Selective Estrogen Receptor Modulators (SERM)

Selective estrogen receptor modulators (SERM) are synthetic molecules. They have the ability to bind to oestrogen receptors throughout the body and act as estrogen agonists or antagonists depending upon the target organ. The concept of SERM is based on the observation that  tamoxifen, used as an anti-estrogen in the treatment of breast cancer, acts as an estrogen agonist on bone in postmenopausal women.

Raloxifene (60 to 120 mg daily) slows down bone turnover (decrease marker levels by 35%) and increases BMD by 2 to 3 % at the lumbar spine and femoral neck [1,2]. It reduces the incidence of vertebral fractures by 40 to 50% [3-5]. No effect was observed on non-vertebral fractures, except a 22 % decrease in the incidence of major osteoporotic fractures in women with prevalent vertebral fractures, mainly severe vertebral fractures [6,7].

Raloxifene markedly reduces the risk of invasive estrogen-receptor positive breast cancer [5,8,9]. In most studies, raloxifene did not influence the risk of cardiovascular (coronary) events (5, 10) and, in some groups, may even decrease the risk of myocardial infarction or unstable angina [11]. It increases the risk of venous thromboembolism to the same extent as HRT and increases the risk of fatal stroke mainly in women with high risk of stroke at baseline [5, 12-14].

Another SERM, bazedoxifene (20 to 40 mg daily), decreases bone turnover marker (BTM) levels to a similar extent as 60 mg raloxifene daily, increases BMD of the lumbar spine by 2 % and prevents bone loss at the total hip [15,16]. It decreases the risk of vertebral fracture by 40%, similarly to raloxifene, and decreases by 40 % the risk of nonvertebral fracture in women at higher risk of fracture (low femoral neck T-score and presence of vertebral fractures at baseline) [16].

In postmenopausal osteoporotic women at high risk of fracture assessed by FRAX®, bazedoxifene decreased the risk of morphometric vertebral fracture by 50 % and the risk of all clinical fractures by 30 % [17]. In these studies, risk of cardiovascular events, cerebrovascular events, thromboembolism and of cancer was similar in the women treated with bazedoxifene, raloxifene and placebo.

References

1. Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, Reginster JY, Pols HA, Recker RR, Harris ST, Wu W, Genant HK, Black DM, Eastell R 2002 Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 87:3609-3617
2. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C 1997 Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997 337:1641-1647
3. 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. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators JAMA 282:637-645
4. Ensrud KE, Stock JL, Barrett-Connor E, Grady D, Mosca L, Khaw KT, Zhao Q, Agnusdei D, Cauley JA 2008 Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial. J Bone Miner Res 23:112-120
5. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, McNabb MA, Wenger NK 2006 Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 355:125-137
6. Siris ES, Harris ST, Eastell R, Zanchetta JR, Goemaere S, Diez-Perez A, Stock JL, Song J, Qu Y, Kulkarni PM, Siddhanti SR, Wong M, Cummings SR 2005 Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res20:1514-1524
7. Delmas PD, Genant HK, Crans GG, Stock JL, Wong M, Siris E, Adachi JD 2003 Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone 33:522-532.
8. Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, Secrest RJ, Cummings SR 2004 Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 96:1751-1761
9. Grady D, Cauley JA, Geiger MJ, Kornitzer M, Mosca L, Collins P, Wenger NK, Song J, Mershon J, Barrett-Connor E 2008 Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J Natl Cancer Inst 100:854-861
10. Collins P, Mosca L, Geiger MJ, Grady D, Kornitzer M, Amewou-Atisso MG, Effron MB, Dowsett SA, Barrett-Connor E, Wenger NK 2009 Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors. Circulation 119:922-930
11. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, Rautaharju P, Harper KD 2002 Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 287:847-857
12. Adomaityte J, Farooq M, Qayyum R 2008 Effect of raloxifene therapy on venous thromboembolism in postmenopausal women. A meta-analysis. Thromb Haemost 99:338-342.
13. Barrett-Connor E, Cox DA, Song J, Mitlak B, Mosca L, Grady D 2009 Raloxifene and risk for stroke based on the framingham stroke risk score. Am J Med 122:754-761
14. Mosca L, Grady D, Barrett-Connor E, Collins P, Wenger N, Abramson BL, Paganini-Hill A, Geiger MJ, Dowsett SA, Amewou-Atisso M, Kornitzer M 2009 Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease. Stroke 40:147-155
15. Miller PD, Chines AA, Christiansen C, Hoeck HC, Kendler DL, Lewiecki EM, Woodson G, Levine AB, Constantine G, Delmas PD 2008 Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res 23:525-535
16. Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, de Villiers TJ, Constantine GD, Chines AA 2008 Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 23:1923-1934
17. Kanis JA, Johansson H, Oden A, McCloskey EV 2009 Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone 44:1049-1054