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Departments of Internal Medicine (H.W.G.-P., M.v.d.K., W.d.R., F.H.d.J., H.A.P.P.) and Epidemiology and Biostatistics (H.W.G.-P., M.v.d.K., A.H., H.A.P.P.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: Prof. Huibert A. P. Pols, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: h.pols{at}erasmusmc.nl.
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Abstract |
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15.5 pmol/liter) had a 2.1 times increased risk (95% confidence interval, 1.3–3.5) of incident vertebral fractures, independently of bone mineral density measured at either site. SHBG levels in the lowest two tertiles were associated with a 50% reduction in incident vertebral fracture risk. Women with a combination of both low estradiol and high SHBG had a 7.8 times higher risk of an incident vertebral fracture (95% confidence interval, 2.7–22.5; P < 0.001), adjusted for age and weight. This increased risk did not change when non-SHBG-bound estradiol was used instead of total estradiol. For men, no clear association was found, possibly due to insufficient power. No clear association between testosterone and incident vertebral fractures was observed in either men or women. |
Introduction |
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Low endogenous estradiol levels are associated with low BMD (1, 2, 3, 4). Furthermore, higher estradiol plasma concentrations are associated with a decreased risk of hip fractures (5). Studies of the association between sex steroid hormones and incident vertebral fractures have shown inconsistent results (6, 7, 8, 9). These studies were all performed in or before 1985 and therefore could not use recent, more sensitive estradiol assays (10, 11). Recently, the Study of Osteoporotic Fractures has shown that women with an estradiol level below the detection limit of the assay (18 pmol/liter) were at an increased risk of subsequent fracture at both vertebrae and hip. This risk was even greater in women with a simultaneously elevated serum level of SHBG (12). The data suggested a threshold value of estradiol below which the risk suddenly increases.
In men, sex steroid hormones have only been studied in relation to prevalent vertebral fractures, and conflicting results were obtained (13, 14, 15, 16). The majority of these studies showed no association between prevalent vertebral fractures and estradiol or testosterone. The Rancho Bernardo study (13), however, found an inverse association between estradiol levels and prevalent vertebral fractures in men; such an association was not found in women. To our knowledge no studies of the association between serum sex steroid hormones and incident vertebral fractures have been performed in men.
The aim of this study was to investigate the impact of levels of endogenous sex steroid hormones and SHBG on the incidence of vertebral fractures in both men and women. We performed a nested case-control study within the population-based cohort of the Rotterdam Study.
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Subjects and Methods |
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We designed a nested case-control study among the participants of the Rotterdam Study, which is a prospective population-based cohort study of men and women aged 55 yr and over. As described previously (17), the aim of the study was to investigate the occurrence of and risk factors for chronic disabling diseases in an aging population. The total study population consists of inhabitants of Ommoord, a suburb of Rotterdam, The Netherlands. All 10,275 men and women, aged 55 yr and over, were invited to participate in this study between August 1990 and June 1993. From those, 7,983 (3,105 men) agreed to participate. The medical ethics committee of Erasmus Medical Center (Rotterdam, The Netherlands) approved the study.
Determinants
At baseline, all participants were extensively interviewed at home about current and past health, potential risk factors, and medication. Medication use was scored as baseline usage of more than three different medications per day. Alcohol intake was assessed using a food frequency questionnaire and was scored as baseline usage of more than 10 g alcohol/d. Current smoking status was scored. At the subsequent research center visit a physical examination was performed. Height and weight were both measured while the subject was wearing indoor clothing but without shoes. Nonfasting blood samples were drawn and frozen. Postload glucose tolerance tests were performed. BMD measurement of both the lumbar spine and femoral neck was performed by dual energy x-ray absorptiometry as described previously (18) (DPX-L densitometer, Lunar Corp., Madison, WI), and lateral radiographs of the spine were taken. There was no correlation between age and time of visit to the research center (P > 0.07).
Identification of fractures
Both at baseline, between 1990 and 1993, and at the second follow-up visit, between 1997 and 1999, radiographs of the thoraco-lumbar spine were taken following a standard protocol. The distance between source and plate was 120 cm, using a Solarize FV (General Electric CGR, Utrecht, The Netherlands). The follow-up radiographs were available for 3469 individuals (1971 women), who survived until the second follow-up visit and were still able to come to the research center.
All follow-up radiographs were scored morphometrically for the presence of vertebral fractures by the McCloskey/Kanis assessment method as described previously (19, 20). If a vertebral fracture was present, the baseline x-ray was scored as well to ascertain whether a fracture was incident or prevalent. A fracture was considered incident if no baseline fracture of the vertebra was present and any of the three vertebral heights (anterior, central, or posterior) showed a decrease of at least 4.6 mm and 15% on the later spinal film. The detection of fractures was blinded for the baseline steroid hormone status.
