Mechanisms of action of bisphosphonates in oncology: a scientific concept evolving from antiresorptive to anticancer activities

Abstract

Bisphosphonates are approved for treating malignant bone disease from advanced cancer because they are effective inhibitors of osteoclast-mediated bone resorption. However, there may be a greater role for the use of bisphosphonates than has previously been considered. There is a large body of preclinical evidence showing that bisphosphonates exert a variety of direct and indirect anticancer activities that affect both tumor cells and the surrounding microenvironment, and that stimulate immune reactions. Recent data from clinical trials have shown that adding the bisphosphonate zoledronate to endocrine therapy or chemotherapy improves disease-free survival of patients with endocrine-responsive early breast cancer in a low estrogen environment (that is, following ovarian suppression therapy or in women with established menopause at diagnosis). Adjuvant treatment with the bisphosphonate clodronate also improves disease-free survival in postmenopausal breast cancer. Additionally, zoledronate was found to prolong survival in patients with symptomatic multiple myeloma or other advanced cancers. Here, we present an overview of preclinical and clinical studies that demonstrate anticancer benefits of bisphosphonates, and we discuss potential mechanisms of action that might be responsible for the anticancer activity of bisphosphonates in the clinic.

Figure 1

Potential anticancer effects of bisphosphonates in vivo. The figure depicts the primary tumor microenvironment, the blood dissemination of tumor cells, the bone marrow metastatic environment with the osteoblastic niche and osteoclasts, and the recruitment of bone marrow-derived monocytes (TAM) and DTC to the site of the primary tumor. Bisphosphonates render the bone marrow a less hospitable microenvironment for tumor cell colonization, inhibiting osteoclast-mediated bone resorption and stimulating γδ-T cell cytotoxicity. They also interfere with the tumor self-seeding and TAM infiltration of primary tumors. The drawings were produced using Servier Medical Art (www.servier.com).