The Role of Adjuvant Therapy with Bisphosphonates in Cancer

Abstract

An understanding of the pathophysiology of bone metastases requires a knowledge of normal and abnormal bone remodeling. This knowledge is helpful in understanding mechanisms of action of bone active agents such as bisphosphonates. When malignant cells infiltrate bone spaces, the balance of bone formation and bone resorption is disrupted: bone remodeling and turnover become abnormal. The consequent ‘vicious cycle’ plays a central role in the progressive destruction of bone and the progression of bone metastases. This cycle in breast cancer is beginning to be understood and involves the secretion by malignant cells of substances such as parathyroid hormone related protein (PTHrP) which leads to an increase in focal and generalized bone resorption resulting in the release of breakdown products such as transforming growth factor beta which in turn stimulates the further growth of malignant cells. Study of the intricacies of this ‘vicious cycle’ has thrown some light on potential opportunities for the therapy of bone metastases. However, physiological mechanisms resulting in bone pain are poorly understood. Clinical aspects of bone metastases in breast cancer, prostate cancer, and myeloma, together with what is known about their individual pathophysiology are discussed in this review. Biochemical markers of bone resorption and formation are now available for study and early research suggests that skeletal events in patients with malignant bone disease as well as the treatment of these events may correlate with levels of serum and urine markers of bone turnover.