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Endocrine Care |
Endocrine Research Unit (S.K.), Division of Endocrinology, Metabolism, and Nutrition, Department of Internal Medicine; Department of Health Sciences Research (E.J.A., W.M.O.), Mayo Clinic and Foundation, Rochester, Minnesota 55905; and Amgen, Inc. Corporation (C.R.D.), Thousand Oaks, California 91320-1789
Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: . khosla.sundeep{at}mayo.edu
Abstract
Recent studies have shown that estrogen (E) likely plays a dominant role in inhibiting bone resorption in normal elderly men. Because both E and T inhibit osteoclast development and activity, stimulate osteoclast apoptosis, and inhibit osteoblast production of IL-6, it is unclear why T is less potent than E in inhibiting bone resorption in vivo. Osteoprotegerin (OPG) binds to and inactivates RANKL, the final mediator of osteoclastogenesis. In vitro, OPG production is stimulated by E, and preliminary data suggest that T has the opposite effect. Thus, we analyzed serum for OPG levels from a study in which 59 elderly men (mean age, 68 yr) were made acutely hypogonadal using a GnRH agonist and were also placed on an aromatase inhibitor to block conversion of androgens to estrogens. They were studied first under conditions of physiologic E and T replacement, and then randomized to no replacement, replacement with E alone, T alone, or both E and T. E alone resulted in an 18.6 ± 7.9% (mean ± SEM) increase in serum OPG levels (P < 0.05), whereas T alone tended to decrease OPG levels (by 10.0 ± 8.5%; P < 0.05 compared with E alone). Using a two-factor ANOVA model, there was a highly significant T effect (P = 0.006) on decreasing serum OPG levels. Serum TNF-
, IL-6, and IL-6 soluble receptor levels increased significantly in the men who had both E and T withdrawn, and the increases in TNF- and IL-6sR were absent in the men treated with either E or T. However, due to the variability in these cytokine measurements, the ANOVA models were not significant for E or T effects. Taken together, these data suggest that in vivo, T decreases OPG levels, whereas E tends to have the opposite effect. These differential effects of E vs. T on OPG production may explain, at least in part, why T has weaker effects than E on inhibiting bone resorption in vivo in humans.
EVIDENCE FROM ONE ER-negative (1) and two aromatase-deficient (2, 3) males had suggested an important role for E in bone metabolism in men. Subsequent cross-sectional (4, 5, 6, 7, 8, 9, 10) and longitudinal (11) observational studies in adult men found that E, and particularly the bioavailable (or non-SHBG bound) E correlated better with bone density and rates of bone loss, respectively, than T. In a direct interventional study in which normal elderly men were made acutely hypogonadal and then replaced with either E or T, both, or neither (12), we recently demonstrated that E played a dominant role in regulating bone resorption. Based on these data, we estimated that E accounted for two thirds or more of the total effect of sex steroids on bone resorption, with T accounting for at most one third of the effect (12).
These findings are somewhat surprising because in vitro, both E and T inhibit osteoclast development (13, 14, 15) and activity (16, 17), and both have now been shown to directly stimulate osteoclast apoptosis (18, 19). Moreover, both E and T inhibit production of the potent proresorptive cytokine, IL-6, by bone marrow stromal as well as osteoblastic cells (20, 21, 22, 23). Thus, to explain the in vivo observations in men that E is a stronger determinant than T of bone resorption (6, 10, 11, 12), bone density (4, 5, 6, 7, 8, 9, 10), and rates of bone loss (11), one has to postulate that E and T have opposite effects on some other key regulator(s) of bone turnover that explains the more important role played by E in bone metabolism in men.
Osteoprotegerin (OPG) is a soluble neutralizing receptor that binds to and inactivates RANKL, the final mediator of osteoclast development and activity (24, 25). We (26) and others (27, 28) have previously demonstrated that E stimulates OPG production by bone marrow stromal and osteoblastic cells. In preliminary studies, we recently found that the nonaromatizable androgen, 5-dihydrotestosterone (5-DHT), inhibited OPG production by osteoblastic cells (29). Moreover, circulating OPG levels are about 30% higher in premenopausal women compared with age-matched men (30, 31). These data thus suggested the hypothesis that E and T may have opposite effects on OPG production in vivo and, as a corollary, that this may account, at least in part, for the weaker antiresorptive effects of T. To begin to test this hypothesis, we analyzed serum for OPG levels from our previous study assessing the relative contributions of E vs. T toward regulating bone formation and resorption in normal elderly men (12). We also speculated that, in contrast to opposite effects on OPG production, both E and T would suppress levels of other candidate proresorptive cytokines (32). Thus, we also measured circulating levels of TNF-, IL-6, IL-6 soluble receptor (IL-6sR), macrophage colony-stimulating factor (M-CSF), and IL-1ß in these men.
