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Department of Endocrinology (I.V.P., J.M.K.) and Unit for Osteoporosis and Metabolic Bone Diseases (I.V.P., S.G., J.M.K.), Ghent University Hospital, 9000 Ghent, Belgium
Address all correspondence and requests for reprints to: Prof. J. M. Kaufman, Department of Endocrinology (9K12IE), Ghent University Hospital, De Pintelaan 185, Ghent, Belgium. E-mail: Jean.Kaufman{at}rug.ac.be.
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Abstract |
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2 test = 4.03; df = 1; P = 0.05) but also in study subjects with a positive fracture history in their first-degree relatives (Pearson’s 2 test = 6.48; df = 1; P = 0.01). In conclusion, the results of this prospective observational study support the view that BioE2 is a determinant of bone density changes in elderly men and, furthermore, provide an indication that the aromatase enzyme may exert a direct modulatory action on bone metabolism at the tissue level in elderly men. |
Introduction |
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Aging in men is accompanied by a progressive, albeit interindividually variable, decline of testosterone (T) production (5, 6). Although this translates in an only modest age-related decrease of the population means for total serum T, there is a concomitant increase of serum SHBG levels leading to a substantial decline of the biologically active non-SHBG bound serum T fractions. Mean levels of bioavailable (Bio) serum T in the population decrease by as much as 50% between ages 25 and 75 yr (5, 6). The total circulating concentration of estradiol (E2), which originates essentially from aromatization of T in peripheral tissues (i.e. in particular in fat tissue), remains rather constant with age (7). There is, however, a moderate age-associated decrease of approximately 25% of the non-SHBG bound fraction of E2, BioE2 (6, 8, 9). An obvious, but not yet fully explored research question is whether and to what extent the relative sex steroid deficiency in elderly men contributes to the pathogenesis of age-associated bone loss (for review, see Ref. 10).
Several cross-sectional studies have shown significant, but rather weak, associations between serum (free or Bio) T and prevalent BMD, with at present no published reports of association of androgen levels with prospectively assessed bone loss in elderly men (10). Interestingly, in line with a now substantial body of evidence indicating that estrogens play an important role in bone homeostasis in the male are the results of cross-sectional studies in elderly men revealing more consistent associations of BMD with serum E2 than with T levels (for review, see Ref. 11). Moreover, Khosla et al. (8) reported a relationship between serum E2 levels and changes in bone density at the mid-forearm in aging men. An elegant intervention study from the same group, with selective short-term manipulation of sex steroid exposure, has confirmed that estrogens play an important role in the regulation of bone metabolism in elderly men (12).
This involvement of E2 in the regulation of bone metabolism thus implies that aromatase enzymatic activity is critically important for normal male bone physiology, as is illustrated by the skeletal maturation delay and the low BMD in men with inactivating mutations of the CYP19 gene and by the remarkable response to estrogen therapy in these patients (13, 14, 15). Whereas the latter observation emphasizes the importance of circulating E2 levels, aromatase may also contribute to total estrogen exposure of bone by local aromatization of androgens in bone tissue where the aromatase enzyme has been shown to be present (16). Studies in estrogen-related pathologies such as breast cancer have suggested a functional role of a (TTTA)n-repeat polymorphism of the CYP19 gene (17). More recently, a role of this polymorphism in postmenopausal bone metabolism has been suggested (18).
The aim of the present longitudinal study in a cohort of 214 healthy men over age 70 yr was to assess the role of BioE2 and the CYP19 (TTTA)n-repeat polymorphism in bone loss in elderly men.
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Subjects and Methods |
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A total of 352 male subjects aged 71–86 yr, recruited from the population register of a semirural community near the Ghent University Hospital, agreed to participate in an observational study over a period of 4 yr. This longitudinal population study initiated in 1996 was designed to investigate the process of aging, focusing on hormonal changes and bone metabolism. All participants signed an informed consent approved by the ethical committee of the Ghent University Hospital. All participants completed questionnaires about medical history and (family) fracture history. Self-reported clinical fractures at the hip, the wrist, or the spine that occurred after the age of 50 yr were recorded at each visit during the study; radiological documentation was not obtained. At baseline, all participants were asked whether any of their first-degree relatives, with the exception of the younger generation of children, previously experienced a hip or wrist fracture, irrespective of the circumstances. Of the initial number of 352 participants, 79 subjects were excluded at baseline because of past or current history of disorders or treatments potentially affecting androgen status and/or bone metabolism (n = 69) or because of incomplete data (n = 10). Detailed exclusion criteria were described in earlier papers dealing with baseline data (19, 20). The study population was invited for examination at yearly intervals; 5 serial measurements were available in 140 subjects, and for the remaining subjects 2–4 data points were available. The longitudinal study cohort consists of 214 eligible subjects for whom at least 1 follow-up visit was available.
