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Low Thyrotropin Levels Are Not Associated with Bone Loss in Older Women: A Prospective Study¹

Division of General Internal Medicine (D.C.B.) and the Department of Epidemiology and Biostatistics (D.C.B., M.C.N., K.S.), University of California, San Francisco, California 94105; and the Division of Research, Kaiser Permanente Medical Care Program (B.E.), Oakland, California 94611

Address all correspondence and requests for reprints to: Douglas C. Bauer, M.D., University of California, 74 New Montgomery, Suite 600, San Francisco, California 94105.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
The relationship between excess thyroid hormone and bone loss is controversial. To determine whether low TSH levels, indicating excessive thyroid hormone, are associated with low bone mass or accelerated bone loss in older women, we performed a prospective cohort study of 458 women over age 65 yr participating in the multicenter Study of Osteoporotic Fractures.

Three hundred and twenty-three women were randomly selected from the entire cohort of 9704; an additional 135 randomly selected thyroid hormone users were studied. Medical history, medication use, and calcaneal bone mineral density (BMD) were assessed at the baseline visit. Serum was collected and stored at -190 C. Hip and spine BMD were measured approximately 2 yr later, and follow-up calcaneal and hip BMD measurements were obtained after mean follow-up periods of 5.7 and 3.5 yr, respectively. TSH levels were determined in baseline serum samples using a third generation chemiluminescent assay.

After adjustment for age, weight, previous hyperthyroidism, and use of estrogen, bone loss over 4–6 yr was similar in women with low, normal, or high TSH. For example, femoral neck bone loss was -0.3%/yr (95% confidence interval, -0.8%, 0.3%) among women with low TSH (0.1 mU/L) and -0.5%/yr (95% confidence interval, -0.7%, -0.3%) in those with normal TSH (0.1–5.5 mU/L). There were no statistically significant differences in baseline bone mass of the calcaneus, spine, or femoral neck or trochanteric hip subregions. Baseline total hip BMD was 6% lower (P = 0.01) in women with low TSH. Similar results were obtained in analyses confined to women not taking estrogens.

We found no consistent evidence that low TSH, a sensitive biochemical marker of excess thyroid hormone, was associated with low BMD or accelerated bone loss in older ambulatory women.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
THYROID dysfunction is common, particularly in certain high risk groups, such as older women (1). Biochemical evidence of endogenous thyroid dysfunction (either hyper- or hypothyroidism) is found in 5–10% of older women (2, 3). Furthermore, approximately 10% of women over age 65 yr take thyroid hormone, and a significant proportion of individuals taking thyroid hormone are overreplaced (4, 5). Only a small proportion of women receiving suppressive doses of thyroid hormone require it for treatment of thyroid cancer or other indications.

In vitro evidence suggests that excess thyroid hormone may be detrimental to skeletal heath (6, 7, 8), but retrospective clinical studies examining the relationship between thyroid function and bone mass have been conflicting (9). Importantly, there are no prospective studies of thyroid function and fracture risk, and there are no large prospective studies of the relationship between thyroid function and bone loss in an unselected population of older women.

We recently reported that in the Study of Osteoporotic Fractures (SOF), older women with a previous history of hyperthyroidism have a 70% increased risk of subsequent hip fractures compared to women without such a history (10). Women taking thyroid hormone also appeared to have an increased risk of fracture, but this was not statistically significant. Low bone mass did not account for the observed increase in fracture in that study, but those analyses did not include an objective measure of thyroid function.

To further study the relationship between thyroid disease and osteoporosis and to determine whether thyroid excess is related to low bone mass and subsequent bone loss in older women, we performed a prospective study using stored serum specimens from the SOF.

