Future directions in the treatment and prevention of bone metastases.

Preclinical studies are providing a growing body of evidence that bisphosphonates, particularly nitrogen-containing bisphosphonates, have antitumor activity. Bisphosphonates induce tumor cell apoptosis and reduce skeletal tumor burden in tumor xenograft models. Clinical studies with daily oral clodronate suggest that bisphosphonates can prevent bone metastases when used in the adjuvant setting, but the effect on overall survival is less certain. The more potent nitrogen-containing bisphosphonates, i.e., pamidronate and zoledronic acid, have demonstrated antitumor activity at approximately 10- to 100-fold lower concentrations than clodronate in vitro. A number of important unanswered questions must be addressed regarding the optimal use of bisphosphonates for prevention of bone metastases. For example, when should treatment begin, how long must treatment be continued, and what are the optimal dose and schedule to achieve clinically meaningful antitumor effects? Adjuvant studies of zoledronic acid in patients with breast and prostate cancer are under development, and the results are eagerly anticipated.