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Division of Endocrinology and Metabolism (P.T., L.G.R.) and Center on Aging (P.T.) and General Clinical Research Center (D.G.K., P.M.F., A.K.W., J.M.C.) University of Connecticut Health Center, Farmington, Connecticut 06030-1317
Address all correspondence and requests for reprints to: Pamela Taxel, M.D., University of Connecticut Health Center, Division of Endocrinology and Metabolism, 263 Farmington Avenue, Farmington, Connecticut 06030-1317. E-mail: taxel{at}nso.uchc.edu
Abstract
There is evidence that estrogen decreases bone turnover in men as well as women. We therefore hypothesized that older men would show increased bone resorption in response to inhibition of the aromatase enzyme, which converts androgens to estrogen.
Fifteen eugonadal men over 65 yr were treated for 9 weeks with 2.0 mg/day of anastrozole, an aromatase inhibitor. After 9 weeks of treatment, there were significant decreases in estradiol, estrone, and sex hormone-binding globulin levels by 29%, 73%, and 16%, respectively, and total testosterone increased significantly by 56%. Despite the limited decrease of estrogen and the increase in testosterone, C-telopeptide of type 1 collagen showed a progressive significant increase of 11%, 24%, and 33% (P for trend = 0.033) above baseline at 3, 6, and 9 weeks, respectively. N-telopeptide of type 1 collagen values were highly correlated with C-telopeptide of type 1 collagen, but the change in N-telopeptide of type 1 collagen was not statistically significant. Bone-specific alkaline phosphatase and N-terminal type I procollagen peptides showed significant decreases of 8% and 11% of baseline at 9 weeks. Osteocalcin decreased significantly by 30% at 18 weeks.
We conclude that aromatase inhibition can reduce estrogen levels in older men, but this effect is limited, perhaps because of feedback stimulation of testosterone production, and that endogenous estrogen derived from aromatization of testosterone plays a role in bone metabolism of older men by limiting the rate of bone resorption.
OSTEOPOROSIS IN MEN has recently emerged as an important public health issue. As the population ages and diseases that decrease longevity are treated more effectively, more men are subject to bone thinning and consequent fractures. Approximately 30% of hip fractures in those over age 65 yr occur in men (1), and approximately 20% of the $14 billion of the health care expenditure for osteoporotic fractures in the United States is spent on men (2).
The importance of estrogen in male bone metabolism has been recognized in the past few years. Evidence for a role of estrogen in the regulation of bone turnover in men is based on findings in patients with genetic defects in the estrogen receptor or aromatase (3, 4, 5), the enzyme that converts androgens to estrogens (6). Observational studies have demonstrated that serum estrogen levels are better predictors of bone mineral density in men than serum testosterone levels (7, 8, 9, 10). Thus, estrogen is likely to affect bone turnover in men throughout life. We have previously shown that men over age 65 responded to 9 weeks of treatment with 1 mg/day of micronized 17-ß estradiol, with a decrease in bone resorption of 15–50% (11). Therefore, we hypothesized that older men would demonstrate increased bone resorption, as measured by biochemical markers, in response to lowering of estrogen levels, which could be accomplished by inhibition of aromatase.
Recently Mauras et al. (12) treated a small group of late pubertal boys with 1 mg/day of the aromatase inhibitor, anastrozole, for 10 weeks to determine its metabolic effects and potential use as an agent to increase height. They found that E2 levels decreased significantly by 54% and were accompanied by a significant increase in LH and FSH. Markers of bone formation did not change, and markers of bone resorption were not measured. The present study was of similar duration and evaluated a number of similar parameters (hormone and gonadotropin levels as well as bone markers), but in older men.
Subjects and Methods
Study population
Community-living men, aged 65 yr and older, from the greater Hartford area were recruited by newspaper advertisements, contacts at senior citizen centers, and physician referral. Men in good health and free of any serious medical conditions (acute or chronic) and who were able to travel to the health center for outpatient visits and sign a written informed consent approved by the Institutional Review Board were eligible for this study. Subjects with chronic medical conditions or diseases of bone metabolism or on medications known to cause or treat osteoporosis were excluded. Men with clinical evidence of hypogonadism; history of gastric surgery; prolonged immobilization; body mass index (BMI) > 30 or < 23 kg/m2 were also excluded.
