The induction of hypercalcemia in malignant disease is almost invariably associated with increased bone resorption. However, tumor-induced changes in bone formation and renal tubular resorption of calcium are also important factors that induce hypercalcemia in some patients. In addition, alterations in calcium fluxes to and from the extracellular fluid secondary to hypercalcemia are important in maintaining or aggravating the hypercalcemic effects of increased bone resorption. These factors significantly affect the responses to treatment of hypercalcemia with inhibitors of bone resorption. This study examined the relative importance of these factors and the effects of intravenous etidronate disodium (etidronate) in neoplastic bone disease with and without hypercalcemia and in Paget's disease of bone. It is concluded that intravenous etidronate is an effective inhibitor of bone resorption, which accounts in large measure for its effects on serum calcium concentrations. These studies of etidronate in hypercalcemia suggest the response is sustained for several weeks.