Abstract
Summary
Our data demonstrate that tamoxifen does not reduce fracture risk. Close surveillance is necessary to prevent bone loss in premenopausal women with breast cancer upon treatment initiation.
Introduction
Endocrine treatment of breast cancer may interfere with bone turnover and influence fracture risk.
Methods
Out of a cohort of almost 5 million patients in total, we identified 5520 women between 18 and 90 years of age with breast cancer receiving tamoxifen, matched them with 5520 healthy controls using the Disease Analyzer Database, and investigated the fracture risk.
Results
We found a cumulative incidence of fractures of 6.3% in patients aged between 18 and 50 years (n = 3634) treated with tamoxifen versus a cumulative incidence of 3.6% in the control group (p < 0.001). As such, the risk of fracture was 75% higher for patients receiving tamoxifen than that for healthy controls (HR 1.75; 95% CI 1.25–2.48). With regard to patients aged between 55 and 90 years (n = 7406), the cumulative incidence of fractures in patients treated with tamoxifen was 10.1% compared to 9.3% in the control group (p = 0.740), i.e., there was no significant difference between the two groups (HR 0.97; 95% CI 0.81–1.16).
Conclusions
Compared to healthy controls, premenopausal women with breast cancer treated with tamoxifen showed an increased risk of fracture, while postmenopausal women on tamoxifen did not show any risk reduction.
Similar content being viewed by others
References
DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A (2017) Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 67(6):439–448
Ding H, Field TS (2007) Bone health in postmenopausal women with early breast cancer: how protective is tamoxifen? Cancer Treat Rev 33(6):506–513
Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC et al (1992) Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326(13):852–856
Kalder M, Hadji P (2014) Breast cancer and osteoporosis - management of cancer treatment-induced bone loss in postmenopausal women with breast cancer. Breast Care (Basel) 9(5):312–317
Kalder M, Hans D, Kyvernitakis I, Lamy O, Bauer M, Hadji P (2014) Effects of exemestane and tamoxifen treatment on bone texture analysis assessed by TBS in comparison with bone mineral density assessed by DXA in women with breast cancer. J Clin Densitom 17(1):66–71
Hadji P, Gnant M, Body JJ, Bundred NJ, Brufsky A, Coleman RE et al (2012) Cancer treatment-induced bone loss in premenopausal women: a need for therapeutic intervention? Cancer Treat Rev 38(6):798–806
Turken S, Siris E, Seldin D, Flaster E, Hyman G, Lindsay R (1989) Effects of tamoxifen on spinal bone density in women with breast cancer. J Natl Cancer Inst 81(14):1086–1088
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM et al (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90(18):1371–1388
VanderWalde A, Hurria A (2011) Aging and osteoporosis in breast and prostate cancer. CA Cancer J Clin 61(3):139–156
Melton LJ 3rd, Hartmann LC, Achenbach SJ, Atkinson EJ, Therneau TM, Khosla S (2012) Fracture risk in women with breast cancer: a population-based study. J Bone Miner Res 27(5):1196–1205
Chen Z, Maricic M, Bassford TL, Pettinger M, Ritenbaugh C, Lopez AM et al (2005) Fracture risk among breast cancer survivors: results from the Women’s Health Initiative Observational Study. Arch Intern Med 165(5):552–558
Vestergaard P, Rejnmark L, Mosekilde L (2008) Effect of tamoxifen and aromatase inhibitors on the risk of fractures in women with breast cancer. Calcif Tissue Int 82(5):334–340
Ogdie A LS, Parkinson J, Dattani H, Kostev K, Gelfand JM (2012) Pharmacoepidemiology.In: Strom BLKS, Hennessy S (eds). University of Pennsylvania
Kyvernitakis I, Kostev K, Nassour T, Thomasius F, Hadji P (2017) The impact of depot medroxyprogesterone acetate on fracture risk: a case-control study from the UK. Osteoporos Int 28(1):291–297
Bohlken J, Jacob L, Schaum P, Rapp MA, Kostev K (2017) Hip fracture risk in patients with dementia in German primary care practices. Dementia (London) 16(7):853–864
Schmidt N, Jacob L, Coleman R, Kostev K, Hadji P (2016) The impact of treatment compliance on fracture risk in women with breast cancer treated with aromatase inhibitors in the United Kingdom. Breast Cancer Res Treat 155(1):151–157