Protocol
This was an open label trial evaluating the effect of 2.0 mg/day of anastrozole, a nonsteroidal aromatase inhibitor that blocks the conversion of androgens to estrogens, and is FDA approved for the treatment of metastatic breast cancer (14). It undergoes hepatic metabolism primarily, and has an elimination half-life of 50 h. Steady-state plasma levels are achieved within 7 days.
All subjects gave informed consent according to the guidelines of the Institutional Review Board of the University of Connecticut Health Center (UCHC). Men who agreed to participate in the study underwent complete medical history and physical examination. Fifteen men were enrolled and all completed the study. They had eight visits to the General Clinical Research Center (GCRC) at the UCHC over a 4.5-month period, including a screening and baseline visit, followed by six interim visits every 3 weeks. All men received supplemental elemental calcium (given as citrate) to meet a daily calcium requirement of 800-1000 mg with 400 IU vitamin D per day throughout the study. Dietary calcium intake was estimated by a 4-day food diary. Anastrozole was given for 9 weeks followed by 9 weeks of posttreatment observation. Each man served as his own control. Blood and urine was collected for measurement of biochemical markers of bone turnover and sex hormones at baseline and every 3 weeks during treatment and 9 weeks post treatment. Calciotropic hormones, insulin-like growth factor (IGF)-1, and lipid profile were measured at baseline, after 9 weeks of treatment, and 9 weeks post treatment. Each man was instructed to bring remaining anastrozole tablets to the end of treatment visit for compliance check, as estimated by pill count. Subjects were asked to complete a side effects questionnaire at all visits. Bone mineral density at the lumbar spine, femoral neck, total hip, and total body was measured by dual-energy x-ray absorptiometry at baseline only.
Bone mineral density measurement
Areal bone mineral content (g/cm2) of the femoral neck, lumbar spine (25), and total body were measured by dual-energy x-ray absorptiometry using a Lunar Corp. DPX-IQ or L (Lunar Corp., Madison, Wl). Same-day reproducibility (with repositioning) of the left proximal femur in men and women ages 65–77 yr is: femoral neck, 1.1%; Ward’s triangle, 2.8%; trochanter, 1.8%. Spine and femur scans were done at medium speed unless body size dictated the slow speed. Total body scans were done at the fast speed.
Biochemical markers of bone turnover
Biochemical markers of bone turnover were measured at baseline and every 3 weeks during the 18-week study protocol. Serum and urine samples were collected between 07 h and 0930 h after a 10- to 12-h fast and divided into 0.5-ml aliquots and immediately stored at -70 C. Bone marker assays were run in duplicate after one thaw; all samples for an individual were assayed using the same kit. All bone marker assays were performed in the Core Laboratory of the GCRC at the UCHC unless otherwise specified.
Markers of bone resorption were urinary cross-linked N-telopeptides of type 1 collagen (NTX) and C-telopeptides of type 1 collagen (CTX), total pyridinoline and deoxypyridinoline cross-links (Pyr and Dpyr). NTX and CTX were measured by ELISA (Ostex International, Inc., Seattle, WA; Osteometer A/S, Copenhagen, Denmark; and Metra Biosystems, Mountain View, CA, respectively). Intraassay variability was 7.6% for NTX and 4.4% for CTX. Total Pyr and Dpyr was measured by HPLC in the laboratory of Dr. William Fraser, University of Liverpool (Liverpool, UK), with an intraassay variability of less than 10%.
Markers of bone formation were bone alkaline phosphatase (BSAP), osteocalcin (OC), and N-terminal type I procollagen peptides (PINP). BSAP was measured by enzyme-linked immunosorbent assay (ELISA, Metra Biosystems, Inc., Mountain View, CA), OC by immunoradiometric assay (IRMA, Nichols Institute Diagnostics, San Juan Capistrano, CA), and PINP by RIA (Orion Diagnostica, Inc., Espoo, Finland). The percent within-run coefficient of variation in the Core lab is 5% for BSAP, 4.6% for OC, and 6% for PINP.
