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Hormonal and Biochemical Determinants of Trabecular Microstructure at the Ultradistal Radius in Women and Men

Endocrine Research Unit, Division of Endocrinology and Metabolism, Department of Internal Medicine (S.K., B.L.R.), Divisions of Epidemiology (L.J.M.) and Biostatistics (S.J.A., A.L.O.), Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Mayo Clinic, Endocrine Research Unit, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: khosla.sundeep{at}mayo.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Using high-resolution three-dimensional peripheral quantitative computed tomography (3D-pQCT) imaging, we recently described sex and age effects on bone microstructure at the ultradistal radius in men and women. Although bone volume/tissue volume decreased with age in both sexes, changes in trabecular number (TbN) and thickness (TbTh) in men were complex, with evidence for conversion of thick trabeculae into more numerous, thinner trabeculae in young men.

Objective: Our objective was to define the relationship between hormonal and bone turnover variables and trabecular microstructure at the ultradistal radius.

Design, Setting, and Participants: We conducted a population-based, cross-sectional study in the general community that included 205 women and 269 men, aged 21–97 yr.

Main Outcome Measures: We measured correlation of bone volume/tissue volume, TbN, TbTh, and trabecular separation with hormonal and bone turnover variables.

Results: In young men (20–39 yr), TbTh and TbN were associated with serum IGF-I levels (r = 0.31, P < 0.05 and r = –0.35, P < 0.01, respectively). No associations were found between sex steroid levels (bioavailable estradiol or testosterone) or biochemical markers of bone turnover and trabecular parameters in young men or women. By contrast, in elderly men and women (>60 yr), sex steroids were the most consistently associated with trabecular microstructure, and bone turnover markers were variably associated with these parameters.

Conclusions: In young men, the apparent conversion of thick trabeculae into more numerous, thinner trabeculae is most closely associated with declining IGF-I levels. By contrast, sex steroids are the major hormonal determinants of trabecular microstructure in elderly men and women.

	Introduction

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THERE ARE EXTENSIVE data on the association between areal bone mineral density (aBMD) using dual-energy x-ray absorptiometry (DXA) and hormonal parameters (1, 2) as well as biochemical markers of bone turnover (3). These studies have demonstrated, for example, the importance of bioavailable (bio) estradiol (E₂) in determining aBMD, particularly in aging men and women (1, 2, 4). In addition, aBMD has generally been inversely associated with bone turnover markers (3), and this observation has had important therapeutic implications in terms of helping to understand the antifracture efficacy of antiresorptive agents based on reductions in bone turnover as compared solely with increases in BMD (5). As useful as DXA has been for these studies, an inherent limitation of DXA is its inability to separate trabecular from cortical bone or to assess bone microstructure. Conventional central or peripheral quantitative computed tomography (QCT) does provide the ability to separately evaluate trabecular vs. cortical bone compartments and to also assess bone geometry but lacks the resolution to assess bone microstructure. Using these methods, we have previously defined the relationship of sex steroids to trabecular and cortical bone and to bone geometry at various sites in men (6) and in women (7).

Because trabecular structure may impact bone strength independently of bone mass (8), there is increasing clinical interest in assessing bone microstructure, with the ultimate goal of improving the prediction of fracture risk. Until recently, however, this had only been possible using the invasive technique of bone biopsy followed by relatively tedious bone histomorphometric (9, 10, 11) or ex vivo micro-CT (12) analyses, which are not amenable for application either in population studies or for routine clinical use. The recent development (13) and validation (14, 15, 16) of high-resolution three-dimensional peripheral QCT (3D-pQCT) instrumentation with a pixel size of less than 200 µm, and more recently less than 100 µm, has paved the way for evaluating trabecular microstructure noninvasively, at least at the wrist. Using this technology, we recently reported on effects of sex and age on bone microstructure at the ultradistal radius in a population-based sample of men and women (17). We found that, between ages 20 and 90 yr, cross-sectional decreases in bone volume/tissue volume (BV/TV) were similar in women (–27%) and in men (–26%), but whereas women had significant decreases in trabecular number (TbN) (–13%) and increases in trabecular separation (TbSp) (+24%), these parameters had little net change over life in men (+7% and –2% for TbN and TbSp, respectively; P < 0.001 vs. women). However, trabecular thickness (TbTh) decreased to a greater extent in men (–24%) than in women (–18%; P = 0.010 vs. men). Perhaps the most novel aspect of our data was a previously unrecognized increase in TbN and decrease in TbSp in men between the ages of 20 and 49 yr, which appeared to offset subsequent age-related decreases in TbN and increases in TbSp. In addition, between ages 20 and 49 yr, TbTh also decreased markedly in men (more than twice as much as in women), and this was the principal reason for the greater overall decrease in TbTh over life in men compared with women. The most plausible explanation for these findings was that young adult men have thicker trabeculae than those present in young women and that, between ages 20 and 49 yr, these thick trabeculae in men are converted into more numerous, thinner trabeculae, resulting in the observed marked decrease in TbTh, increase in TbN, and decrease in TbSp over that age range. In the present study, we extend our previous observations by assessing the relationships between the trabecular microstructural parameters and hormonal/bone turnover marker variables in young, middle-aged, and elderly men and women.

