The role of bisphosphonates in breast cancer: Direct effects of bisphosphonates on breast cancer cells

Over 80% of women with advanced breast cancer ultimately develop bone metastases that result in significant morbidity and mortality. Breast cancer metastases in bone can cause intractable pain, bone fracture, spinal cord compression and hypercalcaemia [1,2,3]. From the moment breast cancer cells arrive in the bone microenvironment, however, they stimulate bone resorption with subsequent selective increase in the attraction and growth of new cancer cells to bone [4]. Therefore, any treatment aimed at palliation or perhaps even prevention of bone metastases should focus on disrupting this attraction and growth, which are involved in the initiation and amplification of the metastatic process.Bisphosphonates are widely used for the treatment of bone metastases, and an increasing body of evidence suggests that these compounds provide benefit to breast cancer patients with secondary cancers in bone [5]. Bisphosphonates are analogues of endogenous pyrophosphates in which a carbon atom replaces the central atom of oxygen. In vivo, bisphosphonates bind strongly to hydroxyapatite on the bone surface and are preferentially delivered to sites of increased bone formation or resorption. They are potent inhibitors of osteoclast-mediated bone resorption [6] and are effective in lowering serum calcium concentrations in patients with hypercalcaemia of malignancy [7,8]. Treatment with bisphosphonates has also been shown to reduce skeletal morbidity significantly and to improve quality of life in breast cancer patients with bone metastases [7].The mechanisms by which bisphosphonates inhibit osteoclast-mediated bone resorption appear to involve an inhibition of formation of osteoclasts from immature precursor cells [6,9,10] or direct inhibition of resorption via induction of apoptosis in mature osteoclasts [9,11,12]. Furthermore, as outlined elsewhere, bisphosphonate treatment has been shown to inhibit the progression and development of bone metastases in a mouse model of breast cancer