Hormonal assays and biochemical markers of bone metabolism
At baseline, fasting blood samples and second-void urine samples were obtained between 0800 and 1000 h and were stored at -80 C until analyzed. Commercial immunoassay kits were used to determine serum levels of total T (Medgenix, Fleurus, Belgium), SHBG (Orion Diagnostica, Espoo, Finland), and LH (results expressed as IU/liter of IRP 68/40; Medgenix). Serum E2 was assayed using a commercial immunoassay kit (Clinical Assay, DiaSorin, Inc. s.r.l., Saluggia, Italy); to increase the sensitivity of the assay, a modified protocol with doubling of the serum amount was applied. According to this modified procedure, the detection limit for serum E2 was 0.25 ng/dl (9.2 pmol/liter), and in all serum samples the serum E2 concentration was above the detection limit; the intraassay and interassay coefficients of variation (CV) of the E2 assay were between 4.2% and 8.0% and between 4.9% and 9.7%, respectively. BioT and BioE2 levels were calculated from serum total T, E2, SHBG, and albumin concentrations using a previously validated equation (21); the association constants used for these calculations were 1 x 109 and 6 x 108 for binding to SHBG of T and E2, respectively.
The following markers of bone turnover and calciotropic hormones were measured using immunoassays: serum bone-specific alkaline phosphatase (Hybritech Inc., San Diego, CA), serum intact osteocalcin, and urinary C-terminal telopeptides of type I collagen (U-CTX; Osteometer BioTech A/S, Copenhagen, Denmark), serum C-terminal type I procollagen peptide (Orion Diagnostica), serum C-terminal telopeptides of type I collagen (S-CTX; Roche Diagnostics GmBH, Penzberg, Germany), urinary deoxypyridinoline (U-DPD) levels (Diagnostic Products Corp., Los Angeles, CA), serum intact PTH levels (Nichols Institute Diagnostics, San Juan Capistrano, CA), and serum 25-hydroxyvitamin D (DiaSorin, Inc., Stillwater, MN). U-DPD and U-CTX were normalized for urinary creatinine (Cr) concentration. The intraassay and interassay CV for all assays were less than 10% and 15%, respectively.
BMD
Areal BMD (grams per square centimeter) at the proximal femur (total hip and femoral neck region) and at the distal forearm (total distal forearm, ultradistal-, and mid-subregion of the radius) was measured at baseline and at yearly intervals in a 4-yr follow-up period using dual x-ray absorptiometry with a Hologic QDR 1000+ device (software version 5.71Q; Hologic, Inc., Bedford, MA). The CV for phantom measurements was less than 1% and ranged in vivo between 1.0% and 2.4%, as calculated from duplicate measurements in all study subjects.
Body composition and grip strength
The body composition, including fat and lean mass percentage, was estimated at baseline using bioelectrical impedance analysis (Bodystat1500, Bodystat Limited, Isle of Man, British Isles; Ref. 22). Grip strength at the dominant hand was measured using an adjustable handheld standard grip device (Smedley type hand dynamometer, Baseline; Smith & Nephew Rolyan Inc., Germantown, WI). For this muscle strength assessment at baseline, the maximum value of two consecutive measurements was used for further analysis and expressed in kilograms. The CV was 9.0% for grip strength, as calculated from duplicate measurements in all elderly study subjects.
