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Overview of the use of osteoclast inhibitors in early breast cancer

Catherine Van Poznak, MD
Section Editor
Daniel F Hayes, MD
Deputy Editor
Sadhna R Vora, MD


Breast cancer is the most common female cancer worldwide. The prognosis of fully treated early breast cancer is usually very good, in part due to systemic therapies reducing the risk of recurrence. For example, in the United States, estimates are that over 89 percent of patients will survive five years or more following their initial diagnosis [1]. Therefore, the long-term toxicities of breast cancer therapies need to be considered. (See "Adjuvant chemotherapy for HER2-negative breast cancer" and "Adjuvant systemic therapy for HER2-positive breast cancer" and "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer".)

Systemic therapies used to treat early breast cancer can be associated with loss of bone mineral density (BMD) and increased risk of osteoporotic fractures. Bisphosphonates and denosumab are potent inhibitors of osteoclast activity, are approved for managing osteoporosis and bone metastases from a variety of malignancies, appear to prevent therapy-related bone loss, and compliment nutritional (calcium and vitamin D), exercise, and lifestyle modifications. This topic will review the use of bisphosphonates and denosumab for preservation of bone mass in the adjuvant breast cancer setting. Adjuvant anticancer treatment modalities of breast cancer, methods to assess risk of fracture (eg, using history, physical exam, algorithms such as FRAX), imaging BMD, optimal intake of calcium and vitamin D, and the utility of osteoclast inhibitors in the management of breast cancer bone metastases are reviewed elsewhere. (See "Osteoporotic fracture risk assessment" and "Screening for osteoporosis" and "Calcium and vitamin D supplementation in osteoporosis" and "Prevention of osteoporosis", section on 'Minimizing bone loss' and "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)


Women with a history of breast cancer may be at increased risk of osteoporosis secondary to the adjuvant systemic therapies administered [2-6]. Osteoporosis is associated with an increased risk of fracture and can be associated with significant morbidity, mortality, disfigurement and loss of self-esteem, and health care expenditure [7].

Estrogen, an important target for hormone receptor-positive breast cancer therapies, is also an important hormone for bone homeostasis. Therefore, anticancer therapies that decrease circulating estrogen levels or estrogen signaling may be associated with a decrease in bone mass.

Adjuvant systemic therapies for breast cancer that are associated with an increased risk for bone loss include [5,8]:


