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Original Studies |
Department of Family and Preventive Medicine, Division of Epidemiology (E.B.-C., D.G.v.M., G.A.L., D.L.S., D.J.S.), School of Medicine, University of California–San Diego, La Jolla, California 92093-0607; and Department of Obstetrics and Gynecology (J.E.M.), Technische Universität München, D-81675 Munich, Germany
Address correspondence and requests for reprints to: Dr. Elizabeth Barrett-Connor, Division of Epidemiology, School of Medicine, University of California–San Diego, 9500 Gilman Drive, Department 0607, La Jolla, California 92093-0607.
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Abstract |
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Introduction |
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The purpose of the present longitudinal study was to determine whether levels of estradiol or other sex hormones were associated with radiologically defined vertebral fractures in older community-dwelling women and men.
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Materials and Methods |
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Between 1972 and 1974, 82% of adult residents in Rancho Bernardo, a Southern California community, were enrolled in a study of heart disease risk factors. All were ambulatory, middle to upper-middle class and Caucasian. Between 1984 and 1987, 82% of the surviving community-dwelling residents attended a clinic visit when plasma was obtained from 885 men and 759 women not currently using estrogen. From 1992–1996, 359 men and 295 women returned for a follow-up visit and agreed to have vertebral radiographs. All protocols were approved by the University Institutional Review Board, and all participants gave written consent at both visits.
The 1984–1987 and 1992–1996 visits included a clinical examination and a standardized questionnaire regarding personal and family history of fractures not due to major trauma, current cigarette smoking (yes/no), alcohol consumption (grams per week during previous 2 weeks), physical activity (exercise at least 3 times per week), gynecological history (age at menopause, oophorectomy, hysterectomy, estrogen use), and current use of thiazide diuretics, thyroid hormones, calcium supplementation, laxatives, or corticosteroids. Height and weight were measured with participants wearing light clothing and no shoes; body mass index (BMI) was calculated as kg/m2, and weight change between the visits was determined.
Serum samples and hormone assays
At the 1984–1987 visits, venous blood was drawn between 0730 h and 1100 h after a requested 12-h fast. Plasma was separated and stored in polypropylene tubes at -70 C until first thawed for hormone assays in 1993. Measurements were performed in the endocrinology research laboratory of S. S. C. Yen (Department of Reproductive Medicine, University of California–San Diego, La Jolla, CA). Levels of total estradiol and testosterone, estrone, androstenedione, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA) were determined by RIA after solvent extraction and column-chromatography (13); dehydroepiandrosterone sulfate (DHEAS) was measured directly by RIA; bioavailable (non-sex hormone-binding globulin bound) estradiol and testosterone were determined using a method modified from Tremblay and Dube (14). The sensitivity and the intra- and interassay coefficients of variation, respectively, were 11 pmol/L, 5.9% and 7.1% for estradiol; 11 pmol/L x percent free, 6.1% and 7.9% for bioavailable estradiol; 0.07 nmol/L, 4.0% and 4.9% for testosterone; 0.07 nmol/L x percent free, 6.5% and 10.7% for bioavailable testosterone; 11 pmol/L, 6.0% and 7.7% for estrone; 0.06 nmol/L, 4.3% and 4.3 for androstenedione; 0.12 nmol/L, 7.5% and 7.5% for DHT; 0.14 nmol/L, 6.1% and 7.1% for DHEA; and 0.22 µmol/L, 3.1% and 7.3% for DHEAS. Androstenedione and estrone were measured only in women, DHT only in men. Levels below the assay sensitivity were found for estradiol in 35 women, for testosterone in 4 women, for DHEAS in 2 women, and for DHT in 1 man. For analysis, these individuals were assigned hormone values 1 unit below the assay sensitivity.
Spine radiographs
Lateral radiographs of the thoracic (T7-T12) and the lumbar (L1-L4) spine were read by a single musculoskeletal radiologist (DJS), who graded quality as good, adequate, or poor. Prevalent fractures were defined using a qualitative and semiquantitive grading scheme for vertebral deformity described by Genant et al. (15). Each vertebra was assessed as fractured or not, and participants were grouped by vertebral fracture status. Several months after the first reading, 60 radiographs were reread by the same radiologist (without knowledge of his first reading) with 95–100% concordance for each vertebral level.
Statistical analysis
Fourteen individuals were excluded from this analysis for the following reasons: high hormone levels suggesting unreported hormone use or an endocrinological disorder (n = 2); oral corticosteroid use (n = 10); uninterpretable spine radiograph (n = 1); and less than 1 yr postmenopausal (n = 1). The present report includes 288 women and 352 men who were 50 yr of age or older in 1984–1987.
