Associations of accelerometry-measured and self-reported physical activity and sedentary behavior with skeletal muscle energetics: The Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: Skeletal muscle energetics decline with age, and physical activity (PA) has been shown to offset these declines in older adults. Yet, many studies reporting these effects were based on self-reported PA or structured exercise interventions. Therefore, we examined the associations of accelerometry-measured and self-reported PA and sedentary behavior (SB) with skeletal muscle energetics and explored the extent to which PA and sedentary behavior would attenuate the associations of age with muscle energetics. METHODS: As part of the Study of Muscle, Mobility and Aging, enrolled older adults (n = 879), 810 (age = 76.4 ± 5.0 years old, mean ± SD; 58% women) had maximal muscle oxidative capacity measured ex vivo via high-resolution respirometry of permeabilized myofibers (maximal oxidative phosphorylation (maxOXPHOS)) and in vivo by 31phosphorus magnetic resonance spectroscopy (maximal adenosine triphosphate (ATPmax)). Accelerometry-measured sedentary behavior, light activity, and moderate-to-vigorous PA (MVPA) were assessed using a wrist-worn ActiGraph GT9X over 7 days. Self-reported sedentary behavior, MVPA, and all PA were assessed with the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire. Linear regression models with progressive covariate adjustments evaluated the associations of sedentary behavior and PA with muscle energetics, as well as the attenuation of the age/muscle energetics association by MVPA and sedentary behavior. As a sensitivity analysis, we also examined activPAL-measured daily step count and time spent in sedentary behavior and their associations with muscle energetics. RESULTS: Every 30 min/day more of ActiGraph-measured MVPA was associated with 0.65 pmol/(s × mg) higher maxOXPHOS and 0.012 mM/s higher ATPmax after adjusting for age, site/technician, and sex (p < 0.05). Light activity was not associated with maxOXPHOS or ATPmax. Meanwhile, every 30 min/day spent in ActiGraph-measured sedentary behavior was associated with 0.39 pmol/s × mg lower maxOXPHOS and 0.006 mM/s lower ATPmax (p < 0.05). Only associations with ATPmax held after further adjusting for socioeconomic status, body mass index, lifestyle factors, and multimorbidity. CHAMPS MVPA and all PA yielded similar associations with maxOXPHOS and ATPmax (p < 0.05), but sedentary behavior did not. Higher activPAL step count was associated with higher maxOXHPOS and ATPmax (p < 0.05), but time spent in sedentary behavior was not. Additionally, age was significantly associated with muscle energetics for men only (p < 0.05); adjusting for time spent in ActiGraph-measured MVPA attenuated the age association with ATPmax by 58% in men. CONCLUSION: More time spent in accelerometry-measured or self-reported daily PA, especially MVPA, was associated with higher skeletal muscle energetics. Interventions aimed specifically at increasing higher intensity activity might offer potential therapeutic interventions to slow age-related decline in muscle energetics. Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics.

Associations Between D3Cr Muscle Mass and Magnetic Resonance Thigh Muscle Volume With Strength, Power, Physical Performance, Fitness, and Limitations in Older Adults in the SOMMA Study.

BACKGROUND: How magnetic resonance (MR) derived thigh muscle volume and deuterated creatine dilution derived muscle mass (D3Cr muscle mass) differentially relate to strength, fitness, and other functions in older adults-and whether associations vary by sex-is not known. METHODS: Men (N = 345) and women (N = 482) aged ≥70 years from the Study of Muscle, Mobility, and Aging completed leg extension strength (1-repetition max) and cardiopulmonary exercise testing to assess fitness (VO2peak). Correlations and adjusted regression models stratified by sex were used to assess the association between muscle size measures, study outcomes, and sex interactions. RESULTS: D3Cr muscle mass and MR thigh muscle volume were correlated (men: r = 0.62, women: r = 0.51, p < .001). Each standard deviation (SD) decrement in D3Cr muscle mass was associated with lower 1-repetition max strength (-14 kg men, -4 kg women, p < .001 for both; p-interaction = .003) and lower VO2peak (-79 mL/min men, -30 mL/min women, p < .001 for both, p-interaction: .016). Each SD decrement in MR thigh muscle volume was also associated with lower strength (-32 kg men, -20 kg women, p < .001 for both; p-interaction = .139) and lower VO2peak (-217 mL/min men, -111 mL/min women, p < .001 for both, p-interaction = .010). There were associations, though less consistent, between muscle size or mass with physical performance and function; associations varied by sex. CONCLUSIONS: Less muscle-measured by either D3Cr muscle mass or MR thigh muscle volume-was associated with lower strength and fitness. Varied associations by sex and assessment method suggest consideration be given to which measurement to use in future studies.

