Project Summary/Abstract: The most reliable predictor of fracture risk is a previous fracture at any skeletal site. The etiology of this relationship is not fully known, but one contributing mechanism is that fracture initiates a systemic bone loss response, which increases future fracture risk at all skeletal sites. Our lab has generated multiple preclinical studies characterizing this systemic bone loss response following femur fracture in mice. However, the time course and magnitude of systemic bone loss and recovery in humans has not been investigated, and it is currently unknown if systemic bone loss differentially affects older people compared to young people. To address these knowledge gaps, we will use both standard clinical and cutting-edge high-resolution imaging to characterize the systemic bone loss response following a humerus fracture in human subjects. We hypothesize that post-fracture systemic bone loss: 1) will persist for 6 months or more after a humerus fracture followed by partial recovery, 2) will have a greater effect on trabecular bone than on cortical bone, and 3) will have delayed and diminished recovery in older subjects relative to younger subjects. To investigate these hypotheses, we will first determine the time course and magnitude of systemic bone mineral density (BMD) loss and recovery following humerus fracture in young (20-40 years old) and old (60-80 years old) human patients at axial and appendicular skeletal sites (lumbar spine, bilateral hips, tibiae, and forearms) at baseline, 3, 6, 18, and 36 months post-fracture and compare these patients to non-fractured control subjects. At each time point we will also investigate mechanisms of systemic bone loss by measuring serum biomarkers of bone remodeling and inflammation and tracking patient physical activity using accelerometers. Next, we will determine microstructural and biomechanical changes in the trabecular and cortical compartments during systemic bone loss and recovery following fracture in the same patients and how these differ by age. Using clinical quantitative computed tomography (QCT) and high-resolution peripheral QCT (HR-pQCT) at the ipsilateral and contralateral proximal femur, tibia, and radius, we will measure trabecular and cortical density and microstructure and use finite element analysis to estimate mechanical properties of bone. Altogether, these novel studies will reveal that systemic bone loss and recovery following fracture: 1) occurs in human patients similar to what we have shown in mice, but on a much longer timeline, 2) has differential effects at axial vs. appendicular skeletal sites and in trabecular vs. cortical bone, and 3) affects older people differently than younger people, potentially leaving older subjects with permanent deficits in bone mass and strength. The findings from these studies may ultimately help us identify mechanisms of systemic bone loss following fracture, and will inform therapeutic strategies and establish wi...