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Choosing the right message. Synthetic hormones that bypass the traditional estrogen pathway (left) and activate the "nongenotropic" pathway (right) might prevent bone loss without side effects.

The Best of Estrogen

Despite concerns about the risks of hormone replacement therapy for postmenopausal women, one benefit is clear: It makes bones stronger. Now a study suggests that it might be possible to maintain estrogen's benefits while reducing its risks. A synthetic hormone has been shown to boost bone strength in mice without affecting reproductive organs.

Estrogen makes women less likely to develop osteoporosis and suffer debilitating fractures. But this boon comes with increased risk of breast cancer, pulmonary embolism, heart attack, and stroke (Science, 19 July, p. 325). Reasoning that estrogen's effects on various tissues might rely on different cell signaling cascades, a team led by Stavros Manolagas of the University of Arkansas for Medical Sciences in Little Rock a identified synthetic hormone called estren that activates only a subset of these pathways.

Estren tinkers with the cellular construction crews that continuously remodel bone. At any given time, Manolagas says, there are 5 million to 10 million sites on a human skeleton where cells called osteoclasts dig tiny trenches in the bone that are filled in by bone-forming osteoblasts. After menopause, osteoclasts outpace osteoblasts, making bone more porous and brittle.

Manolagas's team found that in the test tube, both estren and estrogen encouraged osteoclasts to self-destruct while prolonging the life of osteoblasts. And in mice whose ovaries had been removed, both compounds increased bone density and strength. But they had markedly different effects on reproductive organs, the team reports in the 25 October issue of Science. In ovariectomized mice, the uterus loses nearly two-thirds of its weight. Estrogen, but not estren, prevents this loss. And whereas estrogen stimulated the growth of cultured breast cancer cells, estren did not. The reason, Manolagas says, is that estren activates a "nongenotropic" signaling pathway that affects bone but not the reproductive organs.

Whether compounds such as estren will prove useful in humans remains to be seen. "If compounds like estrogen could be used to maintain bone density with few or no side effects in aging women, that would be huge," says molecular endocrinologist Geoffrey Greene of the University of Chicago.

Related sites
Manolagas's site
Greene's site
Basic information about osteoporosis from the National Institute on Aging
Information and resources on HRT from NIH