Analyses were performed using the Statistical Package for Social Science (version 8.0; SPSS, Inc., Chicago, IL) and the Statistical Analysis System (version 6.12; SAS Institute, Inc., Cary, NC). To correct for skewed distributions, levels of total and bioavailable estradiol, testosterone and estrone for women, and DHEA and DHEAS for both sexes were logarithmically transformed (other hormones were normally distributed). Hormone values presented in the tables are antilogs. Because age is known to be a strong predictor of fracture risk in both sexes and was associated with sex hormone levels in this cohort, analyses were adjusted for age. Pearson’s correlation was used to assess the strength of association between hormone levels and age. To test for significant differences by fracture status, the Mann-Whitney U test was used for median age, Cochran-Mantel-Haenszel statistics for categorical covariates, and a general linear model for hormone concentrations and continuous covariates. Fracture prevalence across hormone quintiles was tested using the Cochran-Armitage test for trend. All P values are two-tailed. Statistical significance was defined as P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Women with vertebral fractures were significantly older than women
without fractures at the time blood was obtained for hormone assays
(median age, 75 vs. 71 yr, P < 0.001); no
difference was seen in men (median 65 vs. 66 yr,
P = 0.66). Vertebral fractures were not associated with
any of the other studied covariates, including BMI, weight loss,
alcohol consumption, current smoking, exercise, current use of thiazide
diuretics, thyroid hormones, or calcium supplementation (Table 1
). In women, vertebral fractures were
also not associated with age at menopause, bilateral oophorectomy, or
estrogen use reported in the 1992–1996 visit (data not shown).
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. None of the
hormones in women differed significantly by fracture status. In
contrast, men with at least one vertebral fracture had significantly
lower levels of total and bioavailable estradiol, with no significant
differences for other hormones. An analysis comparing the 26 women who
had two or more fractures with women without fracture showed no
significant difference in hormone levels by fracture status. There were
too few men with two or more fractures (n = 9) for a meaningful
analysis.
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) or testosterone (data not shown).
Women with estradiol levels below the assay sensitivity (total
estradiol, <11 pmol/L, n = 35) did not have a higher fracture
risk than other women [odds ratio (OR), 0.69; 95% confidence interval
(CI), 0.31, 1.52). In men, there was a graded association between
increasing concentrations of total and bioavailable estradiol and
decreasing fracture prevalence (trend P < 0.01 for
each hormone) (Fig. 1B). Men in the lowest quintile of total or
bioavailable estradiol had significantly higher odds for vertebral
fracture than those in the highest quintile (for total estradiol: OR,
4.16, and 95% CI, 1.22, 14.19; for bioavailable estradiol: OR, 5.08,
and 95% CI, 1.20, 21.51). Testosterone levels were not associated with
vertebral fractures in men in quintile analysis (data not shown), and
the 38 men with total testosterone levels compatible with hypogonadism
(<7 nmol/L) (16) were not at significantly increased odds for
vertebral fracture (OR, 1.24; 95% CI 0.54, 2.83).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The lack of association between estradiol or estrone and vertebral fractures in postmenopausal women is compatible with other studies. No significant differences in total estradiol or estrone levels between postmenopausal women with and without osteoporotic vertebral fractures were found in an age-matched case-control study (4). In two other case-control studies, higher levels of total and bioavailable estradiol, but no differences in estrone levels, were found in postmenopausal women with vertebral fractures compared with healthy women (5, 6), although one of these studies (6) reported a lower estrone clearance rate in osteoporotic women. Two other case-control studies showed lower levels of estrone (8), or estradiol and estrone (7), in postmenopausal women with vertebral fractures, compared with women without fractures. The Study of Osteoporotic Fractures reported both a higher prevalence and incidence of vertebral fractures among postmenopausal women with very low estradiol levels (<18 pmol/L) (9), but the association with prevalent fractures was not confirmed in a validation study from the same cohort (10).
Although estradiol receptors have been found in bone cells (18, 19), there is little evidence that the low levels of estradiol in postmenopausal women influence bone metabolism. It is possible that only premenopausal estrogen levels, or levels greater than some threshold concentration, have an effect on bone (20). In the present study, only 14 women had estradiol levels approaching the premenopausal range (>50 pmol/L for this laboratory). Alternatively, differences in low estradiol levels between osteoporotic and healthy women could be missed due to difficulties in measuring very low levels of estradiol (10). This seems unlikely because levels below the assay sensitivity (<11 pmol/L) were found in 12% of women in the present study, and these very low estradiol concentrations were not associated with vertebral fractures. The estradiol assay sensitivity was as good or better than the sensitivity reported by other studies to be associated with vertebral fractures.