Selection of cases and controls
Participants were eligible for the present study if both the baseline and the follow-up spinal x-ray radiographs were available (n = 3469). From this group, 176 subjects (5%) had at least one incident vertebral fracture; 162 of those had sufficient baseline blood available. For each case, three age-matched (within 1 yr) and gender-matched controls were randomly selected from participants with both x-rays available. Fifteen women were excluded because of baseline usage of hormone therapy; no men were receiving hormone therapy. Thus, 454 women (115 cases) and 179 men (45 cases) were included. Of these 633 participants, 588 also had information on BMD available. The average follow-up time was 6.5 ± 0.5 yr (range, 3.6–9.0 yr).
Assay methods
Nonfasting blood samples were drawn by venipuncture at the baseline examination in the research center between 0830 and 1600 h. For the collection of plasma, blood was sampled in 5-ml tubes containing 0.5-ml sodium citrate solution. Platelets were removed by centrifugation, and the samples were stored at –80 C until hormone measurements. The period of storage of frozen serum varied from 7.5–12.5 yr. Estradiol, testosterone, and SHBG were determined by direct immunoassays; albumin and postload insulin were also measured. Testosterone was estimated in single measurements by RIA using coated tubes. SHBG was measured in duplicate using double antibody RIA (both from Diagnostic Systems Laboratories, Webster, TX). The estradiol levels were estimated in duplicate using the ultrasensitive RIA purchased from the same company. The mean minimum detection limit of this test was 4.8 pmol/liter, which enabled us to study the risk of incident vertebral fractures at very low levels of estradiol. Undetectable estradiol was scored as zero. Interassay coefficients of variation, determined on basis of duplicate results of internal quality control serum pools with three different levels of analyte were less than 10% for estradiol and SHBG and 12% for testosterone. Intraassay coefficients of variation were less than 10% for both estradiol and SHBG. As measures of biologically active estradiol, the free fraction of estradiol and non-SHBG-bound estradiol were calculated according to the method described by Södergård et al. (21). Albumin was measured by photometry (Roche, Mannheim, Germany). Due to the limited amount of plasma per patient, not all hormone levels could be measured in all subjects. Estradiol levels were available for 632 subjects, SHBG levels for 647 subjects, testosterone for 496 subjects, and albumin for 494 subjects. The case-control ratio varied from 1:2.8 to 1:3.1.
A nonfasting glucose tolerance test was used to determine postload insulin levels. Participants’ blood was drawn 2 h after they drank a glucose drink containing 75 g in 200 ml water. Insulin was measured in duplicate by RIA (Medgenix, Brussels, Belgium); the intraassay coefficient of variation was 8.0%, and the interassay coefficient of variation was 13.7%. Participants were classified as diabetics when they reported the use of antidiabetic medication or when the pre- or postload serum glucose level, measured by the glucose hexokinase method, was equal to or greater than 11.1 mmol/liter. Participants already classified as diabetics were excluded from the glucose tolerance test. Therefore, insulin data are only available for the 529 participants with no or undiagnosed insulin resistance or diabetes mellitus.
Data analysis
Differences in baseline characteristics were compared by a two-sided t test for continuous variables and a 
2test for categorical variables. One man was excluded from further analysis due to an extremely high estradiol level (>500 pmol/liter). All analyses were performed for men and women separately.
An aggregated mean of the various hormone levels was calculated for all controls matched to one case. These aggregated means were subsequently compared with the hormone levels of the cases. Differences between these levels were tested by a paired sample t test. Because the hormone levels were not normally distributed, the impacts of estradiol, non-SHBG-bound estradiol, and SHBG on the incidence of vertebral fractures were analyzed in tertile groups using a conditional logistic regression model to account for the age matching. Adjustment was made for weight. All analyses were subsequently repeated with additional adjustment for femoral neck BMD. To explore the possibility of interaction, the analyses on tertiles of serum estradiol level in association with incident vertebral fractures were repeated in strata of tertiles of SHBG, thus creating nine groups of women. We used the group of women with a serum estradiol level in the highest tertile and a serum SHBG level in the lowest tertile as the reference. A general linear model was used to analyze the association between BMD and estradiol levels, SHBG levels, and non-SHBG-bound estradiol levels with adjustment for age and weight. The P for trend was calculated by a linear regression method with the above-mentioned parameters. SPSS 9.0 for Windows was used for all analyses (SPPS, Inc., Chicago, IL).
