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Am Fam Physician. 2000;61(5):1272-1280

to the editor: The article by Dr. Ullom-Minnich1 is a nice review of osteoporotic fractures and includes a cost analysis of various pharmacologic agents. However, the author mentions that no published data were available at the time of publication that demonstrated a benefit of raloxifene in reducing fracture risk.

A study2 of raloxifene showed a dose-related reduction in the incidence of fractures of the hip, total body and radius in 143 post-menopausal women who were followed for one year. Additionally, the Multiple Outcomes of Raloxifene Evaluation (MORE) study3 showed a significant reduction in the incidence of recurrent vertebral fracture at 30-month follow-up of 7,700 postmenopausal women. This reduction in fracture risk is equivalent to that shown for alendronate after three years of follow-up.4 Although the increase in bone mineral density produced by raloxifene at all bone sites is somewhat less than that of estrogen, the increase over the short term is impressive in postmenopausal women.5

Raloxifene's ability to provide a short-term effect on bone density is important because the “window of opportunity” to improve bone density using traditional estrogen therapy is limited, and because the efficacy of this treatment decreases during postmenopause. Estrogen improves bone density best over a period of many years, and although its use puts some postmenopausal women at a higher risk for endometrial cancer and, possibly, breast cancer, estrogen therapy may additionally reduce cardiovascular morbidity in women. This benefit may outweigh the risks, because cardiovascular disease is the leading cause of death among women, while breast and uterine cancer account for a much smaller percentage of deaths. Before the release of raloxifene and in instances where cardiovascular risk was minimal, the addition of a bisphosphonate to calcium, vitamin D and exercise seemed to be the next logical steps.

Further, the author mentioned that randomized trials should elucidate the extent to which uterine and breast cancer may complicate and increase the cost of therapy. This cost may turn out to be significant, considering the high cost of treating women with breast cancer. The results of clinical trials elucidating raloxifene's cost-effectiveness related to breast and uterine cancer might also be interesting, considering: (1) the results of the MORE trial3 indicated that raloxifene caused no increase in the incidence of uterine bleeding or thickness compared with placebo, (2) raloxifene's positive effect on serum lipids and coagulation factors6 and (3) raloxifene reduced the risk of breast cancer by 76 percent compared with placebo.3

Raloxifene may also prove to play a significant role in cardiovascular risk reduction when the results of the Raloxifene Use for the Heart (RUTH) study are released in several years.

If the current studies prove that raloxifene reduces cardiovascular risk, that information, along with the beneficial effects of raloxifene and other selective estrogen receptor modulators on the breast, the uterus, bone mineral density and reduced vertebral fracture risk, could make the use of traditional estrogens obsolete.

in reply: Dr. Cefalu's point is well taken. Evidence regarding raloxifene's impact on fractures is growing. The trial by Lufkin,1 however, does not provide good evidence of raloxifene's effect. Dr. Cefalu's claim of a “dose-related reduction in the incidence of fractures of the hip, total body and radius” is not supported by any claim in this published account.1 This small trial found that no statistical difference existed between overall or vertebral fracture rates. Even subgroup analysis did not address the fractures mentioned in Dr. Cefalu's letter, but rather a subset of severe vertebral fractures not discussed.

In August 1999, a large published trial2 provided evidence that raloxifene reduces overall vertebral fracture incidence. This account of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial is the published version associated with the data mentioned by Dr. Cefalu. More than 7,700 postmenopausal women with osteoporosis or vertebral fractures participated in the three-year trial. With a daily dose of raloxifene (60 mg), the relative risk of vertebral fracture dropped by 65 percent. Nonspinal fractures were not affected.

Several medications have been used in similar three-year trials of postmenopausal and osteoporotic women. Raloxifene2 prevented one vertebral fracture for every 45 patients treated. This appears slightly less efficacious than etidronate,3 which required treating 32 patients per fracture. Alendronate4 and calcium5 reduced vertebral as well as nonspinal fractures. Alendronate prevented one fracture for every 21 patients.4 Calcium prevented one for every 15 patients treated.5 The cost of these agents remains an important consideration for patients. According to data from the MORE trial and average wholesale costs, the cost per vertebral fracture prevented would be more than $97,000 with raloxifene.2,6 Etidronate and alendronate cost $16,700 and $58,300 per fracture prevented, respectively.3,4,6 The cost per fracture prevented with calcium is only $1,000.5,6

The data supporting the use of raloxifene for prevention of fractures is indeed growing. While it is one appropriate alternative at the present time, it appears to be less effective and much less cost-effective in the above populations, compared with the alternatives.

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This series is coordinated by Kenny Lin, MD, MPH, deputy editor.

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