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The Role of Adjuvant Therapy with Bisphosphonates in Cancer

A Review

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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.

Bisphosphonates fall into two broad classes: nitrogen containing and non-nitrogen containing compounds. Each grouping has differing biochemical modes of action, but the end action is an inhibitory effect on osteoclast activity. Trials of bisphosphonates in hypercalcemia of malignancy and bone pain as a result of metastatic disease are discussed as well as trials which have shown that these agents can prevent the common skeletal complications of fracture, bone pain, and hypercalcemia in some patients with carcinoma of the breast, myeloma and possibly prostate cancer. Their role in the adjuvant therapy of operable breast cancer is currently being explored in a large American based study, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34. It would appear from the largest of the pioneer trials that it is possible to prevent and delay the onset of bone metastases with subsequent improved survival in patients with operable breast cancer. Bisphosphonates are recommended for the treatment of malignant hypercalcemia, bone pain, and the prevention of skeletal complications. Trials of bisphosphonsates in the adjuvant treatment of breast cancer for prevention of bone mestastases are showing encouraging results.

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Paterson, A.H.G. The Role of Adjuvant Therapy with Bisphosphonates in Cancer. Am J Cancer 3, 25–39 (2004). https://doi.org/10.2165/00024669-200403010-00003

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  • Bone Resorption
  • Vertebral Fracture
  • Bone Metastasis
  • Hypercalcemia
  • Bone Pain