Bisphosphonates in the Prevention and Treatment of Bone Metastases

Bisphosphonates have an established role in treating tumor-induced hypercalcemia and decreasing the incidence of skeletal-related events. Recent data suggest that these agents may also prevent skeletal metastases. This review explains how cancer metastasizes to bone and how bisphosphonates may block this process, with a summary of clinical trials supporting the use of bisphosphonates to treat and prevent bone metastases. For skeletal metastases in patients with breast cancer, multiple myeloma, or other solid tumors, bisphosphonates are important adjuncts to systemic therapy. Despite promising results in metastatic prostate cancer, additional trials are needed before bisphosphonates become part of standard treatment in this setting. Ongoing trials are evaluating the preventive role of the third-generation bisphosphonates in breast cancer patients. Until the results of these trials are presented, bisphosphonates should only become a component of adjuvant treatment in the context of a clinical trial. Bone loss, a common consequence of cancer treatment, should be treated with the usual measures indicated for the management of osteoporosis, including bisphosphonates. The skeleton is a frequent site of metastases in human cancer, and as such is associated with morbid skeletal-related events such as pain, pathologic fractures, hypercalcemia, and cord compression. Bisphosphonates, specific inhibitors of osteoclasts, have an established role in the treatment of tumor-induced hypercalcemia and in decreasing the frequency of skeletal-related events. More recently, evidence is emerging that these agents may prevent skeletal metastases. This review summarizes what happens when cancer metastasizes to bone, how bisphosphonates work, and the clinical trials that support the use of bisphosphonates in the treatment and prevention of bone metastases. Pathophysiology of Skeletal Metastases Normal bone is maintained by a dynamic balance between the cells that breakdown or resorb bone (osteoclasts) and the cells that form new bone (osteoblasts).[1] Bone breakdown and new bone formation is constantly ongoing in discrete areas called remodeling units. The regulation of the remodeling unit occurs at several levels. First, the force of gravity puts mechanical stress on bone. Without gravity, as in space, humans lose bone-a major problem for astronauts in prolonged spaceflight. Second, circulating hormones (including parathyroid hormones, calcitonin, insulin, thyroid hormones, vitamin D, sex steroid hormones, and growth hormones) stimulate bone breakdown or new bone formation. Third, the autocrine and paracrine factors are derived from osteoclasts, osteoblasts, and stromal cells in the bone microenvironmment. Gravity, circulating