Age Is Associated With Dampened Circadian Patterns of Rest and Activity: The Study of Muscle, Mobility, and Aging (SOMMA).

BACKGROUND: The effects of aging on circadian patterns of behavior are insufficiently described. To address this, we characterized age-specific features of rest-activity rhythms (RAR) in community-dwelling older adults both overall, and in relation, to sociodemographic characteristics. METHODS: We examined cross-sectional associations between RAR and age, sex, race, education, multimorbidity burden, financial, work, martial, health, and smoking status using assessments of older adults with wrist-worn free-living actigraphy data (N = 820, age = 76.4 years, 58.2% women) participating in the Study of Muscle, Mobility, and Aging (SOMMA). RAR parameters were determined by mapping an extension to the traditional cosine curve to activity data. Functional principal component analysis determined variables accounting for variance. RESULTS: Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR versus men (all p < .05). Total activity (56%) and time of activity (20%) accounted for most of the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (p < .001). Compared to the latest decile of acrophase, those in the earliest and midrange categories had more total activity (p = .02). Being in a married-like relationship and a more stable financial situation were associated with stronger rhythms; higher education was associated with less rhythm strength (all p < .05). CONCLUSIONS: Older age was associated with dampened circadian behavior; behaviors were sexually dimorphic. Some sociodemographic characteristics were associated with circadian behavior. We identified a behavioral phenotype characterized by early time of day of peak activity, high rhythmic amplitude, and more total activity.

Lower muscle mitochondrial energetics is associated with greater phenotypic frailty in older women and men: the Study of Muscle, Mobility and Aging.

BACKGROUND: Phenotypic frailty syndrome identifies older adults at greater risk for adverse health outcomes. Despite the critical role of mitochondria in maintaining cellular function, including energy production, the associations between muscle mitochondrial energetics and frailty have not been widely explored in a large, well-phenotyped, older population. METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed muscle energetics in older adults (N = 879, mean age = 76.3 years, 59.2% women). 31Phosporous magnetic resonance spectroscopy measured maximal production of adenosine triphosphate (ATPmax) in vivo, while ex vivo high-resolution respirometry of permeabilized muscle fibers from the vastus lateralis measured maximal oxygen consumption supported by fatty acids and complex I- and II-linked carbohydrates (e.g., Max OXPHOSCI+CII). Five frailty criteria, shrinking, weakness, exhaustion, slowness, and low activity, were used to classify participants as robust (0, N = 397), intermediate (1-2, N = 410), or frail (≥ 3, N = 66). We estimated the proportional odds ratio (POR) for greater frailty, adjusted for multiple potential confounders. RESULTS: One-SD decrements of most respirometry measures (e.g., Max OXPHOSCI+CII, adjusted POR = 1.5, 95%CI [1.2,1.8], p = 0.0001) were significantly associated with greater frailty classification. The associations of ATPmax with frailty were weaker than those between Max OXPHOSCI+CII and frailty. Muscle energetics was most strongly associated with slowness and low physical activity components. CONCLUSIONS: Our data suggest that deficits in muscle mitochondrial energetics may be a biological driver of frailty in older adults. On the other hand, we did observe differential relationships between measures of muscle mitochondrial energetics and the individual components of frailty.

The Study of Muscle, Mobility and Aging (SOMMA): A Unique Cohort Study About the Cellular Biology of Aging and Age-related Loss of Mobility.

BACKGROUND: The Study of Muscle, Mobility and Aging (SOMMA) aims to understand the biological basis of many facets of human aging, with a focus on mobility decline, by creating a unique platform of data, tissues, and images. METHODS: The multidisciplinary SOMMA team includes 2 clinical centers (University of Pittsburgh and Wake Forest University), a biorepository (Translational Research Institute at Advent Health), and the San Francisco Coordinating Center (California Pacific Medical Center Research Institute). Enrollees were age ≥70 years, able to walk ≥0.6 m/s (4 m); able to complete 400 m walk, free of life-threatening disease, and had no contraindications to magnetic resonance or tissue collection. Participants are followed with 6-month phone contacts and annual in-person exams. At baseline, SOMMA collected biospecimens (muscle and adipose tissue, blood, urine, fecal samples); a variety of questionnaires; physical and cognitive assessments; whole-body imaging (magnetic resonance and computed tomography); accelerometry; and cardiopulmonary exercise testing. Primary outcomes include change in walking speed, change in fitness, and objective mobility disability (able to walk 400 m in 15 minutes and change in 400 m speed). Incident events, including hospitalizations, cancer diagnoses, fractures, and mortality are collected and centrally adjudicated by study physicians. RESULTS: SOMMA exceeded its goals by enrolling 879 participants, despite being slowed by the COVID-19 pandemic: 59.2% women; mean age 76.3 ± 5.0 years (range 70-94); mean walking speed 1.04 ± 0.20 m/s; 15.8% identify as other than Non-Hispanic White. Over 97% had data for key measurements. CONCLUSIONS: SOMMA will provide the foundation for discoveries in the biology of human aging and mobility.

