Bisphosphonates and breast cancer - From cautious palliation to saving lives.

Bone metastases are common in breast cancer and may cause considerable morbidity including fractures, severe pain, nerve compression and hypercalcaemia. Alongside developments in the multidisciplinary management for patients with metastatic breast cancer, the use of bisphosphonates, and more recently denosumab, has transformed the course of advanced breast cancer for many patients resulting in a major reduction in skeletal complications, reduced bone pain and improved quality of life. Additionally, because the bone marrow microenvironment is so intimately involved in the metastatic processes required for cancer dissemination, the use of adjuvant bisphosphonates has been studied extensively over the past 25 years in many randomised trials. We now have clear evidence that bisphosphonates significantly reduce both metastasis to bone and mortality in postmenopausal women with early breast cancer. Efficacy seems similar across different biological subgroups of postmenopausal breast cancer with the use of either a nitrogen-containing bisphosphonate such as intravenous zoledronate or daily oral ibandronate as well as the non-nitrogen containing agent, daily oral clodronate. In this overview of evolving role of bisphosphonates in breast cancer, focussing particularly on pamidronate and zoledronate, the long winding development road from the 1970s through to the present day is described and some of the serendipitous findings, "lucky breaks" and regulatory decisions along the way outlined.