Over 1.5 million osteoporotic bone fractures occur each year in the United States, with annual treatment costs predicted to exceed $25.3 billion by 2025. Osteoporotic fractures are associated with skeletal fragility resulting from low bone mass and microstructural bone deterioration. While existing drug therapies slow bone loss, they cannot fully restore bone structure. Therefore, is it more effective to maximize peak bone mass in early adulthood, with each 1% increase in peak bone mass estimated to provide 1.3 years of osteoporosis-free life. Exercise is a potentially safe and cost-accessible strategy for increasing bone mass and preventing fractures. Several in vivo animalloading models have demonstrated that bone adapts to mechanical loading, with bone formation occurring in proportion to bone strain (relative deformation). In humans, elite athletes experience site-specific skeletal adaptations, and have higher bone density than their peers. Clinical studies have shown that high-impact and resistive exercise generally leads to consistent, modest increases in bone density. However, there are no evidence-based bone loading targets or methods to tuneinterventions for individuals. This is largely due to a lack of data relating human bone adaptation to bone strain, which is challenging to estimate non-invasively.

This Dissertation used an upper extremity bone loading model to establish quantitative relationships between bone strain and adaptation in the distal radius of healthy adult women. This was accomplished using a 12-month randomized controlled trial, in which participants performed a voluntary, cyclic forearm loading task or served in a control group. Computed tomography (CT) and high resolution peripheral quantitative CT (HRpQCT) wereused to measure changes in bone structure and generate participant-specific finite element (FE) models to estimate bone strain during simulated forearm loading. Wefound that average changes in bone structure parameters were correlated to a mechanical loading dose considering bone strain magnitude, strain rate, and number of loading sessions. Additionally, we observed at the microstructural level significant spatialrelationships between low bone strain and bone resorption, and between high strains and both formation and resorption. Finally, we developed a forward simulation of strain-driven adaptation and compared predicted changes to experimentally measured bone adaptation. Overall, we have established a combined experimental-computational approach to systematically study the mechanism of human bone adaptation and inform the design of exercise interventions for the prevention of fractures.