	Subjects and Methods

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Subjects

Subjects in this prospective cohort study were participants in the SOF, which was described in detail previously (11). Some 9704 white women over age 65 yr were recruited for the SOF from population-based listings at 4 clinical centers (Portland, Minneapolis, Pittsburgh, and Baltimore). These analyses are based on a subset of 352 women randomly selected from the cohort. In addition, we identified all thyroid hormone users at baseline (n = 720) and randomly selected 135 who were added to the sample. Thus, the final sample consisted of 487 women, including 198 thyroid hormone users.

Measurements

All SOF participants were interviewed and examined at one of the clinical centers during the baseline visit in 1986–1988. At that visit, detailed data about physician-diagnosed medical conditions and past medication use were collected, and current medication use was confirmed by examination of pill bottles by trained interviewers. Participants were asked specifically about previous diagnoses of hyperthyroidism or Grave’s disease and previous use of thyroid hormone. Height and weight were measured using standardized protocols, and serum was collected from each participant and stored at -190 C. Medication use, including thyroid hormone, was determined at a follow-up visit approximately 6 yr later.

Bone mass of the calcaneus was measured on all participants at the baseline visit using single photon absorptiometry and at a follow-up visit approximately 6 yr later using single x-ray absorptiometry (Siemens-Osteon, Wahiawa, HI). Bone masses of the hip and spine were not measured at the baseline visit, but were measured in 7963 women (82% of the original cohort) approximately 2 yr later. Follow-up hip bone mineral density (BMD) measurements were obtained 3–4 yr later (10). Follow-up spine measurements were not obtained. Hip and spine BMD were measured by dual energy x-ray absorptiometry (Hologic QDR 1000, Waltham, MA) using standard protocols. The details of these densitometric measurements, including reproducibility, have been previously reported (12).

TSH and other biochemical assays

In 1994, serum from the baseline visit for selected participants was thawed and assayed for TSH and biochemical markers of bone turnover. All hormone analyses were performed without knowledge of the participant’s fracture status or use of thyroid hormone.

TSH levels were measured using a highly sensitive, third generation chemiluminescent assay (Endocrine Science, Calabasas, CA). The normal range for this assay is 0.5–5.5 mU/L; the minimum detection level is 0.01 mU/L. At a TSH concentration of 0.5 mU/L, the intra- and interassay coefficients of variation are 4.7% and 6.3%, respectively. Previous data showed that among ambulatory adults, a TSH level of 0.1 mU/L or less using this assay is highly correlated with a suppressed response to TRH stimulation and is the best indicator of thyroid excess (13). Previous studies have also shown that TSH is highly stable in frozen serum over prolonged periods (14, 15).

Each of the specimens assayed for TSH was also assayed for markers of bone turnover. Serum total osteocalcin was measured with a human-specific two-site immunoradiometric assay (ELSA-OSTEO, CIS Biointernational, Bagnols/Ceze, France) that recognizes a large N-terminal midfragment in addition to the intact molecule (16). The mean ± SD of this assay in healthy premenopausal women are 21.8 ± 7.3. Serum bone-specific alkaline phosphatase (B-ALP) was measured with a human-specific immunoradiometric assay (Ostase, Hybritech, San Diego, CA). The mean ± SD of this assay in healthy premenopausal women are 8.7 ± 2.7 (17). Intact PTH was also measured with a two-site immunoradiometric assay (University of California-San Francisco Calciotropic Hormone Reference Laboratory).

Analysis

Differences in risk factors for bone loss, such as current estrogen use, were tested for statistical significance with Student’s t test or ² test. TSH levels were divided into the following categories: 0.1 mU/L or less (low), more than 0.1 but less than 5.5 mU/L (normal), and more than 5.5 mU/L (high). Analyses were also performed using different cut points for the low TSH group, such as 0.05 mU/L or less and 0.5 mU/L or less.

