Chemokine CXCL9, a marker of inflammaging, is associated with changes of muscle strength and mortality in older men.

Our study examined associations of the CXC motif chemokine ligand 9 (CXCL9), a pro-inflammatory protein implicated in age-related inflammation, with musculoskeletal function in elderly men. We found in certain outcomes both cross-sectional and longitudinal significant associations of CXCL9 with poorer musculoskeletal function and increased mortality in older men. This requires further investigation. PURPOSE: We aim to determine the relationship of (CXCL9), a pro-inflammatory protein implicated in age-related inflammation, with both cross-sectional and longitudinal musculoskeletal outcomes and mortality in older men. METHODS: A random sample from the Osteoporotic Fractures in Men (MrOS) Study cohort (N = 300) was chosen for study subjects that had attended the third and fourth clinic visits, and data was available for major musculoskeletal outcomes (6 m walking speed, chair stands), hip bone mineral density (BMD), major osteoporotic fracture, mortality, and serum inflammatory markers. Serum levels of CXCL9 were measured by ELISA, and the associations with musculoskeletal outcomes were assessed by linear regression and fractures and mortality with Cox proportional hazards models. RESULTS: The mean CXCL9 level of study participants (79.1 ± 5.3 years) was 196.9 ± 135.2 pg/ml. There were significant differences for 6 m walking speed, chair stands, physical activity scores, and history of falls in the past year across the quartiles of CXCL9. However, higher CXCL9 was only significantly associated with changes in chair stands (ß = - 1.098, p < 0.001) even after adjustment for multiple covariates. No significant associations were observed between CXCL9 and major osteoporotic fracture or hip BMD changes. The risk of mortality increased with increasing CXCL9 (hazard ratio quartile (Q)4 vs Q1 1.98, 95% confidence interval 1.25-3.14; p for trend < 0.001). CONCLUSIONS: Greater serum levels of CXCL9 were significantly associated with a decline in chair stands and increased mortality. Additional studies with a larger sample size are needed to confirm our findings.

Epidemiology of fractures in adults of African ancestry with diabetes mellitus: A systematic review and meta-analysis.

Diabetes mellitus (DM) is associated with increased fracture risk in White adults. However, the impact of DM on fractures in Black adults is unknown. This systematic review and meta-analysis investigated the association between DM and fractures in adults of African ancestry. MEDLINE, Scopus, CINAHL and Embase databases were searched from their inception up to November 2023 for all studies in the English language investigating the epidemiology of fractures (prevalence, incidence, or risk) in Black men and women (age ≥ 18 years) with type 1 or type 2 DM. Effect sizes for prevalence of previous fractures (%) and incident fracture risk (hazard ratio [HR]) were calculated using a random-effects model on Stata (version 18.0). There were 13 eligible studies, of which 12 were conducted in Black adults from the United States, while one was conducted in adults of West African ancestry from Trinidad and Tobago. We found no fracture data in Black adults with DM living in Africa. Five studies were included in a meta-analysis of incident fracture risk, reporting data from 2926 Black and 6531 White adults with DM. There was increased risk of fractures in Black adults with DM compared to non-DM (HR = 1.65; 95 % confidence interval [CI]: 1.14, 2.39). The risk of fractures was also higher in White adults with DM compared to non-DM (HR = 1.31; 95 % CI: 1.06, 1.61) among these studies. Five studies were included in a meta-analysis of fracture prevalence, of which three also reported fracture prevalence in White adults. There were 175 previous fractures among 993 Black adults with DM and 384 previous fractures among 1467 White adults with DM, with a pooled prevalence of 17.5 % (95 % CI: 15.4, 19.6) and 25.8 % (95 % CI: 4.8, 46.8), respectively. Our results indicate a high burden of fractures in Black adults with DM.

Pre-treatment bone mineral density (BMD) and the benefit of pharmacologic treatment on fracture risk and BMD change: analysis from the FNIH-ASBMR SABRE project.

