Estrogens and androgens play a key role in regulating bone mass. However, their clinical use as bone anabolic agents is limited due to unwanted side effects, particularly in reproductive organs. In 2002, the synthetic ligand estren was described to reproduce the bone anabolic, nongenotropic effects of sex steroids while having no effect on the uterus or seminal vesicles. But in the current issue of the JCI, Windahl et al. provide data showing that estrens are not as suitable a replacement for estrogen as was initially reported (see the related article beginning on page 2500). Though not catabolic, estrens triggered only minor, nonsignificant increases in bone mass in gonadectomized mice, all the while inducing hypertrophy of reproductive organs. Does this mean estrens should not be pursued as a therapy for osteoporosis?