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Original Article |
Endocrine Unit (B.Z.L., K.M.L., J.S.F.) and Biostatistics Center (D.A.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; and Division of Clinical Sciences (R.E.), Northern General Hospital, Sheffield, United Kingdom
Address all correspondence and requests for reprints to: Benjamin Z. Leder, M.D., Endocrine Unit, Massachusetts General Hospital, Bulfinch 327, Fruit Street, Boston, Massachusetts 02114. E-mail: bzleder{at}partners.org.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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gene or the aromatase gene suggested a vital role for estrogen in male bone physiology (8, 9, 10). These men, who were unable to either respond to or synthesize estrogen had reduced bone mineral density (BMD), elevated biochemical markers of bone turnover, and unfused epiphyses (8, 9, 10). Furthermore, when estrogen was administered to the men with aromatase deficiency, the skeleton matured and BMD increased dramatically (10, 11, 12). Although the phenotypes of men with these genetic mutations imply an essential role for estrogen in male skeletal development, data suggesting a role for estrogen in male bone homeostasis in humans come largely from epidemiological association studies and a single short-term physiological study in which states of selective androgen and estrogen deficiency were created in elderly men for a short period of time (13).
To test the hypothesis that estrogen is the major regulator of bone maintenance in men, we studied 70 healthy young men for 12 wk. All men received a GnRH analog to induce temporary hypogonadism, and hormones were selectively replaced in the three groups to create the following physiological states: 1) testosterone and estrogen deficiency (-T, -E), 2) testosterone and estrogen sufficiency (+T, +E), and 3) selective estrogen deficiency (+T, -E). We then measured biochemical markers of bone turnover every 4 wk and analyzed the differences in the changes among groups to assess the relative roles of androgens and estrogens in male bone homeostasis.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Ninety-two men between the ages of 20 and 44 yr were recruited using advertisements in accord with institutional guidelines for clinical studies. All subjects were required to have normal serum testosterone, estradiol, LH, and FSH concentrations; normal renal and hepatic function; and normal BMD of the lumbar spine, femoral neck, and total hip. Subjects were excluded from participation if they had any history of congenital or acquired bone disease (osteomalacia, vitamin D deficiency, hyperparathyroidism, Paget’s disease), recent fracture or immobilization, hyperthyroidism, cardiopulmonary disease, malignancy, benign prostatic hyperplasia, major psychiatric disease, or drug or alcohol abuse. Subjects were also excluded if they were using any drug known to interact with the study medications or any drug known to affect bone turnover markers (such as anticoagulants, gonadal steroids, glucocorticoids, anticonvulsants, and suppressive doses of thyroxine, lithium, bisphosphonates, calcitonin, or sodium fluoride). Because the goal of this study was to determine the effects of specific hormonal milieus on bone turnover, it was predetermined that we would not use data from men whose serum testosterone (groups 2 and 3) and estradiol (group 2) levels were less than 2 SD below the mean of the entire study population on more than one visit. Bone turnover markers were not analyzed on the samples from those men (n = 6). An additional eight men withdrew because of side effects of the study medications and eight for other reasons, leaving 70 men who form the basis of this report. This study was approved by the Human Research Committee of Partners HealthCare Systems, and all subjects provided written informed consent.
Study protocol
Subjects were randomized by computer-generated assignment to one of three treatment groups (Fig. 1
). Subjects in group 1 received the GnRH analog goserelin acetate (Zoladex; AstraZeneca, Wilmington, DE) 3.6 mg by sc injection every 4 wk for 12 wk. Subjects in group 2 received goserelin acetate 3.6 mg by sc injection every 4 wk plus physiological testosterone and estradiol replacement via an aromatizable topical testosterone delivery system (Androderm 5-mg patch daily; Watson, Corona, CA). Subjects in group 3 received goserelin acetate 3.6 mg by sc injection every 4 wk plus topical testosterone plus a potent third-generation aromatase inhibitor anastrozole (Arimidex; AstraZeneca) 1 mg orally daily. The combined effect of these specific medication regimens was to create groups of subjects that were either testosterone and estrogen deficient [group 1 (-T, -E), n = 25], eugonadal [group 2 (+T, +E), n = 22], or selectively estrogen deficient [group 3 (+T, -E), n = 23]. If a subject had a local reaction to Androderm topical testosterone, the equivalent dose of Testoderm TTS (Alza Corp., Mountain View, CA) topical testosterone was administered. If the local reaction continued, Androgel (5 g packet QD, Unimed Pharmaceuticals, Inc., Deerfield, IL) topical testosterone was administered. Subjects whose diets did not include at least 1000 mg elemental calcium daily were encouraged to increase calcium intake by either diet or calcium supplements.
