SERMs and SERMs with estrogen for postmenopausal osteoporosis
First Online: 06 May 2010 DOI:
Cite this article as: Bolognese, M.A. Rev Endocr Metab Disord (2010) 11: 253. doi:10.1007/s11154-010-9137-1 Abstract
Bone loss with aging places postmenopausal women at a higher risk for osteoporosis and its consequences such as fractures, pain, disability, and increased morbidity and mortality. Approximately 200 million patients worldwide are affected. The Third National Health and Nutrition Examination Survey (NHANES III) estimated that up to 18% of US women aged 50 and older have osteoporosis and up to 50% have osteopenia. Greater than 2 million osteoporotic related fractures occurred in the United States with direct healthcare costs exceeding $17 billion. Hormone Replacement Therapy (HRT) was a popular option for postmenopausal women before the Women’s Health Initiative (WHI). Several agents are available in the U.S., including bisphosphonates, hormone therapy, calcitonin, parathyroid hormone and the selective estrogen receptor modulator (SERM) raloxifene. There are concerns about long term safety and compliance. Therefore, other agents are under investigation. SERMs are a diverse group of agents that bind to the estrogen receptor and each SERM appears to have a unique set of clinical responses, which are not always consistent with the typical responses seen with other SERMs. This article will discuss the SERMs approved in the United States, tamoxifene and raloxifene, and investigational SERMs. The ideal SERM would include the beneficial effects of estrogen in bone, heart and the central nervous system, with neutral or antagonistic effects in tissues where estrogen effects are undesirable(breast and endometrium). A new target in treating postmenopausal osteoporosis is the tissue estrogen complex or the pairing of a SERM with a conjugated estrogen known as a tissue selective estrogen complex (TSEC). This novel approach is currently being evaluated with bazodoxifene which could yield the beneficial effects of estrogens and SERMS, while potentially being more tolerable and safer than either therapy alone.
Keywords Osteoporosis SERMs FRAX Tissue selective estrogen complex (TSEC) References
Taylor H. Approaching the ideal selective estrogen receptor modulator for prevention and treatment of postmenopausal osteoporosis. Formulary. 2010;45:52–9.
Looker AC, Orwell ES, Johnston Jr CC, et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res. 1997;12:1761–8.
Kanis JA, Oden A, Johansson H, Borgstrom F, Strom O, McCloskey E. Frax and its application in clinical practice. Bone. 2009;44:734–43.
Siris ES, Chen YT, Abbott TA, et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Int Med. 2004;164:1108–12.
Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteston A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22:465–75.
Veronesi U, Boyle P, Goldhirsch A, et al. Breast cancer. Lancet. 2005;365:1451–67.
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst. 1998;90:1371–88.
Love RR, Cameron L, Connell BL, Leventhal H. Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med. 1991;151:1842–7.
Dignam JJ, Fisher B. Occurrence of stroke with tamoxifen in NSABP B-24. Lancet. 2000;355:848–9.
Evista (Raloxifene HCL) (Package insert). Indianapolis, IN: Eli Lilly and Company, 2007.
Draper MW, Flowers DE, Huster WJ, et al. A controlled trial of raloxifene (LY 139481) HCL; impact on bone turnover and serum lipid profile in healthy Postmenopausal women. J Bone Miner Res. 1996;11:835–42.
Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 1997;337:1641–7.
Johnston Jr CC, Bjarnason NH, Cohen FJ, et al. Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipids in early postmenopausal women. 3-year data from two double-blind, randomized, placebo-controlled trials. Arch Int Med. 2000;160:3444–50.
Jolly EE, Bjarnason NH, Nevan P, et al. Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years. Menopause. 2003;10:337–44.
Reid IR, Eastell R, Fogelman I, et al. A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women. Arch Intern Med. 2004;164:871–9.
Cummings S, Eckert S, Krueger K, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA. 1999;281:2189–97.
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene; results from a 3-year randomized clinical trial. JAMA. 1999;282:637–45.
Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis; four year results from a randomized clinical trial. JAMA. 1999;282:637–45.
Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96:1751–61.
Siris ES, Harris ST, Eastell R, et al. Skeletal effects of raloxifene after 8 years: results from the Continuing Outcomes Relevant to Evista (CORE) study. J Bone Miner Res. 2005;20:1514–24.
Neven P, Quail D, Martin F, et al. Comparing raloxifene with continuous combined estrogen-progesterone therapy in postmenopausal women: review of Euralox 1. Maturitas. 2005;52:87–101.
Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–37.
Shelly W, Draper M, Krishman V, et al. Selective estrogen receptor modulators: an update on recent clinical findings. Obstet Gynecol Surv. 2008;63:163–80.
Siris E, Harris S, Eastell R, et al. Effects of raloxifene on the risk of non-vertebral fractures after 8 years: results from the Continuing Outcomes Relevant to Evista (CORE) study. J Bone Miner Res. 2004;19:896.
Cauley J, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene; 4-year results from the MORE trial. Breast Cancer Res Treat. 2001;65:125–34.
Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs. raloxifene on the risk of developing invasive breast cancer and other disease outcomes. JAMA. 2006;295:2727–41.
Martino S, Disch D, Dowsett SA, et al. Safety assessment of raloxifene over eight years in a clinical trial setting. Curr Med Res Opin. 2005;21:1441–52.
Davies GC, Huster WJ, Lu Y, et al. Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet Gynecol. 1999;93:558–65.
