Hormone therapy and osteoporosis in breast cancer survivors: assessment of risk and adherence to screening recommendations
The long-term impact of hormone therapy for breast cancer on risk of osteoporosis and the extent to which bone screening recommendations are implemented in daily practice remain unknown. We found that the aromatase inhibitor-induced risk of osteoporosis did not continue in the off-treatment follow-up. Adherence to screening recommendations was suboptimal.
A case-cohort study was undertaken to better understand the impact of hormone therapy on breast cancer patients’ risk of osteoporosis, and to estimate the extent to which current bone mineral density screening recommendations are implemented in real-life daily practice.
This study is based on 1692 female breast cancer survivors recruited from “Leumit” healthcare fund, who were diagnosed with primary nonmetastatic invasive breast cancer between 2002 and 2012. A 20% random subcohort was sampled at baseline, and all osteoporosis cases were identified. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated by weighted Cox proportional hazards models.
Of 1692 breast cancer survivors, 312 developed osteoporosis during a median follow-up of 5 years. The crude cumulative incidence of osteoporosis accounting for death as a competing risk was 25.7% (95% CI, 21.9–29.5%). In multivariable analyses, osteoporosis was positively associated with the aromatase inhibitor (AI) sequential treatment after tamoxifen (HR, 3.14; 95% CI, 1.44–6.88; P = .004) but was more pronounced with AI use as upfront monotherapy (HR, 5.53; 95% CI, 1.46–20.88; P = .012). This effect did not continue in the off-treatment follow-up. In subgroup analysis by menopausal status, tamoxifen did not seem to confer a protective effect on bone health in postmenopausal patients. Adherence to screening recommendations in AI-treated postmenopausal women was suboptimal, particularly at baseline and after 48 months of continuous AI use.
The natural, age-related reduction in bone density is exacerbated by breast cancer active AI treatment. Future research should focus on investigating screening adherence-related barriers/facilitators and effective strategies to bring practice in line with agreed standards.
KeywordsAromatase inhibitor Bone health Breast cancer Osteoporosis Survivorship Tamoxifen
Attributable risk fraction
Anatomic therapeutic chemical
Bone mineral density
Cumulative incidence function
International classification of diseases, ninth revision
Incidence density rate
Incidence density rate ratio
Israel National Cancer Registry
Leumit Health Services
Population attributable fraction
Standardized incidence density rate ratio
We gratefully acknowledge all participating breast cancer survivors, Dr. Natan Kahan, and the Ph.D. advisory committee for their invaluable contribution.
Funding of this study was in part provided by a grant from the Council for Higher Education (grant no. 11658745) in collaboration with the Graduate Studies Authority at the University of Haifa (grant no. 11658760). The sponsors have no role in the collection, analysis, and interpretation of data.
Compliance with ethical standards
The study protocol was duly approved by the Institutional Review Boards of LHS and the University of Haifa.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Conflicts of interest
The results, conclusions, view and opinions contained herein are those of the authors and not to be construed as the official policy of Israel’s Ministry of Health, or of Leumit Health Organization.
- 3.Hadji P, Aapro MS, Body JJ, Gnant M, Brandi ML, Reginster JY, Zillikens MC, Glüer CC, de Villiers T, Baber R, Roodman GD, Cooper C, Langdahl B, Palacios S, Kanis J, al-Daghri N, Nogues X, Eriksen EF, Kurth A, Rizzoli R, Coleman RE (2017) Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol 7:1–12CrossRefGoogle Scholar
- 12.Gralow JR, Biermann JS, Farooki A, et al (2013) NCCN Task Force Report: Bone Health In Cancer Care. J Natl Compr Cancer Netw 11 Suppl 3: S1–50; quiz S51Google Scholar
- 14.Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A, Brown S, American Society of Clinical Oncology (2003) American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042–4057CrossRefGoogle Scholar
- 15.Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA (2016) American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol 34:611–635CrossRefGoogle Scholar
- 23.Aday LA (1996) Designing and conducting health surveys: a comprehensive guide. Jossey-Bass Publishers, San FranciscoGoogle Scholar
- 28.Goldshtein I, Chandler J, Shalev V et al (2015) Osteoporosis in the community: findings from a novel computerized registry in a large health organization in Israel. J Aging Res Clin Pract 4:59–65Google Scholar
- 34.Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, Shenkier TN, Tozer RG, Palmer MJ, Shepherd LE, Liu S, Tu D, Goss PE (2006) Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol 24:3629–3635CrossRefGoogle Scholar
- 36.Eidtmann H, de Boer R, Bundred N, Llombart-Cussac A, Davidson N, Neven P, von Minckwitz G, Miller J, Schenk N, Coleman R (2010) Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Ann Oncol 21:2188–2194CrossRefGoogle Scholar
- 43.Hewitt M, Greenfield S, Stovall E (2006) From cancer patient to cancer survivor: lost in transition. the National Academies Press, Washington DCGoogle Scholar