Tumor cells alter the bone microenvironment by stimulating osteoclasts parathyroid hormone–related protein (PTHRP), IL-6, IL-1, and TNF-α and by stimulating osteoblasts endothelin-1 (ET-1), FGF, PDGF, IGFs, TGF-β, and bone morphogenic proteins (BMPs). Osteolysis, in turn, releases TGF-β, TNF-α, and EGF, stimulating cancer cell proliferation. Receptor activator of NF-κB ligand (RANKL) expression by osteoblasts binds to the RANK receptor, promoting osteoclast formation and function. Therapies targeting bone metastases include those that target the prostate cancer cells themselves by inhibiting growth factor receptors or by targeting cancer cell antigens (Mucin 1 [MUC-1], BLP25 liposomal vaccine; and PSMA; J591 antibody conjugates). Alternatively, several therapies target the supporting host cells. Zoledronate, denosumab, dasatinib, CNTO328, samarium, and strontium all target osteoclast function to inhibit osteolysis. Atrasentan targets the ET-1 receptor on osteoblasts. Antiangiogenesis drugs target the endothelial cell and include bevacizumab, which targets VEGF, and cilengitide, which targets α_vβ_3/5 integrins. Immunotherapy approaches include inhibiting the infiltration of tumor-associated macrophages by inhibiting CCL2, prolonging T cell response by inhibiting the inhibitory receptor CTL-associated antigen–4 (CTLA-4) using the antibody ipilimumab (MDX-010), and stimulating antigen-presenting cells through vaccines such as GVAX and Sipuleucel-T. CCR2, CC chemokine receptor 2.