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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 4949-4953
Copyright © 2004 by The Endocrine Society

Perturbed Sex Steroid Status in Men with Idiopathic Osteoporosis and Their Sons

I. Van Pottelbergh, S. Goemaere, H. Zmierczak and J. M. Kaufman

Department of Endocrinology (I.V.P., J.M.K.) and Unit for Osteoporosis and Metabolic Bone Diseases (I.V.P., S.G., H.Z., J.M.K.), Ghent University Hospital, B-9000 Ghent, Belgium

Address all correspondence and requests for reprints to: Dr. Inge Van Pottelbergh, Department of Endocrinology (9K12IE), Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: inge.vanpottelbergh{at}ugent.be.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We reported previously that a gender-specific defect of acquisition of lumbar bone mass plays an important role in the pathogenesis of male idiopathic osteoporosis (IO) and that there is a strong heritability of this maturational defect, which is particularly manifest in sons of men with IO. A hypothetical role of an altered sex steroid status and/or of a (TTTA)n- repeat polymorphism of the aromatase (CYP19) gene in male IO remains to be established. We evaluated bone mineral density (BMD) at the lumbar spine and femoral neck in 64 male IO probands (selected on the basis of a z-score of –2 or less), 21 of their sons, 41 of their brothers, and 126 healthy, age-matched controls. Serum testosterone (T), estradiol (E2), and SHBG levels were measured by immunoassays. Free T (FT) and free E2 (FE2) levels were calculated from total T, E2, SHBG, and albumin concentrations using a previously validated equation. Probands, sons, and brothers had lower body weight than age-matched controls, with mean differences of 5.0, 4.6, and 4.0 kg, respectively. In probands, sons, and brothers, SHBG levels were higher compared with controls. Significantly lower FE2 levels were observed in probands and sons compared with their respective controls (P < 0.05 and P < 0.01, respectively). The brothers had nonsignificantly lower FE2 levels compared with their controls. In the total group of sons with significantly lower FE2 levels, tertile analysis according to lumbar spine BMD showed that only in the subgroup of sons belonging to the lowest tertile both FE2 and FT were decreased compared with their controls. The differences in FE2 levels in IO probands and their sons remained significant after adjustment for body mass index (BMI), even though in multivariate analyses BMI was a major determinant of BMD. The frequency distribution of the CYP19 gene (TTTA)n- repeat length (determined by fragment analysis, GeneScan) was not different between men with IO and their controls. In conclusion, the finding of a relative FE2 deficit in both men with IO as well as their affected sons, even after adjustment for BMI, suggests that estrogen-related perturbances may be involved in the pathogenesis of the deficient acquisition of peak bone mass in male IO.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
FAMILY STUDIES HAVE demonstrated the existence of a bone deficit in first degree relatives of men with idiopathic osteoporosis (IO) (1, 2). In our study this bone deficit was particularly obvious in the younger adult generation of sons, without evidence for major alterations in bone turnover (2). This indicates a predominant role for a genetically determined deficient acquisition of bone mass in the pathogenesis of IO in men. The involved genetic factor appears to adversely affect the attainment of peak bone mass and size, with preferential involvement of the spine. This may suggest that a particular stage of skeletal maturation is perturbated, e.g. late puberty, which is known to be of more critical importance for full development of the axial skeleton. However, the possibility that alterations in sex steroid exposure are involved in the deficient acquisition of bone mass and size in male IO is largely unexplored.

Several lines of evidence suggest a major role for estrogens in the physiology of both the growing and the adult male skeleton. In healthy young adult men, Khosla et al. (3) found a positive correlation between circulating bioavailable estradiol (E2) levels and the amount of bone mass gained over a period of 4 yr. Furthermore, an essential role of estrogens in bone maturation was illustrated by the osteopenia and failure of epiphyseal growth plate fusion in an estrogen receptor {alpha}-negative man and in male patients with complete aromatase deficiency (4, 5, 6). These observations thus imply that adequate aromatase activity is needed for full expression of testosterone (T) effects on bone maturation in men. Recent data suggest that a tetranucleotide (TTTA)n- repeat polymorphism of the aromatase (CYP19) gene, which encodes the aromatase enzyme that converts androgens into estrogens, contributes to the degree of bone loss in elderly men (7, 8).