	Subjects and Methods

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Study subjects

We recruited subjects from an age-stratified, random sample of Rochester, Minnesota, residents who were selected using the medical records linkage of the Rochester Epidemiology Project (18). This population is highly characteristic of the U.S. White population, but Blacks and Asians are underrepresented. The sample spanned ages from 21–97 yr and included 324 women and 278 men. Reflecting the ethnic composition of the community, 98% of the subjects were White. Of the 324 women, we excluded 79 women on hormone therapy, four on bisphosphonates, two on selective estrogen receptor modulators, 33 on oral contraceptives, and one who had primary hyperparathyroidism. Of the 278 men, we excluded one subject on testosterone, two on bisphosphonates, one on a selective estrogen receptor modulator, four with serum creatinine greater than 2, and one with an unexplained bio E₂ greater than 60 pg/ml. Thus, the final study sample included 205 women (ages 21–97 yr) and 269 men (ages 22–91 yr). The study was approved by the Mayo Institutional Review Board, and written, informed consent was obtained from all subjects.

As for our previous studies examining the relationship of sex steroids with bone density and structure in this cohort (6, 7), we divided the subjects into young (aged 20–39 yr), middle-aged (aged 40–59 yr), and elderly (>60 yr) groups. We defined menopause as the absence of menses for greater than 6 months. Using this definition, all of the young women were premenopausal and all of the elderly women were postmenopausal. The middle-aged women represented the late premenopausal/early postmenopausal group, and 55% of the women in this group were premenopausal using the above criteria.

3D-pQCT

Details regarding the high-resolution 3D-pQCT imaging used in this cohort have previously been reported (17) and are summarized briefly here. The nondominant wrist (or in the case of a previous wrist fracture, the nonfractured wrist) was scanned using a high-resolution 3D-pQCT device (a prototype of the Xtreme CT, Scanco Medical AG, Bassersdorf, Switzerland). The in vivo measurement protocol included the acquisition of a three-dimensional stack of 116 high-resolution QCT slices at the distal end of the radius, using an effective energy of 40 keV, slice thickness of 89 µm, field of view of 90 mm, image matrix of 1024 x 1024 pixels, and pixel size of 89 µm.

The processing and analysis of the images have also been extensively described and validated (14, 15, 16, 19). Briefly, BV/TV is first derived from the trabecular volumetric BMD (vBMD). Recognizing that individual trabeculae will not be resolved at their correct thickness because of partial volume effects, a thickness-independent structure extraction is employed to assess trabecular microarchitecture. To this end, the three-dimensional ridges (the center points of the trabeculae) are detected in the gray-level images as described in detail in Laib et al. (14). TbN (one per millimeter) is then taken as the inverse of the mean spacing of the ridges (15). Combining TbN and BV/TV, TbTh (millimeters) is then derived as BV/TV ÷ TbN, and TbSp (millimeters) is derived as (1 – BV/TV) ÷ TbN, as is done in standard histomorphometry (9). The validity of this approach has been rigorously tested by comparing the 3D-pQCT methodology with 28-µm-resolution micro-CT (16), with very high correlation (correlation coefficients of 0.96–0.99) between the micro-CT and 3D-pQCT measurements. The key point in this analysis is that the resolution has to be sufficient to adequately resolve the distance between the trabecular ridges (1/TbN, or 300–500 µm) and not necessarily to resolve individual trabeculae (100 µm or less).

