Understanding Biological Factors That Determine Implant Fixation in Bone could direct efforts to improve total joint replacement in humans. To determine which microarchitectural and bone matrix composition parameters contributed to implant fixation in rats, we surgically implanted a titanium rod into the femoral canal of rodent models of osteoporosis and type 2 diabetes, and then implemented a stepwise regression analysis after pushout testing. We next determined what factors contributed to osseointegration, a highly important factor to determining implant fixation in the previous study, by conducting a second experiment that attempted to vary hyperglycemia, bone remodeling, and systemic inflammation and again used the intramedullary implant and a rodent model of type 2 diabetes and a second stepwise regression analysis. Our first stepwise regression analysis determined that osseointegrated bone, trabecular bone, and cortical thickness explained the majority of the variance in implant fixation. Importantly, it was also determined that trabecular crystallinity, a compositional parameter, also significantly contributed. Our second stepwise regression analysis determined that trabecular and endocortical mineral apposition rates as well as hyperglycemia at the time of surgery explained the majority of the variance in osseointegration. Our studies highlight the importance of bone structure and composition to maintaining implant fixation and the importance of hyperglycemia and bone remodeling to proper osseointegration. Taken together, treatment strategies aimed at improving bone structure and composition, while also maintaining glycemic control and proper bone remodeling, should be prioritized.