Determination of CYP19 (TTTA)n-repeat length
Genomic DNA was extracted from EDTA-treated blood using a commercial kit (QIAGEN Midi Kit; QIAGEN, Inc., Valencia, CA). The CYP19 (TTTA)n-repeat length was assessed by fragment analysis of the PCR product using primers published by Haiman et al. (23). The forward primer was 5'-labeled with a fluorescent dye (hexachlorofluoresceine) for automated fragment analysis on an ABI Prism 310 sequencer (ABI Prism, PE Applied Biosystems, Foster City, CA) using GeneScan 500 size standard, GeneScan and Genotyper Analysis software (PE Applied Biosystems). To confirm repeat length, homozygotic representatives of the different observed allele lengths (7, 8, 9, 10, 11, 12 and 13) were sequenced.
Statistical analysis
Data are expressed as means ± SD. Individual annual rates of change of BMD were based on regression coefficients from individualized linear models, fitting the available data points using least-square estimation. ANOVA were performed to compare sex steroid levels, BMD, biochemical markers of bone turnover, and %BMD change between CYP19 genotype groups according to the presence or absence of the shortest allele length. To evaluate a gene-dosage effect for a varying CYP19 allelic repeat-length and to study the independent contribution of the CYP19 genotype and circulating hormone levels in the determination of %BMD change, regression models were fitted. In these regression models, the CYP19 genotype was evaluated as a dichotomous variable (allele carriers vs. noncarriers). Regression models were screened for multicollinearity according to a procedure based on variance inflation factors. Potential interactions of CYP19 allelic repeat-length with sex steroids were evaluated by including interaction terms between CYP19 genotype and sex steroids in the models predicting %BMD change. To compare the frequency of the CYP19 genotypes in subjects with and without a positive (family) history for fractures, the Pearson’s 2 test was used. Spearman correlation coefficients were calculated to check for an association between sex steroid levels and fracture data. The level indicating statistical significance was chosen as 
= 0.05. All statistical analyses were performed using SPSS software (version 10.0, SPSS, Inc., Chicago, IL).
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Results |
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We observed 7 different alleles of CYP19 varying between 7 (TTTA)7 and 13 (TTTA)13-repeats. The allelic frequency distribution is given in Table 1
. The allelic variant consisting of (TTTA)7-repeats was the most frequently observed in the study population of healthy elderly men. Subjects were classified in three genotype groups according to the presence or absence of the shortest allele length. The first group (presented as 7/7) consists of 62 subjects with 7 (TTTA)7-repeats on both alleles; the second group (presented as 7/X) consists of 98 heterozygotic subjects with only one (TTTA)7-allele; and the third group (presented as X/X) includes men whose number of (TTTA)n-repeats exceeds 7 on both alleles (n = 54).
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for the total group and according to CYP19 genotype group. Between the three considered genotype groups, no difference in age, in any of the anthropometric parameters, in grip strength, or in BMD at any of the assessed skeletal sites was observed in this group of elderly men (Table 2).
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shows the baseline serum levels of sex steroids in the study population. No significant role for the CYP19 (TTTA)n-repeat length was established in the determination of circulating levels of BioE2, BioT, SHBG, T/E2 ratio, or serum LH levels (P > 0.05; Table 3). BioE2 levels ranged between 0.44 ng/dl (16.1 pmol/liter) and 2.71 ng/dl (99.4 pmol/liter); in this age group, there was no association between BioE2 levels and age. In a multiple linear regression model including age, T, fat mass, and the CYP19 genotype, both fat mass and T contributed independently to the determination of BioE2 (P < 0.01; data not shown).
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shows regression models of BMD at different skeletal sites with age, fat mass, the CYP19 genotype, BioE2, and BioT as predicting variables. No relationship between prevalent BMD and the CYP19 genotype was observed at any of the assessed skeletal sites. BioE2 was associated with baseline BMD at the distal forearm and the total hip (P < 0.01); BioT was only significantly associated with BMD at the total hip (P < 0.05). Age and fat mass were additional significant predictors of baseline BMD in these models.