Some osteoporosis drug trials have suggested that treatment is more effective in those with low bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA). This study used data from a large set of randomised controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We used individual patient data from 25 RCTs (103 086 subjects) of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. Participants were stratified into femoral neck (FN) BMD T-score subgroups (≤ -2.5, > -2.5). We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes and logistic regression for the radiographic vertebral fracture outcome. We also performed analyses based on BMD quintiles. Overall, 42% had a FN BMD T-score ≤ -2.5. Treatment with anti-osteoporosis drugs led to significant reductions in fractures in both T-score ≤ -2.5 and > -2.5 subgroups. Compared to those with FN BMD T-score > -2.5, the risk reduction for each fracture outcome was greater in those with T-score ≤ -2.5, but only the all fracture outcome reached statistical significance (interaction p = 0.001). Results were similar when limited to bisphosphonate trials. In the quintile analysis, there was significant anti-fracture efficacy across all quintiles for vertebral fractures and with greater effects on fracture risk reduction for non-vertebral, all and all clinical fractures in the lower BMD quintiles (all interaction p ≤ 0.03). In summary, anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD. Significant fracture risk reduction with treatment for 4 of the 5 fracture endpoints was seen in participants with T-scores above -2.5, though effects tended to be larger and more significant in those with baseline T-scores <-2.5.

It is important to know whether our treatments for osteoporosis are effective at reducing the risk of fracture no matter what the bone mineral density (BMD) before starting treatment. This study used data from many clinical trials to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We found that anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD, though effects tended to be larger and more significant in those with lower BMD scores.

A protocol for the prospective study of urinary cadmium with risk of fracture, bone loss, and muscle loss.

Cadmium (Cd) is a heavy metal and natural element found in soil and crops with increasing concentrations linked to phosphate fertilizers and sewage sludge applied to crop lands. A large fraction of older US men and woman have documented Cd exposure. Cd exposure has proven health concerns such as risk of lung cancer from inhalation and impaired renal function; however, growing evidence suggests it also influences bone and muscle health. Given that low levels of Cd could affect bone and muscle, we have designed prospective studies using the two largest and most detailed US studies of bone health in older men and women: the Osteoporotic Fractures in Men Study and the Study of Osteoporotic Fractures. We are investigating the association of urinary cadmium (U-Cd), as a surrogate for long-term Cd exposure, with bone and muscle health. Building off suggestive evidence from mechanistic and cross-sectional studies, this will be the first well-powered prospective study of incident fracture outcomes, bone loss, and muscle loss in relation to U-Cd, an established biomarker of long-term Cd exposure. The following is a proposed protocol for the intended study; if successful, the proposed studies could be influential in directing future US policy to decrease Cd exposure in the US population similar to recent policies adopted by the European Union to limit Cd in fertilizers.

Role of Cardiorespiratory Fitness and Mitochondrial Oxidative Capacity in Reduced Walk Speed of Older Adults With Diabetes.

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

Childhood adverse life events and skeletal muscle mitochondrial function.

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

Influence of age on the efficacy of pharmacologic treatments on fracture risk reduction and increases in BMD: RCT results from the FNIH-ASBMR-SABRE project.

There is a common belief that antiosteoporosis medications are less effective in older adults. This study used data from randomized controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments and their effects on BMD differ in people ≥70 compared to those <70 yr. We used individual patient data from 23 RCTs of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. We assessed the following fractures: radiographic vertebral, non-vertebral, hip, all clinical, and all fractures. We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes, logistic regression for the radiographic vertebral fracture outcome, and linear regression to estimate treatment effect on 24-mo change in hip and spine BMD in each age subgroup. The analysis included 123 164 (99% female) participants; 43% being ≥70 yr. Treatment with anti-osteoporosis drugs significantly and similarly reduced fractures in both subgroups (eg, odds ratio [OR] = 0.47 and 0.51 for vertebral fractures in those below and above 70 yr, interaction P = .19; hazard ratio [HR] for all fractures: 0.72 vs 0.70, interaction P = .20). Results were similar when limited to bisphosphonate trials with the exception of hip fracture risk reduction which was somewhat greater in those <70 (HR = 0.44) vs ≥70 (HR = 0.79) yr (interaction P = .02). Allocation to anti-osteoporotic drugs resulted in significantly greater increases in hip and spine BMD at 24 mo in those ≥70 compared to those <70 yr. In summary, anti-osteoporotic medications similarly reduced the risk of fractures regardless of age, and the few small differences in fracture risk reduction by age were of uncertain clinical significance.

