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Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors

Authors
Robert E Coleman, MD, FRCP, FRCPE
Catherine Van Poznak, MD
Section Editor
Harold Burstein, MD, PhD
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

Metastases to bone are a common site of cancer recurrence for many types of solid tumors. Bone metastases cause substantial morbidity, including fractures, spinal cord compression, the need for surgery or radiation therapy to bone for a symptomatic metastasis, and hypercalcemia of malignancy. (See "Overview of the epidemiology, clinical presentation, diagnosis, and management of adult patients with bone metastasis" and "Clinical features and diagnosis of neoplastic epidural spinal cord compression, including cauda equina syndrome" and "Evaluation and management of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma" and "Radiation therapy for the management of painful bone metastases" and "Hypercalcemia of malignancy: Mechanisms".)

Osteoclast inhibitors such as bisphosphonates and denosumab significantly reduce the frequency of skeletal-related events (SREs) in patients with bone metastases from a wide variety of cancer types. The benefits of osteoclast inhibitors in patients with bone metastases from solid tumors will be presented here. The use of bisphosphonates in patients with multiple myeloma, the use of osteoclast inhibitors for patients with bone loss related to cancer treatment (eg, aromatase inhibitors for breast cancer and androgen deprivation therapy for prostate cancer), the use of osteoclast inhibitors in the adjuvant setting for breast cancer, and the risks of therapy with osteoclast inhibitors in patients with advanced malignancy are all discussed separately. (See "The use of bisphosphonates in patients with multiple myeloma" and "Evaluation and management of aromatase inhibitor-induced bone loss" and "Bone metastases in advanced prostate cancer: Management", section on 'Prevention of ADT-related bone loss' and "Overview of the use of osteoclast inhibitors in early breast cancer" and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Medication-related osteonecrosis of the jaw in patients with cancer".)

BONE METASTASES IN SOLID TUMORS

Bone is the most common site of metastasis in cancer, and bone metastases are most prevalent among patients with cancer of the breast, prostate, and lung. Complications from bone metastases, which are commonly referred to as skeletal-related events (SREs), include fracture, spinal cord compression, the need for surgery or radiation therapy, and hypercalcemia of malignancy. SREs are most common in patients with lytic metastases but can also occur in patients with blastic metastases (table 1). SREs that are accompanied by symptoms (as opposed to identified on imaging tests) are known as symptomatic skeletal events (SSEs) and represent a more clinically meaningful endpoint. (See "Overview of the epidemiology, clinical presentation, diagnosis, and management of adult patients with bone metastasis", section on 'Epidemiology' and "Overview of the epidemiology, clinical presentation, diagnosis, and management of adult patients with bone metastasis", section on 'Distribution'.)

SREs are clinical outcomes that can be distinctly measured; therefore, they are often used as endpoints in clinical trials investigating therapies for bone metastases, although not all studies include hypercalcemia of malignancy. Bone metastases are also associated with pain, particularly with motion, which significantly impacts quality of life (QOL). However, the definition of a SRE does not include pain or changes in QOL, which are typically measured as separate outcomes in clinical trials.

Osteoclast inhibition has become an important component of managing patients with bone metastases to reduce the frequency of SREs. The frequency of SREs in patients not treated with an osteoclast inhibitor can be illustrated by the following data:

                          

