Mechanisms of bisphosphonate effects on osteoclasts, tumor cell growth, and metastasis.

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption that also exhibit antitumor activity. There is now extensive in vitro evidence that bisphosphonates inhibit proliferation and induce apoptosis of tumor cell lines. In addition, they appear to inhibit tumor cell adhesion and invasion of the extracellular matrix. These data are supported by a growing body of evidence from animal models demonstrating that bisphosphonates can reduce skeletal tumor burden. This may reflect direct antitumor effects or indirect effects via osteoclast inhibition and alteration of the bone microenvironment. Research has begun to shed light on the complex mechanisms by which bisphosphonates inhibit bone resorption and interfere with the formation and growth of bone lesions. Nitrogen-containing bisphosphonates inhibit protein prenylation and thereby short-circuit intracellular signaling via small guanine triphosphatases, such as Ras, which require membrane localization. As a result of these biochemical effects on the mevalonate pathway, bisphosphonates appear to modulate the expression of bcl-2 leading to caspase-dependent apoptosis, inhibit matrix metalloproteinases, downregulate alphavbeta3 and alphavbeta5 integrins, and increase expression of osteoprotegerin, thereby antagonizing osteoclastogenesis. Further preclinical studies are ongoing to fully elucidate these biochemical mechanisms, and well-designed clinical trials are necessary to investigate whether the antitumor potential of bisphosphonates can be realized in the clinical setting.