Fragility fractures affect 8.9 million people annually, which is characterized by low bone mineral density (BMD) and deteriorating bone microarchitecture. Clinical diagnosis of people with fracture prone bones includes assessment of BMD via DEXA. However, BMD accounts for only 60% of the variation in bone fracture risk, since bone fracture risk comprises of bone strength and toughness. In addition to BMD, strength and toughness are influenced by bone material quality and bone microarchitecture as well. Additionally, these contributors to bone fracture risk are genetically controlled and are functionally related to each other. Thus, it was hypothesized that bone material quality, structure, and their functional relationships with strength and toughness, contribute to fracture risk. In aim 1, femurs from mice subjected to skeletal unloading in microgravity had reduced fracture resistance. Microgravity disrupted the ability of osteocytes to remodel their surrounding bone matrix, resulting deteriorated bone material heterogeneity, softened mineralized collagen fibrils, and weakened extrinsic toughening mechanisms.

BMD, bone strength and toughness are all correlated, and these correlations called functional relationships are governed by genetics. However, functional relationships between bone microarchitecture and material quality have not been studied for genetically diverse group of mice. Additionally, how unloading affects the functional relationships is yet to be understood. Thus, in aim 2, it was hypothesized that functional relationships exist between bone material quality, bone structure and bone fracture risk across eight strains of mice with widely varying bone traits determined by genetics (i.e., in the Diversity Outbred, DO, founder strains), and these functional relationships become weaker with unloading. In aim 2, we found that functional relationships between bone microarchitecture, material quality and bone fracture risk exist for femurs of DO founder strains. Ratio of total area and bone length called slenderness ratio, bone material quality traits such as mineral:​matrix, crystallinity and their heterogeneities contributed to the functional relationships and estimation of bone fracture risk. Following unloading, the functional relationships associated with strength and toughness become separate. Additionally, functional relationships after unloading were heavily guided by bone microarchitectural changes.

Fracture resistance of bone is determined by its bone strength, i.e., stiffness, yield strength and bone toughness, i.e., resisting crack initiation and propagation. Intrinsic mechanisms represent the inherent resistance of bone material to elastic and plastic deformation via generating plasticity. Ribosylation of bones increases the advanced glycation end-products (AGEs) which increases non-enzymatic crosslinks and impair bone strength and toughness. Despite numerous studies, few studies have evaluated bone material quality assisted changes to tissue toughening mechanisms and risk of bone fracture with increased AGEs. Thus, in aim 3, it was hypothesized that bone material quality measures including tissue modulus (E), hardness (H), brittleness (H³/E²), tissue scratch toughness, material composition and material heterogeneity can explain changes to tissue toughening mechanisms that ultimately influence risk of bone fracture. In aim 3, we found that bones with ribosylation had reduced scratch toughness, tissue modulus, hardness and brittleness, along with poor macroscale strength and toughness. These results provide insight into how bone material quality changes associated with tissue toughening mechanisms contributes to increased fracture risk with increased AGEs. Collectively, work presented in this dissertation will enable better understanding of role of bone material quality in influencing bone fracture risk.