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The CYP19 genotype did not significantly contribute to the variance in any of the biochemical markers of bone formation [serum bone-specific alkaline phosphatase (mean ± SD, 13.0 ± 5.5 µg/liter); serum intact osteocalcin (16.2 ± 8.6 µg/liter or 2.8 ± 1.5 nmol/liter); serum C-terminal type I procollagen peptide (145 ± 50 µg/liter), bone resorption S-CTX (386 ± 198 pg/ml); U-CTX (324 ± 225 µg/mmol Cr); U-DPD (5.81 ± 1.67 nmol/mmol Cr)], or in PTH (45.0 ± 17.4 pg/ml or 4.5 ± 1.7 pmol/liter) or 25-hydroxyvitamin D (23.4 ± 9.4 ng/ml or 58.4 ± 23.4 nmol/liter) levels with or without additional adjustment for age and fat mass (data not shown). BioE2 levels were associated with biochemical markers of bone resorption [Pearson correlation coefficient (r) of -0.16 for U-CTX and S-CTX; P < 0.05].
Longitudinal data
The annual percentage change of BMD during a mean of 3.4 yr of follow-up period (median follow-up, 4 yr) was -0.39% (95% CI, -0.56, -0.22) at the total hip, -0.04% (95% CI, -0.29, 0.21) at the femoral neck, -0.37% (95% CI, -0.45, -0.29) at the total distal forearm, -0.44% (95% CI, -0.52, -0.35) at the mid-subregion, and -0.38% (95% CI, -0.54, -0.23) at the ultradistal region of the forearm.
BioE2 levels were consistently associated with %BMD change with correlation coefficients (r) of 0.18 (P < 0.01) for the total distal forearm, 0.14 (P < 0.05) for the mid-subregion, 0.17 (P < 0.05) for the ultradistal subregion of the distal forearm, 0.19 (P < 0.01) for the total hip, and 0.16 (P < 0.05) for the femoral neck. An increased bone loss was associated with lower levels of BioE2. BioT was not consistently associated with %BMD changes.
Moreover, the CYP19 genotype was significantly associated with %BMD change at the distal forearm. A greater bone loss was observed in subjects carrying the shortest (TTTA)7-repeat allelic variant compared with noncarriers at the total distal forearm region (P = 0.02) and at the mid-subregion of the distal forearm (P = 0.02; Fig. 1). The impact of genotype on %BMD change at the distal forearm was substantial, with mean differences in %BMD change between homozygotic subjects for the shortest (TTTA)7-repeat length and those subjects for whom both alleles were of a longer (TTTA)n-repeat length ranging from 55.8–60.2% depending on the assessed skeletal site. A similar impact of the CYP19 genotype on %BMD change at the ultradistal subregion of the distal forearm or at the proximal femur was not observed. However, the highest bone loss at the total hip and at the femoral neck was again observed in homozygotic carriers of the shortest allele length, but the differences between genotype groups did not approach statistical significance (P = 0.23 and P = 0.51, for the total hip and femoral neck, respectively); moreover, no allele dosage effect of the CYP19 gene variants was evident for the latter skeletal sites (Fig. 2).
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In multivariate models of %BMD change considering age, fat mass, PTH, and grip strength as covariates, BioE2 emerged as a consistent predictor of %BMD change at the different assessed skeletal sites (P < 0.05; Table 5); the CYP19 genotype contributed additionally to %BMD change at the total distal forearm and at the mid-subregion of the distal arm (P < 0.01; Table 5). A similar association between the CYP19 genotype and %BMD change was not apparent at the total hip or at the femoral neck (Table 5). No significant interaction in the determination of %BMD change was obvious between the CYP19 genotype and BioE2 levels. An estimation of the size of the effect of the CYP19 genotype showed that bone loss increased by 0.25% and 0.27% per year per copy of the shortest allele length at the total distal forearm and at the mid-subregion of the distal arm, respectively (Table 5). As to the impact of BioE2 on %BMD change, bone loss increased by 0.29%/yr to 0.66%/yr per nanogram per deciliter decrease in BioE2 levels depending on the assessed skeletal site (Table 5). When BioT was included in the multivariate model, BioE2 remained a significant independent determinant of %BMD change, whereas there was no significant contribution of BioT.
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A total of 18 participants reported an event of a clinical vertebral, hip, and/or wrist fracture that had occurred between age 50 yr and the last study visit. Between carriers and noncarriers of the CYP19 (TTTA)7-allele, a significant difference in the number of subjects with a positive fracture history was observed with an increased number of fracture cases in the group of (TTTA)7-carriers (11.9%) vs. noncarriers (1.9%) (Pearson’s 2 test = 4.03; df = 1; P = 0.05).