Pscherer S, Kostev K, Dippel FW, Rathmann W (2016) Fracture risk in patients with type 2 diabetes under different antidiabetic treatment regimens: a retrospective database analysis in primary care. Diabetes Metab Syndr Obes 9:17–23
Edwards BJ, Gradishar WJ, Smith ME, Pacheco JA, Holbrook J, McKoy JM et al (2016) Elevated incidence of fractures in women with invasive breast cancer. Osteoporos Int 27(2):499–507
Chen Z, Maricic M, Aragaki AK, Mouton C, Arendell L, Lopez AM et al (2009) Fracture risk increases after diagnosis of breast or other cancers in postmenopausal women: results from the Women’s Health Initiative. Osteoporos Int 20(4):527–536
Vestergaard P, Rejnmark L, Mosekilde L (2009) Fracture risk in patients with different types of cancer. Acta Oncol 48(1):105–115
Lamont EB, Lauderdale DS (2003) Low risk of hip fracture among elderly breast cancer survivors. Ann Epidemiol 13(10):698–703
Hadji P (2015) Cancer treatment-induced bone loss in women with breast cancer. Bonekey Rep 4:692
Shapiro CL, Manola J, Leboff M (2001) Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 19(14):3306–3311
Kyvernitakis I, Albert US, Kalder M, Winarno AS, Hars O, Hadji P (2015) Effect of anastrozole on hormone levels in postmenopausal women with early breast cancer. Climacteric 18(1):63–68
Kyvernitakis I, Rachner TD, Urbschat A, Hars O, Hofbauer LC, Hadji P (2014) Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1, bone turnover markers and bone mineral density in women with breast cancer. J Cancer Res Clin Oncol 140(10):1671–1680
Kanis JA, Cooper C, Rizzoli R, Abrahamsen B, Al-Daghri NM, Brandi ML et al (2017) Identification and management of patients at increased risk of osteoporotic fracture: outcomes of an ESCEO expert consensus meeting. Osteoporos Int 28(7):2023–2034
Hadji P, Aapro MS, Body JJ, Gnant M, Brandi ML, Reginster JY et al (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 7:1–12
Cooke AL, Metge C, Lix L, Prior HJ, Leslie WD (2008) Tamoxifen use and osteoporotic fracture risk: a population-based analysis. J Clin Oncol 26(32):5227–5232
Utz JP, Melton LJ 3rd, Kan SH, Riggs BL (1987) Risk of osteoporotic fractures in women with breast cancer: a population-based cohort study. J Chronic Dis 40(2):105–113
Kristensen B, Ejlertsen B, Mouridsen HT, Andersen KW, Lauritzen JB (1996) Femoral fractures in postmenopausal breast cancer patients treated with adjuvant tamoxifen. Breast Cancer Res Treat 39(3):321–326
Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators et al (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 282(7):637–645
Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S (1998) Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol 54(1):105–112
Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL et al (2000) The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci 54(1):138–153
Christiansen C, Lindsay R (1990) Estrogens, bone loss and preservation. Osteoporos Int 1(1):7–13
Kanis JA, McCloskey EV, Powles T, Paterson AH, Ashley S, Spector T (1999) A high incidence of vertebral fracture in women with breast cancer. Br J Cancer 79(7–8):1179–1181
Rabaglio M, Sun Z, Price KN, Castiglione-Gertsch M, Hawle H, Thurlimann B et al (2009) Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol 20(9):1489–1498
Hadji P, Aapro MS, Body JJ, Bundred NJ, Brufsky A, Coleman RE et al (2011) Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment. Ann Oncol 22(12):2546–2555
Kyvernitakis I, Kann PH, Thomasius F, Hars O, Hadji P (2018) Prevention of breast cancer treatment-induced bone loss in premenopausal women treated with zoledronic acid: final 5-year results from the randomized, double-blind, placebo-controlled ProBONE II trial. Bone 114:109–115
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
None.
Rights and permissions
About this article
Cite this article
Kyvernitakis, I., Kostev, K. & Hadji, P. The tamoxifen paradox—influence of adjuvant tamoxifen on fracture risk in pre- and postmenopausal women with breast cancer. Osteoporos Int 29, 2557–2564 (2018). https://doi.org/10.1007/s00198-018-4642-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-018-4642-2