Biology of bone metastases: causes and consequences.

Breast cancer is a highly osteotropic neoplasm, and as many as 75% of patients with metastatic disease will have involvement of the bony skeleton. On radiologic examination, these metastases are predominantly osteolytic but can be osteoblastic or mixed. The mechanisms by which metastases are formed are complex, involving many steps that include angiogenesis, invasion, and proliferation in the bone microenvironment. Tumor cells in the bone microenvironment produce a large number of cytokines that stimulate osteoclastic activity. Increased osteoclastic activity, in turn, leads to production of a variety of lymphokines and growth factors that can increase tumor cell proliferation. Thus, a cytokine network is established, which results in an imbalance of the processes of bone formation and bone resorption. As tumor burden in bone increases, osteoclast-mediated bone resorption is accelerated, resulting in loss of bone strength, fractures, pain, and other morbidities. Tumor cells metastatic to bone can also secrete growth factors, leading to increased osteoblastic activity. Osteoblasts lay down an excess of new bone that is structurally weak. There is considerable crosstalk between osteoclasts, osteoblasts, macrophages, and other cellular elements within the bone environment. The increasing understanding of the biology of bone metastases has opened the door to improved management of this important clinical problem. Current treatment strategies include approaches to reduce tumor burden and developing treatments that directly inhibit osteoclast function. The bisphosphonates are a class of drugs that inhibit osteoclast recruitment and function. Several highly potent bisphosphonates are now available for clinical use and represent an important adjunct in the management of bone metastases from breast cancer, multiple myeloma, and several other types of malignancies. Some newer therapeutic approaches include agents designed to inhibit the osteoclast-osteoblast signaling interactions or alter processes of adhesion and invasion.