Compared with subjects without a family history of fractures, participants with a positive family history for fracture (n = 24) were more frequent carriers of the CYP19 (TTTA)7-allele [71.7% and 96.8% CYP19 (TTTA)7-allele carriers in subjects without and with a positive family history, respectively; Pearson’s 2 test = 6.48; df = 1; P = 0.01].
No correlation was observed between the reported clinical fractures and circulating levels of BioE2 in the study group whether BioE2 was considered as a continuous variable or in quartile analysis.
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Discussion |
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The observed consistent association between serum BioE2 levels and prevalent BMD assessed both at the forearm and at the proximal femur is in agreement with several previous reports in aging men (for review, see Ref. 11). However, baseline associations between BioE2 and BMD do not allow the establishment of a role for BioE2 in age-associated bone loss. In this context, we found only marginal associations between biochemical markers of bone resorption and prevalent BioE2 in our study population, consistent with our previously published analysis on biochemical markers of bone turnover in a larger subset of the same study population (19). Nevertheless, in other studies in elderly men, an inverse association between biochemical markers of bone turnover and BioE2 was observed (24, 25). Few studies have prospectively assessed BMD changes in elderly men; a single report by Khosla et al. (8) reported an association between BioE2 and BMD changes at the mid-region of the forearm in men aged over 60 yr. The present study, in a sizeable and homogenous group of ambulatory men over age 70 yr at initiation of the study, allows us to confirm and extend the latter finding by revealing a consistent association between BioE2 and %BMD changes at different subregions of the forearm as well as at the proximal femur. Khosla et al. (8) described a threshold effect for BioE2 on bone loss; such a threshold phenomenon was not obvious in our study population (data not shown).
Expression of estrogen activity in men necessarily involves the aromatase enzyme; we therefore explored the hypothesis that the functional CYP19 (TTTA)n-repeat polymorphism may quantitatively modulate estrogenic activity on bone metabolism. First, we explored a relationship between the CYP19 genotype and circulating BioE2 levels but failed to find an association between the genotype and BioE2, with BioT or LH levels, or with the T/E2 ratio. These negative findings do not definitely rule out that the CYP19 (TTTA)n-repeat polymorphism may affect production of circulating E2, which originates for a large part from aromatization of T in fat tissues. Indeed, one cannot rule out that some of these effects may be masked by age-associated alterations in neuroendocrine regulation of sex steroid production in older men (26, 27, 28). In any case, our study allows us to conclude that the CYP19 (TTTA)n-repeat polymorphism is unlikely to explain a substantial proportion of circulating levels of serum BioE2 in elderly men, because power calculations indicate that our study has 80% power to detect a 10% difference in hormone levels. An association between the CYP19 (TTTA)n-repeat polymorphism and circulating E2 levels was previously reported in women (23); a similar association in elderly men was recently reported in abstract form (29).
We then looked for an association between the CYP19 (TTTA)n-repeat polymorphism and bone mineral metabolism. Whereas there was no correlation between the CYP19 genotype and prevalent BMD, the CYP19 genotype was associated with %BMD change at the distal forearm in both univariate and multivariate analysis. Interestingly, in multivariate models, the CYP19 genotype was found to affect %BMD change independently of circulating BioE2 levels, thus suggesting a local effect of the CYP19 genotype at the bone tissue level. Hence, estrogen activity at the site of action in bone may not be correctly reflected in the measured circulating BioE2 levels (30). In this context, it is interesting to note that a tissue-specific regulation of aromatase enzyme expression has been reported (30). Moreover, a previous study focusing on modulating effects of CYP19 polymorphisms on breast cancer risk observed strong linkage disequilibrium between the (TTTA)n-repeat polymorphism and a single nucleotide C-T substitution in exon 10 of CYP19 (17). The authors observed an association of the TT genotype with higher aromatase mRNA levels, with an increased use of an alternative promotor as demonstrated by in vitro analyses on breast cancer tissue; moreover, an association between the TT genotype and tumor size was observed (17). In view of the association of the TT genotype and a longer CYP19 (TTTA)n-repeat length (17), one can hypothesize a functional effect for the CYP19 (TTTA)n-repeat polymorphism. A longer CYP19 (TTTA)n-repeat length would then be associated with a high aromatase activity phenotype and less pronounced age-related bone loss. Despite the in vitro data on a potential functional impact of the assessed CYP19 gene polymorphism, the possibility that the polymorphism is in linkage disequilibrium with other not yet identified gene(s) remains.