However, despite the burden of data showing a more consistent association between free or bioavailable E2 and prevalent bone mineral density (BMD) compared with free or bioavailable T (for review, see Ref.9), low BMD values were observed in patients with the androgen insensitivity syndrome despite the presence of high circulating E2 levels (10).

In a group of IO probands, their male siblings, as well as their sons, who belonged to an age group not yet undergoing age-related bone loss, we assessed the sex steroid status in comparison with that in healthy, matched controls. Furthermore, we compared the CYP19 genotype between men with IO and their age-matched controls.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Sixty-four male study subjects were diagnosed with IO in our center using the following inclusion criteria: age 65 yr or less at presentation, BMD z-score of –2.0 or less at the lumbar spine (LS) or proximal femur. Moreover, extensive clinical and laboratory investigation did not reveal any endocrine abnormalities. A total of 21 sons and 41 brothers agreed to participate. For each proband, his son(s), and his brother(s), we recruited gender-matched controls among hospital employees and students. Control subjects were matched for age (±2 yr). All controls were healthy volunteers with no family history of osteoporotic fractures. Detailed inclusion and exclusion criteria have been previously reported (2). From all participants written informed consent was obtained for the study, which was approved by the ethical committee of Ghent University Hospital. Standing height was measured using a wall-mounted Holtain stadiometer (Holtain Ltd., Crymych, UK). Body weight was measured in light indoor clothing without shoes. Body mass index (BMI) was calculated as weight (kilograms) divided by the square of the height (meters).

BMD

Areal BMD (aBMD; grams per square centimeter) at the LS [reported for the third lumbar vertebra (L3)] and at the femoral neck region (FN) was measured using dual x-ray absorptiometry with a QDR 2000 device (software version 7.20, Hologic, Inc., Bedford, MA). Differences from the mean BMD for an age- and gender-matched reference population expressed as units of SD below or above the population mean (z-scores) for aBMD were calculated using the age- and gender-matched controls provided by the NHANES III study group for the hip (11) and by the manufacturer for the LS. The vertebral body volume (VV) of L3 was estimated using the projected area of L3 obtained by antero-posterior dual x-ray absorptiometry and assuming the vertebral body resembles a cube [VV = (antero-posterior area)3/2] (12, 13). Volumetric BMD (vBMD) at the L3 level was estimated as total bone mineral content divided by VV. FN volume was calculated by assuming a cylindrical shape: [FN volume = {pi} x (W/2)2 x h], with W being the average FN width obtained by dividing FN area by the height (h) of the scanned region (14). FN vBMD was estimated as FN bone mineral content divided by FN volume. The coefficient of variation (percentage) for phantom measurements was less than 1%.

Laboratory methods

Venous blood was obtained between 0800 and 1000 h after overnight fasting in IO probands, their sons, their male siblings, and their respective controls. Samples were stored at –80 C until analysis. Commercial immunoassay kits were used to determine serum levels of total T and SHBG (Orion Diagnostica, Espoo, Finland). Serum E2 was assayed using a commercial immunoassay kit (Clinical Assay, DiaSorin s.r.l., Saluggia, Italy); to increase the assay’s sensitivity, a modified protocol, with doubling of the amount of serum, 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 bioavailable fractions of T (FT) and E2 (FE2) were calculated from serum total T, E2, SHBG, and albumin concentrations using previously validated equations (15, 16). The intra- and interassay coefficients of variation for all assays were less than 12%.

Determination of CYP19 (TTTA)n- repeat length

Genomic DNA was extracted from EDTA-treated blood using a commercial kit (Midi Kit, Qiagen, Valencia, CA). The CYP19 (TTTA)n- repeat length was assessed in IO probands and their matched controls by fragment analysis of the PCR product using primers described by Haiman et al. (17). The forward primer was 5'-labeled with a fluorescent dye (hexachlorofluorescein) for automated fragment analysis on an ABI PRISM 310 sequencer (PerkinElmer, Applied Biosystems, Foster City, CA) using GeneScan 500 size standard, GeneScan, and Genotyper analysis software (Applied Biosystems). To confirm the repeat length, homozygotic representatives of the different observed allele lengths (7, 8, 10, 11, 12) were sequenced.