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Literature review current through: Nov 2016. | This topic last updated: Tue Aug 18 00:00:00 GMT 2015.
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References
Top
  1. Domchek SM, Younger J, Finkelstein DM, Seiden MV. Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 2000; 89:363.
  2. Coleman RE, McCloskey EV. Bisphosphonates in oncology. Bone 2011; 49:71.
  3. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000; 88:1082.
  4. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer 2004; 100:2613.
  5. Saad F, McKiernan J, Eastham J. Rationale for zoledronic acid therapy in men with hormone-sensitive prostate cancer with or without bone metastasis. Urol Oncol 2006; 24:4.
  6. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011; 29:1221.
  7. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010; 28:5132.
  8. Oster G, Lamerato L, Glass AG, et al. Use of intravenous bisphosphonates in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems. Support Care Cancer 2014; 22:1363.
  9. Trinkaus M, Simmons C, Myers J, et al. Skeletal-related events (SREs) in breast cancer patients with bone metastases treated in the nontrial setting. Support Care Cancer 2010; 18:197.
  10. Mortimer JE, Schulman K, Kohles JD. Patterns of bisphosphonate use in the United States in the treatment of metastatic bone disease. Clin Breast Cancer 2007; 7:682.
  11. Santini D, Bertoldo F, Dell'Aquila E, et al. The Italian cross-sectional survey of the management of bone metastasis: ZeTa study. J Bone Oncol 2012; 1:35. http://www.sciencedirect.com/science/article/pii/S221213741200019X (Accessed on June 11, 2013).
  12. Medication-Related Osteonecrosis of the Jaw - 2014 Update. American Association of Oral and Maxillofacial Surgeons. (Accessed on September 04, 2014). http://www.aaoms.org/docs/position_papers/mronj_position_paper.pdf?pdf=MRONJ-Position-Paper (Accessed on July 14, 2015).
  13. Wang-Gillam A, Miles DA, Hutchins LF. Evaluation of vitamin D deficiency in breast cancer patients on bisphosphonates. Oncologist 2008; 13:821.
  14. Body JJ, Bone HG, de Boer RH, et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer 2015; 51:1812.
  15. Dear Healthcare Professional Letter of Rapid Safety Communication, September 2012: Ranmark subcutaneous injection 120 mg (denosumab) - Risk of severe hypocalcaemia, including fatal cases. http://www.pmda.go.jp/english/service/pdf/letter/120911-denosumabu.pdf (Accessed on July 23, 2013).
  16. Ross AC, Taylor CL, Yaktine AL, and Del Valle HB. Dietary Reference Intakes for Calcium and Vitamin D, Committee to Review Dietary Reference Intakes for Vitamin D and Calcium (Ed), The National Academies Press, Washington 2010. http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx (Accessed on March 24, 2011).
  17. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377:813.
  18. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011; 29:1125.
  19. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 2012; 48:3082.
  20. Martin M, Bell R, Bourgeois H, et al. Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res 2012; 18:4841.
  21. Vadhan-Raj S, von Moos R, Fallowfield LJ, et al. Clinical benefit in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid. Ann Oncol 2012; 23:3045.
  22. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009; 27:1564.
  23. Lipton A, Steger GG, Figueroa J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 2007; 25:4431.
  24. Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force Report: Bone Health in Cancer Care. J Natl Compr Canc Netw 2009; 7 Suppl 3:S1.
  25. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998; 19:80.
  26. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev 2012; :CD003474.
  27. Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001; 91:1191.
  28. Lipton A, Small E, Saad F, et al. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest 2002; 20 Suppl 2:45.
  29. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001; 7:377.
  30. Kohno N, Aogi K, Minami H, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 2005; 23:3314.
  31. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94:1458.
  32. Hatoum HT, Lin SJ, Smith MR, et al. Zoledronic acid and skeletal complications in patients with solid tumors and bone metastases: analysis of a national medical claims database. Cancer 2008; 113:1438.
  33. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial--the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003; 21:3150.
  34. Wardley A, Davidson N, Barrett-Lee P, et al. Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration. Br J Cancer 2005; 92:1869.
  35. Amadori D, Aglietta M, Alessi B, et al. Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol 2013; 14:663.
  36. Hortobagyi GN, Lipton A, Chew HK, et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: Results of the OPTIMIZE-2 trial. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9500). http://abstracts.asco.org/144/AbstView_144_129791.html (Accessed on June 04, 2014).
