Despite concerns about the risks of hormone replacement therapy for postmenopausal women, one benefit has not been challenged: It makes bones stronger. Now a study on page 843 suggests that it might be possible to tease apart the various effects of estrogen, maintaining its 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 apparently 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 be mediated by different cell signaling cascades, a team led by Stavros Manolagas of the University of Arkansas for Medical Sciences in Little Rock has been identifying synthetic hormones that activate only a subset of these pathways.

Whether such compounds will prove useful in humans remains to be seen, but other researchers and clinicians say the new study is a promising first step.“If it holds up, then it’s quite important,” says molecular endocrinologist Geoffrey Greene of the University of Chicago.“If compounds like estrogen could be used to maintain bone density with few or no side effects in aging women, that would be huge.” The researchers gave a compound named estren to adult female mice whose ovaries had been removed. As with menopause, ovariectomy curtails estrogen production and eventually leads to a decline in bone density. Estren reversed this change and restored bone strength as effectively as—and in some cases more effectively than—estrogen. Estren apparently strengthens bones by tinkering with the cellular construction crews that constantly remodel them. 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 estren (as well as estrogen) tips the balance in the other direction: Both compounds encourage osteoclasts to self-destruct while prolonging the life of osteoblasts. Despite their similar effects on bone, estren and estrogen have markedly different effects on the reproductive organs, the team found. 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. Manolagas says these differences arise because estren doesn’t activate the pathway by which estrogen acts on the reproductive organs. In that pathway—traditionally thought to be the only means for estrogen signaling—the hormone diffuses into the nuclei of cells, where it binds to its receptor and a complex of other proteins that together regulate the transcription of certain genes. Recently, Manolagas and others have suggested that estrogen can activate a “nongenotropic” pathway, whereby estrogen alters gene expression by means of a biochemical cascade that kicks off when the hormone binds receptors outside the nucleus—an idea that is still controversial. Last year Manolagas’s team reported that estrogen’s effects on osteoblasts and osteoclasts seem to be mediated by this pathway. The new study suggests that estren activates this pathway but not the traditional one, which would explain its preferential effect on bone.