New bisphosphonates in the treatment of bone metastases

Normal skeletal integrity is maintained by physiological bone turnover through a coupled process of bone resorption, mediated by osteoclasts, followed by new bone formation, mediated by osteoblasts. Major features of the pathogenesis of cancer-associated skeletal destruction are enhanced osteoclast-mediated bone resorption and disruption of normal bone formation. In this article, the literature on the pathogenesis and clinical manifestations of metastatic bone disease is discussed. Animal and clinical trials investigating novel bone targeted agents, emphasizing the bisphosphonates, are critically assessed. The most frequent clinical manifestations of bone metastases are pain, fracture, immobility, spinal cord compression, and hypercalcemia. New treatments under study for patients with bone metastases include agents specifically targeted to the skeleton such as bone-seeking radioisotopes and bisphosphonates. Studies in animal models of metastatic bone disease show that these bisphosphonates are able to inhibit tumor-induced osteolysis and are potentially useful in this condition. Bisphosphonates have been investigated in several clinical trials of patients with skeletal metastases from breast cancer, prostate cancer, and multiple myeloma. Overall, the studies investigating bone targeted radioisotopes or bisphosphonates for the treatment of morbidity due to skeletal metastases have been inconclusive. An improved understanding of the pathogenesis of metastatic bone disease and preclinical studies with bisphosphonates suggest that these agents may have a role in the treatment of this disorder. Additional trials of new generation bisphosphonates, employing a rigorously controlled, randomized study design with adequate numbers of subjects, are needed to demonstrate the safety and efficacy of this class of agents in this setting.