Hormone-replacement therapy (HRT) with oestrogens has been the treatment ofchoice for counteracting the bone loss that leads to osteoporosis in postmenopausal women,but recent clinical trials have shown increased risks of breast cancer in women taking HRT, challenging previous beliefs that the benefits of HRT outweigh the risks. Writing in Science, Manolagas and colleagues now describe a synthetic sex hormone that can increase bone mass and strength in mice without the effects on reproductive organs that could increase the risks of cancer.

Classically, the effects of sex hormones are mediated through nuclear receptors — largely distributed in a sex-specific pattern — that modulate gene transcription when activated by bound hormone. However, recent research has shown that sex hormones can also have effects through a distinct 'non-genotropic' pathway, which is independent of sex, and which can be dissociated from the transcriptional activity of the receptor with synthetic ligands.

Prompted by their previous work showing that one such synthetic ligand, called estren, could reduce apoptosis of bone-synthesizing cells, the authors investigated the effects of estren on bone in male and female mice with their ovaries or testes removed, respectively, to stop the production of natural sex hormones. The resultant loss in bone mass could be reversed by treatment with the appropriate sex hormone — the oestrogen 17β-oestradiol (E 2) in female mice, and dihydrotestosterone (DHT) in male mice — but this also led to above-normal increases in the sizes of the reproductive organs in both cases. By contrast, estren was more effective than E2 in females, and as effective as DHT in males, at increasing bone mass and strength, but did not significantly affect reproductive organs. It thus seems that such mechanism-specific ligands could offer advantages over oestrogens and selective oestrogen-receptor modulators that are used at present to treat osteoporosis in post-menopausal women, and could also be of therapeutic benefit in men.