Subjects and Methods
Study subjects
We analyzed serum for OPG and other cytokine levels from our previous study assessing the role of E vs. T on bone resorption and formation (12). The study subjects and procedures are described in detail there and are summarized briefly here. All studies were approved by the Mayo Institutional Review Board, and written, informed consent was obtained before study. A total of 59 elderly men [age (mean ± SD), 68.4 ± 6.0 yr] were recruited for the studies. As previously described (12), all were free of any diseases known to affect bone metabolism, and none were taking any medications that would impact bone turnover.
Study protocol
This has been described in detail in our previous report (12). Briefly, upon entry into the study, the subjects were administered a long-acting GnRH agonist (leuprolide acetate; Lupron-Depot, Takeda Chemical Industries Co., Ltd., Osaka, Japan), 7.5 mg im, to suppress endogenous T and E production. They were also started on the aromatase inhibitor, letrozole (Femara, Novartis, East Hanover, NJ), 2.5 mg/d. Physiological T and E2 levels were maintained by starting the subjects on a T patch (Testoderm TTS, Alza Corp., Palo Alto, CA), 5 mg/d, as well as an E2 patch (Vivelle, Novartis), 0.0375 mg/d. After 3 wk, the subjects were admitted to the Mayo General Clinical Research Center for their baseline visit. A fasting blood sample was drawn at 0800 h, and this was used in this study for measurements of OPG and cytokines. Blood and urine samples were also obtained for measurement of bone formation and resorption markers (12). After the baseline studies, the subjects were randomized into one of four groups: group A (-T, -E; n = 14) discontinued both T and E patches; group B (-T, +E; n = 15) discontinued the T patch but continued the E patch; group C (+T, -E; n = 15) discontinued the E patch but continued the T patch; and group D (+T, +E; n = 15) continued both patches. All subjects received a second dose of the GnRH agonist, and all subjects continued letrozole treatment throughout the study period. Three weeks after randomization, the subjects were readmitted to the General Clinical Research Center for their final visit, at which time the baseline studies were repeated.
Laboratory methods
All serum was stored at -70 C until analysis. Serum OPG levels were measured with an enzyme-linked immunosorbent assay using a mouse monoclonal antibody as capture antibody and a rabbit polyclonal antibody for detection (Amgen, Inc., Thousand Oaks, CA) (24). This assay detects both monomeric and dimeric forms of OPG, as well as OPG bound to RANK-L. Interassay coefficient of variation was less than 15%.
Serum TNF-, IL-6, IL-6sR, M-CSF, and IL-1ß levels were measured using high sensitivity immunoassay kits (R \|[amp ]\| D Systems, Minneapolis, MN). Interassay coefficients of variation were as follows: TNF-, less than 20%; IL-6, less than 17%; IL-6sR, less than 5%; M-CSF, less than 5%; and IL-1ß, less than 20%.
Statistical analysis
A two-factor ANOVA model was used to compare the percentage changes in serum OPG and other cytokine levels in the +E groups (B and D) vs. the -E groups (A and C) and the +T groups (C and D) vs. the -T groups (A and B). This analysis also allowed us to test for any interactions between E and T for effects on these variables. Baseline OPG and cytokine levels were compared across groups using a one-factor ANOVA model. A one-sample t test was used to assess percentage change from baseline for each variable. Where appropriate, the Tukey method, which adjusts for multiple comparisons, was used for pairwise comparisons. Results were considered significant at the P < 0.05 level, and the data are reported as the mean ± SEM.
Results
Changes in bone resorption markers
The effects of our interventions on the bone resorption markers, urinary deoxypyridinoline (Dpd) and N-telopeptide of type I collagen (NTx) have previously been reported (12) and are summarized in Table 1
. As is evident, for both Dpd and NTx, there was a highly significant E effect in our ANOVA models, with no clear T effect. Nonetheless, the data do suggest that E and T together were more effective than either alone, although the interaction terms in the ANOVA model were not significant. Based on these data, we estimated that in these elderly men, where we mimicked their circulating E and T levels, E accounted for two thirds or more of the total effect of sex steroids on bone resorption, with T accounting for at most one third (12).
