Overview of the use of osteoclast inhibitors in early breast cancer
- Catherine Van Poznak, MD
Catherine Van Poznak, MD
- Associate Professor Department of Internal Medicine
- University of Michigan
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 . 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. They are US Food and Drug Administration (FDA)-approved for managing osteoporosis and bone metastases from a variety of malignancies, aid in preventing therapy-related bone loss, and complement nutritional (calcium and vitamin D), exercise, and healthy lifestyle behaviors.
This topic will review the use of bisphosphonates and denosumab for preservation of BMD 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 the fracture risk assessment tool [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".)
It is of note that not all pharmacologic interventions available for management of bone health may be appropriate for patients with a history of breast cancer. In general the estrogen-like, estrogen-progesterone, and parathyroid hormone therapies are to be avoided due to the potential to have negative impacts on cancer outcomes . The novel sclerostin-targeting therapies have not yet been studied in patients with a history of breast cancer and there is theoretical concern regarding the use of this class of drug in patients who may have occult bone metastases [3,4].
BREAST CANCER THERAPY-ASSOCIATED BONE LOSS
Women with a history of breast cancer may be at increased risk of osteoporosis secondary to the systemic therapies administered [5-9]. 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 .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- SEER Stat Fact Sheets: Breast Cancer http://seer.cancer.gov/statfacts/html/breast.html (Accessed on January 15, 2014).
- Clines GA, Choksi P, Van Poznak C. Adjuvant Endocrine Therapy and Bone Health in Breast Cancer. Curr Osteoporos Rep 2015; 13:263.
- Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med 2016; 375:1532.
- MacNabb C, Patton D, Hayes JS. Sclerostin Antibody Therapy for the Treatment of Osteoporosis: Clinical Prospects and Challenges. J Osteoporos 2016; 2016:6217286.
- 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.
- 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.
- 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.
- Van Poznak C, Sauter NP. Clinical management of osteoporosis in women with a history of breast carcinoma. Cancer 2005; 104:443.
- Lustberg MB, Reinbolt RE, Shapiro CL. Bone health in adult cancer survivorship. J Clin Oncol 2012; 30:3665.
- Bone Source from the National Osteoporosis Foundation (nof.org). http://www.nof.org/professionals (Accessed on September 01, 2011).
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med 2010; 363:2027.
- Body JJ. Prevention and treatment of side-effects of systemic treatment: bone loss. Ann Oncol 2010; 21 Suppl 7:vii180.
- Abraham A, Cohen A, Shane E. Premenopausal bone health: osteoporosis in premenopausal women. Clin Obstet Gynecol 2013; 56:722.
- 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.
- 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.
- 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.
- 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.
- 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.
- Raisz LG. Clinical practice. Screening for osteoporosis. N Engl J Med 2005; 353:164.
- Rosen CJ. Clinical practice. Postmenopausal osteoporosis. N Engl J Med 2005; 353:595.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2017; 35:2062.
- 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.
- 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.
- 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.
- Jacobs C, Amir E, Paterson A, et al. Are adjuvant bisphosphonates now standard of care of women with early stage breast cancer? A debate from the Canadian Bone and the Oncologist New Updates meeting. J Bone Oncol 2015; 4:54.
- Hadji P, Coleman RE, Wilson C, et al. Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol 2016; 27:379.
- Stopeck AT. Osteoclast inhibition in postmenopausal breast cancer: Is the evidence too strong to ignore? Cancer 2017; 123:2392.
- 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.
- 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.
- Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev 2012; :CD003474.
- 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).
- 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.
- 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.
- BREAST CANCER THERAPY-ASSOCIATED BONE LOSS
- Premenopausal women
- Postmenopausal women
- PREVENTION OF TREATMENT-RELATED BONE LOSS
- Premenopausal women with treatment-related bone loss
- Postmenopausal women with treatment-related bone loss
- IMPACT ON BREAST CANCER OUTCOMES
- - Efficacy
- - Is there a preferred adjuvant bisphosphonate?
- - Efficacy
- TOXICITY ASSOCIATED WITH OSTEOCLAST INHIBITORS
- CLINICAL TRIALS
- SUMMARY AND RECOMMENDATIONS