Design and recruitment of the randomized order safety trial evaluating resident-physician schedules (ROSTERS) study.

INTRODUCTION: While the Accreditation Council for Graduate Medical Education limited first year resident-physicians to 16 consecutive work hours from 2011 to 2017, resident-physicians in their second year or higher were permitted to work up to 28 h consecutively. This paper describes the Randomized Order Safety Trial Evaluating Resident-physician Schedules (ROSTERS) study, a clustered-randomized crossover clinical trial designed to evaluate the effectiveness of eliminating traditional shifts of 24 h or longer for second year or higher resident-physicians in pediatric intensive care units (PICUs). METHODS: ROSTERS was a multi-center non-blinded trial in 6 PICUs at US academic medical centers. The primary aim was to compare patient safety between the extended duration work roster (EDWR), which included shifts ≥24 h, and a rapidly cycling work roster (RCWR), where shifts were limited to a maximum of 16 h. Information on potential medical errors was gathered and used for classification by centrally trained physician reviewers who were blinded to the study arm. Secondary aims were to assess the relationship of the study arm to resident-physician sleep duration, work hours and neurobehavioral performance. RESULTS: The study involved 6577 patients with a total of 38,821 patient days (n = 18,749 EDWR, n = 20,072 RCWR). There were 413 resident-physician rotations included in the study (n = 203 EDWR, n = 210 RCWR). Resident-physician questionnaire data were over 95% complete. CONCLUSIONS: Results from data collected in the ROSTERS study will be evaluated for the impact of resident-physician schedule roster on patient safety outcomes in PICUs, and will allow for examination of a number of secondary outcome measures. ClinicalTrials.gov Identifier: NCT02134847.

Clinical Results of Direct Anterior Approach THA with Minimal Fluoroscopic Exposure Optimization Techniques.

PURPOSE: To determine if low-level intraoperative fluoroscopy usage is associated with increased complications during an initial series for an experienced surgeon transitioning to direct anterior approach (DAA) for total hip arthroplasty (THA). MATERIALS AND METHODS: Subjects who underwent DAA were eligible for analysis. Inclusion criteria included the first 50 subjects who underwent DA hip arthroplasty by a single surgeon (January 2013 to December 2014). Total operating room (OR) time, fluoroscopy absorbed dose, flouoroscopy time, procedure time, and complications were collected and analyzed. Subject demographics were also collected with subjects divided by date of surgery to one of two possible groups. Simple linear regression analysis was performed to determine the relation between case number and both radiation dose and fluoroscopy time. RESULTS: Subjects underwent DAA total hip arthroplasty (n=45). Total OR time ranged from 1.1hrs up to 2.5 hours. Surgeries required an average fluoroscopic time of 7.8 seconds, with improvement over the series of 3.7 seconds. The average radiation dose or fluoroscopy was 2.6 mrem per case. This resulted in a total estimated exposure of 127 mrem over a 23-month period. No patients suffered intraoperative or postoperative fractures or revisions. No significant difference was found for the groups by weight, age, height, and body mass index. Regression analysis yielded a statistically significant (p<0.05) decrease in fluoroscopy time of 0.36 seconds per case over the 45 cases studied. CONCLUSION: An experienced single surgeon's learning curve in DAA THA can be accelerated, with proper training and technique, within a lifetime case experience less than 50 procedures. Surgeons should be aware that with proper techniques and sufficiently-experienced teams, a flattened learning curve is attainable while minimizing fluoroscopy exposure and maintaining clinical outcomes.

Cystatin C and the Risk of Frailty and Mortality in Older Men.

