Anti-tumour activity of zoledronic acid

Bisphosphonates are proven to be effective in the treatment of benign or malignant skeletal diseases characterized by enhanced osteoclastic bone resorption. Nitrogen-containing bisphosphonates (N-BPs) have also been demonstrated to exhibit direct anti-tumour effects. They not only inhibit proliferation and induce apoptosis in cultured cancer cells, but additionally interfere with adhesion of cancer cells to the bone matrix and inhibit cell migration and invasion. These effects are potentiated when N-BPs are combined with anticancer drugs like taxoids, doxorubicin or imatinib. Zoledronic acid is a highly potent N-BP that has been particularly well investigated, preclinically and in clinical practice. Growing preclinical evidence shows that zoledronic acid also exhibits direct anti-tumour activity. The overall effects on tumour cells appear to be mediated via diverse pathways, such as apoptosis, angiostasis, cell-cell-interactions and immunomodulation. The current insights and fronts of ongoing research are reviewed. Higher doses of zoledronic acid or more frequent applications than currently approved may be required to achieve clinically meaningful anti-tumour effects. The future challenge is to focus on optimizing dosing regimens and drug combinations to maximize the anti-tumour potential of zoledronic acid and to take advantage of the observed synergy with standard neoplastic agents.