABELLED: The effect of abdominal adiposity and muscle on fracture is unclear in older men; therefore, we examined the association among 749 men aged 65+. Among various adipose tissues and muscle groups, lower psoas muscle volume and higher fatty infiltration of abdominal muscle contribute to higher fracture risk independent of BMD. INTRODUCTION: The association of abdominal adiposity and muscle composition with incident fracture is unclear, especially in older men. Therefore, we examined the relationship of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), abdominal intermuscular adipose tissue (IMAT), and muscle volume with incident non-spine fractures among 749 men aged 65 and older. METHODS: A case-cohort study design was used with a total of 252 fracture cases and 497 non-cases. We measured volumes (in centimeters) of adipose and muscle tissues obtained from quantitative computed tomography scan at the L4-5 intervertebral space. Three groups of muscle and IMAT were evaluated: total abdominal, psoas, and paraspinal. Cox proportional hazards regression with a robust variance estimator was used to estimate the hazard ratio (HR) of non-spine fractures per standard deviation (SD) increase in the abdominal body composition measures. The mean age among men in the random subcohort was 74.2 ± 6.1 years, and the average follow-up time was 5.2 ± 1.1 years. RESULTS: After adjusting for age, race, clinic site, percent body fat, and femoral neck bone mineral density (BMD), no significant relationship was found between incident fractures and SAT or VAT. One SD increase in muscle volume at the psoas, but not paraspinal, was associated with 28 % lower fracture risk (95 % CI = 0.55-0.95). When IMAT models were further adjusted for corresponding muscle volumes, only abdominal IMAT was significantly associated with fracture risk (HR = 1.30 (95 % CI = 1.04-1.63)). CONCLUSION: Our findings suggest that lower total psoas muscle volume and higher IMAT of the total abdominal muscle contribute to higher fracture risk in older men independent of BMD.

Longitudinal Associations between Concurrent Changes in Phenotypic Frailty and Lower Urinary Tract Symptoms among Older Men.

BACKGROUND: Lower urinary tract symptoms (LUTS) are associated with prevalent frailty and functional impairment, but longitudinal associations remain unexplored. OBJECTIVES: To assess the association of change in phenotypic frailty with concurrent worsening LUTS severity among older men without clinically significant LUTS at baseline. DESIGN: Multicenter, prospective cohort study. SETTING: Population-based. PARTICIPANTS: Participants included community-dwelling men age ≥65 years at enrollment in the Osteoporotic Fractures in Men study. MEASUREMENTS: Data were collected at 4 visits over 7 years. Phenotypic frailty score (range: 0-5) was defined at each visit using adapted Fried criterion and men were categorized at baseline as robust (0), pre-frail (1-2), or frail (3-5). Within-person change in frailty was calculated at each visit as the absolute difference in number of criteria met compared to baseline. LUTS severity was defined using the American Urologic Association Symptom Index (AUASI; range: 0-35) and men with AUASI ≥8 at baseline were excluded. Linear mixed effects models were adjusted for demographics, health-behaviors, and comorbidities to quantify the association between within-person change in frailty and AUASI. RESULTS: Among 3235 men included in analysis, 48% were robust, 45% were pre-frail, and 7% were frail. Whereas baseline frailty status was not associated with change in LUTS severity, within-person increases in frailty were associated with greater LUTS severity (quadratic P<0.001). Among robust men at baseline, mean predicted AUASI during follow-up was 4.2 (95% CI 3.9, 4.5) among those meeting 0 frailty criteria, 4.6 (95% CI 4.3, 4.9) among those meeting 1 criterion increasing non-linearly to 11.2 (95% CI 9.8, 12.6) among those meeting 5 criteria. CONCLUSIONS: Greater phenotypic frailty was associated with non-linear increases in LUTS severity in older men over time, independent of age and comorbidities. Results suggest LUTS and frailty share an underlying mechanism that is not targeted by existing LUTS interventions.

Recommendations for Reducing Heterogeneity in Handgrip Strength Protocols.

Handgrip dynamometers are widely used to measure handgrip strength (HGS). HGS is a safe and easy to obtain measure of strength capacity, and a reliable assessment of muscle function. Although HGS provides robust prognostic value and utility, several protocol variants exist for HGS in clinical settings and translational research. This lack of methodological consistency could threaten the precision of HGS measurements and limit comparisons between the growing number of studies measuring HGS. Providing awareness of the protocol variants for HGS and making suggestions to reduce the implications of these variants will help to improve methodological consistency. Moreover, leveraging recent advancements in HGS equipment may enable us to use more sophisticated HGS dynamometer technologies to better assess muscle function. This Special Article will 1) highlight differences in HGS protocols and instrumentation, 2) provide recommendations to better specify HGS procedures and equipment, and 3) present future research directions for studies that measure HGS. We also provided a minimum reporting criteria framework to help future research studies avoid underreporting of HGS procedures.

Older American Women May Especially Benefit from Distributing and Consuming Protein for Decreasing Odds of Functional Limitations.

