Bisphosphonates as anticancer therapy for early breast cancer

Bisphosphonates (BPs) are approved for preventing the skeletal-related events associated with malignant bone disease. Several studies indicate that they may also prevent cancer therapy-induced bone loss. Multiple preclinical and early clinical studies provide evidence of the anticancer activity of BPs, including an inhibition of tumor cell proliferation and survival, a reduction of angiogenesis, and a stimulation of innate anticancer immunity. In addition to their evident single-agent activity, BPs may also act synergistically with other antineoplastic agents. Translational studies corroborate the effects of bisphosphonates on angiogenesis and innate immunity. Moreover, many of these anticancer effects occur at clinically relevant drug concentrations. Indeed, clinical data suggest that in addition to being well-tolerated and efficacious in maintaining bone health, BPs including clodronate, pamidronate, and zoledronic acid also improve cancer-related outcomes such as tumor response, disease-free survival, and overall survival in patients with breast cancer. Among the BPs, zoledronic acid is the most extensively studied in the adjuvant and neoadjuvant settings and has accumulated the most data pointing to anticancer activity, although a survival benefit has not been documented. Future studies are necessary to elucidate the anticancer activity of BPs. Other aspects of BP therapy that require further study include the optimization of dosing regimens for single agents and combinations in various clinical settings and the identification of prognostic factors that predict treatment outcomes. This review summarizes the preclinical and clinical evidence of anticancer activity of BPs, with a focus on zoledronic acid.