Mechanisms of action of bisphosphonates on tumor cells and prospects for use in the treatment of malignant osteolysis

Malignant osteolysis is a common complication of many cancers, most notably breast cancer, prostate cancer, and multiple myeloma. Hypercalcemia, pain, and fractures are the main manifestations. Malignant osteolysis can be fat al or cause a rapid deterioration in quality of life. The underlying mechan ism in tumor cem-mediated activation of osteoclasts, whose function is norm ally to resorb bone. It follows that pharmacological agents capable of inhi biting osteoclast activity, including bisphosphonates, are likely to be use ful in the treatment of malignant osteolysis. Also, experimental evidence s uggest that bisphosphonates act on the tumor cells themselves, either by in hibiting mechanisms involved in the development of bone metastasis (tumor i nvasion, adhesion of tumor cells to the bone matrix) or by inducing apoptos is of tumor cells. Many clinical trials have found bisphophonates to be eff ective in the treatment of complications due to malignant osteolysis. Based on these studies, bisphosphonates are now indicated to treat hypercalcemia and to prevent skeletal complications of metastatic breast cancer and myel oma, in a dosage of 1600 mg.d orally for clodronate or 90 mg every four wee ks intravenously for pamidronate. Osteoclast inhibition is clearly the mech anism underlying the efficacy of bisphosphonates in these clinical trials. Recent clinical trials found that prophylactic bisphosphonates therapy in p atients with nonmetastasic breast cancer decreased the incidence of bone me tastases, thus supporting a direct effect of biphosphonates on tumor cells. However, conflicting experimental and clinical data have been reported, so that it remains uncertain whether bisphosphonates have antitumor effects i n vivo in humans. Nevertheless, biphosphonates now have an undisputed place in the therapeutic armamentarium far cancer. (C) 2000 Editions scientifiqu es et medicales Elsevier SAS.