Prostate cancer incidence is rising, and represents a major public health issue. Bone is by far the most common site for metastases in this disease, accounting for considerable morbidity. Until recently, there have been few viable options for the treatment of patients with hormone-refractory metastatic disease. This review examines the pathophysiology underlying the development of bone metastases. It also summarises some of the clinical approaches for the management of this common condition, focusing on recent evidence supporting the use of zoledronic acid, a member of one of the most promising groups of pharmacological agents, the third-generation bisphosphonates.
Aetiology and impact of prostate cancer-related bone metastasesProstate cancer is the most commonly diagnosed malignancy in males in the UK, with nearly 25 000 cases being reported in 1999 (www. cancerresearchuk.org/statistics). Prostate cancer-related morbidity and mortality are closely associated with the formation of metastases. Bone is the preferred site for these metastases, and estimates indicate that bone metastases are present in more than 80% of men with advanced prostate cancer. 1,2 A UK study has shown that bone metastases are present in up to 50% of men at the time of first presentation. 3 Considerable morbidity arises from various complications from bone metastases, and it is estimated that the average frequency of a 'skeletal-related event' in patients with bone metastases is 3-4 months, with these events invariably leading to a reduced quality of life. 4 Common presentations include pain, spinal cord compression, pathological fracture, and abnormalities in serum calcium levels. 5 Patients with hormone-refractory metastatic prostate cancer are particularly prone to incapacitating progressive bone disease. 6 The normal resculpturing of bone is governed by the coupled processes of bone resorption and formation. Modelling occurs in localised areas of cortical and trabecular bone known as bone metabolic units. Osteoclast-mediated resorption usually takes about 7-10 days, while the subsequent formation phase, governed by osteoblasts, lasts approximately 3 months (Figure 1). Local 'coupling' factors produced in the bone marrow regulate the remodelled bone. 7 The rich milieu of growth factors in the bone environment provides an attractive 'soil' for the seeding of certain tumour cells. In the presence of such cells, factors from tumour-induced breakdown of bone stimulate growth of further cancer cells, which in turn leads to further increases in bone resorption (Figure 2). This has been described as the vicious cycle. 7 As an example, tumour cells have been shown to release PTHrP, which stimulates osteoclastic resorption, via messaging from the osteoblast. 8 The resultant osteolysis releases several bone-derived growth factors, such as TGFb. Normally, TGFb serves to limit bone resorption via a negative feedback mechanism, but in the bone metastasis, TGFb stimulates invading tumour cells, partly accounting for this vicious cycle. 9 Prostate can...