Medications used for osteoporosis maybe are less effective in older adults. This study used data from clinical trials to determine whether these medications work equally well in reducing the risk of fractures in people ≥70 compared to those <70 yr. The analysis included 123 164 participants with data from 23 trials. Treatment with anti-osteoporosis drugs significantly reduced fractures in both groups in a similar way. The BMD increased more in the older group.

Signatures of cysteine oxidation on muscle structural and contractile proteins are associated with physical performance and muscle function in older adults: Study of Muscle, Mobility and Aging (SOMMA).

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (R = 0.48) between a higher oxidation level of eight Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging.

Percutaneous biopsies of skeletal muscle and adipose tissue in individuals older than 70: methods and outcomes in the Study of Muscle, Mobility and Aging (SOMMA).

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

Energetics and clinical factors for the time required to walk 400 m: The Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: Walking slows with aging often leading to mobility disability. Mitochondrial energetics has been found to be associated with gait speed over short distances. Additionally, walking is a complex activity but few clinical factors that may be associated with walk time have been studied. METHODS: We examined 879 participants ≥70 years and measured the time to walk 400 m. We tested the hypothesis that decreased mitochondrial energetics by respirometry in muscle biopsies and magnetic resonance spectroscopy in the thigh and is associated with longer time to walk 400 m. We also used cardiopulmonary exercise testing to assess the energetic costs of walking: maximum oxygen consumption (VO2peak) and energy cost-capacity (the ratio of VO2, at a slow speed to VO2peak). In addition, we tested the hypothesis that selected clinical factors would also be associated with 400-m walk time. RESULTS: Lower Max OXPHOS was associated with longer walk time, and the association was explained by the energetic costs of walking, leg power, and weight. Additionally, a multivariate model revealed that longer walk time was also significantly associated with lower VO2peak, greater cost-capacity ratio, weaker leg power, heavier weight, hip and knee stiffness, peripheral neuropathy, greater perceived exertion while walking slowly, greater physical fatigability, less moderate-to-vigorous exercise, less sedentary time, and anemia. Significant associations between age, sex, muscle mass, and peripheral artery disease with 400-m walk time were explained by other clinical and physiologic factors. CONCLUSIONS: Lower mitochondrial energetics is associated with needing more time to walk 400 m. This supports the value of developing interventions to improve mitochondrial energetics. Additionally, doing more moderate-to-vigorous exercise, increasing leg power, reducing weight, treating hip and knee stiffness, and screening for and treating anemia may reduce the time required to walk 400 m and reduce the risk of mobility disability.

Signatures of Cysteine Oxidation on Muscle Structural and Contractile Proteins Are Associated with Physical Performance and Muscle Function in Older Adults: Study of Muscle, Mobility and Aging (SOMMA).

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (r = 0.48) between a higher oxidation level of 8 Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impair muscle power and strength, walking speed, and cardiopulmonary fitness with aging.

Role of Cardiorespiratory Fitness and Mitochondrial Energetics in Reduced Walk Speed of Older Adults with Diabetes in the Study of Muscle, Mobility and Aging (SOMMA).

Rationale: Cardiorespiratory fitness and mitochondrial energetics are associated with reduced walking speed in older adults. The impact of cardiorespiratory fitness and mitochondrial energetics on walking speed in older adults with diabetes has not been clearly defined. Objective: To examine differences in cardiorespiratory fitness and skeletal muscle mitochondrial energetics between older adults with and without diabetes. We also assessed the contribution of cardiorespiratory fitness and skeletal muscle mitochondrial energetics to slower walking speed in older adults with diabetes. Findings: Participants with diabetes had lower cardiorespiratory fitness and mitochondrial energetics when compared to those without diabetes, following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. 4-m and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walk speed between older adults with and without diabetes. Further adjustments of BMI and co-morbidities further explained the group differences in walk speed. Conclusions: Skeletal muscle mitochondrial energetics and cardiorespiratory fitness contribute to slower walking speeds in older adults with diabetes. Cardiorespiratory fitness and mitochondrial energetics may be therapeutic targets to maintain or improve mobility in older adults with diabetes. ARTICLE HIGHLIGHTS: Why did we undertake this study? To determine if mitochondrial energetics and cardiorespiratory fitness contribute to slower walking speed in older adults with diabetes. What is the specific question(s) we wanted to answer? Are mitochondrial energetics and cardiorespiratory fitness in older adults with diabetes lower than those without diabetes? How does mitochondrial energetics and cardiorespiratory fitness impact walking speed in older adults with diabetes? What did we find? Mitochondrial energetics and cardiorespiratory fitness were lower in older adults with diabetes compared to those without diabetes, and energetics, and cardiorespiratory fitness, contributed to slower walking speed in those with diabetes. What are the implications of our findings? Cardiorespiratory fitness and mitochondrial energetics may be key therapeutic targets to maintain or improve mobility in older adults with diabetes.

