The anti-tumour activity of bisphosphonates

Abstract

Bisphosphonates are stable analogues of pyrophosphate (PPi), an endogenous regulator of bone mineralisation. A number of placebo-controlled trials have demonstrated their positive impact on skeletal-related events (SRE) that occur as a consequence of metastatic or myelomatous bone disease. Based upon their chemical structure bisphosphonates can be classified into nitrogen-containing bisphosphonates, (N-bisphosphonates) (for example zoledronate and pamidronate) and non-nitrogen containing (for example, clodronate and etidronate), which more closely resemble PPi. Clinical trials investigating bisphosphonates in the preventative setting have shown bisphosphonates to not only delay occurrence of bone metastases in certain cancers, but in one trial, occurrence of non-osseous lesions was delayed, and survival was prolonged. Other trials however have shown the opposite. Likewise, in animal models of cancer and metastases, conflicting results have been obtained. In vitro work has concentrated on bisphosphonates direct action upon tumour cells and has found a variety of anti-tumour effects such as apoptosis induction, inhibition of cell growth, inhibition of invasive behaviour and inhibition of angiogenic factors. Furthermore it would appear that bisphosphonates have the potential to enhance anti-tumour activity of known cytotoxic drugs. Ongoing research aims to assess this further, in addition to determining more precisely the role of adjuvant bisphosphonates in cancers such as breast and prostate cancer.