The relationships between TSH and bone mass at baseline and bone loss were analyzed with linear regression models; multivariate models were constructed to adjust for potential confounders. Potential confounders were selected on the basis of biological plausibility (e.g. body weight) or a strong association (P < 0.05) with BMD (e.g. age and estrogen use) or TSH level (e.g. previous hyperthyroidism). Among women with low baseline TSH (0.1 mU/L), bone loss analyses were repeated in those who reported the same thyroid hormone dose at both the baseline visit and the follow-up visit 6 yr later. Bone loss results are reported as the percent annual bone loss calculated from the least square means with 95% confidence intervals. Parallel analyses were performed examining the relationship between TSH and absolute bone loss (in grams per cm²); those results were similar and are not presented.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
Baseline characteristics and biochemical markers

Among women with both baseline and follow-up BMD measurements (n = 324), mean age and weight (±SD) were 70.9 ± 4.7 yr and 68.2 ± 11.5 kg, respectively. Compared to women with normal TSH levels (0.1–5.5 mU/L), those with low TSH levels (0.1 mU/L) tended to be older and lighter at the baseline visit (Table 1), but those differences were not statistically significant (P > 0.05). Compared to women with normal TSH levels, those with low TSH were much more likely to report previous hyperthyroidism (P < 0.01) and take thyroid hormone (P < 0.01). Among thyroid hormone users, the mean duration of use (±SD) was 20.1 ± 15.6 yr.

Compared to women with both baseline and follow-up BMD measurements (n = 324), women without follow-up BMD (n = 163) were older (73.9 ± 5.9 yr; P = 0.01), and weighed somewhat less (66.2 ± 13.1 kg; P = 0.10). TSH levels and baseline calcaneal and hip BMD were similar among those women with and without follow-up BMD measurements.

TSH and baseline BMD

After adjustment for age, weight, previous hyperthyroidism, current use of estrogen, and clinic, there were no significant differences in baseline calcaneal, spine, femoral neck, or trochanteric BMD among women with low, normal, or high TSH (Table 2). Adjusted baseline total hip BMD was 6.3% lower in women with low TSH compared to that in women with normal TSH (P = 0.01).

Of the 487 women with baseline calcaneal BMD, follow-up calcaneal measurements were obtained for 324 women (73.1% of surviving participants) after a mean follow-up of 5.7 yr. Age-adjusted calcaneal bone loss was similar among women with low, normal, and high TSH levels (Table 3). After adjustment for age, weight, previous hyperthyroidism, current use of estrogen, and clinic, there was no evidence of accelerated calcaneal bone loss in women with low TSH compared to those with normal TSH (-1.4% vs. -1.5%/yr, respectively; P = 0.78).

Of the 41 women with low TSH at baseline, bone loss was similar among those who reported taking the same (or higher) dose of thyroid at the follow-up visit 6 yr later (n = 18) and those who reported taking less thyroid at follow-up (n = 23). For example, mean adjusted femoral neck bone loss was 0.2%/yr, and total hip bone loss was 0.3%/yr among women taking the same dose of thyroid at baseline and follow-up compared to 0.4% and 0.8%, respectively, among those taking less thyroid hormone at follow-up.

Analyses of TSH and bone loss using different cut points for low TSH, such as 0.05 mU/L or less, gave results similar to those using a cut point of 0.1 mU/L. For example, after multivariate adjustment, calcaneal bone loss was similar among women with TSH levels of 0.05 mU/L or less (n = 37) and normal TSH (-1.3% vs. -1.5%/yr, respectively; P = 0.37). In addition, there was no evidence of accelerated femoral neck, total hip, or trochanteric bone loss among women with TSH levels of 0.05 mU/L or less (-0.3%, -0.5%, and -0.3%/yr, respectively).

To determine whether estrogen therapy might mask thyroid-related bone loss, the relationship between TSH and bone loss was examined in analyses limited to women not taking estrogen replacement (n = 266). After adjustment for age, weight, previous hyperthyroidism, and clinic, there was no difference in calcaneal or hip bone loss in women not taking estrogen with low, normal, or high TSH levels (Fig. 1).