OBJECTIVES: Protein is a key macronutrient for preserving physical function, but the role of protein intake on functional status may differ in men and women. We sought to examine the associations of daily protein intake and distribution on functional limitations in older American men and women. DESIGN: Cross-sectional. SETTING: Population-based survey. PARTICIPANTS: The analytic sample included 3,976 men and 4,081 women aged ≥60-years from the 2007-2016 waves of the National Health and Nutrition Examination Survey. MEASUREMENTS: Participants reported their ability to perform basic activities of daily living, instrumental activities of daily living, leisure and social activities, lower extremity mobility activities, and general physical tasks. Those reporting difficulty or an inability in completing such functional tasks were considered as having a functional limitation. Protein intake was determined with dietary recalls and participants revealed functional limitations. Protein recommendations of ≥0.80, ≥1.00, and ≥1.50 g/kg/day were used. Based on these cut-points, we also investigated distribution of protein across 4 eating occasions at ≥0.20, ≥0.25, and ≥0.38 g/kg/meal, respectively. RESULTS: Older women meeting each recommendation had decreased odds for functional limitations: 0.55 (95% confidence interval (CI): 0.40-0.75) for ≥0.80 g/kg/day, 0.75 (CI: 0.58-0.97) for ≥1.00 g/kg/day, and 0.72 (CI: 0.55-0.94) for ≥1.5 g/kg/day. No significant associations were observed in older men. Further, older women with protein consumption ≥0.20 g/kg/meal had decreased odds for functional limitations: 0.24 (CI: 0.10-0.61) for 1 occasion, 0.20 (CI: 0.08-0.49) for 2 occasions, 0.16 (CI: 0.07-0.40) for 3 occasions, and 0.12 (CI: 0.04-0.32) for 4 occasions. A similar trend was observed for intake ≥0.25 g/kg/meal: 0.31 (CI: 0.16-0.62) for 2 occasions, 0.30 (CI: 0.14-0.61) for 3 occasions, and 0.31 (CI: 0.12-0.78) for 4 occasions. Women with 1 and 2 eating occasions at ≥0.38 g/kg/meal of protein had 0.66 (CI: 0.48-0.91) and 0.54 (CI: 0.37-0.79) decreased odds for functional limitations, respectively. CONCLUSION: Trials that are powered to detect the effects of protein on functional status in women will help to establish causality.

Sarcopenia: etiology, clinical consequences, intervention, and assessment.

The aging process is associated with loss of muscle mass and strength and decline in physical functioning. The term sarcopenia is primarily defined as low level of muscle mass resulting from age-related muscle loss, but its definition is often broadened to include the underlying cellular processes involved in skeletal muscle loss as well as their clinical manifestations. The underlying cellular changes involve weakening of factors promoting muscle anabolism and increased expression of inflammatory factors and other agents which contribute to skeletal muscle catabolism. At the cellular level, these molecular processes are manifested in a loss of muscle fiber cross-sectional area, loss of innervation, and adaptive changes in the proportions of slow and fast motor units in muscle tissue. Ultimately, these alterations translate to bulk changes in muscle mass, strength, and function which lead to reduced physical performance, disability, increased risk of fall-related injury, and, often, frailty. In this review, we summarize current understanding of the mechanisms underlying sarcopenia and age-related changes in muscle tissue morphology and function. We also discuss the resulting long-term outcomes in terms of loss of function, which causes increased risk of musculoskeletal injuries and other morbidities, leading to frailty and loss of independence.

Low Protein Intake Irrespective of Source is Associated with Higher Mortality Among Older Community-dwelling Men.

OBJECTIVES: Our aim was to determine the association between protein intake (overall and by source) and all-cause and cause-specific mortality among older men. DESIGN: Prospective cohort study. SETTING: 5790 ambulatory community-dwelling older men from multicenter Osteoporotic Fractures in Men (MrOS) study. MEASUREMENTS: Total energy and protein intake, and protein intake by source (dairy, non-dairy animal, plant) were assessed using a 69-item food frequency questionnaire. We included up to 10-year follow-up with adjudicated cardiovascular, cancer and other mortality outcomes. We used time-to-event analysis with protein exposures, mortality outcome, and adjusted for possible confounders including age, center, education, race, smoking, alcohol use, physical activity, weight, total energy intake (TEI), and comorbidities. Hazard ratios were expressed per each unit=2.9% TEI decrement for all protein intake variables. RESULTS: The mean (SD) baseline age of 5790 men was 73.6 (5.8) y. There were 1611 deaths and 211 drop-outs prior to 10 years, and 3868 men who were alive at the 10-year follow-up. The mean (SD) total protein intake was 64.7 (25.8) g/d, while the mean (SD) intake expressed as percent of total energy intake (%TEI) was 16.1 (2.9) %TEI. Lower protein intake was associated with an increased risk of death, with unadjusted HR=1.11 (95% CI: 1.06, 1.17) and adjusted HR=1.09 (95% CI: 1.04, 1.14) and the associations for protein intake by source were similar. The adjusted HR for cancer mortality was HR=1.13 (95% CI: 1.03, 1.25) while the association for CVD mortality was HR=1.08 (95% CI: 0.99, 1.18). CONCLUSIONS: Low protein intake, irrespective of source, was associated with a modest increase in risk of all-cause and cause-specific mortality among older men. Special consideration should be given to level of protein intake among older adults.

