Response: Both FSH and Sex Steroids Influence Bone Mass

In our study (Sun et al., 2006), we conclude that FSH has a direct role in causing bone loss in hypogonadal mice. Our study does not, however, imply that estrogen and testosterone are not critical regulators of bone mass. To the contrary, we assert that sex steroids regulate bone formation and bone resorption, whereas FSH directly stimulates bone resorption. Problems in interpretation can arise when the phrase “bone loss” is used without defining its underlying etiology, that is, whether it is meant to signify reduced bone formation, increased bone resorption, or a combination of both. In their Correspondence, Dr. Seibel and colleagues correctly point out that bone loss occurs in hypogonadal hpg mice that lack gonadotropin-releasing hormone (GnRH) despite low or absent FSH. However, as their data show, this osteopenia arises, in major part, from a dramatic decrease in bone formation even in sexually immature 9-week-old mice. Although Sims et al. (2005) report that the number of bone-resorbing osteoclasts are modestly increased in hpg mice, we found that there is a reduction in osteoclast production and bone resorption in mature 4-month-old hpg mice (M.Z., unpublished data). In our Cell paper, we report a similar phenotype in 6-month-old FSHβ null mice and 4month-old FSH receptor (FSHR) null mice (Sun et al., 2006). Therefore, we emphasize that in adult hpg mice or in mice lacking either FSHβ or FSHR, the absence of FSH signaling prevents the increase in bone resorption otherwise seen in hypogonadal states, such as after ovariectomy. We concur with Dr. Seibel and colleagues that abrogation of FSH signaling will not protect against bone loss caused by a defect in the rate of bone formation. In our paper, we