Human cortical bone, like many engineering materials, exhibits damage and fracture, due to cyclic loading and overloading, such as that experienced by the load-bearing long bones. Unlike engineering materials, bone possesses a unique ability to repair damage and reduce fracture risk. However, in cases such as athletes and military recruits, the rate and extent of damage formation can exceed the rate of repair, resulting in increased fracture risk until the damage is diagnosed and rest prescribed. In the elderly, and especially those afflicted with metabolic bone diseases such as osteoporosis, the rate of bone resorption exceeds the rate of formation of new bone, resulting in reduced cortical thickness, increased intracortical porosity and, thus, increased fracture risk. The overall objective of this project was to nondestructively investigate the spatial distribution of fatigue microdamage accumulation in cortical bone and factors that, upon interaction with microdamage, influence fracture susceptibility. Contrast-enhanced micro-CT detected increased microdamage in whole rat femora loaded in cyclic three-point bending relative to non-loaded controls, as well as the volumetric spatial distribution of microdamage relative to the whole bone morphology and non-uniform strain distribution resulting from bending. Spatial correlations between intracortical porosity, elevated mineralization, and fatigue microdamage were investigated by combining, for the first time, sequential, nondestructive, three-dimensional micro-CT measurements of each in cortical bone specimens subjected to cyclic loading followed by an overload to fracture. Microdamage at the fracture initiation site was found to be spatially correlated with intracortical porosity, but not highly mineralized tissue. The new spatial correlation methods were subsequently utilized to investigate the effects of age and loading mode on the fracture susceptibility of human cortical bone specimens. Interestingly, the influence of porosity on the initiation and propagation of microdamage was decreased in elderly (i.e., greater than 80 y/o) versus postmenopausal women donors. The observed spatial correlation between intracortical porosity and microdamage motivated future work exploring statistical predictions of fracture susceptibility based on spatial measurements of intracortical porosity, for example pore area, which predicted fracture susceptibility in a preliminary specimen cohort.