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Literature review current through: Sep 2016. | This topic last updated: Feb 19, 2016.
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  1. SEER Stat Fact Sheets: Breast Cancer http://seer.cancer.gov/statfacts/html/breast.html (Accessed on January 15, 2014).
  2. Greep NC, Giuliano AE, Hansen NM, et al. The effects of adjuvant chemotherapy on bone density in postmenopausal women with early breast cancer. Am J Med 2003; 114:653.
  3. Zmuda JM, Cauley JA, Ljung BM, et al. Bone mass and breast cancer risk in older women: differences by stage at diagnosis. J Natl Cancer Inst 2001; 93:930.
  4. Zhang Y, Kiel DP, Kreger BE, et al. Bone mass and the risk of breast cancer among postmenopausal women. N Engl J Med 1997; 336:611.
  5. Van Poznak C, Sauter NP. Clinical management of osteoporosis in women with a history of breast carcinoma. Cancer 2005; 104:443.
  6. Lustberg MB, Reinbolt RE, Shapiro CL. Bone health in adult cancer survivorship. J Clin Oncol 2012; 30:3665.
  7. Bone Source from the National Osteoporosis Foundation (nof.org). http://www.nof.org/professionals (Accessed on September 01, 2011).
  8. Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force Report: Bone Health In Cancer Care. J Natl Compr Canc Netw 2013; 11 Suppl 3:S1.
  9. Surveillance Epidemiology and End Results (SEER) Stat Fact Sheets for breast cancer. http://seer.cancer.gov/statfacts/html/breast.html (Accessed on September 01, 2011).
  10. Vehmanen L, Elomaa I, Blomqvist C, Saarto T. Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. J Clin Oncol 2006; 24:675.
  11. Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 2001; 19:3306.
  12. Powles TJ, McCloskey E, Paterson AH, et al. Oral clodronate and reduction in loss of bone mineral density in women with operable primary breast cancer. J Natl Cancer Inst 1998; 90:704.
  13. Saarto T, Blomqvist C, Välimäki M, et al. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 1997; 15:1341.
  14. Delmas PD, Balena R, Confravreux E, et al. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. J Clin Oncol 1997; 15:955.
  15. Sverrisdóttir A, Fornander T, Jacobsson H, et al. Bone mineral density among premenopausal women with early breast cancer in a randomized trial of adjuvant endocrine therapy. J Clin Oncol 2004; 22:3694.
  16. Powles TJ, Hickish T, Kanis JA, et al. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 1996; 14:78.
  17. Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 2007; 25:820.
  18. Chen Z, Maricic M, Bassford TL, et al. Fracture risk among breast cancer survivors: results from the Women's Health Initiative Observational Study. Arch Intern Med 2005; 165:552.
  19. Van Poznak C, Morris PG, D'Andrea G, et al. Bone Mineral Density (BMD) Changes at 1 Year in Postmenopausal Women Who Are Not Receiving Adjuvant Endocrine Therapy for Breast Cancer (BCA). Cancer Res 2009; 69:559s (abstr 1066).
  20. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326:852.
  21. Reid DM, Doughty J, Eastell R, et al. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Cancer Treat Rev 2008; 34 Suppl 1:S3.
  22. Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med 2010; 363:2027.
  23. Body JJ. Prevention and treatment of side-effects of systemic treatment: bone loss. Ann Oncol 2010; 21 Suppl 7:vii180.
  24. Abraham A, Cohen A, Shane E. Premenopausal bone health: osteoporosis in premenopausal women. Clin Obstet Gynecol 2013; 56:722.
  25. Vehmanen L, Saarto T, Risteli J, et al. Short-term intermittent intravenous clodronate in the prevention of bone loss related to chemotherapy-induced ovarian failure. Breast Cancer Res Treat 2004; 87:181.
  26. Fuleihan Gel-H, Salamoun M, Mourad YA, et al. Pamidronate in the prevention of chemotherapy-induced bone loss in premenopausal women with breast cancer: a randomized controlled trial. J Clin Endocrinol Metab 2005; 90:3209.
  27. Vehmanen L, Saarto T, Elomaa I, et al. Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment. Eur J Cancer 2001; 37:2373.
  28. Shapiro CL, Halabi S, Hars V, et al. Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. Eur J Cancer 2011; 47:683.
  29. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol 2008; 9:840.
  30. Raisz LG. Clinical practice. Screening for osteoporosis. N Engl J Med 2005; 353:164.
  31. Rosen CJ. Clinical practice. Postmenopausal osteoporosis. N Engl J Med 2005; 353:595.
  32. 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.
  33. Brufsky A, Bundred N, Coleman R, et al. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 2008; 13:503.
  34. Lester JE, Dodwell D, Purohit OP, et al. Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer. Clin Cancer Res 2008; 14:6336.
  35. Van Poznak C, Hannon RA, Mackey JR, et al. Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. J Clin Oncol 2010; 28:967.
  36. Brufsky AM, Bosserman LD, Caradonna RR, et al. Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results. Clin Breast Cancer 2009; 9:77.
  37. Ellis GK, Bone HG, Chlebowski R, et al. Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat 2009; 118:81.
  38. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015; 386:433.
  39. 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.
  40. Body JJ, Bergmann P, Boonen S, et al. Management of cancer treatment-induced bone loss in early breast and prostate cancer -- a consensus paper of the Belgian Bone Club. Osteoporos Int 2007; 18:1439.
  41. Gnant M, Dubsky PC, Hubalek M, Greil R. The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. SABCS 2015; S2-02.
  42. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Coleman R, Powles T, et al. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 2015; 386:1353.
  43. Valachis A, Polyzos NP, Coleman RE, et al. Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis. Oncologist 2013; 18:353.
  44. Mauri D, Valachis A, Polyzos NP, et al. Does adjuvant bisphosphonate in early breast cancer modify the natural course of the disease? A meta-analysis of randomized controlled trials. J Natl Compr Canc Netw 2010; 8:279.
  45. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev 2012; :CD003474.
  46. Gnant M, Dubsky P, Fitzal F, et al. Maintaining bone density in patients undergoing treatment for breast cancer: is there an adjuvant benefit? Clin Breast Cancer 2009; 9 Suppl 1:S18.
  47. Winter MC, Holen I, Coleman RE. Exploring the anti-tumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev 2008; 34:453.
  48. Vincenzi B, Santini D, Dicuonzo G, et al. Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients. J Interferon Cytokine Res 2005; 25:144.
  49. Aft R, Naughton M, Trinkaus K, et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 2010; 11:421.
  50. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002; 2:584.
  51. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004; 350:1655.
  52. Hall DG, Stoica G. Effect of the bisphosphonate risedronate on bone metastases in a rat mammary adenocarcinoma model system. J Bone Miner Res 1994; 9:221.
  53. Chlebowski RT, Chen Z, Cauley JA, et al. Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol 2010; 28:3582.
  54. Rennert G, Pinchev M, Rennert HS. Use of bisphosphonates and risk of postmenopausal breast cancer. J Clin Oncol 2010; 28:3577.
  55. Newcomb PA, Trentham-Dietz A, Hampton JM. Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. Br J Cancer 2010; 102:799.
  56. Liu Y, Zhao S, Chen W, et al. Bisphosphonate use and the risk of breast cancer: a meta-analysis of published literature. Clin Breast Cancer 2012; 12:276.
  57. Gralow J, Barlow WE, Paterson AG, et al. Phase III trial of bisphosphonates as adjuvant therapy in primary breast cancer: SWOG/Alliance/ECOG-ACRIN/NCIC Clinical Trials Group/NRG Oncology study S0307. J Clin Oncol 33, 2015; (suppl; abstr 503).
  58. Mauri D, Valachis A, Polyzos IP, et al. Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis. Breast Cancer Res Treat 2009; 116:433.
  59. Coleman R, Woodward E, Brown J, et al. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer. Breast Cancer Res Treat 2011; 127:429.