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Results |
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Women with an incident vertebral fracture had lower weights and lumbar spine BMD than women without incident vertebral fractures. They smoked more and at baseline had a higher prevalence of vertebral fractures (Table 1
). Women with incident vertebral fractures had lower levels of both total and non-SHBG-bound estradiol levels, although the difference was not statistically significant, whereas higher levels of SHBG and lower postload insulin levels were observed (Table 2).
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), albeit the magnitude of the difference in BMD across the tertiles of estradiol was small. BMD in women was also inversely correlated with incident vertebral fractures (Table 1
). Women with a total estradiol level in the lowest tertile (15.5 pmol/liter) had a 2-fold increased risk of an incident vertebral fracture compared with women in the highest tertile (Table 3A). This association appeared to be independent of femoral neck BMD, although BMD was associated with both incident vertebral fractures (Table 1) and estradiol (Fig. 1). Results did not change when adjusted for lumbar spine BMD instead of femoral neck BMD. Analyses repeated with either non-SHBG-bound or free estradiol resulted in similar risk estimates (data not shown for free estradiol). Postload insulin levels were not significantly correlated with BMD (Fig. 1). Female participants in the lowest tertile of SHBG levels had a 50% decreased risk for a vertebral fracture (Table 3A). However, when adjustment was made for insulin levels, the association of SHBG with incident vertebral fractures appeared to be nonsignificant, with odds ratios (OR) of 0.67 (0.37–1.20) for the first tertile and 0.63 (0.36–1.11) for the second tertile and a P for trend of 0.22. The association of SHBG with incident vertebral fractures was dependent on femoral neck BMD (Table 3A). Results for any of the hormones considered did not change when analyses were restricted to first event cases, excluding the participants with prevalent fractures (data not shown). Furthermore, results remained similar with additional adjustment for current smoking status.
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). This group was comprised of almost 15% of the women in our study population (68 of 463). The other women in the study group, with either a high SHBG level or a low estradiol level, were also at an increased risk compared with this reference group. This risk, however, was only 2-fold increased. Analyses using categories of non-SHBG-bound estradiol instead of total estradiol vs. categories of SHBG led to similar results.
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Men who suffered an incident vertebral fracture were only different from their controls in lumbar spine and femoral neck BMD and in the prevalence of vertebral fractures (Table 1). There was an indication that, compared with the control group, men with incident vertebral fractures less often suffered from diabetes mellitus. Although not statistically significant, men with an incident vertebral fracture appeared to smoke more often. None of the hormone levels was statistically different between cases and controls, although a trend similar to that for women could be observed for SHBG and insulin (Table 2). In men, estradiol levels were associated with BMD, independent of age and weight (Fig. 3). Lower non-SHBG-bound estradiol, higher SHBG, and lower postload insulin levels were associated with lower BMD, although not statistically significant. None of the measured hormones was associated with incident vertebral fractures (Tables 2 and 3B).
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Discussion |
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Women in the lowest tertile of serum estradiol were at a 2.1-fold increased risk of an incident vertebral fracture (95% confidence interval, 1.3–3.5). This observation is very similar to the results of a study by Garnero et al. (22), who found an OR of 2.2 (range, 1.2–4.0) for both vertebral and hip fractures, and those of a study performed by Cummings et al. (OR, 2.5; range, 1.4–4.2) (12). Ettinger et al. (4) extended the results of Cummings in the same cohort, but for prevalent vertebral fractures (OR, 2.5; range, 1.4–5.0). However, they were not able to find any influence of estradiol on prevalent vertebral fractures in their validation set, as summarized in Table 4.
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Estrogen deficiency is also thought to result in increased apoptosis of osteocytes (27). The capacity of bone to repair microdamage and to modulate the effects of mechanical strain is believed to be dependent on these osteocytes (28). If estrogen acts as a permissive factor for osteocyte viability, this would explain why the risk of an incident vertebral fracture is increased in women in the lowest tertile of estradiol levels only. In addition, osteocyte death might play a role in explaining the independence of BMD of the association between estradiol levels and incident vertebral fractures (29).
