The recent reports of atypical femoral fractures (AFF), a catastrophic fracture of the subtrochanteric region or diaphysis of femur, and its possible association with long-term bisphosphonate (BP) use highlighted the importance of a thorough understanding of mechanical modifications in bone due to BP treatment. As one of the most commonly prescribed medications for osteoporosis, bisphosphonates modify mechanical and structural properties of bone by suppressing bone turnover. Recent experimental studies identified these possible alterations in bone due to long-term BP treatment as increased microcrack density and reduced material property heterogeneity. Experimental studies are limited in the assessment of the individual effect of these alterations on fracture resistance because multiple modifications coexist in the bone specimens. Thus, the goal of this study is to quantify the influence of the possible modifications caused by long-term BP treatment on fracture resistance of cortical bone using a novel finite element modeling approach. The first part of this study evaluated the influence of reduced material property heterogeneity on cortical bone fracture resistance utilizing compact tension specimens incorporating seven different microstructures. Next, the study evaluated individual and combined influence of both material property heterogeneity and preexisting microcrack density on three of these models. This was followed by evaluating the entire crack growth process including crack initiation and propagation in cortical bone. This modeling approach was then applied to femural fracture integrating whole femur geometry with a detailed cortical bone microstructure region resulting in multiscale simulations. The new modeling technique that was developed was also successfully integrated into a patient-specific human cortical bone biopsy model under three-point bending testing. In summary, the combined results of this study established new information that showed the influence of reduced material property heterogeneity, microcracks, microstructure, and femoral geometry on fracture resistance in cortical bone. It demonstrated that fracture resistance has a nonlinear relationship with material property heterogeneity and a limited increase in microcrack density improved fracture resistance. The results also showed that femoral fracture at regions similar to AFF site is influenced by femoral geometry (neck-shaft angle and anterior radius of curvature), microstructure and material property distribution of cortical bone. This new computational modeling approach provides a tool that can be used to improve the understanding of the effects of material level changes and microcrack densities due to prolonged BP use on the overall bone fracture behavior. It may also bring additional insight into the causes of unusual fractures, such as AFF and their possible association with long term BP use.