ABSTRACT Falls and decreased physical function increase markedly with age and result in injury, hospitalization, and death. Safe, cost-effective primary prevention strategies are needed to reduce these adverse outcomes in the aging U.S. population. Basic, preclinical, and clinical studies suggest that flavanols, a class of nutrients present in high concentrations in cocoa, have favorable effects on muscle and physical performance. Flavanols decrease oxidative stress and improve biomarkers of mitochondrial biogenesis and muscle growth. Emerging studies show potential benefits of supplemental cocoa flavanols on physical performance, including grip strength and walking speed in older adults. However, there are no large, long-term randomized controlled trials (RCTs) of the effects of supplemental flavanols on falls, muscle performance, and/or fall-related injuries. In an ancillary study to the COcoa Supplement and Multivitamins Outcomes Study (COSMOS), which is testing the effects of supplemental cocoa flavanols and/or multivitamin for the prevention of cardiovascular disease and cancer, we propose the first large, placebo-controlled, prospective study to determine whether supplemental flavanols reduce falls and improve musculoskeletal health in women aged ≥ 65 and men aged ≥ 60. In the proposed study, we will determine effects of a cocoa flavanol supplement [600 mg/d flavanols, including 80 mg (-)- epicatechins] and/or multivitamin on the following clinically meaningful outcomes: falls in the overall COSMOS cohort (n=21,444) and physical performance in a clinic sub-cohort (n=603). We will test the following hypotheses: Aim 1: In the overall COSMOS cohort, cocoa flavanol supplementation will reduce risk of: (a) injurious fall(s) resulting in a visit to a healthcare provider or hospital with medical record review and (b) two or more falls per year and (c) injurious fall(s) (not resulting in healthcare utilization) as assessed by annual questionnaires. Aim 2: In the clinic sub-cohort, cocoa flavanol supplementation will benefit physical performance measures at 2-year post randomization, as assessed by grip strength, walking speed, and Short Physical Performance Battery (a composite of standing balance, walking speed, and chair stands). Aim 3: In the overall COSMOS cohort, cocoa flavanol supplementation reduces incident fractures as assessed by annual questionnaires. We will explore whether effects of cocoa flavanols on fracture outcomes are mediated through falls and/or bone density changes. In exploratory aims we will also assess effects of multivitamins on these same outcomes. RCTs testing effects of multivitamins on falls and musculoskeletal outcomes are lacking. This ancillary study maximizes cost-efficiency to fill gaps in knowledge regarding effects of flavanols for the primary prevention of falls. We expect the proposed, rigorous translational study will elucidate whether supplemental flavanols improve musculoskeletal health and prevent falls an...