Hormone measurements
Sex-hormone and gonadotropin measurements included E2, E1, total T, sex hormone-binding globulin (SHBG), FSH, and LH. All hormone levels were measured at baseline and at 3, 6, 9, and 18 weeks. Assays for T, E2, E1, SHBG, FSH, and LH were measured by Endocrine Sciences, Inc., (Calabasas Hills, CA). T, E2, and E1 were measured by RIA, SHBG by a competitive binding assay, FSH, and LH by immunochemiluminometric assay. Free Estrogen Index (FEI) was calculated as follows: E2 + E1/SHBG and Free Androgen Index (FAI): total T/SHBG. FSH and LH were measured by a microparticle enzyme immunoassay using an automated analyzer with an interassay variability of < 6% for FSH and < 5% for LH (Abbott Laboratories, Abbott Park, IL).
Calciotropic hormones included intact parathyroid hormone (PTH) and 25-hydroxyvitamin D. PTH was measured in the GCRC Core lab at UCHC by sandwich immunoassay (ELISA, Diagnostics Systems Laboratories, Inc., Webster, TX); 25-hydroxyvitamin D by radiobinding assay (Endocrine Sciences, Inc.).
IGF-1 was measured by ELISA in the GCRC laboratory of Marie Gelato, M.D., and Dennis Mynarcik, Ph.D., State University of New York at Stony Brook (kits from Diagnostics Systems Laboratories, Inc.).
Statistical methods
A repeated-measure ANOVA was used to test the significance of the changes in bone marker and hormone levels over time. The design featured one group and observations at four points in time. Contrasts were evaluated within groups to compare the mean baseline values with subsequent mean readings. We examined both the absolute and percent changes from baseline for each marker and hormone. The statistical significance of the Pearson correlation coefficients was evaluated using a t test. BMDP (15) statistical software was used for all statistical procedures and data analysis. Trend results were derived from a repeated-measure ANOVA with one within factor (time). Comparisons of consecutive mean bone marker levels were done by evaluating the appropriate specified contrasts.
Results
Baseline demographic characteristics are shown in Table 1
. Baseline sex steroid, calciotropic
hormone and lipid data, and changes during and after treatment are
given in Tables 2 and 3 and Figure 1. Baseline markers of bone turnover and
mean changes during and after treatment are shown in Table 4 and Figure 2.
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Hormones. Baseline values of sex hormone and calciotropic
hormone levels were within the normal range (Tables 2
and 3). There
were positive correlations of baseline hormones
(E2, E1, total T, and
SHBG), with r values ranging from 0.59 to 0.95. As expected, BMI showed
a negative correlation with SHBG (r = -0.677, P =
0.006) and T (r = -0.576, P = 0.024), but the BMI
showed a positive correlation with FAI (r = 0.528,
P = 0.043).
There were significant decreases in E2,
E1, SHBG, and FEI levels at 3, 6, and 9 weeks
(Fig. 1). Total T and FAI increased significantly at 3, 6, and 9 weeks.
At 9 weeks these increases were 56% and 94% (Table 2, Fig. 1, A and
B). FSH and LH increased significantly after 3, 6, and 9 weeks of
treatment (Fig. 1C). All hormone levels returned to baseline values at
18 weeks (9 weeks post treatment). FEI showed the greatest decrease at
3 weeks, and FAI showed the greatest increase at 9 weeks. At 3 weeks,
the change in FEI correlated negatively with the change in LH (r =
-.617, P = 0.019), and the change in FAI correlated
positively with the change in FSH (r = 0.663, P =
0.007). At 9 weeks, the FEI correlated positively with the FAI (r
= 0.718, P = 0.003), and the change in FEI correlated
negatively with the change in LH (r = -0.589, P =
0.027), and the change in FAI correlated positively with the change in
FSH (r = 0.649, P = 0.009). PTH, 25-OH vitamin D,
IGF-1, and ionized calcium did not change significantly during
treatment, but PTH did increase significantly from baseline at 18 weeks
(Table 3).
