Raloxifene's Role for Estrogen- and Age-Related Problems

Pharmacology Watch

What is the role of raloxifene for the treatment of osteoporosis and breast cancer prevention? Raloxifene is a selective estrogen-receptor modulator similar to tamoxifen. There has been considerable interest in the drug in the role of treatment for osteoporosis and, perhaps, breast cancer prevention, especially in light of the Women's Health Initiative findings on conjugated estrogen/progesterone. A new study does little to clarify the issue, however, suggesting, like previous studies, that raloxifene has benefits, but also significant risks associated with its use.

As part of the Raloxifene Use for The Heart (RUTH) trial, more than 10,000 postmenopausal women with CHD or multiple risk factors for CHD were randomized to raloxifene 60 mg daily or placebo and followed for a median of 5.6 years. The 2 primary outcomes were coronary events and the rate of breast cancer. Raloxifene had no effect on the risk of primary coronary events (533 vs 553 events; HR, 0.95; 95% CI, 0.84 -1.07) but was associated with a reduced risk of invasive breast cancer (40 vs 70 events; HR, 0.56; 95% CI, 0.38-0.83). However, the all-cause death rate was the same in both groups, and raloxifene use was associated with an increased rate of fatal stroke (59 vs 39 events; HR, 1.49; 95% CI, 1.00-2.24) and venous thromboembolism (103 vs 71 events; HR 1.44: 95% CI, 1.06-1.95). The drug was associated with a reduced risk of clinical vertebral fractures (64 vs. 97 events: HR, 0.65; 95% CI, 0.47-0.89) (N Engl J Med. 2006;355:125-137). In an accompanying editorial, Marcia L. Stefanik, PhD, from the Stanford University Medical School reviews risk benefit profiles of raloxifene for women.

Reviewing data from the RUTH trial, as well as other studies, the author suggests that a key issue in contemplating raloxifene use is balancing the benefits of reduction in the risk of breast cancer and vertebral fractures with the increase risk of venous thromboembolism and fatal stroke. She suggests that raloxifene should be contemplated in women with an increased risk of breast cancer, but asks" What level of breast cancer risk would justify the use of raloxifene for prevention of breast cancer for a given person . . ." and suggest that the answer to that question is currently unknown. She also states that, "For now, there's no magic bullet that can reduce the risks of major health problems related to estrogens and aging without introducing other potentially serious health concerns." (N Engl J Med. 2006;355:190-192).

The Truth About Multivitamins

More than half of the adult population in the United States takes multivitamins on a regular basis, yet little is known about the benefits or lack of benefits of vitamins. The National Institutes of Health has published a "State-of-the-Science Conference Statement" on multivitamin/mineral supplements and chronic disease prevention as an early release article on the Annals of Internal Medicine web site on August 1. The statement deals with the current patterns of vitamin use, nutrient intake of vitamin users and nonusers, the efficacy of single vitamins and minerals, the efficacy of multivitamins, the safety of multivitamins, and where future research is needed. Regarding single vitamins and minerals, the results have been disappointing.

Beta-carotene was found to cause an increase in lung cancer incidence and deaths in smokers and male asbestos workers and no benefit in preventing other types of cancers. Other cancer preventative studies have shown no benefit from beta-carotene and, some have even suggested, increase rate of stroke and CVD in women smokers. Vitamin A has not been the subject of individual trials but, when paired with beta-carotene or zinc, there is no impact on the incidence of cancer.

Four trials have looked at vitamin E, and the results have been mixed. The largest was the Women's Health Study, which suggested a decrease rate of cardiovascular deaths with vitamin E but no decrease in the incidence of CVD events. Vitamin B6 was looked at, and 2 small studies showed no benefit regarding cognitive decline in elderly men and women. Folic acid with or without vitamin B12 has been shown to decrease the rate of neural tube defects in women of childbearing age, but was not shown to prevent cognitive decline in older adults. Selenium was found to decrease the rate of liver cancer in Chinese patients who were at risk, and there may be some benefit in reducing the rate of lung, prostate, and colorectal cancer. Calcium has been shown to increase bone mineral density in post menopausal women, and calcium coupled with vitamin D has been shown to decrease the risk for hip and non-vertebral fractures. Calcium and vitamin D may increase risk of kidney stones, and has not been shown to reduce the risk of colorectal cancer.

The use of multivitamins and mineral supplementation (MVM) has been studied in 5 randomized, controlled trials. Although the study methodology was quite variable, there is a suggestion that MVM may decrease risk of cancer. No studies have shown any benefit as far as cardiovascular disease, and the benefit for cataract prevention is mixed. Progression of macular degeneration may be slowed by certain multivitamins, and may represent the single most important benefit from multivitamins. The conference statement also stated that the FDA should be given more oversight over the vitamin industry, and that more rigorous randomized controlled studies should be done of individual vitamins, minerals, and MVM, including safety of these products, as well as the interactions with nutrients and medications (www.annals.org 1 August 2006, to be published in print 5 September 2006).

Statins and Hepatitis C

Statins may be effective therapy for hepatitis C infections, and may even be used in combination with interferon to inhibit replication of the hepatitis C virus, according to new study. Japanese researchers recently evaluated the effect of various statins with or without interferon on hepatitis C replication. The synthetic statin fluvastatin was the strongest inhibitor of HCV replication, while atorvastatin and simvastatin were less effective. Lovastatin's effect was relatively weak, while pravastatin displayed no anti-HCV activity. The authors suggest that statins, especially fluvastatin, could be "potentially useful as new anti-HCV reagents" in combination with interferon (Hepatology. 2006;44:117-125).

Preventing Hot Flashes

Gabapentin may be as effective as estrogen in preventing hot flashes in postmenopausal women, based upon a recent study. In a randomized, double-blind, placebo-controlled trial on 60 postmenopausal women randomized to conjugated estrogen 0.625 mg daily, gabapentin titrated to 2400 mg daily, or placebo for 12 weeks. The primary outcome, the hot flash composite score, was no different between estrogen or gabapentin (72% improvement vs 71%), with placebo reducing symptoms by 54%. No differences were seen in severity of hot flashes or depression symptoms, although side effects were slightly higher in the gabapentin group (Obstet Gynecol. 2006;108:41-48). The authors acknowledge that this is a small study with a significant placebo effect. However, in light of the Women's Health Initiative findings, non-estrogen alternatives for heart flashes are welcome.

FDA News

The FDA is opening the door to allow Duramed's Plan B emergency contraceptive to be available over-the-counter to women 18 and older. Previously the FDA had tabled the OTC application indefinitely, but new FDA leadership is more receptive. The drug is currently available only by prescription.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: leslie.hamlin@thomson.com.