Energetics and Clinical Factors for the Time Required to Walk 400 Meters The Study of Muscle, Mobility and Aging (SOMMA).

Background: Walking slows with aging often leading to mobility disability. Mitochondrial energetics has been found to influence gait speed over short distances. Additionally, walking is a complex activity but few clinical factors that may influence walk time have been studied. Methods: We examined 879 participants ≥70 years and measured the time to walk 400m. We tested the hypothesis that decreased mitochondrial energetics by respirometry in muscle biopsies and magnetic resonance spectroscopy in the thigh, is associated with longer time to walk 400m. We also used cardiopulmonary exercise testing to assess the energetic costs of walking: maximum oxygen consumption (VO 2 peak) and energy cost-capacity (the ratio of VO2, at a slow speed to VO 2 peak). In addition, we tested the hypothesis that selected clinical factors would also be associated with 400m walk time. Results: Lower Max OXPHOS was associated with longer walk time and the association was explained by the energetics costs of walking, leg power and weight. Additionally, a multivariate model revealed that longer walk time was also significantly associated with lower VO 2 peak, greater cost-capacity ratio, weaker leg power, heavier weight, hip and knee stiffness, peripheral neuropathy, greater perceived exertion while walking slowly, greater physical fatigability, less moderate-to-vigorous exercise, less sedentary time and anemia. Significant associations between age, sex, muscle mass, and peripheral artery disease with 400m walk time were explained by other clinical and physiologic factors. Conclusions: Lower mitochondrial energetics is associated with needing more time to walk 400m. This supports the value of developing interventions to improve mitochondrial energetics. Additionally, doing more moderate-to-vigorous exercise, increasing leg power, reducing weight, treating hip and knee stiffness, and screening for and treating anemia may reduce the time required to walk 400m and reduce the risk of mobility disability.

Childhood adverse life events and skeletal muscle mitochondrial function.

Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events "get under the skin" to influence physical wellbeing. Using data from the Study of Muscle, Mobility and Aging (n=879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (1) maximal adenosine triphosphate production (ATP max ) and (2) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing 1+ adverse childhood event. After adjustment, each additional event was associated with -0.07 SD (95% CI= - 0.12, -0.01) lower ATP max . No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism in understanding how early social stress influences health in later life.

Generalizability of Deep Learning Classification of Spinal Osteoporotic Compression Fractures on Radiographs Using an Adaptation of the Modified-2 Algorithm-Based Qualitative Criteria.

RATIONALE AND OBJECTIVES: Spinal osteoporotic compression fractures (OCFs) can be an early biomarker for osteoporosis but are often subtle, incidental, and underreported. To ensure early diagnosis and treatment of osteoporosis, we aimed to build a deep learning vertebral body classifier for OCFs as a critical component of our future automated opportunistic screening tool. MATERIALS AND METHODS: We retrospectively assembled a local dataset, including 1790 subjects and 15,050 vertebral bodies (thoracic and lumbar). Each vertebral body was annotated using an adaption of the modified-2 algorithm-based qualitative criteria. The Osteoporotic Fractures in Men (MrOS) Study dataset provided thoracic and lumbar spine radiographs of 5994 men from six clinical centers. Using both datasets, five deep learning algorithms were trained to classify each individual vertebral body of the spine radiographs. Classification performance was compared for these models using multiple metrics, including the area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, and positive predictive value (PPV). RESULTS: Our best model, built with ensemble averaging, achieved an AUC-ROC of 0.948 and 0.936 on the local dataset's test set and the MrOS dataset's test set, respectively. After setting the cutoff threshold to prioritize PPV, this model achieved a sensitivity of 54.5% and 47.8%, a specificity of 99.7% and 99.6%, and a PPV of 89.8% and 94.8%. CONCLUSION: Our model achieved an AUC-ROC>0.90 on both datasets. This testing shows some generalizability to real-world clinical datasets and a suitable performance for a future opportunistic osteoporosis screening tool.