Hormonal and biochemical measurements

Fasting serum samples were obtained on all subjects at the time of the QCT measurements. Total E₂ was measured using a double-antibody RIA (Diagnostic Products Corp., Los Angeles, CA) with interassay coefficient of variation (CV) of less than 8% and lower limit of detection of 18 pmol/liter (5 pg/ml). Cross-reactivity of this assay was 12% with estrone and 6% or less for other estrogen metabolites. Total testosterone (T) was measured by a modified competitive immunoassay using direct, chemiluminescent technology (ACS 180; Bayer, Tarrytown, NY) with an interassay CV of less than 15%. The sensitivity of this assay was increased to 0.17 nmol/liter (5 ng/dl) using an in-house assay protocol where the volume of standards, controls, and samples was increased and the volume of the releasing agent was also increased to release bound T from endogenous binding proteins. Cross-reactivity of this assay was 5.4% with dihydrotestosterone and less than 1% for all other metabolites. The non-SHBG-bound (bio) fraction of total T and E₂ was measured using a modification of the technique of O’Connor et al. (20) and Tremblay and Dube (21), as previously described (1). The interassay CVs for bio E₂ and bio T were each less than 12%. Serum PTH was measured using a two-site immunoassay for intact PTH (Diagnostic Products) with an interassay CV of less than 13%, and serum 25-hydroxyvitamin D was measured by a competitive protein binding assay (Nichols Institute Diagnostics, Capistrano, CA) with an interassay CV of less than 15%. Serum IGF-I and IGF binding protein-3 (IGFBP-3) were measured by immunoradiometric assays (Diagnostic Systems Laboratories, Webster, TX) with interassay CVs of 9% and less than 2%, respectively. Serum osteocalcin was measured using a two-site immunoradiometric assay (CIS-US, Bedford, MA) with an interassay CV of 8%. Serum amino-terminal propeptide of type I collagen (PINP) was measured by RIA (DiaSorin, Stillwater, MN) with an interassay CV of less than 9%. Urine cross-linked N-telopeptide of type I collagen (NTx) was measured by an automated immunoassay (Ortho-Clinical Diagnostics, Rochester, NY) with an interassay CV of less than 13% in 24-h urine collections, and the results were expressed per liter of glomerular filtrate (GF) (estimated based on measuring serum and urine creatinine).

Statistical analyses

Hormone levels, bone turnover markers, and bone microstructural parameters were summarized using medians and interquartile ranges (25–75%). The Kruskal-Wallis test was used to make an overall comparison of these variables between the three age groups. In cases where the overall test was significant, Wilcoxon rank-sum tests were used to assess pairwise associations. Correlations of hormones and bone turnover markers with the bone microstructural parameters were evaluated using Pearson’s simple and partial correlation coefficients. Assumptions were assessed, and a log transformation was used on the hormone and bone turnover marker values where appropriate. Multiple regression analyses were performed to assess the relative importance of the effects of bio E₂ and bio T on the bone microstructural variables. A P value of <0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 shows the clinical, hormonal, bone turnover marker, and trabecular bone microstructural variables in the three groups of men. The groups demonstrated the expected hormonal changes with aging, with progressive decreases in bio E₂ and bio T levels, increases in PTH, and decreases in IGF-I and IGFBP-3 levels (reflecting decreases in GH secretion). Of note, bone formation markers decreased progressively with age, whereas urine NTx did not show a significant change. However, when we analyzed the correlation with age in men over the age of 50 yr as we have done before (1), there was a positive correlation of urine NTx with age in these men [r = 0.22; P = 0.005 for log (NTx) vs. age in men over the age of 50 yr].

Table 2 shows the same parameters in the three groups of women. The women also displayed the expected changes in hormone levels. Bone formation markers did not differ between groups, but the elderly women did have higher urine NTx values compared with the other groups.

Table 3 shows the unadjusted and age-adjusted correlation coefficients between the trabecular variables and the hormonal/bone turnover marker levels in the young men and women. In the young men (but not in the young women), serum IGF-I levels were inversely correlated with TbN and positively correlated with TbTh (Fig. 1), suggesting that the decrease in TbTh and increase in TbN in the young men was related to declining IGF-I levels in these men as they transitioned to mid-life. In addition, serum IGFBP-3 levels were associated with BV/TV and with TbTh in the young men but not in the young women. None of the other variables (sex steroid levels, PTH/25-hydroxyvitamin D, or bone turnover markers) were associated with any of the trabecular microstructural variables in the young men or women, with the exception of a negative association between serum PTH levels and TbTh in the young men.

