Pharmaceutical agents used to treat osteoporosis significantly reduce fracture risk via different mechanisms that ultimately enhance either structural or material biomechanical properties. Bisphosphonates such as Alendronate (ALN) increase structural bone strength almost entirely by promoting increased bone volume and density, but at the expense of impaired material properties. Raloxifene (RAL) minimally affects bone mass yet significantly improves material properties leading to an enhancement in overall bone strength. These two distinct pathways for improving bone strength suggest that combination treatment could significantly reduce fracture risk more than either ALN or RAL monotherapy. The goal of this proposal is to determine if the combination of ALN and RAL will have a greater positive effect on bone structural mechanical properties compared to either agent alone by combining their positive effects on BMD (from ALN) and material properties (from RAL). A second goal of this project is to determine if a lower dose of ALN can be used when given in combination with RAL, to achieve at least equivalent BMD and bone strength as ALN alone at higher doses. Demonstrating efficacy for enhancing bone strength with a reduced dose of ALN could improve safety by reducing negative side effects that accompany treatment with oral BPs. The third goal is to determine if combination treatment with RAL is effective as a combination therapy with non-bisphosphonate anti- resorptives such as Denosumab, the newest FDA-approved anti-remodeling agent. The human antibody denosumab cannot be given to animals, yet other mechanisms of inhibiting the RANK-L pathway such as by using osteoprotogerin fusion compound (OPG-Fc) have been shown in pre-clinical studies to mimic the skeletal effects of denosumab. Specifically, the experiments in this project will test the hypotheses that 1) the combination of ALN and RAL at current clinical doses will improve bone's mechanical properties more than each drug alone, 2) lower doses of ALN used in combination with the clinical dose of RAL will produce at least equivalent effects on bone strength as mono-therapy with ALN at the current therapeutic dose, and 3) The combination of a OPG-Fc and RAL will improve bone's mechanical properties more than each drug alone. We will test these hypotheses using both traditional outcome measures (ex vivo bone density, histology, mechanics) as well as a novel in vivo assessment tool (BioDent) to longitudinally track changes in bone material properties in animals. The data generated in this proposal will be highly translatable as our analyses will establish the relationship between changes in mechanical properties assessed in vivo to more traditional measures that can only be only made on excised bone. Additionally, as all drugs in these studies are already FDA approved for treatment of osteoporosis, combination treatment could be rapidly translated to the clinic.