BACKGROUND: This study examines the association between cystatin C (cysC) levels and risks of progression of frailty status or death in older men. METHODS: Prospective study of 2,613 men without overt frailty aged 67 years and older enrolled in the MrOS ancillary sleep study. Baseline measurements included serum cysC, serum creatinine, and frailty status. Repeat frailty status, performed an average of 3.4 years later, was assessed as an ordinal outcome of robust, intermediate stage (prefrail), frail or dead. RESULTS: Mean age was 75.7 years. Men with higher cysC were older and had a higher comorbidity burden. After adjusting for age, clinical site, and race, higher cysC was associated with nearly twofold greater odds of being classified as intermediate stage versus robust (OR quartile 4 vs 1; 1.82, 95% confidence interval [CI] 1.35-2.45), a threefold greater odds of frailty versus robust (OR quartile 4 vs 1; 3.13, 95% CI 2.03-4.82), and a more than fivefold greater odds of death versus robust (OR quartile 4 vs 1; 5.48, 95% CI 2.98-10.08). Results were similar for cysC-based estimated glomerular filtration rate (eGFR). This relationship was attenuated but persisted after adjusting for additional potential confounders including baseline frailty status, body mass index, smoking status, comorbidity burden, self-reported disability, and serum albumin. In contrast, neither serum creatinine nor creatinine-based eGFR was associated in a graded manner with higher risks of development of frailty or death. CONCLUSIONS: In this cohort of older men without overt frailty, higher cysC and cysC-based eGFR, but not creatinine or creatinine-based estimates of GFR, were associated with increased risks of frailty or death. These findings suggest that higher cysC level may be a promising biomarker for unsuccessful aging as manifested by increased risks of frailty and death.

Estimated GFR and Mortality in Older Men: Are All eGFR Formulae Equal.

BACKGROUND: Recently, the first estimated glomerular filtration rate (eGFR) formula specifically developed for community-dwelling older adults, the Berlin Initiative Study Equation 2 (BIS2), was reported. To date, however, no study has examined the performance of the BIS2 to predict death in older adults as compared to equations used clinically and in research. METHODS: We prospectively followed 2,994 community-dwelling men (age 76.4 ± 5.6) enrolled in the MrOS Sleep Study. We calculated baseline eGFR from serum creatinine and cystatin-C using the BIS2, Chronic Kidney Disease Epidemiology (CKD-EPIcr,cysc), CKD-EPIcysc and CKD-EPIcr equations. Analyses included Cox-proportional hazards regression and net reclassification improvement (NRI) for the outcomes of all-cause and cardiovascular death. RESULTS: Follow-up time was 7.3 ± 1.9 years. By BIS2, 42 and 11% had eGFR <60 and <45, respectively, compared to CKD-EPIcr (23 and 6%), CKD-EPIcysc (36 and 13%) and CKD-EPIcr,cysc (28 and 8%). BIS2 eGFR <45 was associated with twofold higher rate of all-cause mortality when compared to eGFR ≥75 after multivariate adjustment (HR 2.1, 95% CI 1.5-2.8). Results were similar for CKD-EPIcr,cysc <45 (HR 2.1, 95% CI 1.6-2.7) and CKD-EPIcysc <45 (HR 2.1, 95% CI 1.7-2.7) and weaker for CKD-EPIcr <45 (HR 1.5, 95% CI 1.2-2.0). In NRI analyses, when compared to CKD-EPIcr,cysc, both BIS2 and CKD-EPIcr equations more often misclassified participants with respect to mortality. We found similar results for cardiovascular death. CONCLUSION: The BIS2 did not outperform and the CKD-EPIcr was inferior to the cystatin C-based CKD-EPI equations to predict death in this cohort of older men. Thus, the cystatin C-based CKD-EPI equations are the formulae of choice to predict death in community-dwelling older men.

Sleep Apnea and Obstructive Airway Disease in Older Men: Outcomes of Sleep Disorders in Older Men Study.

STUDY OBJECTIVES: To evaluate the association between obstructive airway disease (OAD) and sleep apnea in older men. METHODS: A community-based cross-sectional study of 853 community-dwelling older men (mean age 80.7 ± 4.1 years [range 73 to 90]) across 6 centers in the United States from the Outcomes of Sleep Disorders in Older Men Study. Sleep was objectively measured using full in-home polysomnography and lung function was objectively measured using spirometry. The association of OAD (pre-bronchodilator FEV1/FVC ratio < 0.7 and FEV1 < 80% predicted) and sleep apnea (apnea-hypopnea index [AHI] ≥ 15 events/hour) was assessed using logistic regression. RESULTS: OAD and sleep apnea were identified in 111 (13.0%) and 247 (29.0%) men, respectively. In univariate analysis, participants with OAD had a lower AHI (mean ± SD; 8.7 ± 11.7 vs. 12.7 ± 13.8, P = 0.0009) and a lower prevalence of sleep apnea (14.4 vs. 31.1%, P = 0.0003) compared to participants without OAD. OAD remained independently associated with a lower odds of sleep apnea (odds ratio 0.30, 95% CI 0.16 to 0.55, P = 0.0001) after adjustment for demographics, body composition, smoking, and potential mediators (arousal index, time spent in rapid eye movement sleep). Individuals with OAD and sleep apnea (n = 16) had an increased arousal index and lower oxygen saturation level as compared to individuals with OAD alone (P values < 0.05). CONCLUSIONS: Obstructive airway disease was associated with a lower prevalence of sleep apnea in a cohort of community-dwelling elderly men, and unexplained by differences in adiposity or sleep architecture. Although uncommon in this cohort, coexisting sleep apnea and OAD was associated with increased sleep fragmentation and nocturnal oxygen desaturation compared to OAD alone.

