All bone surfaces are periodically remodeled by the coupled and balanced action of osteoclasts and osteoblasts, of which the activities are regulated by a variety of cytokines and growth factors. Patients with cancer metastatic to the skeleton often develop osteolytic bone lesions, in which the actions of osteoclasts and osteoblasts remain coupled, but become imbalanced in sites adjacent to the tumor. The result is net bone loss. Many cancers secrete osteoclast-stimulating cytokines, which increase bone resorption by osteoclasts. In turn, factors released from the bone matrix during osteolysis can stimulate tumor growth. In this so-called ''vicious cycle,'' there are multiple sites that are targets for new bone-directed therapies. A variety of new agents for the treatment and prevention of osteolytic bone metastasis are currently being developed. These include new agents that inhibit osteoclast differentiation, bone adhesion, and osteoclast function. These new strategies have evolved from a better understanding of the interaction between tumor cells and cells in the bone marrow microenvironment. There is great promise that these new bone-targeted therapies can decrease the frequent skeletal-related events that greatly diminish quality of life of patients with bone metastases.The skeleton is the most common site of tumor metastasis, and malignant bone pain is the most common cause of severe cancer-associated pain (1). Patients with bone metastases are at risk of skeletal-related events (e.g., fracture, need for radiation therapy, and surgery) that can result in decreased quality of life (2, 3). Among patients with bone metastases from solid tumors or multiple myeloma, the annual incidence of skeletal complications is in the range of 1.5 to 4.0 events per year.Patients with cancer metastatic to the skeleton often develop osteolytic bone lesions, in which osteoclast and osteoblast functions typically become uncoupled as well as imbalanced. Although a degree of coupling persists, the tight relationship between bone cell functions is typically lost. These cancers secrete osteoclast-stimulating cytokines, which increase bone resorption by osteoclasts. In turn, factors released from the bone matrix during osteolysis can stimulate tumor growth. In this so-called ''vicious cycle,'' there are multiple sites that are targets for new bone-directed therapies (Fig. 1).Some tumors, such as prostate cancer, may secrete cytokines that stimulate adjacent osteoblasts to increase their boneforming activity, resulting in osteoblastic lesions (Fig. 2). Disruption or imbalance of the bone remodeling activities of osteoclasts and osteoblasts leads to the progressive deterioration of skeletal integrity that underlies skeletal complications.
Nitrogen-Containing BisphosphonatesNitrogen-containing bisphosphonates have been introduced into clinical practice during the last decade, and successive generations of more potent agents with higher therapeutic indices have been developed (2, 3). Bisphosphonates preferentially bind to bone ...