Bisphosphonates in Advanced Malignant Disease

Abstract

Tumor-induced osteolysis is responsible for a considerable morbidity and often dramatically alters patients’ quality of life. Bone destruction is essentially mediated by the osteoclasts, the formation and activity of which are stimulated by tumor secretory products. Bisphosphonates are able to interrupt the vicious circle between metastatic cancer cells and bone cells/bone matrix by inducing osteoclast apoptosis. For breast cancer patients with metastatic disease and radiographic evidence of bone destruction, current guidelines consist in the administration of either pamidronate 90 mg over 2 h or zoledronic acid 4 mg over 15 min every 3–4 weeks. Other bisphosphonates were not considered. Nevertheless, placebo-controlled trials have established that, when administered over a prolonged period by the oral route (clodronate and ibandronate) or by the intravenous route (pamidronate, ibandronate, and zoledronic acid), bisphosphonates reduce the skeletal morbidity rate by 25–40% in breast cancer metastatic to the skeleton. It has been shown in a 2-year controlled comparative trial between pamidronate and zoledronic acid that this latter compound has a superior efficacy in breast cancer but not in myeloma. Zoledronic acid is also the only bisphosphonate whose activity has been demonstrated in hormone-refractory metastatic prostate cancer. Serum creatinine has to be checked before each zoledronic acid infusion. Lastly, the long-term consequences on bone health of a prolonged therapy with very potent bisphosphonates remain poorly known and some experts prefer to adjust therapy to the individual patient, even more that the recently described cases of osteonecrosis of the jaw appear to be partly due to excessive bisphosphonate therapy.