Adjuvant Therapy of Breast Cancer – Bisphosphonates

Abstract

The skeleton is a first site of recurrence in every third relapse in breast cancer. Approximately 70% (50–80%) of metastatic breast cancer patients have bone metastases [1]. Bisphosphonates have been used successfully in the treatment of malignant hypercalcaemia and skeletal metastases [2]. The use of bisphosphonates in addition to hormone therapy or chemotherapy reduces the risk of developing skeletal events (new skeletal lesions, progression of existing bone lesions, hypercalcaemia, pathological fractures, palliative radiotherapy or surgery) and the skeletal event rate, as well as increases the time to skeletal event in women with advanced breast cancer and clinically evident bone metastases. Bisphosphonates also reduce bone pain but did not appear to affect survival. During the last 15 years bisphosphonates have been investigated in treatment of primary breast cancer either in prevention of breast cancer recurrences or treatment related bone loss. Bisphosphonates are synthetic analogues of natural pyrophosphates, characterized by two carbon-phosphate bonds (P-C-P) instead of an oxygen atom [3]. In contrast to the natural pyrophosphate, bisphosphonates are resistant to breakdown by enzymatic hydrolysis. Bisphosphonates act specifically on bone, because of their strong affinity for calcium phosphate. According to the structure of side chain, the bisphosphonates can be divided into those resembling the natural bisphosphonate or non-aminobisphosphonates (clodronate and etidronate) and those with a nitrogen-containing side chain, aminobisphosphonates (pamidronate, alendronate, zoledronic acid, risedronate, ibandronate). Bisphosphonates inhibit bone resorption by a variety of mechanisms. When osteoclasts ingest bisphosphonate-containing bone, their cytoskeleton becomes disrupted and the apoptosis of the osteoclasts is activated. The nonaminobisphosphonates act as analogues of ATP and inhibit ATP dependent intracellular enzymes leading to apoptosis and death of the osteoclasts. The aminobisphosphonates, on the other hand, inhibit enzymes of the mevalonate pathway by disrupting the signalling functions of key regulatory proteins and lead to osteoclast apoptosis. Bisphosphonates also inhibit development of osteoclast from monocyte-precursors by diminishing the recruitment and