Markers of bone turnover. At baseline, markers of bone
resorption (NTX, CTX, and TDpyr) and formation (OC and BSAP)
were correlated with one another (r values ranging from 0.63 to 0.65).
CTX showed a progressive increase of 11%, 24%, and 33% (P
for trend = 0.033) above baseline at 3, 6, and 9 weeks,
respectively (Table 4, Fig. 2). NTX, Tpyr, and TDPyr showed small
increases that were not statistically significant. However, NTX and
TDPyr values were highly correlated with CTX at 9 weeks (r = 0.9,
P < 0.001, r = 0.678, P = 0.006,
respectively). CTX returned toward baseline at 18 weeks. BSAP and PINP
showed small but significant progressive decreases (P for
trend, 0.002 and 0.02, respectively) of 8% and 15%, respectively
(P = 0.002, P = 0.007) of baseline at 9
weeks but not at 18 weeks. OC showed a nonsignificant 13% decrease at
9 weeks but was significantly decreased by 30% at 18 weeks
(P for trend = 0.001). Few correlations were seen
between markers of bone turnover and hormones; however, the decrease of
PINP correlated with the decrease in E2 at 9
weeks (r = 0.787, P = 0.001, Fig. 3).
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). Discussion
Evidence for a role of estrogen in the regulation of bone turnover in men is based on findings in patients with genetic defects in the estrogen receptor or aromatase (3, 4, 5), the enzyme that converts androgens to estrogens (6). These patients exhibited tall stature, delayed epiphysial closure, decreased bone density, and increased bone turnover. One of these men with the aromatase defect gained significant bone mass after the institution of estrogen therapy (15). Male-to-female transsexuals on estrogen therapy have been found to have decreased bone turnover as measured by histomorphometric indices, with no associated bone loss (16). Bernecker et al. (17) have shown that levels of serum E2 and not T were significantly decreased in 56 middle-aged men with idiopathic osteoporosis. Recently, in a short-term study of 60 older men in whom both gonadotrophin secretion and aromatase conversion were suppressed, Falahati et al. (18) demonstrated that E2 is the principal sex steroid regulating bone resorption.
Several observational studies have demonstrated that serum estrogen levels are better predictors of BMD in men than serum testosterone levels (8, 9, 10, 11). Khosla et al. (8) demonstrated in a cross-sectional analysis that as men age, both bioavailable T and E2 decline slowly and that bioavailable E2 is the best predictor of BMD in older men. Greendale et al. (9) showed similar results in the Rancho Bernardo population. In an Australian study (10) of more than 400 older community-dwelling men, low E2 and high SHBG were the main determinants of femoral neck and lumbar spine BMD after multiple regression analysis.
In this study, we demonstrated that a dose of 2 mg/day anastrozole, twice the dose used in breast cancer in postmenopausal women to lower E2 to undetectable levels, decreased E2 by 29%, E1 by 73%, and FEI by only 45% in these men. This incomplete effect on lowering of estrogen levels was unexpected. We postulate that this occurred because of central feedback from the hypothalamus and pituitary, which produced an increase in FSH and LH leading to an elevation of T, which provided more substrate and may have blunted the effectiveness of the aromatase inhibitor. The initial FEI decrease at 3 weeks was associated with an increase in LH (r = -0.617, P = 0.019), which would lead to the increased testosterone production. T aromatization might explain not only the limited decrease in E2 but also the tendency for E2 to increase at weeks 6 and 9, after a nadir at 3 weeks. It is also possible that the increase in T caused a local increase in E2 production in bone, which we could not measure. In a recent study of young, healthy late adolescent men aged 14–18 yr, Mauras et al. (13) showed a 48% decrease in E2 and a 57% increase in T after 1 mg/day anastrozole for 10 weeks, similar to our results.
Significant increases in FSH and LH were seen in the present study, 61% and 96%, respectively, and these were larger than those reported in young men (13), 38% and 40%, respectively, perhaps because the initial values were lower. These results do confirm that E2 is a major feedback regulator of gonadotropin secretion in the male, as has been seen in prior studies (1, 3, 19, 20). The explanation for the significant increase in PTH at 18 weeks (9 weeks after treatment was discontinued) is unclear. All the values were in the normal range. It is possible that calcium supplementation, which was started at screening, produced a transient decrease in PTH levels at baseline, which then increased over the course of the study. Most of the high values were obtained between May and October, indicating that they were not due to seasonal decreases in vitamin D. There were no correlations between PTH changes and changes in biochemical markers.
