Adjuvant bisphosphonates in breast cancer: are we witnessing the emergence of a new therapeutic strategy?

Great strides have been made over the last 20 years in the treatment of breast cancer and, despite an increasing incidence, the number of deaths has fallen sharply since the late 1980s. The widespread use of new adjuvant therapies including trastuzumab, taxanes and aromatase inhibitors should decrease this even further. However, for women, metastatic breast cancer still remains the number one cause of cancer death in Europe, and the detection and treatment of micrometastatic disease represent the most important challenge in breast cancer management. Bone is the most frequent site of distant relapse, accounting for 30-40% of all first recurrence. In addition to the well-recognised release of bone cell activating factors from the tumour, a wealth of pre-clinical data indicates that the release of bone-derived growth factors and cytokines into the microenvironment can both attract cancer cells to the bone surface and facilitate their growth and proliferation. Bisphosphonates are potent inhibitors of bone osteolysis and may interrupt this so-called 'viscous cycle', thereby impeding both the development of bone metastases and the survival of dormant cells in the marrow microenvironment for the subsequent dissemination to extra-osseus sites. Additionally, the potent amino-bisphosphonates may also have direct effects on tumour cells, especially when administered in combination with chemotherapy. Clinical trial results with the early oral bisphosphonate and clodronate were judged to be inconclusive but the recent data with zoledronic acid suggest that bone targeted treatments may indeed modify the course of the disease. The results of ongoing large metastasis prevention trials are however, required before routine use of adjuvant bisphosphonates can be recommended.