Role of bisphosphonate therapy in breast cancer and other advanced malignancies

David Cameron

Western General Hospital, Edinburgh, UK

It has been more than 30 years since Fleisch and colleagues showed that bisphosphonates have pharmaco- logic effects on osteoc1asts.t Since then, bisphosphonates have become an important addition to the armamentarium available to clinicians for the management of benign and malignant bone diseases that are characterized by excess osteoclast activity and increased bone resorption. For example, bisphosphonates reduce bone loss in post- menopausal women and are effective in the treatment of Paget’s disease. In patients with cancer, bisphosphonates effectively control hypercalcemia and have been shown to reduce skeletal complications in patients with bone lesions.

Research in this area over the past 30 years has identified more and more potent compounds with greater clinical activity compared with early compounds. First-generation bisphosphonates, including etidronate and clodronate, are relatively weak inhibitors of osteoclast-mediated bone resorption and require high intravenous or daily oral doses to achieve clinical benefit. These compounds preceded several generations of nitrogen-containing bisphosphonates, including pamidronate disodium, alendronate, risedronate, ibandronate, and, most recently, zoledronic acid. These bisphosphonates are orders of magnitude more potent than their predecessors and have demonstrated clinical activity in patients with bone lesions when low doses are infused at monthly intervals. Among these, zoledronic acid, with an imidazole substituent containing two nitrogen atoms, has been shown to be the most potent bisphosphonate in several in vitro and in vivo assays of osteoclast-mediated bone resorption.2

More recently, preclinical studies have also shown that bisphosphonates have antitumor activity against a variety of tumor cell lines both in vitro and in animal models. Within the present supplement, Dr Peter Croucher and colleagues describe these studies in detail and discuss how the

Address correspondence too: David Cameron, MD, Senior Lecturer in Medical Oncology, Westem General Hospital, Edinburgh EH4 2XU, UK. Tel.: 44-131-537-2193; Fax: 44-131-537-1014; E-mail: dcameron@srvO.med.ed.ac.uk

antitumor effects of bisphosphonates may contribute to their clinical activity. These studies suggest that bisphosphonates alter the bone microenvironment by inhibiting osteoclast activity, and may also have direct antitumor effects through induction of apoptosis. The combined effect of these various actions would be to make the bone a less favorable site for the growth and survival of tumor cells.

The earliest clinical applications of bisphosphonates in cancer patients were for the control of hypercalcemia of malignancy and for the treatment of primarily osteolytic bone lesions in patients with multiple myeloma and breast cancer. Patients with advanced breast cancer frequently develop bone metastases, and patients with osteolytic lesions are at particularly high risk for developing debilitating skeletal complications. These complications include bone pain, requiring strong analgesics and palliative radiotherapy; pathologic fractures and spinal cord compression, which limit mobility and often require surgical intervention; and potentially life-threatening hypercalcemia. Because patients with bone metastases from breast cancer or multiple myeloma may live for several years following the diagnosis of bone involvement, these events can cause long-term morbidity and poorer quality of life. Therefore, a treatment that can reduce the incidence of these skeletal complications has obvious benefit for the patient. Notably, an infusion of 90 mg pamidronate disodium or 4 mg zoledronic acid once a month has been shown to significantly reduce the occurrence and to delay the onset of these types of skeletal complications in patients with breast cancer and multiple myeloma. Consequently, the American Society of Clinical Oncology has published guidelines recommending the use of intravenous bisphosphonates in these patients.3,4

Although 90 mg pamidronate disodium has been the standard of care since 1996 for the treatment of osteolytic bone lesions associated with breast cancer and multiple myeloma, there remained a large unmet need for effective therapy for the thousands of patients with bone metastases from other solid tumors, particularly prostate, renal, and lung cancer. Patients with advanced prostate cancer are not

