Abstract
We studied risk of fractures among women who had used tamoxifen or aromatase inhibitors compared to nonusers in a case–control study. There were 64,548 fracture cases and 193,641 age- and gender-matched controls. Adjustment was made for comorbidity, social factors, and use of orther drugs. Use of tamoxifen in general was not associated with any significant change in the risk of any fracture, wrist fractures, and spine fractures. A significantly decreasing relative risk of fractures was seen with increasing dose, although the risk never declined statistically significantly below that in nonusers. An increased risk of hip fractures was seen, but the increase was limited to patients who had used low average doses (<20 mg of tamoxifen/day) and were prior users (i.e., had not used tamoxifen within the last year). Aromatase inhibitors were associated with significant increases in overall risk of fractures and risk of hip fractures. Tamoxifen does not seem to be bone-protective in such a degree that the risk of fractures decreases below that of nonusers. Tamoxifen per se does not seem to increase the risk of fractures. Aromatase inhibitors were associated with a significant increase in the risk of fractures. In women at high risk of fractures, supplementary measures, i.e., bisphosphonates, may be considered.
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Love RR, Barden HS, Mazess RB, Epstein S, Chappell RJ (1994) Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years. Arch Intern Med 154:2585–2588
Love RR, Maxess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, Carbone PP, DeMets DL (1992) Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852–856
Neal AJ, Evans K, Hoskin PJ (1993) Does long-term administration of tamoxifen affect bone mineral density? Eur J Cancer 29A:1971–1973
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 39:321–326
Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Glüer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 282:637–645
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER Jr, Wade JL III, Robidoux A, Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N (2006) Effects of tamoxifen vs. raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727–2741
Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G, Adams JE (2006) Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res 21:1215–1223
Coleman RE, Banks LM, Girgis SI, Kilburn LS, Vrdoljak E, Fox J, Cawthorn SJ, Patel A, Snowdon CF, Hall E, Bliss JM, Coombes RC (2007) Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncol 8:119–127
Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359:2131–2139
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 79:1179–1181
Utz JP, Melton LJ III, Kan SH, Riggs BL (1987) Risk of osteoporotic fractures in women with breast cancer: a population-based cohort study. J Chron Dis 40:105–113
Frank L (2000) Epidemiology. When an entire country is a cohort. Science 287:2398–2399
Andersen TF, Madsen M, Jørgensen J, Mellemkjær L, Olsen JH (1999) The Danish National Hospital Register. Dan Med Bull 46:263–268
Vestergaard P, Mosekilde L (2002) Fracture risk in patients with celiac disease, Crohn’s disease, and ulcerative colitis: a nation-wide follow-up study in 16,416 patients in Denmark. Am J Epidemiol 156:1–10
Wacholder S, McLaughlin JK, Silverman DT, Mandel JS (1992) Selection of controls in case–control studies. I. Principles. Am J Epidemiol 135:1019–1028
Capella D (1993) Descriptive tools and analysis. In: Dukes MNG (ed) Drug utilization studies: methods and uses. WHO Regional Publications, European Series 45, Copenhagen, WHO, pp 55–78
Nielsen GL, Sørensen HT, Zhou W, Steffensen FH, Olsen J (1997) The pharmaco-epidemiologic prescription database of north Jutland. Int J Risk Saf Med 10:203–205
Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40:373–383
de Groot V, Beckerman H, Lankhorst GJ, Bouter LM (2003) How to measure comorbidity: a critical review of available methods. J Clin Epidemiol 56:221–229
Munk-Jørgensen P, Mortensen PB (1997) The Danish Psychiatric Central Register. Dan Med Bull 44:82–84
Vestergaard P, Rejnmark L, Mosekilde L (2006) Fracture risk associated with use of morphine and opiates. J Intern Med 260:76–87
Vestergaard P, Rejnmark L, Mosekilde L (2006) Fracture risk associated with use of nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and acetaminophen and the effects of rheumatoid arthritis and osteoarthritis. Calcif Tissue Int 79:84–94
Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333
Miettinen OS (1985) Theoretical epidemiology: principles of occurrence research in medicine. Wiley, New York
Mouridsen HT, Rose C, Overgaard M, Dombernowsky P, Panduro J, Thorpe S, Rasmussen BB, Blichert-Toft M, Andersen KW (1988) Adjuvant treatment of postmenopausal patients with high risk primary breast cancer. Results from the Danish adjuvant trials DBCG 77 C and DBCG 82 C. Acta Oncol 27:699–705
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 79:1179–1181
Bruning PF, Pit MJ, de Jong-Bakker M, van den Ende A, Hart A, van Enk A (1990) Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer 61:308–310
Body JJ, Diel IJ, Lichinitzer M, Lazarev A, Pecherstorfer M, Bell R, Tripathy D, Bergstrom B (2004) 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 90:1133–1137
Cleton FJ, Holten-Verzantvoort AT, Bijvoet OL (1989) Effect of long-term bisphosphonate treatment on morbidity due to bone metastases in breast cancer patients. Recent Results Cancer Res 116:73–78
Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, Wheeler H, Simeone JF, Seaman J, Knight RD (1996) 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 335:1785–1791
Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D, Sinoff C, Wheeler H, Simeone JF, Seaman JJ, Knight RD, Heffernan M, Mellars K, Reitsma DJ (1998) Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16:2038–2044
Kanis JA, Powles T, Paterson AH, McCloskey EV, Ashley S (1996) Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 19:663–667
Acknowledgement
Danmarks Statistik (Statistics Denmark) is acknowledged for the help without which this project would not have been possible. Research Librarian Ms. Edith Clausen is acknowledged for invaluable help with the references. The Danish Medical Research Council granted financial support (Grant 22-04-0495).
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Vestergaard, P., Rejnmark, L. & Mosekilde, L. Effect of Tamoxifen and Aromatase Inhibitors on the Risk of Fractures in Women with Breast Cancer. Calcif Tissue Int 82, 334–340 (2008). https://doi.org/10.1007/s00223-008-9132-7
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DOI: https://doi.org/10.1007/s00223-008-9132-7