Pharmacology Update
Raloxifene for the Prevention of Osteoporosis
By William T. Elliott, MD, and James Chan, PharmD, PhD
Raloxifene (evista, lilly) was approved by the FDA in December 1997. The drug is a selective estrogen receptor modulator (SERM) approved for the prevention of osteoporosis. SERMs have been the subject of intense investigation by the pharmaceutical industry because they possess partial agonist/antagonist actions on estrogen receptors in various tissues. Raloxifene has estrogen-like effects on bone and lipid metabolism but does not appear to stimulate, and may actually act as an antiestrogen in the breast and uterine tissue.1-3 In this respect, raloxifene differs from tamoxifen, another SERM, which is a partial agonist of uterine tissue.4
Indication
Raloxifene is indicated for the prevention of osteoporosis in postmenopausal women.
Potential Advantages
Raloxifene is effective at increasing bone mineral density (BMD). Increases in BMD were seen at 24 months ranging from 1.3% to 2.7% compared to a calcium-supplemented placebo.1,2 In short-term exposure (up to 39 months in some patients), raloxifene does not appear to stimulate the endometrium and is associated with significantly less vaginal bleeding and breast pain and tenderness than hormone replacement therapy.1,2 Preclinical data suggest that the drug possesses estrogen receptor antagonist in uterine and breast tissue.1 In contrast to hormone replacement therapy, raloxifene does not raise serum triglycerides.2
Potential Disadvantages
Raloxifene does not relieve the symptoms of menopause such as hot flashes, hot flushes, or urinary or vaginal symptoms. In fact, the drug seems to induce hot flushes in about 25% of patients, most commonly during the first six months of therapy.2 Leg cramps occur at a frequency of about 6%. Raloxifene increases the risk of venous thromboembolic events defined as deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.2 A risk-to-benefit assessment should be made prior to initiating treatment in patients at risk of thromboembolic disease.
Dosing Information
Raloxifene is supplied as 60 mg tablets. The standard dose is 60 mg daily without regard to meals. Supplemental calcium and vitamin D are recommended if daily dietary intake is inadequate.
Comments
Raloxifene is an interesting new drug for the prevention of osteoporosis. The agonist/antagonist action of raloxifene causes an increase in BMD and improves the lipid profile with no apparent stimulation of the uterine and breast tissue. But, while the drug is efficacious in raising BMD, it is about 50% as efficacious as 0.625 mg of conjugated estrogen. It also has a less positive effect on lipids than conjugated estrogen, specifically in the elevation of HDL-2 (33.3% vs 15.4%) or decrease in liproprotein (a) (4.1% vs 16.3%).2
Clinical Implications
Raloxifene shows promise, but long-term outcomes are not known. Raloxifene does not relieve the symptoms of menopause, and the drug's effect on cardiovascular disease is unknown. Estrogen therapy has been shown to reduce the risk of cardiovascular disease.5 This action may be mediated through improvement of the lipid profile, preventing oxidation of low density lipoproteins, affecting monocyte migration and adhesion to endothelial cells, and affecting later stages of atherogenesis.6 While raloxifene improves the lipid profile (albeit to a lesser degree than estrogen 0.625 mg) and has been shown to inhibit the oxidation of LDL in vitro,7 it is not known whether these effects have clinical significance.
Other long-term effects of estrogen replacement therapy, such as prevention of fractures and reduction in the risk of Alzheimer's disease have not been elucidated. Raloxifene is currently being studied for the treatment of osteoporosis. The most appealing aspect of raloxifene is the apparent lack of effect on uterine and breast tissue. Estrogen use has been associated with an increased risk of breast and endometrial cancer.8,9 Progestins reduce endometrial cancer risk but do not reduce breast cancer risk of estrogens.8,10 While preliminary data are promising, the FDA Advisory Committee indicated that further studies should be done to support the assertion that raloxifene is not associated with breast or uterine cancer.11
Raloxifene provides an alternative to estrogens in the prevention of osteoporosis. The daily wholesale cost of raloxifene is $1.65, which is about five times the cost for Premarin 0.625 mg.
References
1. Delmas PD, et al. N Engl J Med 1997;337:1641-1647.
2. Evista Product Information. Eli Lilly and Company. December 1997.
3. Boss SM, et al. Am J Obstet Gynecol 1997;177:1458-1464.
4. Bryant TA, et al. Proc Soc Exp Biol Med 1998;217:45-52.
5. Grodstein F, et al. N Engl J Med 1996;335:453-461.
6. Nathan L, et al. Ann Rev Pharmacol Toxicol 1997;37:477-515.
7. Zuckerman SH, et al. Atherosclerosis 1996;126:65-75.
8. Colditz GA, et al. N Engl J Med 1995;332:1589-1593.
9. Grady D, et al. Obstet Gynecol 1995;85:304-313.
10. Pike MC, et al. J Natl Cancer Inst 1997;89:1110-1116.
11. F-D-C Report-The Pink Sheet. December 1, 1997.
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