The complex structure of human cortical bone evolves over multiple length-scales from its basic constituents of collagen molecules and hydroxyapatite crystals at the nanoscale to the osteonal structures at near-millimeter dimensions. There is a need to understand how all levels of the structure contribute to the deformation and fracture resistance of cortical bone under physiological loading conditions and how structural changes due to aging and disease lead to diminished mechanical properties. The first part of this thesis addresses the latter by using non-enzymatic crosslinking measurements and in situ small- and wide-angle x-ray scattering/diffraction to characterize changes in the bone structure at sub-micron dimensions, while synchrotron x-ray computed microtomography and in situ fracture-toughness measurements in the scanning electron microscope were performed to characterize corresponding changes at micron-scale dimensions. This multi-scale analysis allows us to better understand how load is transferred across multiple length-scales and how biological aging impacts energy absorption throughout the structure. The second part of this thesis addresses the fracture toughness of human cortical bone under multiaxial loading. Most studies to date have only considered the toughness of bone under mode I (tensile) loading conditions;​ however, due to the complex, anisotropic structure of cortical bone, the mode I fracture toughness is not necessarily the limiting value. Thus, this research investigates the effects of combined tensile and shear loading at the crack tip on the initiation and crack-growth toughnesses to better understand how bone fractures under physiologically relevant loading conditions.