It has been estimated that 70% of advanced breast cancer patients will face the complication of bone metastases. Three processes are pivotal during bone metastatic growth of breast cancer, namely, tumor cell proliferation, angiogenesis, and osteolysis. During tumor-induced osteolysis, a number of cytokines and growth factors are released from the degraded bone matrix. These factors stimulate further tumor growth, tumor angiogenesis, and tumor-induced osteolysis. New therapies should target all relevant processes to halt this powerful feedback loop. Here, we characterized the new 2-methoxyestradiol analogue ENMD-1198 and showed that it is cytotoxic to tumor cells. Moreover, ENMD-1198 showed both antiangiogenic and vascular disruptive properties and was capable of protecting the bone against tumor-induced osteolysis. We confirmed the in vitro data with a series of in vivo experiments showing the beneficial effects of ENMD-1198 and ENMD-1198-based combination treatments of metastatic breast cancer in bone both on tumor progression and on survival with long-term ENMD-1198 treatment. We confirmed the in vivo relevance of the ENMD-1198 protective effect on bone both with X-ray radiographs and microcomputed tomography. In addition, we combined ENMD-1198 treatment with low-dose metronomic cyclophosphamide and the bisphosphonate risedronic acid, leading to a mild increase in treatment efficacy.