Duvernoy CS, Kulkarni PM, Dowsett SA, et al. Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: incidence, patient characteristics, and effect of raloxifene. Menopause. 2005;12:444–52.
Grady D, Ettinger B, Moscarelli E, et al. Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004;104:837–44.
Davies GC, Huster WJ, Shen W, et al. Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women. Menopause. 1999;6:188–95.
Neven P, Goldstein SR, Ciaccia AV, et al. The effect of raloxifene on the incidence of ovarian cancer in postmenopausal women. Gynecol Oncol. 2002;85:388–90.
Goldstein SR, Neven P, Zhou L, et al. Raloxifene effect on frequency of surgery for pelvic floor relaxation. Obstet Gynecol. 2001;98:91–6.
Goldstein SR, Johnson S, Watts NB, et al. Incidence of urinary incontinence in postmenopausal women treated with raloxifene or estrogen. Menopause. 2005;12:160–4.
Waetjen LE, Brown JS, Modelska K, et al. Effect of raloxifene on urinary incontinence; a randomized controlled trial. Obstet Gynecol. 2004;103:261–6.
Ensrud K, Genazzani AR, Geiger MJ, et al. Effect of raloxifene on cardiovascular adverse events in postmenopausal women with osteoporosis. Am J Cardiol. 2006;97:520–7.
Yaffe K, Krueger K, Sarkar S, et al. Cognitive function in postmenopausal women treated with raloxifene. N Eng J Med. 2001;344:1207–13.
Yaffe K, Kreuger K, Cummings SR, et al. Effect of raloxifene on prevention of dementia and cognitive impairment in older women: Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry. 2005;162:683–90.
Bolognese M, Krege J, Utian W, et al. OC45; Arzoxifene in postmenopausal women with normal or low bone mass. Bone (supplement). 2009;44:S230.
Ravn P, Nielsen TF, Christiansen C. What can be learned from the levormeloxifene experience? Acta Obstet Gynecol Scand. 2006;85:135–42.
Vogelvang TE, van der Mooren MJ, et al. Emerging selective estrogen receptor modulators; special focus on effects on coronary heart disease in postmenopausal women. Drugs. 2006;66:191–221.
Budzar A, Hayes D, El-Khoudary A, et al. Phase II randomized trial of droloxifene and tamoxifen as first-line endocrine treatment of ER/PgR-positive advanced breast cancer. Breast Cancer Res Treat. 2002;73:161–75.
van Rietbergen E, Majumdar S, Newitt D, et al. High-resolution MRI and Micro-FE for the evaluation of changes in bone mechanical properties during longitudinal clinical trials; application to calcaneal bone in postmenopausal women after one year of idoxifene treatment. Clin Biomech (Bristol,Avon). 2002;17:81–8.
Fleischer AC, Wheeler JE, Yeh IT, et al. Effects of clomoiphene citrate on the endometrial thickness and echogenic pattern of the endometrium. J Ultrasound Med. 1999;18:503–12.
Ariazi EA, Ariazi JL, Cordera F, et al. Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem. 2006;6:181–202.
Alertazzi P, Sharma S. Urogenital effects of selective estrogen receptor modulators; a systemic review. Climacteric. 2005;8:214–20.
Gardner M, Taylor A, Wei G, et al. Clinical pharmacology of multiple doses of lasofoxifene in postmenopausal women. J Clin Pharmacol. 2006;46:52–8.
McClung MR, Siris E, Cummings S, et al. Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene. Menopause. 2006;13:377–86.
Cummings S, Ensrud K, Delmas P, et al. Lasofoxifene in postmenopausal Women with osteoporosis. N Engl J Med. 2010;362:686–96.
Komm BS, Kharode YP, Bodine PV, et al. Bazodoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005;146:3999–4008.
Ronkin S, Northington R, Baracat E, et al. Endometrial effects of bazodoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women. Obstet Gynecol. 2005;105:1397–404.
Miller PD, Chines AA, Christiansen C, et al. Effects of bazodeoxifene on BMD and bone turnover in postmenopausal women: 2-year results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res. 2008;23:525–35.
Boss SM, Huster WJ, Neild JA, et al. effects of raloxifene hydrochloride on the endometrium of postmenopausal women. Am J Obstet Gynecol. 1997;177:1458–64.
Komm B. A new approach to menopausal therapy: the tissue selective estrogen complex. Reprod Sci. 2008;15:984–92.
Pickar J, I-Tein Y, Bachman G, et al. Endometrial effects of a tissue selective estrogen complex containing bazodoxifene/conjugated estrogens as a menopausal therapy. Fertl Steril 2009;92:1018–1024.
Kharode Y, Bodine PVN, Miller CP, et al. The pairing of a selective estrogen modulator, bazodoxifene, with conjugated estrogens as a new paradigmfor the treatment of postmenopausal symptoms and osteoporosis prevention. Endocrinology. 2008;149:6084–91.
Lobo R, Pinkerton J, Gass M, et al. Evaluation of bazodoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril. 2009;92:1025–34.
Archer D, Lewis V, Carr B, et al. Bazodoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertl Steril. 2009;92:1039–44.
Lindsay R, Gallagher J, Kagan R, et al. Efficacy of tissue-selective estrogen complex of bazodoxifene/conjugated estrogens for osteoporosis preventionin at-risk postmenopausal women. Fertl Steril. 2009;92:1045–51.
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