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Laboratory methods
Gonadal steroid and calcium regulatory hormones. Serum testosterone was measured by RIA using a commercial kit (Diagnostic Products, Los Angeles, CA) with a sensitivity of 4 ng/dl, an intraassay coefficient of variation of 5% within the normal range and 18% in the castrate range, and an interassay coefficient of variation of 7–12%. Serum estradiol was measured using an ultrasensitive competitive RIA after extraction and chromatographic purification (Nichols Institute, San Juan Capistrano, CA). The sensitivity of this assay is 2 pg/ml, and the intra- and interassay coefficients of variation are 5–6% and 6–13%, respectively. Serum SHBG was measured using a chemiluminescent immunoassay (Nichols Institute) with a sensitivity of 1 nmol/liter and intra- and interassay coefficients of variation of 3–5% and 3–5%, respectively. Serum intact PTH was measured by a two-site immunoradiometric assay (Nichols Institute) with a sensitivity of 1 pg/ml and intra- and interassay coefficients of variation of 2–3% and 6%, respectively. Serum 25-(OH) vitamin D was measured using an extraction double-antibody RIA (DiaSorin, Inc., Stillwater, MN) with a sensitivity of 1.5 ng/ml and intra- and interassay coefficients of variation of 9–13% and 8–11%, respectively. Serum calcium was measured by autoanalyzer.
Biochemical markers of bone resorption. Urine deoxypyridinoline (DPD) was measured using a competitive enzyme-linked immunoassay (Quidel Corp., San Diego, CA) with a sensitivity of 1.1 nM bone collagen equivalents and intra- and interassay coefficients of variation of 5–9% and 4–8%, respectively. Urine N-telopeptide (NTX) was measured in Sheffield, UK, using an automated chemiluminescent immunoassay (Ortho-Clinical Diagnostics, Rochester, NY) with an interassay CV of 7%. Because these samples were not run in duplicate, no intraassay coefficient of variation was available. Urine creatinine was measured by a dry slide chemistry method (Ortho-Clinical Diagnostics). Serum NTX was measured using a competitive inhibition enzyme immunoassay (Osteomark, Ostex International, Inc., Seattle, WA) with a sensitivity of 1 nM BCE and intra- and interassay coefficients of variation of 6% and 9%, respectively.
Biochemical markers of bone formation. Serum osteocalcin (OC) was measured using a double-antibody immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA) with a sensitivity of 0.5 ng/ml and intra- and interassay coefficients of variation of 2–4% and 3–6%, respectively. Serum carboxy-terminal propeptide of type I procollagen (PICP) was measured using an equilibrium RIA (DiaSorin, Inc.) with a sensitivity of 1.2 ng/ml and intra- and interassay coefficients of variation of 1–4% and 1–2%, respectively. Serum amino-terminal propeptide of type I procollagen (PINP) was measured using a RIA (Orion Diagnostica, Espoo, Finland) with a sensitivity of 2 ng/ml and intra- and interassay coefficients of variation of 5–14% and 2–3%, respectively.
Each subject’s samples for serum and urine bone turnover markers were analyzed in the same assay.
Data analysis
The primary end points of this study were between-group differences in changes of biochemical markers of bone turnover. Pairwise differences among groups for each marker were assessed using a repeated-measures ANOVA using the PROC MIXED procedure in SAS (SAS Institute, Cary, NC). The model included baseline level, visit number, group, and a group-visit interaction. We did not specify the variance covariance matrix for the repeated measurements. For a subset of markers (OC, PICP, PINP), the group-visit interaction was significant, indicating that the treatment effect was different at each visit. Thus, for these markers, the change from baseline at 12 wk was assessed using a simple analysis of covariance. Baseline characteristics of the three groups were compared by ANOVA. P values less than 0.05 were considered statistically significant. Unless specified otherwise, all data are presented as the mean ± SD.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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shows the baseline clinical characteristics, gonadal steroid levels, and SHBG levels of the study subjects. There were no statistically significant differences among groups. Table 2 shows the baseline biochemical markers of bone turnover and calcium regulatory hormones of study subjects. Subjects were generally well matched in all these areas as well. Baseline urinary NTX excretion was approximately 15% higher in group 1 than in groups 2 and 3, but these differences were not statistically significant (P = 0.179 for group 1 vs. 2 and P = 0.129 for group 1 vs. 3).
