Authors’ Response: Androgens, Estrogens, and Bone Turnover in Men

Benjamin Z. Leder and Joel S. Finkelstein

Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114

Address correspondence to: Benjamin Z. Leder, M.D., Massachusetts General Hospital, Endocrine Unit, Bulfinch 327 Fruit Street, Boston, Massachusetts 02114. E-mail: bzleder{at}partners.org.

To the editor:

We appreciate the opportunity to respond to the thoughtful letter of Drs. Khosla and Riggs. They raise several issues that we feel deserve additional discussion. First, their comment that our data on the differential effects of androgens and estrogens on bone resorption are complementary to theirs is clearly true in that both studies use different designs to show that estrogen is an important regulator of bone turnover in men (1, 2).

Our data demonstrate that androgens also play a fundamental role in the regulation of bone resorption in men. Although the effect of androgens was not statistically significant in the paper by Falahati-Nini et al. (1), the authors’ original manuscript indicates that they, too, believe that androgens regulate bone resorption. It is likely that the longer term nature of our study allowed us to demonstrate this effect of androgens more clearly, although the longer duration prevented us from including men who received estrogen, but not testosterone, replacement.

As for the comments concerning conflicting findings in the two studies on markers of osteoblast function, Drs. Khosla and Riggs raise intriguing issues. Specifically, they attempt to explain the discrepancy by suggesting that their shorter study was better able to separate direct effects of gonadal steroid deprivation (such as increased osteoblast apoptosis) from indirect ones (resorption-coupled increases in osteoblast activity). It remains difficult for us to understand, however, how their study could have any inherent advantages over ours in this regard, because our study also included data at 4 wk, a time-comparable to the 3-wk final time point in the study by Falahati-Nini et al. (1). Importantly, when we look specifically at our earlier time points (wk 4 and 8), our findings still do not mirror those of Falahati-Nini et al. (1). Furthermore, Drs. Khosla and Riggs suggest that the subtle differences they observed in propeptide of type I procollagen and osteocalcin may have been due to differential effects of androgens and estrogens on mature osteoblasts vs. cells of osteoblast lineage in various stages of maturation. Although this hypothesis is intriguing, we again must point out that we did not see a similar discrepancy at the short-term (wk 4), intermediate (wk 8), or final time point (wk 12). In fact, it seems likely to us that neither study (with 3-wk data and 4-wk data, respectively) is adequately designed to separate the direct from the indirect effects of gonadal steroids on osteoblastic function in vivo.

Finally, we thank Drs. Khosla and Riggs for providing further information about two bone turnover markers at the study entry point (wk 0) and again at baseline (wk 3). We remain concerned, however, that the lingering effects of the roughly 7-d agonist phase of GnRH-analog therapy (during which time gonadal steroids are considerably supraphysiologic) could have affected changes in bone turnover in a short-term study (3). In fact, we have speculated that the initial GnRH-analog agonist effect may be responsible for the significant reduction from baseline in osteocalcin, procollagen C-propeptide, and propeptide of type I procollagen that occurred in our eugonadal control subjects (+T, +E) beginning at wk 4.

Given these issues, we continue to believe that the differences in the measurements of biochemical markers of osteoblast function reported in the two studies most likely represent differences in study subjects (young men vs. older men), differences in the attainment of a steady state, or other differences in study design. We agree that the issues concerning the direct vs. indirect effects of gonadal steroid deprivation on osteoblast function raised by Drs. Khosla and Riggs are important, albeit ones that have not yet been adequately addressed in human study.

Received February 6, 2003.

References

  1. Falahati-Nini A, Riggs BL, Atkinson EJ, O’Fallon WM, Eastell R, Khosla S 2000 Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 106:1553–1560[Abstract/Free Full Text]
  2. Leder BZ, LeBlanc KM, Schoenfeld DA, Eastell R, Finkelstein JS 2003 Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab 88:204–210[Abstract/Free Full Text]
  3. Chrisp P, Goa KL 1991 Goserelin: a review of its pharmacodynamic and pharmacokinetic properties, and clinical use in sex hormone-related conditions. Drugs 41:254–288[Medline]