  37. Himelstein AL, Qin R, Novotny PJ, et al. CALGB 90604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dising of zoledronic acid in metastatic cancer (abstr). J Clin Oncol 33, 2015 (suppl; abstr 9501). Abstract available at http://meetinglibrary.asco.org/content/147845-156 (Accessed on July 09, 2015).
  38. Amir E, Freedman O, Carlsson L, et al. Randomized feasibility study of de-escalated (every 12 wk) versus standard (every 3 to 4 wk) intravenous pamidronate in women with low-risk bone metastases from breast cancer. Am J Clin Oncol 2013; 36:436.
  39. Ibrahim MF, Mazzarello S, Shorr R, et al. Should de-escalation of bone-targeting agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis. Ann Oncol 2015; 26:2205.
  40. Coleman RE, Wright J, Houston S, et al. Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer. J Clin Oncol 2012; 30s: abstr 511. Abstract avialble online at http://meetinglibrary.asco.org/content/99595-114 (Accessed on July 16, 2015).
  41. Palmieri C, Fullarton JR, Brown J. Comparative efficacy of bisphosphonates in metastatic breast and prostate cancer and multiple myeloma: a mixed-treatment meta-analysis. Clin Cancer Res 2013; 19:6863.
  42. Mystakidou K, Stathopoulou E, Parpa E, et al. Oral versus intravenous ibandronic acid: a comparison of treatment options for metastatic bone disease. J Cancer Res Clin Oncol 2008; 134:1303.
  43. Efficacy and Safety of Zoledronic Acid ( Every 4 Weeks vs. Every 12 Weeks) in Patients With Documented Bone Metastases From Bone Cancer http://clinicaltrials.gov/ct2/show/NCT00320710 (Accessed on March 24, 2011).
  44. Mangiapane S, Hoer A, Gothe H, et al. Higher persistency with i.v. bisphosphonates in patients with bone metastasis. J Clin Oncol 2006; 24:18S (abstr# 18623).
  45. Paterson AH, Powles TJ, Kanis JA, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11:59.
  46. Kristensen B, Ejlertsen B, Groenvold M, et al. Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999; 246:67.
  47. Tubiana-Hulin M, Beuzeboc P, Mauriac L, et al. [Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases]. Bull Cancer 2001; 88:701.
  48. Ernst DS, Tannock IF, Winquist EW, et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003; 21:3335.
  49. Dearnaley DP, Sydes MR, Mason MD, et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 2003; 95:1300.
  50. Dearnaley DP, Mason MD, Parmar MK, et al. Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 2009; 10:872.
  51. Body JJ, Diel IJ, Lichinitzer M, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004; 90:1133.
  52. Hoskin P, Sundar S, Reczko K, et al. A Multicenter Randomized Trial of Ibandronate Compared With Single-Dose Radiotherapy for Localized Metastatic Bone Pain in Prostate Cancer. J Natl Cancer Inst 2015; 107.
  53. Body JJ, Lichinitser M, Tjulandin S, et al. Oral ibandronate is as active as intravenous zoledronic acid for reducing bone turnover markers in women with breast cancer and bone metastases. Ann Oncol 2007; 18:1165.
  54. Barrett-Lee P, Casbard A, Abraham J, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol 2014; 15:114.
  55. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996; 335:1785.
  56. Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 1998; 16:2038.
  57. Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999; 17:846.
  58. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21:4042.
  59. Hultborn R, Gundersen S, Ryden S, et al. Efficacy of pamidronate in breast cancer with bone metastases: a randomized, double-blind placebo-controlled multicenter study. Anticancer Res 1999; 19:3383.
  60. Small EJ, Smith MR, Seaman JJ, et al. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 2003; 21:4277.
  61. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003; 98:1735.
  62. Addison CL, Pond GR, Zhao H, et al. Effects of de-escalated bisphosphonate therapy on bone turnover biomarkers in breast cancer patients with bone metastases. Springerplus 2014; 3:577.
  63. Henk HJ, Kaura S. Retrospective database analysis of the effect of zoledronic acid on skeletal-related events and mortality in women with breast cancer and bone metastasis in a managed care plan. J Med Econ 2012; 15:175.
  64. Marr HK, Stiles CR, Boyar MA, et al. Feasibility of administering zoledronic acid in palliative patients being cared for in the community: results of a pilot study. Curr Oncol 2010; 17:69.
  65. Ross JR, Saunders Y, Edmonds PM, et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327:469.
  66. Mancini I, Dumon JC, Body JJ. Efficacy and safety of ibandronate in the treatment of opioid-resistant bone pain associated with metastatic bone disease: a pilot study. J Clin Oncol 2004; 22:3587.
  67. Clemons MJ, Dranitsaris G, Ooi WS, et al. Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal-related event or progressive bone metastases despite first-line bisphosphonate therapy. J Clin Oncol 2006; 24:4895.
  68. Coleman R, Brown J, Terpos E, et al. Bone markers and their prognostic value in metastatic bone disease: clinical evidence and future directions. Cancer Treat Rev 2008; 34:629.
  69. Lipton A, Cook R, Saad F, et al. Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 2008; 113:193.