New Approaches for the Prevention of Bone Metastases in Patients with Prostate Cancer

Abstract

Bone metastases are the most frequent complication of advanced prostate cancer and are responsible for the vast majority of disease-related morbidity and mortality. With the extensive number of predictive models for patients with prostate cancer, we can now determine to some degree which patients are at highest risk for progression to metastatic bone disease and therefore might benefit from earlier or more aggressive therapy. Combining this with our better understanding of the molecular biology underlying the progression to bone metastasis, we are able to identify more specific targets or pathways to approach therapeutically to prevent or delay the development of metastatic bone disease. General strategies for the prevention of bone metastases include bone-targeting approaches, antimetastatic therapies, and purely antineoplastic agents. Bisphosphonates comprise the most studied and effective of the bone-targeted agents and now have relatively sound clinical data supporting their role not only in the treatment of bone metastases, but also in the secondary prevention and, in some cases, primary prevention, of new skeletal complications. Their ease of administration and relatively low short- and long-term toxicities make them ideal for potential treatment earlier in the disease process as well. Radioisotopes have been studied and used for decades for the treatment of painful bone metastases but only recently have data accumulated demonstrating their efficacy in the prevention of new metastases. The endothelin receptor antagonist, atrasentan, has recently been shown to delay the progression of systemic disease and potentially improve survival in patients with prostate cancer. It appears to do so, at least in part, by bone-targeting mechanisms. Antimetastatic strategies are also promising for the prevention of bone metastases and include matrix metalloproteinase inhibitors, gene therapy, and other novel approaches, such as inhibiting tyrosine kinases or NFκB and immunomodulation of prostate stem cell antigens. Utilizing standard hormonal or cytotoxic therapies in the adjuvant setting has also been studied extensively and in certain groups of patients may provide meaningful clinical benefit in preventing or delaying systemic progression, including bone metastases. Finally, as we learn more about molecular synergies with various agents, combinations of these approaches with each other or with more traditional hormonal or chemotherapy agents may be even more effective in the prevention of bone metastases in patients with prostate cancer.