Sleep Disordered Breathing and Risk of Stroke in Older Community-Dwelling Men.

STUDY OBJECTIVES: Men with sleep disordered breathing (SDB) may be at increased stroke risk, due to nocturnal hypoxemia, sleep loss or fragmentation, or other mechanisms. We examined the association of SDB with risk of incident stroke in a large cohort of older men. METHODS: Participants were 2,872 community-dwelling men (mean age 76 years) enrolled in the MrOS Sleep Study, which gathered data from 2003 to 2005 at six clinical sites in the Unites States. SDB predictors (obstructive apnea-hypopnea index, apnea-hypopnea index, central apnea index, and nocturnal hypoxemia) were measured using overnight polysomnography. Incident stroke over an average follow-up of 7.3 years was centrally adjudicated by physician review of medical records. RESULTS: One hundred fifty-six men (5.4%) had a stroke during follow-up. After adjustment for age, clinic site, race, body mass index, and smoking status, older men with severe nocturnal hypoxemia (≥ 10% of the night with SpO2 levels below 90%) had a 1.8-fold increased risk of incident stroke compared to those without nocturnal hypoxemia (relative hazard = 1.83; 95% confidence interval 1.12-2.98; P trend = 0.02). Results were similar after further adjustment for other potential covariates and after excluding men with a history of stroke. Other indices of SDB were not associated with incident stroke. CONCLUSIONS: Older men with severe nocturnal hypoxemia are at significantly increased risk of incident stroke. Measures of overnight oxygen saturation may better identify older men at risk for stroke than measures of apnea frequency.

Sleep-disordered Breathing and Incident Heart Failure in Older Men.

RATIONALE: The directionality of the relationship between sleep-disordered breathing and heart failure is controversial. OBJECTIVES: We assessed whether elevations in the obstructive or central sleep apnea index or the presence of Cheyne-Stokes breathing are associated with decompensated and/or incident heart failure. METHODS: We conducted a prospective, longitudinal study of 2,865 participants derived from the Osteoporotic Fractures in Men Study, a prospective multicenter observational study of community-dwelling older men. Participants underwent baseline polysomnography and were followed for a mean 7.3 years for development of incident or decompensated heart failure. Our main exposures were the obstructive apnea-hypopnea index (AHI), central apnea index (CAI ≥ 5), and Cheyne-Stokes breathing. Covariates included age, race, clinic site, comorbidities, physical activity, and alcohol and tobacco use. MEASUREMENTS AND MAIN RESULTS: CAI greater than or equal to five and presence of Cheyne-Stokes breathing but not obstructive AHI were significant predictors of incident heart failure (adjusted hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.16-2.77 for CAI ≥ 5) (HR, 2.23; 95% CI, 1.45-3.43 for Cheyne-Stokes breathing). After excluding those with baseline heart failure, the incident risk of heart failure was attenuated for those with CAI greater than or equal to five (HR, 1.57; 95% CI, 0.92-2.66) but remained significantly elevated for those with Cheyne-Stokes breathing (HR, 1.90; 95% CI, 1.10-3.30). CONCLUSIONS: An elevated CAI/Cheyne-Stokes breathing, but not an elevated obstructive AHI, is significantly associated with increased risk of decompensated heart failure and/or development of clinical heart failure in a community-based cohort of older men.

Genetic associations of periodic limb movements of sleep in the elderly for the MrOS sleep study.