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Figure 2 shows the changes in serum testosterone, estradiol, and SHBG levels during the 12-wk study period. As expected, serum testosterone concentrations did not change significantly from baseline in either groups 2 or 3 but decreased dramatically in group 1 by wk 4 and remained in the castrate range for the duration of the study (P < 0.001 for change from baseline at wk 4–12). Changes in serum testosterone levels between groups 2 and 3 were similar (P = 0.721), whereas serum testosterone levels were significantly lower in group 1 than in groups 2 and 3 (P < 0.001 for both comparisons). Also as expected, serum estradiol levels decreased into the castrate range in groups 1 and 3 by wk 4 and remained suppressed throughout the study period (P < 0.001 for change from baseline at wk 4–12 for both groups). Serum estradiol levels in group 2 remained stable overall but declined transiently at wk 8 (mean ± SD serum estradiol level 62 ± 37 pmol/liter, P = 0.001 for change from baseline). Serum estradiol levels declined more in groups 1 and 3 than in group 2 (P < 0.001 for both comparisons), but serum estradiol levels declined to a similar extent in groups 1 and 3 (P = 0.649). Serum SHBG levels increased in group 1 (P = 0.018, 0.056, 0.081 for change from baseline at wk 4, 8, and 12, respectively) but did not change in groups 2 or 3. This increase in SHBG in group 1 was significant only when compared with group 3 (P = 0.008).
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Figure 3 shows the changes in biochemical markers of bone resorption during the 12-wk study period. Urinary DPD excretion increased significantly from baseline in group 1 (P = 0.035 for change from baseline at wk 4 and P < 0.001 at wk 8 and 12) but did not change in group 2 (P = 0.734, 0.551, and 0.981 at wk 4, 8, and 12, respectively). In group 3, urinary DPD excretion increased significantly from baseline by wk 8, although this increase was of only borderline significance at wk 12 (P = 0.215, 0.028, and 0.076 for change from baseline at wk 4, 8, and 12, respectively). Urinary DPD excretion increased more in group 1 than in groups 2 and 3 (P < 0.001 for group 1 vs. 2, P = 0.023 for group 1 vs. 3). Although urinary DPD excretion increased more in group 3 than group 2, this difference was not statistically significant (P = 0.136). Serum NTX levels increased significantly in group 1 (P = 0.012, P < 0.001 for change from baseline at wk 4 and 8–12, respectively). Serum NTX levels also increased in group 3 (P = 0.082, P = 0.012, P < 0.001 for change from baseline at wk 4, 8, and 12, respectively). In group 2, serum NTX was stable at wk 4 and 8 but increased by approximately 12% by wk 12 (P = 0.011). Serum NTX levels increased more in groups 1 and 3 than in group 2 (P = 0.002 for group 1 vs. 2, P = 0.037 for group 3 vs. 2). Serum NTX levels increased to a similar extent in groups 1 and 3 (P = 0.258). Changes in urinary NTX excretion showed a similar pattern to changes in serum NTX (both in regard to change from baseline and the between-group comparisons), but none of these comparisons was statistically significant, probably because of the higher variability of this marker.
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Figure 4 shows the changes in biochemical markers of bone formation during the 12-wk study period. Serum OC, PICP, and PINP levels decreased initially in all groups and then increased to varying degrees in groups 1 and 3. In contrast, serum OC, PICP, and PINP levels remained significantly suppressed in group 2 (P = 0.005, 0.040, 0.013 for change from baseline at wk 12 for OC, PICP, and PINP, respectively). The between-group comparisons were also consistent for all formation markers. Serum OC, PICP, and PINP levels increased more in group 1 than in group 2 (P = 0.001, 0.037, 0.005 for OC, PICP, and PINP, respectively) or group 3, although the differences between changes in groups 1 and 3 were of borderline statistical significance (P = 0.065, 0.073, 0.099 for OC, PICP, and PINP, respectively). No significant differences were observed in changes in serum OC, PICP, and PINP levels between groups 2 and 3.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The effects of selective gonadal steroid deprivation on markers of osteoblast activity demonstrated in this study were complex. These markers decreased initially, possibly because of the initial increase in serum testosterone and estradiol levels that occurs upon initiating GnRH analog therapy (14). After this decrease, these markers increased in the hypogonadal group (group 1) as is known to occur during long-term hypogonadism (15). Moreover, there was a trend toward a greater increase in bone formation markers in group 1, compared with group 3. This finding suggests that physiological levels of androgens may normally suppress osteoblast activity, although a larger study may be needed to establish this fact.
The findings in this study are largely consistent with emerging data concerning the roles of androgens and estrogens in male bone physiology. Case reports have shown that men with mutations in either the estrogen receptor- gene or the aromatase gene are osteopenic (8, 9, 10), demonstrating the importance of estrogen in normal male skeletal development. Numerous studies have examined associations between serum testosterone or estrogen levels and BMD in adult men. Although some studies have reported a positive association between serum testosterone levels and BMD in men (16, 17, 18), most have found a stronger association between serum estradiol levels and BMD or fracture (19, 20, 21, 22, 23, 24, 25, 26, 27).