In the presence of low postmenopausal estrogen levels, testosterone or other androgens could be more important for bone health in women, but higher levels of androgens were not associated with fewer vertebral fractures in Rancho Bernardo women. This is consistent with one prospective (9) and two cross-sectional (4, 5) studies. Two case-control studies of postmenopausal women, however, showed lower levels of androstenedione (8) or testosterone (7) in women with vertebral fractures compared with healthy women, and Longcope et al. (6) reported a lower clearance rate of testosterone, lower production rates of androstenedione and testosterone, and lower fractional conversion of androstenedione to testosterone in women with vertebral fractures.
The negative graded association of low estradiol levels with vertebral fractures found in men in this study suggests a central role for estrogen in male bone health. No other study of older men has reported an inverse association of estradiol levels and vertebral fractures, but data are limited to two small case-control studies (11, 12). The importance of estrogen for bone maturation and development of peak bone mass in men is supported by a report of a young man who had osteopenia associated with an estrogen-receptor gene mutation and estrogen resistance (21). Osteopenia was also reported in an aromatase-deficient young man whose estradiol levels were below 26 pmol/L, but whose testosterone levels were high (22).
The absent association of testosterone and other androgens with vertebral fractures observed here is consistent with other studies in men. Cross-sectional studies reported no association between testosterone (11, 12) or DHEAS (12) and vertebral fractures. We found no published data on the relation between DHT and vertebral fractures in men. Although hypogonadism is considered an important cause of osteoporosis in men (23), Rancho Bernardo men with very low testosterone levels (<7 nmol/L) did not have an increased risk of vertebral fracture. In a study of testosterone replacement in eugonadal men with vertebral fractures, both testosterone and estradiol levels increased during therapy, but changes in estradiol, not testosterone, were correlated with changes in BMD (24). Estradiol in men derives from the aromatization of androgens, and although androgen receptors have been found in bone tissue (25) and cells (26, 27), the effect of testosterone on bone could be mediated by estradiol (23).
In concordance with most epidemiological studies, risk factors for low BMD were not risk factors for vertebral fractures (28). Although BMI, smoking, and various medications were associated with spinal BMD in both women and men in the Rancho Bernardo cohort (2), only age confounded the association between sex hormone levels and vertebral fractures in this study. Similarly, estradiol levels have been shown to be associated with spinal BMD in both women and men in this cohort (2) and elsewhere (3, 10), but were not associated with vertebral fractures in women in the present study. This dichotomy points to the complex relation between BMD and fractures; bone turnover rates, microarchitecture, and biomechanical factors are also important for the prediction of vertebral fractures, and this might be more apparent in women than men (29). The failure to find an association between common risk fractures for osteoporosis and vertebral fractures in this study could reflect their relatively weak or absent association in the elderly, or could reflect the low levels of exposure in this cohort. Very few men or women were currrent smokers or obese.
Several limitations of this study should be noted. Because spine radiographs were not obtained at the 1984–1987 visits, we cannot be certain that preexistent fractures did not lead to altered hormone levels due to immobility or obesity. This seems unlikely, however, because all participants were ambulatory when blood was obtained, few were obese, and most spine fractures were asymptomatic. The radiological diagnosis of osteoporotic vertebral fractures is complicated by degenerative changes and sequela of trauma (30, 31), but the radiological criteria for vertebral fractures used in this study correlate well with clinical criteria (32) and show good inter- and intraobserver agreement (15).
The ability of single hormone measurements to categorize an individuals hormone status is imperfect, particularly with regard to estradiol (33, 34, 35). In the present study, all blood samples were obtained in the morning to reduce the influence of diurnal variation; diurnal variation is larger with testosterone than estradiol, but this pattern decreases markedly with aging (36). Hormone levels did not vary with season or sample storage time. However, the long interval between obtaining blood for hormone measurement and fracture assessment, 8.4 yr on average, could have lead to a dissociation of exposure and effect (37).
Women using estrogen at the time blood for hormones was obtained were not included in this study, possibly excluding younger healthier women without vertebral fractures. Participation bias seems unlikely to explain the absent association in women because the 21% prevalence of vertebral fractures in the Rancho Bernardo women is similar to the 15–19% reported in the Study of Osteoporotic Fractures (10) and to the 24.6% prevalence reported in Rochester, Minnesota, women (38).
In conclusion, levels of total or bioavailable estradiol and testosterone were not associated with vertebral fractures in postmenopausal women, but higher levels of total and bioavailable estradiol were associated with fewer vertebral fractures in older men. The graded association suggests that even relatively small increases in plasma estrogen might reduce fracture risk in men. The prevention of vertebral fractures in older women is likely to require substantially higher estrogen concentrations than are physiologically present after menopause.
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Footnotes |
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Received August 8, 1999.
Revised October 7, 1999.
Accepted October 12, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and bioavailable (
) estradiol (The Rancho Bernardo
Study, 1984–1987 and 1992–1996).