There has been a previous report of association between the CYP19 (TTTA)n-repeat polymorphism and cross-sectional BMD at the spine in postmenopausal women (18); in a recent abstract, higher rates of bone loss at the spine in elderly men with a short-repeat CYP19 genotype have been reported (29). In our study population, we obtained data on clinical fractures (at the wrist, hip, and vertebrae) after the age of 50 yr as well as data on the occurrence of these fractures in their first-degree relatives. Only 8.4% of our subjects had a positive fracture history. There was no significant association between BioE2 levels and clinical fractures in our study population. In the Rancho Bernardo study, a relationship between BioE2 levels and radiologically defined vertebral fractures in elderly men was observed (31). However, the CYP19 genotype was associated with clinical fracture history both in our study subjects and in their first-degree relatives. Masi et al. (18) have reported a higher incidence of radiologically assessed vertebral fractures in postmenopausal women with shorter CYP19 (TTTA)n-repeat alleles.
As to the limitations of our study, an association study does not prove causality, and obviously there are still missing links to be explored before having a full picture of the role of the CYP19 (TTTA)n-repeat polymorphism in the regulation of bone metabolism in elderly men. In this context, one can only hypothesize that the failure to observe an association between the CYP19 (TTTA)n-repeat polymorphism and biochemical indices of bone turnover may be due to a lower precision of the latter markers. The lack of association with bone changes at the hip might be due to a lower precision of the latter BMD assessment at the hip compared with the forearm and/or possibly to the fact that the hip is a weight-bearing site. Furthermore, it should be emphasized that our results apply specifically to community-dwelling elderly men over age 70 yr. Despite the low incidence of clinical fractures and the fact that data on radiologically assessed vertebral deformities are not available, the strength of the present study is that beside a complete data set on markers of bone density and biochemical indices of bone turnover, longitudinal BMD data over a period of 4 yr are available in a well defined group of healthy elderly men.
In summary, the present study adds further evidence to the view that BioE2 is a determinant of bone density changes in elderly men and, furthermore, provides an indication that the aromatase enzyme may exert a direct modulatory action on bone metabolism at the tissue level in elderly men.
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Acknowledgments |
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Footnotes |
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I.V.P. and S.G. contributed equally to this manuscript.
Abbreviations: Bio, Bioavailable; BMD, bone mineral density; %BMD, percentage BMD; Cr, creatinine; CV, coefficient(s) of variation; E2, estradiol; S-CTX, serum C-terminal telopeptides of type I collagen; T, testosterone; U-CTX, urinary C-terminal telopeptides of type I collagen; U-DPD, urinary deoxypyridinoline; X/X, noncarriers of the (TTTA)7-allele; 7/X, heterozygotic carriers of the (TTTA)7-allele; 7/7, homozygotic carriers of the (TTTA)7-allele.
Received October 30, 2002.
Accepted March 16, 2003.
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1 Sp1 polymorphism, bone density and upper limb muscle strength in community-dwelling elderly men. Osteoporos Int 10:895–901
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L. Gennari, L. Masi, D. Merlotti, L. Picariello, A. Falchetti, A. Tanini, C. Mavilia, F. Del Monte, S. Gonnelli, B. Lucani, et al. A Polymorphic CYP19 TTTA Repeat Influences Aromatase Activity and Estrogen Levels in Elderly Men: Effects on Bone Metabolism J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2803 - 2810. [Abstract] [Full Text] [PDF]
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S. Khosla, B. L. Riggs, E. J. Atkinson, A. L. Oberg, C. Mavilia, F. Del Monte, L. J. Melton III, and M. L. Brandi Relationship of Estrogen Receptor Genotypes to Bone Mineral Density and to Rates of Bone Loss in Men J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1808 - 1816. [Abstract] [Full Text] [PDF]
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