cience Watch readers can be forgiven for thinking that the only way medical treatment advances these days is via evidence from randomized clinical trials. Happily for everyone, there are other tools at the disposal of clinical researchers. Yet it is to the randomized trial that Science Watch ought to return again this time if only because, most unusually, the same trial appears in two places, at #7 and #10. How can that be? Science Watch has previously touched on both chemoprevention in breast cancer with tamoxifen and the use of selective estrogen-response modifiers, or SERMs, in the avoidance of the dire effects of osteoporosis. One important study was called MORE, standing for Multiple Outcomes of Raloxifene Evaluation. The main objective was to look at bone mineral density and fractures, and women could not be selected for the trial if they had a history of breast cancer. When, in 1998, tamoxifen became the first drug to be licensed by the U.S. Food and Drug Adminstration as a chemopreventive, the indication was women at high risk of breast cancer. MORE provided a golden opportunity to study a less selected group of women.

The result was dramatic. During a follow-up of about three years only 13 out of 5,129 women on raloxifene developed breast cancer compared with 27 out of 2,576 women given a placebo. Smaller wonder that the osteoporosis part of MORE (# 10) trailed two months behind the cancer-prevention data (# 7), in the August 18 and June 16, 1999, issues of the Journal of the American Medical Association. This is not to say that the osteoporosis findings do not impress, for the rates for vertebral fractures (but not for non-vertebral ones) were significantly lower in the raloxifene-treated women. Bone-mineral density, which is often used as a shorter-term endpoint in clinical trials in osteoporosis, rose by about 2.5% in the raloxifene groups.

The hope with tamoxifen and with raloxifene is that a more favorable balance can be struck between the negative and the positive effects of estrogen-receptor manipulation. The MORE results suggest that for the adverse effect of venous thromboembolism, a long-running concern with non-physiological estrogen, the newer agent carries a similar risk to that of estrogen and tamoxifen.

Lead author on the later MORE paper (# 10) is Bruce Ettinger, working in the research division of the Kaiser Permanente Medical Care Program in Oakland, California. He is not surprised at the frequent citations. "I suspect it is the rather amazing combination of beneficial effects that have captured the interest of medical scientists," he tells Science Watch. The potential benefits of osteoporosis treatment and prevention, improvement in cholesterol and other coronary heart disease risk factors, and breast cancer risk reduction (#7) all without the troublesome bleeding and breast tenderness associated with estrogen make this, he adds, "an excellent choice for women who are several years beyond the menopause." However, "estrogen is still the choice for women at the transition who have symptoms such as hot flashes."

MORE reported at around three years but Ettinger says that at four years the benefits are being sustained. Even longer-term data are needed, and, surprisingly perhaps in view of the results so far, about half the women in MORE are continuing on double-blind treatment for another four years.