The Biology of Bone Metastases from Prostate Cancer and the Role of Bisphosphonates

Bone metastases from prostate cancer are a associated with morbidity and death from the disease. Prostate cancer cells are found in the circulation from an early stage but their number increases significantly as the extent of the disease increases. Once in the circulation they are cleared rapidly, binding to endothelial surfaces by an integrin mediated mechanism, before migrating through basement membranes to the interstitium. Cells need to be motile and present in significant numbers for metastases to form within the bone marrow and close to the bone, the cytokine milieu is altered, disturbing the balanced bone physiology. The osteoblast overactivity produced is accompanied by gross osteoclast mediated bone destruction and marrow suppression. The osteoblast / osteoclast dysfunction is linked through actions of receptor activator of the nuclear factor Kappa B ligand (RANK ligand), endothelin-1, osteoprotogerin and parathyroid hormone related protein (PTHrP). Clinically, metastatic infiltration induces marrow failure, bone fractures and spinal cord compression. The latter is a grave complication which needs rapid intervention in selected cases to achieve the best outcome. Bisphosphonates can reduce the skeletal complication rate. They work mainly by an osteoclast inhibitory effect although some have anti-tumor activity in vitro. Those containing an Imidazole ring are the most potent. The treatment of prostate cancer by androgen ablation also has an adverse effect on skeletal function. Bone loss is significant in men whose testosterone is reduced: this effect can be prevented by use of bisphosphonates such as Pamidronate and Zoledronic acid. Palliation of bone pain is important in end-stage disease. Localised radiotherapy and bone seeking radioisotopes may be effective in many cases. Ultimately however, the outlook is poor and most men will die from their disease within 6 months of the onset of progression of androgen insensitive disease in bone.