In this competitive revision application, we aim to address three critical aims to understand the determinants and impact of fractures and peripheral bone loss in the ongoing MrOS study. In our first aim, we will characterize circumstances of fractures in the oldest old. We will leverage the longitudinal follow-up of MrOS men to carefully determine the circumstances of incident fractures in the oldest old, community-dwelling men. We hypothesize that the types and circumstances of fractures will differ between active non-frail men compared to inactive frail men. In our second aim, we will improve understanding of age-related loss of peripheral bone. Given the large impact of fractures in the peripheral skeleton, we will analyze recently obtained 5-year follow-up HR-pQCT measures of peripheral bone microarchitecture to gain insight into skeletal fragility in the peripheral skeleton. Specifically, we will a) establish the rate and character of peripheral bone loss in older men. We hypothesize that we will identify distinct patterns of cortical vs. trabecular bone deterioration; with cortical bone loss contributing more to declines in bone strength by µFEA than trabecular bone loss, b) determine whether low muscle mass and low activity are related to peripheral bone loss. We hypothesize that they will be robust, independent predictors of bone loss, and c) utilize systems biology approaches to identify novel pathways related to loss of peripheral bone density, structure and strength. We hypothesize that state-of-the-art multi- omic approaches, leveraging comprehensive proteomic and metabolomic measures, will identify biological pathways associated with increased peripheral bone loss and structural declines in older men. In our third aim, we will determine the utility of hip and spine CT to predict fracture risk in older men. With FDA approval and recent awarding of a CPT code, use of abdominal-pelvic CT images acquired for older medical reasons holds promise as a new clinical paradigm to expand the identification of those at high risk of fractures. We will compute new estimates of bone strength in 3695 men with existing MrOS CT scans to address key knowledge gaps for how to best utilize CT-FEA for fracture prediction. Specifically, we will a) determine whether bone strength from CT-FEA at the hip and spine predicts short- and long-term with fracture risk. We hypothesize that the combination of femoral and vertebral strength predicts incident fracture better than either alone, and that femoral and vertebral strength predict both short- and long-term fracture risk as well as DXA- BMD, and b) simulate multiple fall-loading directions to quantify hip strength. We posit that femoral strength in the “weakest” loading direction better predicts hip fracture than the “standard” sideways fall loading direction. MrOS is uniquely suited to address several key clinical and mechanistic knowledge gaps regarding skeletal fragility in older men. The study's comprehens...