OBJECTIVE: The objective of this study was to assess the relationship between single-nucleotide polymorphisms associated with restless legs syndrome and periodic limb movements of sleep in a population cohort of elderly individuals. METHODS: Single-nucleotide polymorphisms previously associated with periodic limb movements of sleep or restless legs syndrome were analyzed in 2356 white male participants in the Osteoporotic Fractures in Men Sleep Study cohort. The associations between single-nucleotide polymorphisms and polysomnographically measured periodic limb movement index ≥15 were examined with logistic regression adjusted for age, ancestry markers, and periodic limb movements of sleep risk factors. RESULTS: Of the men in this cohort, 61% had a periodic limb movement index ≥15. Significant associations were observed between a periodic limb movement index ≥15 and the number of risk alleles for the two BTBD9 single-nucleotide polymorphisms (rs9357271[T], odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.20-1.58; and rs3923809[A], OR = 1.43, 95% CI 1.26-1.63), one of the MEIS1 single-nucleotide polymorphisms (rs2300478[G], OR = 1.31, 95% CI 1.14-1.51) and the mitogen-activated protein kinase kinase 5 (MAP2K5)/Ski family transcriptional corepressor 1 (SKOR1) single-nucleotide polymorphism (rs1026732[G], OR = 1.16, 95% CI 1.02-1.31). In a multivariable model controlling for each of the two MEIS1 single-nucleotide polymorphisms, the rs6710341[A] single-nucleotide polymorphism became a significant risk allele (OR = 1.59, 95% CI 1.26-2.00). CONCLUSIONS: Our findings confirm an association between the BTBD9, MEIS1, and MAP2K5/SKOR1 single-nucleotide polymorphisms and periodic limb movements of sleep in an elderly cohort not selected for the presence of restless legs syndrome.

Abdominal aortic calcification and risk of fracture among older women - The SOF study.

Data concerning the link between severity of abdominal aortic calcification (AAC) and fracture risk in postmenopausal women are discordant. This association may vary by skeletal site and duration of follow-up. Our aim was to assess the association between the AAC severity and fracture risk in older women over the short- and long term. This is a case-cohort study nested in a large multicenter prospective cohort study. The association between AAC and fracture was assessed using Odds Ratios (OR) and 95% confidence intervals (95%CI) for vertebral fractures and using Hazard Risks (HR) and 95%CI for non-vertebral and hip fractures. AAC severity was evaluated from lateral spine radiographs using Kauppila's semiquantitative score. Severe AAC (AAC score 5+) was associated with higher risk of vertebral fracture during 4 years of follow-up, after adjustment for confounders (age, BMI, walking, smoking, hip bone mineral density, prevalent vertebral fracture, systolic blood pressure, hormone replacement therapy) (OR=2.31, 95%CI: 1.24-4.30, p<0.01). In a similar model, severe AAC was associated with an increase in the hip fracture risk (HR=2.88, 95%CI: 1.00-8.36, p=0.05). AAC was not associated with the risk of any non-vertebral fracture. AAC was not associated with the fracture risk after 15 years of follow-up. In elderly women, severe AAC is associated with higher short-term risk of vertebral and hip fractures, but not with the long-term risk of these fractures. There is no association between AAC and risk of non-vertebral-non-hip fracture in older women. Our findings lend further support to the hypothesis that AAC and skeletal fragility are related.

Physical performance and radiographic and clinical vertebral fractures in older men.

In men, the association between poor physical performance and likelihood of incident vertebral fractures is unknown. Using data from the MrOS study (N = 5958), we describe the association between baseline physical performance (walking speed, grip strength, leg power, repeat chair stands, narrow walk [dynamic balance]) and incidence of radiographic and clinical vertebral fractures. At baseline and follow-up an average of 4.6 years later, radiographic vertebral fractures were assessed using semiquantitative (SQ) scoring on lateral thoracic and lumbar radiographs. Logistic regression modeled the association between physical performance and incident radiographic vertebral fractures (change in SQ grade ≥1 from baseline to follow-up). Every 4 months after baseline, participants self-reported fractures; clinical vertebral fractures were confirmed by centralized radiologist review of the baseline study radiograph and community-acquired spine images. Proportional hazards regression modeled the association between physical performance with incident clinical vertebral fractures. Multivariate models were adjusted for age, bone mineral density (BMD, by dual-energy X-ray absorptiometry [DXA]), clinical center, race, smoking, height, weight, history of falls, activity level, and comorbid medical conditions; physical performance was analyzed as quartiles. Of 4332 men with baseline and repeat radiographs, 192 (4.4%) had an incident radiographic vertebral fracture. With the exception of walking speed, poorer performance on repeat chair stands, leg power, narrow walk, and grip strength were each associated in a graded manner with an increased risk of incident radiographic vertebral fracture (p for trend across quartiles <0.001). In addition, men with performance in the worst quartile on three or more exams had an increased risk of radiographic fracture (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.33-2.45) compared with men with better performance on all exams. Clinical vertebral fracture (n =149 of 5813, 2.6%) was not consistently associated with physical performance. We conclude that poorer physical performance is associated with an increased risk of incident radiographic (but not clinical) vertebral fracture in older men.

Implications of expanding indications for drug treatment to prevent fracture in older men in United States: cross sectional and longitudinal analysis of prospective cohort study.

