Beginning with the report in 1994 that an adult male with homozygous loss of estrogen receptor a (ERa) had unfused epiphyses and osteopenia,(1) there is now considerable evidence from observational and interventional studies (summarized in Khosla and colleagues (2)) that estrogen is the dominant regulator of bone metabolism in men. Indeed, a legitimate argument can be made that testosterone is largely a prohormone for the skeleton, with its effects on bone mediated principally via aromatization to estrogen, although it remains likely that testosterone contributes to bone size via effects on periosteal apposition and perhaps indirectly to bone mass by increasing muscle mass.

A series of human investigations from our group have certainly contributed to building this argument. Perhaps the most convincing of these was a direct interventional study published almost 15 years ago,(3) which is summarized briefly here, because it is instructive to revisit the data from that human study in light of the article in this issue of JBMR by Ucer and colleagues (4) on the contributions of skeletal androgen receptor (AR) versus ERa signaling toward regulating bone metabolism in mice. Thus, the key questions are: 1) Are the findings from the mouse study translatable to humans? 2) Can the new mouse data help us better understand previous findings in humans? In our human study, we used an experimental design in which sex steroid production was suppressed in adult men using a GnRH agonist followed by selective replacement of either estrogen or testosterone, or both.(3) An aromatase blocker was administered to all subjects in order to examine effects of testosterone on bone in the absence of conversion to estrogen. For the purposes of this discussion, the bone resorption marker, N-telopeptide of type I collagen (NTx) will be used to reflect sex steroid effects on bone turnover; independent effects of estrogen and testosterone on bone formation markers were also observed, but these were largely concordant with the findings for NTx, so to simplify the discussion, NTx is used here to reflect bone remodeling changes in this study. As shown in Fig. 1A, compared with the sex steroid replete state (þT, þE), complete sex steroid deficiency (–T,–E) resulted in an increase in NTx of 35% over 3 weeks. Estrogen replacement alone, in the absence of testosterone (–T, þE), was able to almost completely prevent this increase in bone