Combinations of bisphosphonates and classical anticancer drugs: a preclinical perspective

Bone metastases are frequent complications in advanced breast and prostate cancer among others, resulting in increased risk of fractures, pain, hypercalcaemia of malignancy and a reduction in patient independence and mobility. Bisphosphonates (BPs) are in wide clinical use for the treatment of cancer-induced bone disease associated with advanced cancer, due to their potent ability to reduce skeletal-related events (SREs) and improve quality of life. Despite the profound effect on bone health, the majority of clinical studies have failed to demonstrate an overall survival benefit of BP therapy. There is increasing preclinical evidence to suggest that inclusion of the most potent nitrogen-containing BPs (NBPs) in combination therapy results in increased antitumour effects and improved survival, but that the particular schedules used are of key importance to achieve optimal benefit. Recent clinical data have suggested that there may be effects of adjuvant NBP therapy on breast tumours outside the skeleton. These findings have led to renewed interest in the use of BPs in cancer therapy, in particular how they can be included as part of adjuvant protocols. Here we review the key data reported from preclinical model systems investigating the effects of combination therapy including BPs with particular emphasis on breast and prostate cancer.