Tumor-bone interactions were experimentally studied using a bladder tumor in mice (MBT-2). The method consisted of subcutaneously inoculating tumor cells over the calvaria in nude mice after the periosteum was disrupted. This resulted in a local tumor that caused fragmentation of the bone. Bone destruction was found to increase in proportion to the number of osteoclasts in the earlier phase. The osteoclasts decreased in number when the tumors had grown large enough to envelop the residual bone. However, bone destruction continued and seemed to be mediated by the tumor cells by a mechanism that did not involve the osteoclasts. The effects of several agents were investigated in this model. High doses of calcitonin and cyclosporine reduced the bone resorption, and these agents may be effective in the early phase of bone destruction. A bisphosphonate derivative (AHBuBP) inhibited bone resorption markedly in the early and late phases of bone destruction. Autoradiography using carbon 14 (14C)-labeled AHBuBP showed that the isotope was concentrated at the surface of the bone adjacent to the MBT-2 tumors. These results suggest that bisphosphonates may make bone less susceptible to the actions of osteoclasts and tumor cells.