Bisphosphonates for the prevention of bone metastases

Preclinical studies have provided evidence that bisphosphonates have antitumor activity. Bisphosphonates have been shown to induce tumor cell apoptosis in vitro and reduce skeletal tumor burden in tumor xenograft models. Indirect evidence of bisphosphonate antitumor activity has been acquired from studies of clodronate, pamidronate, and zoledronic acid in patients with established bone metastases. Furthermore, clinical studies of daily oral clodronate adjuvant therapy suggest that bisphosphonates can prevent bone metastases, but their effect on overall survival is less certain. Pamidronate and zoledronic acid, potent nitrogen-containing bisphosphonates, have shown antitumor activity at approximately 10- to 100-fold lower concentrations than clodronate in vitro and may hold promise for the prevention of bone metastases. However, before the clinical application of bisphosphonates for the prevention of bone metastases can be initiated, clinical trials must assess the optimal stage of disease at which to initiate treatment, the duration of therapy, and the optimal dose and schedule to achieve clinically meaningful antitumor effects. Adjuvant studies of zoledronic acid in patients with breast cancer are in development and should further clarify the role of zoledronic acid in the prevention of bone metastases.