Introduction
Tumor metastasis to the skeleton affects over 400,000 individuals in the United States annually, more than any other site of metastasis, including significant proportions of patients with breast, prostate, lung and other solid tumors (Table 1). An even larger population of patients is at risk for skeletal morbidity.1,2,3 Bone metastases are often associated with so-called skeletal-related events (SREs) which include severe pain, bone fractures, need for radiation therapy to bone, need for surgery to bone, spinal cord compression and bone demineralization. At present, once cancer metastasizes to bone, it is incurable and can cause severe morbidity and mortality. Thus, new strategies are focused on the development of bone-targeted agents to both prevent the development of bone metastases, as well as to effectively treat metastases and their complications when they occur.
Bisphosphonate therapy, the current standard of care for metastatic bone cancer, has been shown to decrease SREs by up to 50% and also to slow the rate of development of SREs. While this therapeutic advance is significant, bisphosphonate therapy does not completely block the process of bone metastasis; despite treatment with bisphosphonates, approximately 20% of patients with bone metastasis still have elevated bone resorption markers.4,5 In addition, bisphosphonate therapy is associated with renal toxicity and the emerging problem of osteonecrosis of the jaw (ONJ), which is causing deep concern among patients and dental care professionals who fear development of ONJ following dental procedures or even basic dental cleaning.6 Addressing these issues and finding treatments that more effectively prevent and suppress the bone metastatic process are needed.
Several important recent advances in our understanding of the pathophysiology underlying the bone metastatic process are informing new approaches to assess, treat and potentially prevent the advance of metastatic disease. In particular, we have a much better understanding of how tumor cells home to bone and how they can reside in the bone microenvironment, possibly for many years, before they become active in bone metastasis. The mechanisms responsible for the process of bone destruction induced by metastatic cancer as well as the underlying factors involved in osteoblastic bone metastases are under intense investigation and are providing new opportunities to develop novel therapies and address side effects of current therapies. In addition, several novel agents are being developed to treat bone metastasis. While bisphosphonates are currently the mainstay for treatment of bone metastasis, other newer agents directed at cytokines and other factors responsible for the bone metastatic process are moving forward in the clinic and earlier testing. A humanized antibody to receptor activator of nuclear factor kappa B-ligand (RANK L), denosumab (formerly AMG-162,Amgen, Thousand Oaks), is in clinical trials for patients with bone metastasis as well as osteoporosis.7 Chemokine receptor antagonists that block the activity of key regulators of the metastatic process are in preclinical evaluation and inhibitors of transforming growth factors-beta (TGF-ß) receptor and src kinase are also being examined.
This educational activity has been developed to provide an overview of recent progress and near-term developments in this fast-moving field. It is intended to provide a framework for understanding advances in the field with a focus on new insights into the mediators of bone metastasis and targets for intervention, the rationale for using bone-targeted therapies to treat and prevent bone metastasis and bone loss, and available data for approved and development-stage bone-targeted agents in treating and preventing bone metastasis and bone loss.