OBJECTIVES: To quantify incremental effects of applying different criteria to identify men who are candidates for drug treatment to prevent fracture and to examine the extent to which fracture probabilities vary across distinct categories of men defined by these criteria. DESIGN: Cross sectional and longitudinal analysis of a prospective cohort study. SETTING: Multicenter Osteoporotic Fractures in Men (MrOS) study in the United States. PARTICIPANTS: 5880 untreated community dwelling men aged 65 years or over classified into four distinct groups: osteoporosis by World Health Organization criteria alone; osteoporosis by National Osteoporosis Foundation (NOF) but not WHO criteria; no osteoporosis but at high fracture risk (at or above NOF derived FRAX intervention thresholds recommended for US); and no osteoporosis and at low fracture risk (below NOF derived FRAX intervention thresholds recommended for US). MAIN OUTCOME MEASURES: Proportion of men identified for drug treatment; predicted 10 year probabilities of hip and major osteoporotic fracture calculated using FRAX algorithm with femoral neck bone mineral density; observed 10 year probabilities for confirmed incident hip and major osteoporotic (hip, clinical vertebral, wrist, or humerus) fracture events calculated using cumulative incidence estimation, accounting for competing risk of mortality. RESULTS: 130 (2.2%) men were identified as having osteoporosis by using the WHO definition, and an additional 422 were identified by applying the NOF definition (total osteoporosis prevalence 9.4%). Application of NOF derived FRAX intervention thresholds led to 936 (15.9%) additional men without osteoporosis being identified as at high fracture risk, raising the total prevalence of men potentially eligible for drug treatment to 25.3%. Observed 10 year hip fracture probabilities were 20.6% for men with osteoporosis by WHO criteria alone, 6.8% for men with osteoporosis by NOF (but not WHO) criteria, 6.4% for men without osteoporosis but classified as at high fracture risk, and 1.5% for men without osteoporosis and classified as at low fracture risk. A similar pattern was noted in observed fracture probabilities for major osteoporotic fracture. Among men with osteoporosis by WHO criteria, observed fracture probabilities were greater than FRAX predicted probabilities (20.6% v 9.5% for hip fracture and 30.0% v 17.4% for major osteoporotic fracture). CONCLUSIONS AND RELEVANCE: Choice of definition of osteoporosis and use of NOF derived FRAX intervention thresholds have major effects on the proportion of older men identified as warranting drug treatment to prevent fracture. Among men identified with osteoporosis by WHO criteria, who comprised 2% of the study population, actual observed fracture probabilities during 10 years of follow-up were highest and exceeded FRAX predicted fracture probabilities. On the basis of findings from randomized trials in women, these men are most likely to benefit from treatment. Expanding indications for treatment beyond this small group has uncertain value owing to lower observed fracture probabilities and uncertain benefits of treatment among men not selected on the basis of WHO criteria.

High hip fracture risk in men with severe aortic calcification: MrOS study.

A significant link between cardiovascular disease and osteoporosis is established in postmenopausal women, but data for men are scarce. We tested the hypothesis that greater severity of abdominal aortic calcification (AAC) was associated with an increased risk of nonspine fracture in 5994 men aged ≥ 65 years. AAC was assessed on 5400 baseline lateral thoracolumbar radiographs using a validated visual semiquantitative score. Total hip bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Incident nonspine fractures were centrally adjudicated. After adjustment for age, body mass index (BMI), total hip BMD, fall history, prior fracture, smoking status, comorbidities, race, and clinical center, the risk of nonspine fracture (n=805) was increased among men with higher AAC (hazard ratio [HR] quartile 4 [Q4] [AAC score ≥ 9] versus quartile 1 [Q1] [0-1], 1.36; 96% confidence interval [CI], 1.10-1.68). This association was due to an increased risk of hip fracture (n=178) among men with higher AAC (HR Q4 versus Q1, 2.33; 95% CI, 1.41-3.87). By contrast, the association between AAC and the risk of nonspine, nonhip fracture was weaker and not significant (HR Q4 versus Q1, 1.22; 95% CI, 0.96-1.55). The findings regarding higher AAC and increased risk of fracture were not altered in additional analyses accounting for degree of trauma, estimated glomerular filtration rate, presence of lumbar vertebral fractures (which may bias AAC assessment), preexisting cardiovascular disease, ankle brachial index, or competing risk of death. Thus, in this large cohort of elderly men, greater AAC was independently associated with an increased risk of hip fracture, but not with other nonspine fractures. These findings suggest that AAC assessment may be a useful method for identification of older men at high risk of hip fracture.

Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women.