In our study increased levels of SHBG are associated with an increased risk of incident vertebral fractures in women. Several other studies have found that an increased level of SHBG is a risk factor for osteoporotic fractures (5, 12, 22, 30) (see Table 4). As SHBG is a transport protein that binds estradiol, its impact on fractures is most often regarded as a proxy for the bioavailability of estradiol. Nonetheless, a combination of low estradiol and high SHBG significantly increases the risk to about 8-fold, more than could be expected from the levels for both hormonal factors separately. Interestingly, the Study of Osteoporotic Fractures (12) found the same 8-fold elevated risk for a subgroup of women with higher levels of SHBG and lower levels of estradiol with approximately the same boundaries for estradiol levels (16 vs. 18 pmol/liter). Furthermore, our results were essentially the same when analyzing non-SHBG-bound estradiol instead of total estradiol. This suggests that SHBG either has an effect on bone different from the effect on estradiol bioavailability or is a proxy for another factor that reduces vertebral fractures. Previously, SHBG was also shown to be associated with an increase in the rate of bone loss independently of sex steroid hormone levels, which supports the idea of an additional SHBG action other than by affecting the bioavailability of estradiol (31). It has been hypothesized that estrogen-dependent tissues express an SHBG receptor, albeit to date it has not been identified (32, 33, 34). Research in breast cancer patients suggests that SHBG could amplify or dampen the effect of estrogen on target tissue via the receptor (35). If the latter is the case, the combination of low estradiol and high SHBG could have an enhanced effect, resulting in a strong increase in the risk of an incident vertebral fracture.
In 1989, von Schoultz and Carlstrom (36) hypothesized that SHBG was controlled by factors other than steroid hormones, with IGF-I as one of the stronger candidates. There is an inverse relationship between IGF-I and SHBG (37), and insulin has been shown to inhibit the hepatic production of SHBG in women (38, 39), whereas simultaneously insulin levels are associated with an increased BMD (40, 41, 42). Hence, the risk associated with higher SHBG concentrations could also be due to, for instance, lower insulin or lower IGF-1 levels (39, 43).
Weight strongly modifies the effect of insulin on incident vertebral fractures, as the difference in insulin levels between cases and controls loses its significance when adjusted for weight. Hyperinsulinemia and insulin resistance might have been present in this elderly study population.
Most studies performed in men to date have focused on the correlation between sex hormones and BMD. Most, but not all, found that bioavailable or total estradiol levels are associated with BMD (2, 3, 15, 44, 45), just as we showed that BMD was associated with total estradiol. Estradiol has also been found to be associated with bone turnover markers (15, 46). These studies did not find a role for SHBG, except for one small case-control study (47). Two recent studies investigated prevalent osteoporotic fractures as an end point instead of BMD in men (16, 48). Both studies observed that high SHBG levels form a risk factor for osteoporotic fractures in men independently of estradiol and BMD, with a risk estimate similar to that found in women. No studies with incident vertebral fractures as an end point were reported to date.
We did not observe any association between hormonal factors and the risk for incident vertebral fractures in men for SHBG, estradiol, or testosterone, although a nonsignificant difference in the same direction as in women was observed. As the incidence of vertebral fractures is lower in men than in women, relatively few men could be included in the current study. Our negative findings could, therefore, be a result of low statistical power. Men have higher estradiol serum levels than postmenopausal women. If estradiol indeed acts as a permissive factor for osteocytes, it could well be that the serum levels of estradiol found in men are well above the minimal required level for osteocyte viability. Then, in men, no association between estradiol and incident vertebral fractures would be expected.
Also, endogenous sex hormones might be more strongly associated with BMD than with the risk of an incident vertebral fracture in men, as our results suggest as well. During aging, bone loss is partly compensated by concurrent bone formation on the periosteal bone surface; this bone formation is greater in men than in women. Therefore, men appear to compensate their internal bone loss better than women, and as a result are more fracture resistant despite a similar areal bone density (49).
Our study has several limitations. The subjects were elderly people from Northern European descent; our results may therefore not be generalizable to other populations. The study was performed with a case-control design that might have led to selection bias and information bias. For participants to be included two spinal radiographs were needed. Participants, therefore, had to be mobile enough to be able to visit the study center. This undoubtedly will have led to a health selection bias, whereby participants with higher morbidity were less likely to be included. This bias, however, applied equally to cases and controls, which makes it unlikely that the validity of the study was affected. However, this health selection bias will affect the generalizability of the study, as only mobile elderly people were studied. Information bias is unlikely to have influenced the results of this prospective case-control design; because the study was nested in a population cohort, the exposure measure could be determined in blood samples that were drawn at baseline. Furthermore, the outcome validation, spinal fractures, was blinded for the exposure status, i.e. hormone levels. The long interval between blood collection and vertebral fracture assessment, the determination of hormonal status by a single measurement, and the inability to collect the blood at a fixed time of day can have only diluted the association (50, 51, 52, 53).
In conclusion, in postmenopausal women, independently of BMD, both serum estradiol and SHBG are risk factors for incident vertebral fractures. In men, no clear association between sex steroid hormones and incident vertebral fractures was observed. The subgroup of women with both low estradiol and high SHBG levels was at an almost 8-fold increased risk of incident vertebral fracture.
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Acknowledgments |
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Footnotes |
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Received December 26, 2002.
Accepted March 31, 2004.
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