View larger version (37K): [in this window] [in a new window]   Figure 1. TSH and annual bone loss among women not using oral estrogen at the baseline visit. The data shown are based on 266 paired calcaneal measurements and 239 paired hip measurements, adjusted for age, weight, previous hyperthyroidism, and clinic.

Women with previous hyperthyroidism and women taking thyroid hormone had similar rates of calcaneal and hip bone loss as women who did not report hyperthyroidism or take thyroid hormone (data not shown).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
This is the first large prospective study of thyroid function and bone loss in a population-based sample of postmenopausal women. We found that low TSH in ambulatory women over age 65 yr is not associated with accelerated calcaneal or hip bone loss over a extended period of follow-up. Excessive bone loss was not observed even in women with very low TSH (0.05 mU/L) or in those who continued to take the same dose of thyroid hormone over the course of the study. Furthermore, we found no evidence that low TSH was associated with accelerated bone loss among women not taking estrogens, nor did we find evidence that thyroid hormone use or previous hyperthyroidism was independently associated with accelerated bone loss. Bone loss over time appeared to be lower among women with biochemical evidence of thyroid deficiency, but these differences were not statistically significant.

With the exception of the total hip site, the cross-sectional relationships between TSH and baseline BMD were consistent with the longitudinal findings; low TSH was not associated with baseline BMD of the calcaneus, spine, or femoral neck or trochanter hip subregions. Baseline total hip BMD was 6% lower among women with low TSH, but the clinical significance of this isolated discordant finding is uncertain. Furthermore, compared to longitudinal data, cross-sectional analyses may be more susceptible to sampling error and other bias (18).

Many (19, 20, 21, 22, 23), but not all (3, 24, 25), previous cross-sectional studies have found that postmenopausal women with biochemical evidence of thyroid excess have lower BMD than a comparable sample with normal thyroid function. A recent meta-analysis of cross-sectional studies found that, on the average, bone mass was 9% lower in postmenopausal women with biochemical evidence of thyroid excess (9). Since the publication of that meta-analysis, several additional cross-sectional studies have not found lower bone mass in postmenopausal women with biochemical evidence of thyroid excess (26, 27). The discordant results reported in these studies may reflect differences in study design, sampling, and measurement of bone mass.

To date, only one prospective study of thyroid function and bone loss in postmenopausal women has been reported. As part of a clinical trial of calcium supplementation, Stall et al. (14) reported that 10 postmenopausal women (mean age, 60 ± 7 yr) with low TSH at baseline (0.3 mU/L) had greater bone loss of the spine over 1.9 yr of follow-up compared to those with normal TSH (-2.9% vs. -1.1%/yr; P = 0.01). In that study there was a trend toward greater bone loss of the femoral neck among women with low TSH (-1.4% vs. -0.1%/yr; P > 0.05). Prospective data on thyroid excess and bone loss in premenopausal women are also limited; 1 study of 15 premenopausal women found that, compared to age-matched controls, bone loss of the spine was greater in those receiving suppressive doses of T₄ 1–3 yr after thyroidectomy (2.6% vs. 0.2%/yr; P = 0.001), but bone loss of the radius did not differ in the 2 groups (28).

Our results may have differed from previous prospective studies of thyroid excess and bone loss for several reasons. Our study was much larger, used population-based sampling, followed participants over an extended period of time, and employed rigorous techniques to assure the stability of our longitudinal measurements. Furthermore, the mean duration of thyroid hormone use in our study was greater than 20 yr. Despite the long duration of thyroid excess in our study, biochemical markers of bone turnover were elevated in women with low TSH, suggesting accelerated skeletal turnover (29). Inadequate power is unlikely to explain the negative findings in this study, as the 95% confidence intervals for the primary end point (bone loss over an average follow-up of 3.5–5.7 yr) were narrow and not consistent with clinically significant undetected bone loss.