OBJECTIVE: Previous cross-sectional studies have observed alterations in activity rhythms in dementia patients but the direction of causation is unclear. We determined whether circadian activity rhythms measured in community-dwelling older women are prospectively associated with incident dementia or mild cognitive impairment (MCI). METHODS: Activity rhythm data were collected from 1,282 healthy community-dwelling women from the Study of Osteoporotic Fractures (SOF) cohort (mean age 83 years) with wrist actigraphy for a minimum of three 24-hour periods. Each participant completed a neuropsychological test battery and had clinical cognitive status (dementia, MCI, normal) adjudicated by an expert panel approximately 5 years later. All analyses were adjusted for demographics, body mass index (BMI), functional status, depression, medications, alcohol, caffeine, smoking, health status, and comorbidities. RESULTS: After 4.9 years of follow-up, 195 (15%) women had developed dementia and 302 (24%) had developed MCI. Older women with decreased activity rhythms had a higher likelihood of developing dementia or MCI when comparing those in the lowest quartiles of amplitude (odds ratio [OR] = 1.57; 95% CI, 1.09-2.25) or rhythm robustness (OR = 1.57; 95% CI, 1.10-2.26) to women in the highest quartiles. An increased risk of dementia or MCI (OR = 1.83; 95% CI, 1.29-2.61) was found for women whose timing of peak activity occurred later in the day (after 3:51 PM) when compared to those with average timing (1:34 PM-3:51 PM). INTERPRETATION: Older, healthy women with decreased circadian activity rhythm amplitude and robustness, and delayed rhythms have increased odds of developing dementia and MCI. If confirmed, future studies should examine whether interventions (physical activity, bright light exposure) that influence activity rhythms will reduce the risk of cognitive deterioration in the elderly.

Raloxifene, a selective estrogen receptor modulator, is renoprotective: a post-hoc analysis.

Estrogens have a protective effect on kidney fibrosis in several animal models. Here, we tested the effect of raloxifene, an estrogen receptor modulator, on the change in serum creatinine or estimated glomerular filtration rate (eGFR) and incident kidney-related adverse events. We performed a post-hoc analysis of the multiple outcomes of raloxifene evaluation trial, a double-masked, placebo-controlled randomized clinical trial encompassing 7705 post-menopausal women (aged 31-80 years) with osteoporosis. Participants were randomized to either of two doses of raloxifene, 60 or 120 mg/day, or placebo. Serum creatinine was measured at a central laboratory at baseline and annually. Adverse events were assessed every 6 months and uniformly categorized. Compared with those in the placebo group, participants on raloxifene had a slower yearly rate of increase in creatinine (significant at the low dose) and a significantly slower yearly rate of decrease in eGFR for both doses over 3 years of follow-up. Raloxifene was associated with significantly fewer kidney-related adverse events compared with placebo. Thus, treatment with raloxifene was safe and renoprotective. Clinical trials of raloxifene in post-menopausal women with kidney disease designed to look at kidney outcomes are needed to confirm these findings.

Does surgically induced weight loss improve daytime sleepiness?

Morbid obesity is associated with excessive daytime sleepiness and reduced health-related quality of life. We prospectively evaluated the pre- and postoperative responses of bariatric surgery recipients with the Epworth Sleepiness Scale (ESS) and the Short Form-12. Participants (n = 223; 79% women) with a mean body mass index (BMI) and ESS of 44.8 ± 7.9 kg/m(2) and 7.9 ± 4.5, respectively, received a vertical gastrectomy (76%) or Roux-en-Y gastric bypass (12%). Preoperatively, 30% of patients complained of excessive daytime sleepiness (ESS > 10). Patients with preoperative excessive daytime sleepiness were more obese (p = 0.002), had higher fasting glucose levels (p = 0.02), more likely to have a diagnosis of sleep-disordered breathing (p < 0.001), report snoring (p < 0.001), and had lower health-related quality of life measures particularly physical function (p < 0.001), depression (p = 0.006), and sexual satisfaction (p = 0.04) than non-sleepy patients. At 12-months postoperatively, most patients experienced a significant reduction in BMI (28.6 ± 5.5 kg/m(2), p < 0.001) and excessive daytime sleepiness (mean ESS 5.3 ± 3.3, p < 0.001). Patients with a clinically relevant improvement in the ESS at 12-months post-operatively had greater improvements in physical function (p = 0.009) and snoring (p = 0.010) and were more likely still using positive airway pressure therapy (p = 0.032) than patients without a clinically relevant improvement. Statistically and clinically significant improvements in all health-related quality of life measures were noted at 24 months. Bariatric surgery is associated with dramatic weight loss and improvements in physical functioning and daytime sleepiness.