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Bisphosphonate therapy: introduction S21

dissimilar to those with breast cancer or myeloma in that they are also at high risk for developing bone metastases and have a long median survival following diagnosis of bone lesions (approximately 3 years). Bone metastases associated with prostate cancer form predominantly osteoblastic lesions characterized by increased bone formation and are associated with severe bone pain and pathologic fractures. Until recently, although bisphosphonates have been used in some centers to palliate bone pain in prostate cancer patients with bone metastases, bisphosphonate therapy had not been shown to reduce other skeletal complications such as pathologic fractures. Both clodronate and pamidronate disodium have been previously investigated in prostate cancer patients with bone metastases, but neither drug has been shown to offer a significant clinical benefit compared with placebo in terms of reducing bone pain or skeletal complications.5-7 Nevertheless, there is biologic evidence that both osteolytic and osteoblastic bone lesions are associated with excess bone resorption.x,9

The common pathophysiology of osteolytic and osteo- blastic bone lesions is discussed in the present supplement by Dr Jean-Jacques Body. The available data suggest that bisphosphonates should have activity in patients with all types of bone lesions, including prostate cancer, regardless of their radiologic appearance. Importantly, as discussed in detail by Dr Body, this has been confirmed for zoledronic acid, which has recently been shown to significantly reduce skeletal complications associated with predominantly osteoblastic bone metastases in patients with advanced prostate cancer.tO This is the first randomized, placebo- controlled trial to demonstrate a clinical benefit of bisphosphonate therapy in this group of patients.

In addition to the exciting data in patients with advanced prostate cancer, this supplement describes the recent data demonstrating the clinical activity of zoledronic acid in patients with breast cancer, lung cancer, and other solid tumors. For patients with breast cancer, 4 mg zoledronic acid appears to be possibly more effective than 90 mg pamidronate. Among patients with lung cancer or other solid tumors, including renal cell carcinoma, zoledronic acid demonstrated significant clinical benefit compared with

placebo, despite the short median survival of patients in this study. Based on these data, zoledronic acid is the first bisphosphonate to gain broad regulatory authorization for the treatment of bone metastases from any solid tumor. Zoledronic acid represents the next step in the evolution of bisphosphonate therapy, offering for the first time an effective, well-tolerated, and easily administered bisphosphonate with evidence of activity in the broad range of malignant bone disease, including tumor types for which other bisphosphonates have failed to demonstrate efficacy.

References

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Fleisch H. Development of bisphosphonates. Breast Cancer Res 2002; 4: 30-34. Green .I R, M ller K, Jaeggi K A. Preclinical pharmacology of CGP 42’446, a new, potent, heterocyclic bisphosphonate compound. .I Bone Miner Res 1994; 9: 745-751. Hillner B E, Ingle .I N, Berenson J R, et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol2000; 18: 1378-1391. Berenson J R, Hillner B E, Kyle R A, et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphos- phonates in multiple myeloma. J Clin Oncol2002; 20: 3719-3736. Elomaa I, Kylmala T, Tammela T, et al. Effect of oral clodronate on bone pain. A controlled study in patients with metastatic prostate cancer. Int Urol Nephrol 1992; 24: 159-166. Emst D S, Tannock I F, Venner P M, et al. Randomized placebo controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone alone in patients with hormone refractory prostate cancer (HRPC) and pain: National Cancer Institute of Canada Clinical Trials Group study. Proc Am Sot Clin Oncol 2002; 21: 177a [abstract 7051. Davis K D, Attie M F. Management of severe hypercalcemia. Crit Care Clin 1991; 7: 175-190. Berruti A, Dogliotti L, Tucci M, Tarabuzzi R, Fontana D, Angeli A. Metabolic bone disease induced by prostate cancer: rationale for the use of bisphosphonates. J Ural 2001; 166: 2023-2031. Garner0 P, Buchs N, Zekri J, Rizzoli R, Coleman R E, Delmas P D. Makers of bone turnover for the management of patients with bone metastases from prostate cancer. Br J Cancer 2000; 82: 858-864.

10. Saad F, Gleason D M, Murray R, et al. Zoledronic acid reduces skeletal complications in patients with hormone-refractory prostate carcinoma metastatic to bone: a randomized, placebo-controlled trial. J Nat1 Cancer Inst 2002; 94: 1458-1468.