’ Response : Androgens , Estrogens , and Bone Turnover in Men To the

In a recent issue of the JCEM, Leder et al. (1) examined effects of androgens and estrogens on bone turnover in normal men and provided some comparisons to our previous work (2). We agree that this study provides complementary data to our findings, because it is a longer term study than ours (12 wk vs. 3 wk). There are advantages and disadvantages to each study design, although even at 12 wk bone turnover has not reached a steady state, because this may take up to 1 yr (3). In fact, as noted below, there are distinct advantages to the shorter study design we used. Nonetheless, the findings of Leder et al. (1) on bone resorption markers are fundamentally similar to ours, although as they point out, because they did not have an estrogen-alone group, the relative contributions of estrogen vs. testosterone toward the regulation of bone resorption cannot be assessed from their study. The main point we want to address is their comment regarding our findings on the bone formation markers. We found that serum osteocalcin and the amino-terminal propeptide of type I procollagen (PINP) declined at 3 wk of estrogen and testosterone deficiency (2). Estrogen alone was able to prevent the decrease in both formation markers, whereas testosterone alone (in the presence of an aromatase inhibitor) prevented the decrease in osteocalcin, but not in PINP. As expected, continued treatment with estrogen and testosterone resulted in no change in the formation markers. From these findings, we concluded that both estrogen and testosterone were important in the maintenance of mature osteoblastic function (because osteocalcin is a relatively late marker in osteoblast differentiation (4), perhaps by inhibiting apoptosis of these cells, as has been demonstrated in vitro (5) and in vivo (6). By contrast, type I collagen is produced throughout osteoblast differentiation (4), and it was principally estrogen that was important in maintaining PINP levels (a marker for collagen synthesis). Although Leder and colleagues (1) consider the short-term nature of our study a potential weakness, it does have significant advantages, in addition to allowing the incorporation of an estrogen-alone group. In fact, we believe we were able to define these changes in the formation markers because we studied the men early after sex steroid withdrawal or replacement. By doing so, the potential direct effects of sex steroids on osteoblastic function could be demonstrated before they were masked by coupled increases in bone formation driven by the increases in bone resorption. Moreover, we disagree with their concern that bone turnover markers were not at steady state at the initiation of our hormonal manipulations (i.e. our baseline visit) for the following reasons: 1) continued treatment with estrogen and testosterone resulted in absolutely no change in the formation (or resorption) markers; and 2) we went back and measured serum N-telopeptide of type I collagen and osteocalcin in our subjects before entry into the study and at the time of the baseline studies (when Leder and colleagues believe the subjects were not in steady state), and the values were virtually identical [Ntelopeptide of type I collagen before entry (mean sem), 11.1 0.8 nm, and at the baseline visit, 12.0 1.0 nm; osteocalcin before entry, 22.1 1.3 ng/ml, and at the baseline visit, 22.3 1.2 ng/ml (P not significant for both)]. Thus, whereas the two studies largely agree on changes in bone resorption markers, there are clear differences in our findings on the formation markers and theirs. These differences are unlikely to be due to the subjects in our study not being at steady state at the time of the baseline visit; the evidence would, in fact, indicate that they were. However, the differences are more likely due to the fact that by the very nature of our short-term study, we were able to discern direct effects of sex steroids on osteoblast function, which become obscured over time due to the coupling of bone formation and resorption. These issues notwithstanding, we do believe that Leder et al. (1) have provided additional, useful data on the regulation of bone turnover in men by sex steroids, and it is only through a combination of studies such as ours and theirs, and perhaps even longer term studies, that we will arrive at a more comprehensive picture of this important area.