Metastasis to bone: causes, consequences and therapeutic opportunities

Abstract

Common tumours, such as those of the breast, lung and prostate, frequently metastasize to bone, and in many patients with advanced disease the skeleton is the site of the most significant tumour burden. There are different patterns of bone effects in patients with cancer, ranging from purely or mostly destructive or osteolytic (breast cancer, myeloma), to mostly bone-forming or osteoblastic (prostate cancer). In the case of breast-cancer-causing osteolysis, the main mediator is parathyroid-hormone-related peptide (PTHrP), whereas, in osteoblastic lesions, known mediators include endothelin-1 and platelet-derived growth factor. In osteolytic metastasis, there is a 'vicious cycle' in the bone microenvironment, whereby bi-directional interactions between tumour cells and osteoclasts lead to both osteolysis and tumour growth. The molecular mechanisms that are responsible for this vicious cycle are now being clarified and involve tumour-cell production of PTHrP and bone-derived growth factors that are released as a consequence of increased bone resorption. Bisphosphonates interrupt the vicious cycle and cause not only a reduction in osteolytic bone lesions, but also decrease the tumour burden in bone. More-effective treatments for interruption of the vicious cycle are now being developed, including specifically neutralizing antibodies to PTHrP and more efficacious osteoclast inhibitors.