What are the adverse side effects of selective estrogen receptor modulators?
Just as estrogen has effects on multiple organ systems and target tissues, the effects of selective estrogen receptor modulators (SERMs) are broad. SERMs, including tamoxifen and raloxifene, are a group of structurally diverse compounds with both agonistic and antagonistic estrogen effects.
Venous thromboembolism. Raloxifene produces up to a three-fold increase in the relative risk of venous thromboembolism events (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis (1-4), similar to the risk seen with estrogen and tamoxifen therapy. The risk is highest in the first year of therapy. The number needed to treat (NNT) over a 3 year period to cause one additional VTE event is 170 (2). Although the relative risk decreases over time, there is an increased risk with continued therapy. On this basis, raloxifene is contraindicated in patients with a history of venous thromboembolism. In addition, patients should discontinue raloxifene 3 days prior to and during prolonged immobilization, resuming therapy after the period of immobilization ends (5).
Stroke. Raloxifene was associated with a 49% increased risk of fatal strokes (but not total strokes or overall causes of death) as compared to placebo in the Raloxifene Use for the Heart Trial (RUTH) (4). This randomized trial included over 10,000 postmenopausal women who had coronary heart disease (CHD) or multiple risk factors for CHD who were followed for 5 to 6 years. The absolute risk increase for fatal stroke was 0.7 per 1000 women per year.
Hot flashes. Raloxifene and tamoxifen both increase the frequency of hot flashes (6, 7). In a large osteoporosis treatment study (1), hot flashes occurred in approximately 10 percent of those taking raloxifene (with a dose response evident) and 6.5 percent of those taking placebo. The frequency of hot flashes rated as "severe" did not differ between groups. In a meta-anlaysis of 4 trials, the RR of hot flashes was 1.5 as compared with placebo and they diminished over time (8).
Other adverse effects. Other side effects of raloxifene include peripheral edema, influenza like illness, urinary incontinence, and leg cramps (1,5).
There are no adverse effects on the following:
Endometrium. Raloxifene does not stimulate the endometrium, unlike tamoxifen and estrogen (9). Thus, raloxifene does not cause any increase in the incidence of vaginal bleeding, endometrial thickness, endometrial hyperplasia, or uterine cancer (2). This is in contrast to the approximate four-fold increase in risk of uterine cancer associated with use of tamoxifen (9).
Vaginal epithelium. Raloxifene does not appear to stimulate vaginal epithelium or to provide any relief from postmenopausal vaginal atrophy and dryness. A summary of the adverse events reported with the use of raloxifene notes no difference in the incidence of events related to vaginal atrophy between raloxifene and placebo users, suggesting no benefit from raloxifene for atrophic vaginitis (10).
Breast tissue. Raloxifene, like tamoxifen, acts as a competitive antagonist on breast tissue (10). Unlike hormone replacement therapy, raloxifene does not cause breast pain or tenderness. Raloxifene is just as effective as tamoxifen in reducing the risk of invasive breast cancer in postmenopausal women at higher risk for the disease (11).
- Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA 1999; 282: 637-45.
- Grady D, Ettinger B, Moscarelli E, Plouffe Jr L, Sarkar S, Ciaccia A, Cummings S, for the Multiple Outcomes of Raloxifene Evaluation Investigators. Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol 2004; 104: 837-844.
- Cranney A, Adachi JD. Benefit-Risk assessment of raloxifene in postmenopausal osteoporosis. Drug Safety 2005; 25(8): 721-730.
- Barrett-Connor E, Mosca L, Collins P, et al., for the Raloxifene Use for The Heart (RUTH) Trial Investigators.. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006; 355: 125-137.
- Clemett D, Spencer CM. Raloxifene: A review of its use in postmenopausal osteoporosis. Drugs 2000; 60: 379-411.
- Agnusdei D, Iori N. Tolerability profile of SERMs. Journal of Endocrinological Investigation. 1999; 22: 641-5.
- Davies GC, Huster WJ, Lu Y, Plouffe L, Lakshmanan M. Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstetrics and Gynecology 1999; 93: 558-65.
- Cranney A, Tugwell P, Krolicki N, et al. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis. Endoc Rev 2002; 23: 524-528.
- Doren M. Effect of SERMs on the uterus and menopausal symptoms. Journal of Endocrinological Investigation 1999; 22.
- Goldstein SR. Effect of SERMs on breast tissue. Journal of Endocrinological Investigation 1999; 22: 636-40.
- Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, et al. for the National Surgical Adjuvant Breast and Bowel Project (NSABP). 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 2006; 295: 2727-2741.