View larger version (12K): [in this window] [in a new window]   FIG. 1. A, TbN vs. serum IGF-I levels in young men aged 20–39 yr (r = –0.35; P < 0.01). B, TbTh vs. serum IGF-I levels in young men (r = 0.31; P < 0.05).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The ability to obtain accurate measures of trabecular microstructure in vivo in humans represents a significant methodological advance for population studies examining the effects of aging on bone structure. Our present findings, which extend our recent observations (17), demonstrate that the previously described decrease in TbTh and increase in TbN (i.e. the apparent conversion of thick trabeculae to thinner, more numerous trabeculae) in young men as they approach mid-life is most closely related to declining IGF-I and IGFBP-3 levels (with the latter used here as a surrogate for GH levels) (22). Why this occurs in men but not in women, despite the similar pattern of changes seen in IGF-I and IGFBP-3 levels, is unclear. However, a plausible and potentially testable hypothesis is that the high IGF-I/GH levels in puberty and young adulthood in men, in the presence of their high androgen levels compared with adolescent and young adult women, lead to the formation of thick trabeculae. Thereafter, as IGF-I/GH levels fall during life, these thick trabeculae are converted into thinner, more numerous trabeculae. Consistent with this, growing mice either overexpressing IGF-I (23) or with targeted deletion of the IGF-I receptor (24) in osteoblasts have increases and decreases, respectively, in trabecular BV/TV, suggesting an important role for the IGF system in regulating trabecular bone, particularly during growth. Moreover, androgens have been shown to increase IGF-I production in osteoblastic cells (25) and to enhance IGF-I receptor expression in prostate cancer cells (26) as well as in the primate ovary (27). Thus, a differential interaction between the IGF-I/GH system and androgens as compared with estrogen may explain the sexual dimorphism of the changes in TbTh and TbN in young men vs. young women that we observed.

In contrast to the associations with IGF-I and IGFBP-3 in young men, sex steroids and, in particular, bio E₂ levels, became increasingly important predictors of trabecular microstructure in middle-aged and elderly men and women. These findings are consistent with extensive previous data showing an important role for estrogen in determining bone mass as measured by DXA (1, 2, 4) or QCT (6, 7) in elderly men and women. Although serum bio T levels were significantly associated with some of the trabecular microstructural parameters in middle-aged and elderly women in the simple regression analyses, none of these associations with bio T remained significant after adjusting for effects of bio E₂ in multiple regression models.

Bone turnover markers were generally inversely associated with BV/TV, TbN, and TbTh and positively with TbSp in the middle-aged and elderly men and women, consistent with the notion of increased bone turnover having detrimental effects on bone microstructure (5). Indeed, recent data now indicate that perhaps the majority of the beneficial effect of antiresorptive agents on fracture risk may be related not to changes in BMD but rather to changes in bone turnover (5, 28). Additional studies relating bone turnover markers to estimates of bone strength from finite element models based on the types of high-resolution images obtained using the 3D-pQCT (29) will be useful in addressing this issue.

We recognize that our study has several limitations. Our overall sample size, although adequate for the determination of many of the correlations we observed, is still relatively small, and studies in larger numbers of subjects are needed to further validate our findings. Moreover, cross-sectional data such as this is inherently subject to certain bias (e.g. cohort effects), and longitudinal studies are clearly needed to provide additional verification of our data.

In summary, our findings are consistent with a heretofore unrecognized relationship in young adult men between the decline in the high IGF-I levels associated with puberty and the conversion of thick trabeculae into more numerous, thinner trabeculae characteristic of older men and young adult women. By contrast, reductions in sex steroid levels are the major hormonal determinants of changes in trabecular microstructure in elderly men and women. Our data also provide direct evidence for the previously postulated link between increased bone turnover and deterioration of trabecular microstructure in men and in women. Finally, our study demonstrates that changes in bone microstructure assessed noninvasively can be related to changes in osteotrophic hormones in population-based studies and that the ability to do so provides a powerful new tool for assessment of the impact of hormones and other factors on the skeleton.

	Acknowledgments

 
We thank Margaret Holets for making the pQCT measurements; Lisa McDaniel, R.N., and Louise McCready, R.N., for their assistance in recruitment and management of the study subjects; and Ms. Elizabeth Atkinson, M.S., for help with the statistical analyses.

	Footnotes

 
This work was supported by National Institutes of Health Grants R01 AR-027065 and M01 RR00585.

First Published Online December 20, 2005

Abbreviations: aBMD, Areal bone mineral density; bio, bioavailable; BV/TV, bone volume/tissue volume; CV, coefficient of variation; 3D-pQCT, three-dimensional peripheral QCT; DXA, dual-energy x-ray absorptiometry; E₂, estradiol; GF, glomerular filtrate; IGFBP-3, IGF binding protein-3; NTx, cross-linked N-telopeptide of type I collagen; PINP, amino-terminal propeptide of type I collagen; QCT, quantitative computed tomography; T, testosterone; TbN, trabecular number; TbSp, trabecular separation; TbTh, trabecular thickness.

Received September 15, 2005.

Accepted December 13, 2005.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) All Versions of this Article: 91/3/885    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khosla, S. Articles by Riggs, B. L. Search for Related Content PubMed PubMed Citation Articles by Khosla, S. Articles by Riggs, B. L. Related Collections Calcium and Bone Metabolism