In vitro and in vivo antitumor effects of bisphosphonates.

Bisphosphonates are powerful inhibitors of osteoclast-mediated bone resorption. They are currently used in the palliative treatment of bone metastases. However, bisphosphonates do not only act on osteoclasts. There is now extensive in vitro preclinical evidence that bisphosphonates can act on tumor cells: they inhibit tumor cell adhesion to mineralized bone as well as tumor cell invasion and proliferation. Bisphosphonates induce also tumor cell apoptosis and stimulate gammadelta T cell cytotoxicity against tumor cells. In vivo, bisphosphonates inhibit bone metastasis formation and reduce skeletal tumor burden. This may reflect direct antitumor effects and indirect effects via inhibition of bone resorption. In addition, bisphosphonates inhibit experimental angiogenesis in vitro and in vivo. Understanding the molecular mechanisms through which bisphosphonates act on tumor and endothelial cells will be undoubtedly an important task in the future. It will allow the design of clinical trials to investigate whether the antitumor activity of bisphosphonates can be realized in the clinical setting.