Investigation of the association of weight loss with radiographic hip osteoarthritis in older community-dwelling female adults.

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

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.

Mitochondrial Energetics in Skeletal Muscle Are Associated With Leg Power and Cardiorespiratory Fitness in the Study of Muscle, Mobility and Aging.

BACKGROUND: Mitochondrial energetics are an important property of aging muscle, as generation of energy is pivotal to the execution of muscle contraction. However, its association with functional outcomes, including leg power and cardiorespiratory fitness, is largely understudied. METHODS: In the Study of Muscle, Mobility, and Aging, we collected vastus lateralis biopsies from older adults (n = 879, 70-94 years, 59.2% women). Maximal State 3 respiration (Max OXPHOS) was assessed in permeabilized fiber bundles by high-resolution respirometry. Capacity for maximal adenosine triphosphate production (ATPmax) was measured in vivo by 31P magnetic resonance spectroscopy. Leg extension power was measured with a Keiser press system, and VO2 peak was determined using a standardized cardiopulmonary exercise test. Gender-stratified multivariate linear regression models were adjusted for age, race, technician/site, adiposity, and physical activity with beta coefficients expressed per 1-SD increment in the independent variable. RESULTS: Max OXPHOS was associated with leg power for both women (ß = 0.12 Watts/kg, p < .001) and men (ß = 0.11 Watts/kg, p < .050). ATPmax was associated with leg power for men (ß = 0.09 Watts/kg, p < .05) but was not significant for women (ß = 0.03 Watts/kg, p = .11). Max OXPHOS and ATPmax were associated with VO2 peak in women and men (Max OXPHOS, ß women = 1.03 mL/kg/min, ß men = 1.32 mL/kg/min; ATPmax ß women = 0.87 mL/kg/min, ß men = 1.50 mL/kg/min; all p < .001). CONCLUSIONS: Higher muscle mitochondrial energetics measures were associated with both better cardiorespiratory fitness and greater leg power in older adults. Muscle mitochondrial energetics explained a greater degree of variance in VO2 peak compared to leg power.

Diabetes Mellitus and the Benefit of Antiresorptive Therapy on Fracture Risk.

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

Deep learning predicts all-cause mortality from longitudinal total-body DXA imaging.

Background: Mortality research has identified biomarkers predictive of all-cause mortality risk. Most of these markers, such as body mass index, are predictive cross-sectionally, while for others the longitudinal change has been shown to be predictive, for instance greater-than-average muscle and weight loss in older adults. And while sometimes markers are derived from imaging modalities such as DXA, full scans are rarely used. This study builds on that knowledge and tests two hypotheses to improve all-cause mortality prediction. The first hypothesis is that features derived from raw total-body DXA imaging using deep learning are predictive of all-cause mortality with and without clinical risk factors, meanwhile, the second hypothesis states that sequential total-body DXA scans and recurrent neural network models outperform comparable models using only one observation with and without clinical risk factors. Methods: Multiple deep neural network architectures were designed to test theses hypotheses. The models were trained and evaluated on data from the 16-year-long Health, Aging, and Body Composition Study including over 15,000 scans from over 3000 older, multi-race male and female adults. This study further used explainable AI techniques to interpret the predictions and evaluate the contribution of different inputs. Results: The results demonstrate that longitudinal total-body DXA scans are predictive of all-cause mortality and improve performance of traditional mortality prediction models. On a held-out test set, the strongest model achieves an area under the receiver operator characteristic curve of 0.79. Conclusion: This study demonstrates the efficacy of deep learning for the analysis of DXA medical imaging in a cross-sectional and longitudinal setting. By analyzing the trained deep learning models, this work also sheds light on what constitutes healthy aging in a diverse cohort.