Pathophysiology of Bone Metastases in Prostate Cancer

Abstract

Objective: Men with advanced prostate cancer are at high risk for bone metastases that result in significant skeletal morbidity. This review discusses the pathophysiology of bone metastases in prostate cancer. Methods: Relevant information was identified through searches of published studies, abstracts from scientific meetings, and review articles. Results: Bone metastases are common in patients with advanced cancer. Numerous growth factors present in the bone matrix are released during bone remodeling, potentially providing a fertile environment for the growth of tumor cells. Factors such as parathyroid hormone-related protein and interleukin-6 stimulate osteoclast-mediated bone resorption, thus enhancing the release of bone-derived growth factors. Prostate cancer cells secrete factors, including protease-activated receptor 1, that are involved in the multistep process of tumor cell detachment and migration to bone and factors that stimulate osteoblast-mediated bone formation, such as transforming growth factor-beta and bone morphogenetic proteins. In addition, prostate cancer cells produce endothelin-1, a peptide under intense investigation that stimulates the proliferation of osteoblasts and is thought to play a role in the development of osteoblastic bone lesions. These tumor-derived factors cause dysregulation of normal bone remodeling. Interactions between prostate tumor cells and the bone typically result in the formation of osteoblastic lesions characterized by increased osteolysis and uncoupled new bone formation. Preclinical evidence suggests that zoledronic acid has antitumor activity in animal models of prostate cancer. Conclusions: Bone metastasis is a complex process involving multiple molecular interactions between tumor cells and the bone microenvironment resulting in disruption of bone remodeling. In patients with prostate cancer, bone lesions are primarily osteoblastic, but are also associated with increased osteolytic activity, resulting in marked increases in bone turnover and clinically significant morbidity.