Despite these advantages, our study had several limitations. Spine BMD was not measured at the follow-up visit because the utility of this measurement has been questioned in older individuals with a high prevalence of spine osteoarthritis and extraskeletal calcifications. We did not measure T₄ or T₃ levels in women with low TSH, and it is possible that some of the women in this cohort had low TSH levels on the basis of hypothalamic or pituitary disease. However, other population-based studies suggest that this is rare (30). We only measured TSH in sera from the baseline visit and could not confirm that those with low TSH at baseline had low TSH throughout the study. Although study participants and their physicians were not notified of biochemical results during the study period, low TSH may have been detected and corrected in some women. However, analyses restricted to women with low baseline TSH who continued to take the same dose of thyroid hormone throughout the study yielded similar results; it is very likely that these women had persistently low TSH, yet there was no evidence that bone loss was greater in this group than in those taking less thyroid hormone at follow-up. Lastly, these results may not apply to other populations, such as men, younger women, and short term users of thyroid hormone.

In conclusion, in this prospective study of thyroid function and skeletal health in older women, we found no consistent evidence that low TSH was associated with low bone mass or accelerated bone loss. This study has important implications for the evaluation and management of postmenopausal women with low TSH. If low TSH is not associated with low bone mass or accelerated bone loss, it is unlikely that this mechanism explains our earlier observation of increased fracture rates in women with previous hyperthyroidism. Other mechanisms, such as poor bone quality from rapid bone turnover or impaired neuromuscular function, may be responsible. The critical question of whether low TSH is associated with an increased risk of fracture remains unanswered, and such analyses are in progress using data from this cohort.

	Footnotes

 
¹ This work was supported by USPHS Grant K08-AG-00629 (to the NIA). The Study of Osteoporotic Fractures Research Group consists of the Universities of California (San Francisco), Pittsburgh, and Minnesota (Minneapolis) and the Kaiser Center for Health Research (Portland, OR).

	Appendix 1

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
Investigators in the Study of Osteoporotic Fractures Research Group: University of California, San Francisco (Coordinating Center): S. R. Cummings (principal investigator), M. C. Nevitt (coinvestigator), D. G. Seeley (project director), D. M. Black (study statistician), H. K. Genant (director, central radiology laboratory), C. Arnaud, D. Bauer, W. Browner, L. Christianson, M. Dockrell, C. Fox, S. Harvey, M. Jergas, R. Lipschutz, G. Milani, L. Palermo, R. San Valentin, K. Stone, and D. Tanaka; University of Maryland: J. C. Scott (principal investigator), R. Sherwin (coprincipal investigator), M. C. Hochberg (coinvestigator), J. Lewis (project director), Cheryl Bailey (clinic coordinator), A. Bauer, L. Finazzo, G. Greenberg, D. Harris, B. Hohman, S. Kallenberger, E. Oliner, T. Page, A. Pettit, S. Snyder, L. Stranovsky, and S. Trusty; University of Minnesota: K. Ensrud (principal investigator), R. Grimm, Jr. (coinvestigator), C. Bell (project director), E. Mitson (clinic coordinator), M. Baumhover, C. Berger, S. Estill, S. Fillhouer, J. Hansen, K. Jacobson, K. Kiel, C. Linville, N. Nelson, E. Penland-Miller, and Jayne Griffith; University of Pittsburgh: J. A. Cauley (principal investigator), L. H. Kuller (coprincipal investigator), M. Vogt (coinvestigator), L. Harper (project director), L. Buck (clinic coordinator), C. Bashada, A. Githens, A. McCune, D. Medve, M. Nasim, C. Newman, S. Rudovsky, and N. Watson; The Kaiser Permanente Center for Health Research (Portland, OR): T. M. Vogt (principal investigator), W. M. Vollmer, E. Orwoll, H. Nelson (coinvestigators), J. Blank (project director), S. Craddick (clinic coordinator), R. Bright, J. Wallace, F. Heinith, K. Moore, K. Redden, C. Romero, and C. Souvanlasy.

Received March 21, 1997.

Revised May 23, 1997.

Accepted June 6, 1997.

	References

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 

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