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Table 2 shows the baseline values for serum OPG and the other cytokines in the four groups. Serum IL-1ß levels were below the limit of detection of the assay (0.125 pg/ml) in 49 of the 59 subjects (83%) and hence are not reported, because no useful analysis of the data could be performed. As is evident, baseline levels of OPG and the other cytokines were similar across groups.
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Figure 1 shows the changes in serum OPG levels in the four groups as a result of our interventions. Serum OPG levels increased (by 
19%; P < 0.05) in the group treated with E alone (group B), whereas they decreased (by 10%) in the group treated with T alone (group C) (P < 0.05 for the difference between groups B and C). Although the percentage change in serum OPG levels from baseline in group C was not significant (P = 0.26), the more powerful analysis using the two-factor ANOVA model demonstrated a clear inhibitory effect of T on serum OPG levels (P = 0.006) (Fig. 1). This analysis compared the +T groups (C and D) to the -T groups (A and B), and the overall effect of T predominated because this model incorporates not only the decrease in OPG levels in the presence of T (in groups C and D), but also the increase in OPG levels in the absence of T (in groups A and B) (Fig. 1).
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Changes in circulating levels of the other cytokines
Of the other cytokines, the most consistent changes were found in serum TNF- levels (Fig. 2). The induction of complete sex steroid deficiency in group A (-T, -E) resulted in a significant increase (28%) in serum TNF- levels. Although this increase was markedly attenuated in the groups given E alone (group B) or T alone (group C) and appeared to be completely abrogated in the group given both E and T (group D), due to the high variability in the serum TNF- levels, the P values in the ANOVA model for E or T effects were only of borderline significance (Fig. 2).
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shows the changes in serum IL-6, IL-6sR, and M-CSF levels. Serum IL-6 levels also increased significantly in the group with complete gonadal insufficiency (group A). E alone (group B) actually appeared to increase circulating IL-6 levels, whereas IL-6 levels did not change in the group given T alone (group C). By contrast, serum IL-6sR levels, which also increased in group A, did not change in any of the other groups (Table 3). However, none of the P values for E or T effects in the ANOVA models were significant for either IL-6 or IL-6sR levels. Finally, serum M-CSF levels did not show any significant changes in any of the groups.
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Considerable evidence has accumulated over the past several years indicating an important role for E in skeletal metabolism in men. Moreover, in virtually every experimental paradigm in men where E and T effects have been directly compared, E has emerged as being quantitatively more important than T as a determinant of bone resorption (6, 10, 11, 12), bone density (4, 5, 6, 7, 8, 9, 10), and rates of bone loss (11). This contrasts with unequivocal in vitro findings demonstrating that both E and the nonaromatizable androgen, 5-DHT, inhibit osteoblast apoptosis (33) as well as osteoclast development (13, 14, 15) and activity (16, 17). Moreover, previous studies had shown that E directly stimulates osteoclast apoptosis (18), and recent evidence indicates that DHT has similar effects on these cells (19). Finally, both E and DHT inhibit the production of the potent proresorptive cytokine, IL-6, by bone marrow stromal and mature osteoblastic cells (20, 21, 22, 23).
This discrepancy between the in vitro findings in a variety of cell systems and in vivo findings in adult men suggests that E and T likely have additional effects on other mediator(s) of sex steroid action on bone that are in opposite directions. OPG is a potential candidate for such a factor, because it is a potent antiresorptive cytokine (24, 25) that appears to be regulated in opposite directions by E and T in vitro (26, 27, 28). Moreover, circulating OPG levels are higher in premenopausal women compared with age-matched men (30, 31). Thus, to directly test for potential discordant effects of E and T on OPG production in vivo, we returned to our previous study in which we had dissected E and T effects on bone resorption and formation in normal elderly men (12).
Consistent with in vitro findings (26, 27, 28), we demonstrate here that in vivo, E and T have opposite effects on OPG production, at least as assessed in the peripheral circulation. This is in contrast to what appear to be similar, suppressive effects of both E and T on circulating TNF- and IL-6sR levels. Despite the in vitro findings (21), E effects on serum IL-6 and M-CSF levels were inconsistent in the present study. Thus, although there may be other cytokines or factors not included in our study that are differentially regulated in vivo by E and T, certainly OPG is a strong candidate to be included in this list.