Statistical analysis

Data are expressed as the mean ± SD. Age, anthropometric data, BMD, and serum levels of T, FT, E2, FE2, and SHBG levels were compared by independent sample t testing between subjects and controls. To meet the required model assumptions, hormone levels were transformed (natural logarithmic) in these analyses if necessary. Additional ANOVAs were performed to take into account potential confounders such as anthropometrics. Potential interactions of BMI and SHBG on bone density were examined by two-factor ANOVA. To compare the relative contributions of the differences in T, FT, E2, FE2, SHBG, and BMI in the determination of the observed differences in BMD between IO probands and controls, we performed a multiple regression analyses. Power calculations proved that our sample was able to detect 20% differences in average SHBG levels with 92%, 78%, and 65% statistical powers in probands, brothers, and sons, respectively. To compare the frequency of the CYP19 genotypes in men with osteoporosis and their age-matched controls, Pearson’s {chi}2 test was used. The level indicating statistical significance was chosen as {alpha} = 0.05 (two-tailed). All statistical analyses were performed using SPSS software (version 10.0, SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical characteristics and BMD at different skeletal sites in IO probands, their male siblings, their offspring, as well as the respective controls are summarized in Table 1Go. In both IO probands as well as the group of sons and brothers, a lower body weight was observed compared with age-matched controls, with mean differences of 5.0, 4.6, and 4.0 kg, respectively. This difference in body weight was statistically significant only in the group of probands (P ≤ 0.01). Probands and their sons had a shorter stature compared with controls, with nonsignificant differences of 1.7 and 2.5 cm, respectively. A lower aBMD at both L3 and the FN was measured in the group of IO probands compared with age-matched controls, in accordance with the inclusion criteria; a similar decrease in aBMD was observed in sons as well as brothers (Table 1Go). When we consider bone size at L3 and the FN, only the bone volume at the spine was significantly reduced compared with control values, with a mean difference of 10% in probands and 12% in their sons (Table 1Go). vBMD at both the spine (L3) and the FN was reduced in IO probands, their sons, as well as their brothers (Table 1Go).


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  		TABLE 1. Clinical characteristics of osteoporotic probands (n = 64), their sons (n = 21), and brothers (n = 41) vs. age-matched controls

 
All subjects were within the normal range of hormonal parameters. Mean total T and total E2 did not differ between IO probands, their male offspring, and their male siblings and the respective controls (Table 2Go). In the group of men with IO, circulating SHBG levels were higher compared with levels in age-matched controls (mean difference of 15%; P < 0.05; Table 2Go). We observed no significant interaction of SHBG and BMI on bone mass.


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  		TABLE 2. Hormonal data in osteoporotic probands (n = 64), their sons (n = 21), and brothers (n = 41) vs. age-matched controls

 
Furthermore, men with IO had lower serum FE2 compared with age-matched controls, with a 12% difference in mean levels (P = 0.05; Table 2Go and Fig. 1Go). Similarly, both sons and brothers of men with IO had lower circulating FE2 and higher SHBG levels, with only the difference in FE2 levels between sons and controls reaching statistical significance (P < 0.01; Table 2Go and Fig. 1Go). Adjustment for BMI did not significantly alter our observation of a significantly decreased FE2 status in the group of IO probands and their sons (Fig. 1Go). In both IO probands as well as their sons, lower FT levels were observed compared with controls (8% and 16%, respectively; nonsignificant; Table 2Go).



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  		FIG. 1. Calculated FE2 levels (mean ± SEM) in probands (n = 64), sons (n = 21), and brothers (n = 41) vs. age-matched control groups. *, According to analysis of covariance with BMI as covariate for comparison with respective controls; NS, not significant.

 
To explore the relationship among low BMD, hormonal levels, and BMI in the total group of sons with significantly lower FE2 levels, we performed a tertile analysis based on their spinal z-score (P33, –2.67 SD; P66, –1.69 SD). In the lowest tertile of sons, not only decreased circulating FE2, but also lower FT levels, were observed (Figs. 2Go and 3Go). Adjustment for BMI did not significantly alter these observations. Circulating levels of FE2 and FT were similar in the other tertile groups of sons compared with their controls (Figs. 2Go and 3Go). Furthermore, we compared levels of SHBG and sex steroids, age, and anthropometrics among the three subgroups of controls; no differences were detected (results not shown).



