Human breast cancer frequently metastasizes to bone, and effective therapies for patients with bone metastasis are required. However, the molecular mechanism for the bone metastasis of human breast cancer has not yet been fully elucidated. The present study aimed to evaluate the importance of active osteoclasts and bone-derived insulin-like growth factors (IGFs) for the survival and growth of breast cancer cells in bone. Human breast cancer cell line MCF-7 cells were injected into human adult bone (HAB) implanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The mice were then treated with recombinant human osteoclastogenesis inhibitory factor/osteoprotegerin (rhOCIF/OPG), a decoy receptor for receptor activator of NF-kappaB ligand (RANKL), or an anti-human IGF monoclonal antibody. Histomorphometric analyses revealed that both treatments significantly decreased the tumor area of MCF-7 cells in cross-sections of the implanted HAB to about 30% of the tumor area in control mice, but had no effect on the growth of subcutaneously injected MCF-7 cells. Consistent with the results for the tumor area in HAB, there were fewer osteoclasts in the implanted HAB in rhOCIF/OPG-treated mice than in vehicle-treated mice. However, treatment with the anti-human IGF monoclonal antibody had no effect on the number of osteoclasts in HAB. The results indicate that the active osteoclasts induced by RANKL and the IGFs released as a result of bone resorption by these osteoclasts play crucial roles in the survival and growth of human breast cancer cells in bone and suggest that neutralization of bone-derived IGFs will be effective in preventing the development of bone tumors in breast cancer patients.