This research will test a new and innovative approach for treating metastatic breast cancer in bone by delivering ²²⁵Ac-based radiotherapy using osteoclast inhibitors as delivery vehicles.  This approach has never been tested. Thus, the proposed research will demonstrate, for the first time, that delivering high cytotoxic ²²⁵Ac-based alpha particle to osteolytic lesions with bisphosphonates will be a new and important strategy to improve morbidity and mortality of breast cancer patients with bone metastases. Moreover, bisphosphonates may also synergistically inhibit osteoclast activities and tumor growth in the bone.  Moreover, no study to date has examined the direct effects of treatments for bone metastases on bone pain in vivo. Our animal model will allow us to longitudinally measure: (i) tumor growth in the bone, (ii) patterns of skeletal and tumor innervation, (iii) bone remodeling, and (iv) pain behaviors, all in the same animal. Moreover, this animal model will allow us to determine whether osteoclast-targeted alpha particle therapies can be better treatments for both bone metastases and its resultant pain.