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  		FIG. 2. Calculated FE2 levels (mean± SEM) in sons of men with IO divided into tertile groups according to LS z-score vs. age-matched control groups. *, According to analysis of covariance with BMI as covariate for comparison with respective controls; NS, not significant.

 


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  		FIG. 3. Calculated FT levels (mean± SEM) in sons of men with IO divided into tertile groups according to LS z-score vs. age-matched control groups. *, According to analysis of covariance with BMI as covariate for comparison with respective controls; NS, not significant.

 
In multiple regression models including either the difference between probands and matched controls for BMI, SHBG, T, and E or for BMI, FT, and FE, BMI emerged as the only independent determinant of low BMD in IO probands vs. controls (P < 0.05; results not shown).

We observed five different alleles of the CYP19 genotype; the allelic frequency distribution is given in Table 3Go. No difference in the frequency distribution of the CYP19 genotype was observed between IO probands and their controls (by Pearson’s test, {chi}2 = 1.26; df = 2; not significant). We did not find a significant association among the CYP19 genotype, any of the sex steroids, and the ratio of (F)T and (F)E2 in the group of either probands or controls.


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  		TABLE 3. CYP19 allelic frequency distribution in osteoporotic probands (n = 64) and controls (n = 64)

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The apparent relative FE2 deficit in men with IO as well as in their affected sons suggests that a hormonal factor might be involved in the genetically determined deficient acquisition of bone mass and size in male IO. Furthermore, the study indicates that the observed hormonal alterations are closely related to body composition and are not associated with the tetranucleotide (TTTA)n- repeat polymorphism of the CYP19 gene.

In probands with IO, lower mean (F)E2 levels were observed compared with those in age- and sex-matched controls. Adjustment for BMI did not substantially change the significance of the observed associations, even though in a multivariate model also including T, BMI emerged as the most important determinant of aBMD. In accordance with our findings, Kurland et al. (18) reported lower mean (F)E2 levels in a group of male IO probands, recruited by applying the same criteria as in our study vs. a control group matched for age and ethnicity. Moreover, decreased circulating levels of E2 were reported in two smaller case-control studies in men with idiopathic low aBMD and/or osteoporotic fractures, including 12 and 31 men, respectively (19, 20). However, the latter also included elderly subjects, in whom age-associated bone loss may have contributed substantially (20). Indeed, lower E2 levels have been shown to be associated with higher rates of bone loss in elderly men (2, 3, 21). In previous studies, we and others observed a high prevalence of low BMD, both areal and volumetric, in first degree relatives of men with IO (1, 2). In the present study, mean FE2 status was also lower in sons of probands with IO compared with matched controls. This is, to the best of our knowledge, the first published report of altered sex steroid status in male first degree relatives of men with IO. Moreover, in the group of male off-spring, a dose dependency between BMD and (F)E2 status was obvious (Fig. 2Go). However, similar alterations could not be demonstrated in the less severely affected group of brothers; possibly such an effect may have been obscured in the group of brothers whose age range was broader (i.e. 20–75 yr) than that of the sons (i.e. 19–38 yr).

BMI is positively associated with BMD, and fat tissue is the main source of circulating E2 in men (22). Furthermore, BMI is also a strong determinant of serum SHBG (23) and thus, indirectly, of free or bioavailable E2. Conversely, in vitro data suggest that E2 regulates adipose tissue mass by increasing the proliferation of preadipocytes and the size of mature adipocytes (24). Obviously, there is a strong interrelationship among free/bioavailable sex hormone levels, fat mass, and skeletal status. In our study a lower body weight was measured in men with IO compared with age-matched controls, with similar differences in weight measured in first degree relatives. An intermediating role of body composition in the observed association between alterations in sex steroid status and BMD seems plausible. Moreover, in multiple regression analysis, BMI, rather than sex steroid status, was the most consistent determinant of the difference in BMD between IO probands and age-matched controls. In agreement with our finding, a low BMI or body weight was reported in two previous studies of men with either low BMD or vertebral fracture(s) (19, 25). More recently, Kurland et al. (18) also identified BMI as one of the most important variables contributing to the variance in BMD among male IO probands.