Implications of ICD-10 for Sarcopenia Clinical Practice and Clinical Trials: Report by the International Conference on Frailty and Sarcopenia Research Task Force.

Establishment of an ICD-10-CM code for sarcopenia in 2016 was an important step towards reaching international consensus on the need for a nosological framework of age-related skeletal muscle decline. The International Conference on Frailty and Sarcopenia Research Task Force met in April 2017 to discuss the meaning, significance, and barriers to the implementation of the new code as well as strategies to accelerate development of new therapies. Analyses by the Sarcopenia Definitions and Outcomes Consortium are underway to develop quantitative definitions of sarcopenia. A consensus conference is planned to evaluate this analysis. The Task Force also discussed lessons learned from sarcopenia trials that could be applied to future trials, as well as lessons from the osteoporosis field, a clinical condition with many constructs similar to sarcopenia and for which ad hoc treatments have been developed and approved by regulatory agencies.

Association of 25-hydroxyvitamin D with prevalent osteoarthritis of the hip in elderly men: the osteoporotic fractures in men study.

OBJECTIVE: To examine the cross-sectional association of serum levels of 25-hydroxyvitamin D, or 25(OH)D, with prevalent radiographic hip osteoarthritis (OA) in elderly men. METHODS: In a cohort of 1,104 elderly men from the Osteoporotic Fractures in Men Study, 25(OH)D serum levels were determined by mass spectrometry, followed by pelvic radiographs approximately 4.6 years later. Categories of vitamin D levels were defined as follows: deficiency as < or =15 ng/ml, insufficiency as 15.1-30 ng/ml, and sufficiency as >30 ng/ml. Radiographs were assessed for severity of hip OA using a summary grade of 0-4 for individual features of hip OA. Logistic regression was used to assess associations of serum 25(OH)D levels with prevalent radiographic hip OA; covariates included age, clinic site, season at the time of blood withdrawal, self-reported hip pain for >30 days, timed 6-meter walk, presence of at least 1 coexisting condition, and self-rated health status. RESULTS: Men with radiographic hip OA had a slower 6-meter walking time (P < 0.0001), reported more hip pain (P = 0.0001), had a lower vitamin D level (P = 0.0002), and had a higher prevalence of vitamin D insufficiency (P = 0.002) and vitamin D deficiency (P = 0.012) compared with controls. Higher 25(OH)D levels were associated with a lower prevalence of radiographic hip OA (odds ratio [OR] 1.39 per 1 SD decrease in 25[OH]D, 95% confidence interval [95% CI] 1.11-1.74) after adjusting for age, season, and clinic site. Men with vitamin D insufficiency had an increased likelihood of prevalent radiographic hip OA (OR 2.19, 95% CI 1.21-3.97) compared with men with sufficient levels of 25(OH)D, and in men with vitamin D deficiency, there was a tendency toward an increased likelihood of radiographic hip OA (OR 1.99, 95% CI 0.83-4.74). CONCLUSION: Men with vitamin D deficiencies are twice as likely to have prevalent radiographic hip OA, and therefore vitamin D therapy to augment skeletal health in the elderly is warranted.

Rate and circumstances of clinical vertebral fractures in older men.

UNLABELLED: We examined the rate of clinical vertebral fractures, and the circumstances associated with the fractures, in a cohort of 5,995 US older men. Fractures were more common in the most elderly men, and were usually associated with falls and other low-energy trauma. INTRODUCTION: Little is known about clinical vertebral fractures in older men. We postulated that clinical vertebral fractures occur with falls, affect men with osteoporosis, and are more common as age increases. METHODS: Five thousand nine hundred and ninety-five men aged > or =65 years were followed prospectively for an average of 4.7 years. Men with incident clinical vertebral fractures were compared to controls. RESULTS: One percent (n = 61) sustained incident clinical vertebral fractures (2.2/1,000 person-years). The rate of fracture rose with age (0.7% in men 65-69 years and 5% > or =85 years). Fractured men were more likely frail (8.2% vs. 2.2%), more often fell (36.1% vs. 21%) and had lower total hip and lumbar spine BMD (all p values < or =0.002). In 73.8% of cases fractures were precipitated by no known trauma or by low-energy trauma, including falls in 57.3% Fractures were thoracic in 33% and lumbar in 56%. Men with an incident vertebral fracture were more likely to be osteoporotic (13% vs. 2%, p < 0.0001), but most men with incident fractures did not have osteoporosis. CONCLUSIONS: Incident clinical vertebral fractures were relatively common in older men and the rate increased after age 80 years. Fractures were usually associated with minimal trauma, most commonly a fall.