The preponderance of the in vitro and animal data suggests crucial roles for both androgens and estrogens in male bone metabolism, beginning with the fundamental observation that both androgen and estrogen receptors are expressed on osteoblasts (28, 29, 30). Aromatase inhibition reduces BMD as effectively as castration in male rats (31, 32), and mice with targeted inactivation of the aromatase gene are osteopenic (33, 34). In addition, mice with targeted inactivation of the estrogen receptor- or both estrogen receptor- and -ß have cortical (but not trabecular) osteopenia (35). These findings suggest an important independent effect of estrogens on bone homeostasis in animals. Conversely, both aromatizable and nonaromatizable androgens stimulate osteoblast proliferation and differentiation in vitro (3, 4) and prevent osteoblast apoptosis via a nongenotropic mechanism (36). Moreover, in cell culture, both aromatizable and nonaromatizable androgens reduce the resorption activity of osteoclasts (5), and in rodents, administration of either aromatizable or nonaromatizable androgens prevents orchidectomy-induced osteoclastogenesis and bone loss (6, 7, 37). Finally, trabecular osteopenia develops in estrogen receptor- and estrogen receptor- and -ß knockout male mice after orchidectomy, presumably because of the loss of testosterone (38). Taken together these findings suggest important independent effects of androgens on bone turnover.
Few studies have examined the differential effects of androgens and estrogens on bone turnover in humans. Bone turnover markers do not change consistently in elderly men given estradiol (39), but C-telopeptide levels increase in elderly men given an aromatase inhibitor (40). These studies are difficult to interpret, however, because testosterone levels decrease with estradiol administration and increase with aromatase inhibition, thus confounding the effects of the primary interventions. Falahati-Nini et al. (13) used combinations of GnRH analog, testosterone, estrogen, and aromatase administration to induce selective estrogen deficiency, selective androgen deficiency, combined gonadal steroid deficiency, or combined gonadal steroid replacement for 3 wk in elderly men. Using that model, they reported that estrogen is the dominant regulator of bone resorption in men, whereas both androgens and estrogens regulate bone formation. Qualitatively, our bone resorption results are similar to those of Falahati-Nini et al. (13), although the changes in urinary DPD excretion in our study clearly indicated an important independent effect of androgens on bone resorption. The effects of gonadal steroids on bone formation markers in the two studies differ more substantially. Whereas Falahati-Nini et al. concluded that both androgens and estrogens are important in maintaining bone formation, we found only an effect of androgens.
Although there are many similarities between the designs of these two studies, there are several important differences. First, in the study by Falahati-Nini et al., the different hormonal milieus were maintained for only 3 wk. As is clearly shown in our data, bone formation is not in a steady state at this time. Moreover, bone turnover markers in the study by Falahati-Nini et al. (13) may not have been in a steady state at the time the individual hormonal manipulations were initiated because of supraphysiological increases in gonadal steroids that occur during the initial agonist phase of GnRH analog therapy (14). Finally, Falahati-Nini et al. studied elderly men, whereas we studied young adult men. It is possible that the skeletons of young and old men respond differently to androgens and estrogens, an issue that may have contributed to the subtle differences in the findings or the magnitude of the observed changes.
Two limitations of our study deserve mention. First, although we attempted to keep serum estradiol levels stable in group 2 by allowing topical testosterone to be endogenously aromatized to estradiol, mean serum estradiol levels decreased slightly at wk 8 in this group, although they remained within the normal male range. This slight decrease in serum estradiol levels may have occurred because peripheral aromatization accounts for most, but not all, of circulating estradiol in men (41). Moreover, this transient decrease in serum estradiol levels may explain the slight increase in serum NTX levels in group 2 and may have prevented our ability to detect a statistically significant difference in urine DPD excretion between groups 2 and 3, minimizing our appreciation of an estradiol effect. Importantly, however, this transient decrease in serum estradiol levels in group 2 has no effect on the assessment of the selective effect of testosterone on bone turnover. In addition, we considered including a fourth treatment group (i.e. a goserelin plus estradiol) to assess the effects of selective estrogen replacement in the absence of testosterone. Although including this group would likely have provided additional useful information, the risk of inducing feminizing side effects during 12 wk of selective estrogen administration was thought to be prohibitory.
In conclusion, our findings suggest that both androgens and estrogens are independent mediators of bone resorption in young adult men. Although quantifying the effect of each hormone is not possible in the present study, the importance of both androgens and estrogens needs to be considered when assessing the effects of all hormonal therapies or manipulations in men. Although the effects of gonadal steroids on bone formation are more complex, there may be similar selective effects of gonadal steroids on osteoblast function as well. Longer-term studies are now needed to confirm and expand our understanding in this fundamental area.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMD, Bone mineral density; DPD, deoxypyridinoline; NTX, N-telopeptide; OC, osteocalcin; PICP, carboxy-terminal propeptide of type I procollagen; PINP, amino-terminal propeptide of type I procollagen.
Received July 5, 2002.
Accepted October 14, 2002.
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