In our group of 64 men with IO, SHBG levels were significantly higher in male IO probands compared with matched controls; in the group of sons and brothers a similar (nonsignificant) increase in circulating SHBG levels was observed. Several previous studies reported similar observations in rather mixed groups of men with low bone mass and/or fractures (19, 20, 25, 26). The finding of increased SHBG levels in the more lean men with idiopathic osteoporosis and their male relatives is in line with the known negative correlation between SHBG concentrations and body weight or BMI (23). The higher SHBG levels result in lower concentrations of non-SHBG-bound fractions of T and E2, which are believed to be more readily available for biological action. In this context, we found only in the affected sons, not in IO probands, that both FE2 and FT levels were lower compared with control values. The apparent deficit in both FE2 and FT was still significant after correction for BMI. Kurland et al. (18) also found decreases in both bio-E2 and bio-T in men with IO after correcting for BMI. Previously, there have been reports of a decreased free androgen index (19, 20, 26), which, however, is a controversial measure of the biologically active fraction of T (15).

In our subjects with male IO and their sons, not only vBMD, but also bone size, are reduced in controls (2). Interestingly, estrogen deficiency caused by aromatase deficiency in aromatase knockout (ARKO) mice results in changes in bone growth, bone mass, and body composition (27). Moreover, the alterations in long bone growth of ARKO mice are sexually dimorphic, resulting in a smaller bone length in male ARKO compared with female ARKO mice (28). In our study both E2 and BMI were lower in men with IO compared with controls, but these differences were not explained by a different CYP19 genotype distribution between the groups. Whereas the CYP19 genotype does not appear to underlie the differences between probands with IO and controls, the failure to find an association between the CYP19 genotype and circulating levels of sex steroids does not exclude an effect of the CYP19 genotype on local aromatization activity at the tissue level and a role in the normal variation of bone mass in the male population (7).

Notwithstanding its limitation of a cross-sectional design and the only imperfect reflection of body composition by BMI (29), the present study provides a complete dataset for sex steroids in a group of 64 men with IO recruited by applying stringent BMD criteria and in 62 male, first degree relatives in a case-control study design.

Despite the likely existence of heterogeneity in the pathophysiology of IO, the results of the present study support the view that the maturational defect in bone acquisition observed in men with IO and their sons is associated with an estrogen-related disturbance. The present report warrants additional studies of the relationship among sex steroid status, body composition, and skeletal development in males.


   Acknowledgments
 
We are grateful to I. Bocquaert, M. Daems, C. De Ganck, R. De Muynck, H. Myny, and K. Toye for expert technical help; to Drs. A. H. Batens, P. Moerman, E. Dhondt, F. Raeman, X. Janssens, and C. Ackerman for their screening and referral of men with idiopathic osteoporosis; to Prof. D. Debacquer for excellent biostatistical aid; and to F. Schoonjans for providing Medcalc software for graphical designs.


   Footnotes
 
This work was supported by the Fund for Scientific Research (FWO Vlaanderen Grant G0058-97). Part of this work was supported by the Network in Europe on Male Osteoporosis funded by the European Commission under Contract QL6-CT-2002-00491. I.V.P. is a research fellow for the Fund for Scientific Research, 1998–2002 (FWO Vlaanderen).

Part of this work was presented at the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA, June 19–22, 2003.

Abbreviations: aBMD, Areal bone mineral density; ARKO, aromatase knockout; BMD, bone mineral density; BMI, body mass index; E2, estradiol; FE2, free estradiol; FN, femoral neck; FT, free testosterone; IO, idiopathic osteoporosis; L3, third lumbar vertebra; T, testosterone; vBMD, volumetric bone mineral density; VV, vertebral body volume.

Received December 3, 2003.

Accepted April 1, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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M. C M Bunck, A. W F T Toorians, P. Lips, and L. J G Gooren
The effects of the aromatase inhibitor anastrozole on bone metabolism and cardiovascular risk indices in ovariectomized, androgen-treated female-to-male transsexuals.
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P. Szulc
Low Free 17{beta}-estradiol Level in Men with Idiopathic Osteoporosis and Their Sons with Low Bone Mineral Density
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E. Seeman and G. J. Strewler
Clinical and Basic Research Papers - September and October 2004 Selections
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