CTX, a marker of bone resorption, increased significantly in these healthy men who were treated with an aromatase inhibitor for 9 weeks. Other markers of bone resorption, NTX, Tpyr, and TDpyr showed a similar trend. This occurred with a decrease of FEI of only 45% and a greater increase in FAI of 94%. These data support a primary role for estrogen as an inhibitor of bone resorption in men, with little direct effect of androgen, as suggested by Falahati et al. (18). Although we attribute the increase in resorption to the decline in E2, the increase in T could have limited this effect.
Contrary to our expectations, two markers of bone formation, BSAP and PINP, decreased in response to short-term aromatase treatment. This occurred despite an increase in T, which has been shown to increase markers of bone formation in postmenopausal women (21) and in one study in men but not in others (23, 24). Recently, Oz et al. (25) demonstrated that 5- to 7-month-old male aromatase-deficient mice, which could not convert T to E2, showed decreased osteoblastic activity, compared with wild-type littermates. Thus, in males, aromatase deficiency contributed to a suppression of bone formation on histomorphometry that was not seen in female mice. The authors conclude that there is sexual dimorphism in response to aromatase deficiency, and that E2 may have direct anabolic effects on bone in males. Our data, including the high correlation between the decrease in FEI and the decrease in PINP, support this hypothesis. In addition, Falahati et al.’s data (18) show a decrease in OC and PINP in men who are not only E2 and T deficient but also E2 deficient but T replete. E2 appears to have a greater effect to restore PINP levels, whereas both E2 and T act to restore OC levels. The authors suggest that the decrease in bone formation associated with sex-steroid withdrawal may be due to osteoblast apoptosis, as has been shown in recent in vitro observations (26), and this may be a possible explanation for our observations as well.
This study had several limitations. There was no placebo group with calcium supplementation alone in this small trial; each man served as his own control. In addition, the study was of short duration. Resorption markers were increasing throughout the treatment time period and may have increased further. It is also possible that bone formation did not reach steady-state, and a longer study would have shown an increase in bone formation associated with increased remodeling of E2 deficiency. Incomplete reduction of estrogen levels was demonstrated in this study. In a preliminary study, 1 mg/day anastrozole (the usual dose for postmenopausal women with breast cancer) produced a similar lowering of E2 levels. The fact that the response to 1 and 2 mg/day was similar suggests that there may be an intrinsic limitation in this drug’s ability to block conversion of androgens to estrogens in men with intact feedback mechanisms.
In conclusion, inhibition of aromatization of E2 from T using anastrozole resulted in a decrease in estrogen and an increase in androgen in older men. FEI decreased 45% and correlated negatively with changes in LH. FAI increased 94% and correlated positively with changes in FSH. These changes were accompanied by a significant increase in CTX and decreases in BSAP and PINP. Although the results of this study are complicated by central feedback from the pituitary and hypothalamus, which results in an increase in T levels when E2 levels are decreased by aromatase inhibitors, endogenous estrogen does appear to play a role in bone metabolism of older men by limiting their rate of bone resorption and perhaps by enhancing bone formation.
Acknowledgments
We thank William Fraser, M.D., of the University of Liverpool, Liverpool, England, for the measurements of total Pyr and Dpyr and Marie Gelato, M.D., and Dennis Mynarcik, Ph.D., State University of New York at Stony Brook for the measurement of IGF-1 in their GCRC Core Laboratory. We are also grateful to Lisa Godin for help in the preparation of this manuscript and to all the male volunteers who have made this study possible.
Footnotes
1 Supported by a CAP award under the auspices of the General Clinical
Research Center NIH Grant MO-1-RR-06192 and Claude Pepper Older
Americans Independence Center Grant award 5P60-AG13631. 
Received October 11, 2000.
Revised January 10, 2001.
Accepted March 1, 2001.
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