We recognize that our study has two major limitations. First, we only assessed OPG levels in the peripheral circulation, and it is unclear to what extent this reflects changes in the bone microenvironment. Although bone cells are likely the major source of OPG, OPG is also produced by a number of other tissues (24, 25). Thus, the changes we observed may be underestimates because the nonskeletal sources may increase background noise. Second, although we have demonstrated what appears to be discordant regulation by E and T of OPG production in vivo, we are clearly also making an inference when we assume that these changes in OPG are modulating the changes in bone resorption observed in these men. This is, however, a relatively plausible inference, because OPG is an extremely potent antiresorptive factor (24, 25), and the roughly 30% difference (19% increase with E alone and 10% decrease with T alone) between the E and T groups, if also present in the bone microenvironment, is likely to be physiologically relevant. Nonetheless, we are cognizant of the potential pitfalls of both of our assumptions, and more direct studies assessing OPG production in bone or bone marrow stromal cells either in vivo or ex vivo are needed to further test our hypothesis.
A potential confounding factor in assessing effects of sex steroids on OPG levels is that in addition to possible regulation by E and T, OPG also appears to increase with increases in bone turnover, perhaps as a homeostatic mechanism serving to limit bone resorption. Thus, Yano et al. (34) found that serum OPG levels were positively associated with bone turnover markers in postmenopausal women, and we have recently observed a similar relationship in men (30). Moreover, postmenopausal women with increased bone turnover appear to have higher serum OPG levels than age-matched control women (35). In the present study, group A, in whom bone turnover increased markedly, tended to have an increase (10%) in serum OPG levels that was not, however, statistically significant. These potential confounding effects of bone turnover need to be kept in mind when interpreting studies examining possible effects of sex steroids on OPG production. Thus, for example, in studies simply comparing serum OPG levels in E-treated vs. untreated postmenopausal women, possible E effects on OPG levels may well be masked by the differences in OPG production due to the different rates of bone turnover in those groups. Therein lies perhaps the strength of the present study design, because in this acute model of sex steroid deficiency and replacement, the underlying effects of sex steroids on OPG may have become evident before the confounding effects of bone turnover became a significant problem.
These caveats notwithstanding, we would suggest the following working model for E and T regulation of bone resorption in vivo (Fig. 3). Consistent with the in vitro data, it is likely that both E and T inhibit osteoclast development and activity in vivo. Moreover, they also likely inhibit the production of proresorptive cytokines, such as (among others) IL-6, IL-6sR, and TNF- (32). It is also becoming clear that both E and T promote osteoclast apoptosis, and this appears to be through a nongenomic, sex steroid nonspecific mechanism (19). However, our data suggest the distinct possibility that E and T have discordant effects on OPG production, and this may explain, at least in part, why E is more effective than T in normal men as a predictor of bone resorption (6, 10, 11, 12), bone density (4, 5, 6, 7, 8, 9, 10), and rates of bone loss (11). We recognize, however, that more work needs to be done, particularly assessing OPG production in the bone microenvironment in response to E and T, before such a hypothesis is proven. Moreover, there may be other factor(s), in addition to OPG, that are differentially regulated by E and T in vivo that account for the clinical observations noted. Nonetheless, based on our data, OPG certainly appears to be a strong candidate factor that may explain the dominant role played by E in bone metabolism in men.
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Acknowledgments
We thank Dr. B. L. Riggs for helpful discussions and suggestions, our study volunteers, the staff of the Mayo General Clinical Research Center, Ms. Roberta Soderberg (for processing the samples), Ms. Sara Achenbach (for help with the statistical analyses), and Ms. Kelly Hoey (for performing the OPG assays).
Footnotes
This work was supported by research Grant AG04875 from the National Institute on Aging, USPHS.
Abbreviations: 5-DHT, 5-Dihydrotestosterone; Dpd, deoxypyridinoline; E, estrogen; IL-6sR, IL-6 soluble receptor; M-CSF, macrophage colony-stimulating factor; NTx, N-telopeptide of type I collagen; OPG, osteoprotegerin.
Received October 23, 2001.
Accepted January 4, 2002.
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