REPLACE ESTROGEN, GET RICH; DRUG MAKERS RACE TO REFINE SUBSTITUTE.

Byline: John Hendren Associated Press 

Barbara Zimmerman stumbled off a New Jersey curb and into a race between drug makers dashing to be the first to replace the most widely prescribed drug in the nation: estrogen.

While nursing her broken ankle, the retired jewelry designer discovered she had osteoporosis. But she balked at taking estrogen - the conventional treatment for the bone-thinning disease - when her doctor warned it could raise her chances of getting breast cancer.

``We have a lot of cancer in our family and I was afraid to take estrogen,'' said Zimmerman, 70, of Tenafly, N.J. ``It was just scary to me.''

Instead, two years after her fall, Zimmerman is wrapping up her stint as a research subject in a blind test of Eli Lilly's drug, raloxifene. Researchers expect the drug to be the first estrogen replacement on the market that could replace estrogen therapy for women who have gone through menopause.

If the new drugs work, women would be able to protect their bones and hearts without increasing their chances of breast cancer. With women living longer and baby boomers just starting to take post-menopausal drugs, the potential market is immense.

Lilly's version, trade-named Evista, could be approved by the end of the year for osteoporosis. But competitors are following close behind. Pfizer Inc.'s droloxifene is being tested for osteoporosis. British companies Glaxo Wellcome PLC, SmithKline Beecham PLC and Zeneca PLC all have their own compounds in the works.

``These drugs should sell over $1 billion a year at peak levels, at least, and probably a lot more than that,'' said Carl Gordon of Mehta & Isaly, a New York-based drug industry research firm.

Hemant Shah, an independent industry analyst in Warren, N.J., agrees: ``For any drug which shows itself to be effective for treatment of osteoporosis, the market is billions of dollars.''

Estrogen is a natural reproductive hormone that helps keep women's hearts and bones strong. During menopause it helps women avoid hot flashes. After menopause, when the body stops producing estrogen, women take estrogen to prevent heart disease and osteoporosis. New studies suggest estrogen may also help prevent Alzheimer's disease.

Wyeth-Ayerst Laboratories' estrogen drug Premarin, made from horse urine, is the most widely prescribed drug in the nation, earning the company nearly $1 billion in sales last year.

The new drugs don't quite make Premarin obsolete, Shah said.

``Premarin is going to be indispensable for women with hot flashes, and most women have hot flashes with post-menopausal symptoms,'' he said. ``These drugs don't treat that.''

Doctors usually combine estrogen with progestin, which researchers say reduces the breast cancer risk and virtually eliminates the increased risk of uterine cancer. But only about 20 percent of post-menopausal women who could benefit from estrogen's heart and bone protection take the hormone, in part because many fear the link to breast cancer.

The new class of drugs may even prevent breast and uterine cancer by blocking estrogen from acting on those tissues. A study published in the June issue of the New England Journal of Medicine suggested that for women with a high risk of heart disease, long-term use of estrogen may be worthwhile, but for women with an elevated risk of breast cancer, the benefits are less clear.

Women who take estrogen after menopause significantly cut their risk of death for about a decade, but then the benefits diminish because the risk of breast cancer gradually increases by nearly 50 percent after 10 years of estrogen use, the study found.

The ``anti-estrogens'' were designed to block estrogen, but later studies showed they also mimic the hormone in bones and other tissues. That has researchers trying to make the estrogen blockers into estrogen replacements.

Lilly and Glaxo say studies suggest anti-estrogens are effective at increasing bone mass and preventing heart disease. But many researchers remain skeptical, saying the information the companies have released is limited and covers only a short period of time.