Manuel R. Blum

Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism

BACKGROUND The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. METHODS We conducted a double‐blind, randomized, placebo‐controlled, parallel‐group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid‐related quality‐of‐life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). RESULTS The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between‐group difference, 0.0; 95% confidence interval [CI], ‐2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between‐group difference, 0.4; 95% CI, ‐2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary‐outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. CONCLUSIONS Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126.)

Subclinical hypothyroidism and the risk of stroke events and fatal stroke: An individual participant data analysis

OBJECTIVE The objective was to determine the risk of stroke associated with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels. DATA EXTRACTION AND SYNTHESIS We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations. CONCLUSIONS Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

Subclinical Thyroid Dysfunction and the Risk for Fractures: A Systematic Review and Meta-analysis

About 10% of women and 3% of men older than 60 years have subclinical hypothyroidism (13), and prevalence increases with age. Subclinical hypothyroidism is defined as elevated thyroid-stimulating hormone (TSH) and normal free thyroxine (FT4) levels (4). Subclinical hyperthyroidism, defined as decreased TSH and normal FT4 and triiodothyronine (T3) levels (4), is less common and affects about 1.5% of women and 1% of men older than 60 years. Subclinical thyroid dysfunction has previously been associated with an increased risk for coronary heart disease and heart failure events (57). Thyroid hormones influence the homeostasis and remodeling of bone (8). Overt hyperthyroidism is a risk factor for fractures (9). A few observational studies have also found an increased risk for fracture in persons with overt hypothyroidism (10, 11). The association between subclinical thyroid dysfunction and fractures remains unclear. A prospective cohort study of 3567 elderly participants found an increased risk for hip fractures in men with endogenous subclinical hyperthyroidism and a similar trend in women, whereas subclinical hypothyroidism was associated with an increased risk for hip fracture in men only (12). Conversely, a casecohort study of 1526 ambulatory men older than 65 years found no significant relationship between subclinical hyperthyroidism and fractures, but low-normal TSH levels were significantly associated with an increased risk for hip fractures (13). Other prospective studies (14) did not adjust for common relevant potential confounders between subclinical thyroid dysfunction and fractures, such as age, sex, body mass index, smoking, and corticosteroid use (1524). Two meta-analyses of postmenopausal women with exogenous subclinical hyperthyroidism due to thyroxine substitution showed a reduction in bone mineral density (BMD), which is a surrogate marker for osteoporosis (25, 26). To our knowledge, no meta-analysis has been done on the risk for fractures related with subclinical thyroid dysfunction. Therefore, we did a meta-analysis to determine whether subclinical thyroid dysfunction and TSH levels were associated with an increased risk for fractures in prospective cohort studies. Methods Data Sources and Searches We followed a standardized protocol to do this meta-analysis. Similar to our previous study (27), we conducted a systematic literature search for articles in any language on the association between subclinical thyroid dysfunction (both subclinical hypothyroidism and hyperthyroidism) and fractures published between 1946 and 16 March 2014 in the MEDLINE and EMBASE databases. In Ovid MEDLINE, we used the following broadly defined Medical Subject Headings: thyroid diseases, hypothyroidism, hyperthyroidism, thyroid hormones, thyrotropin, subclinical hyperthyroidism, subclinical hypothyroidism, subclinical dysthyroidism, subclinical thyroid, and fractures or osteoporosis. These headings were combined with the filter designed by British Medical Journal knowledge information specialists to identify randomized, controlled trials; cohorts; and casecontrol studies without year limitation or exclusion of comments, editorials, meta-analyses, practice guidelines, reviews, letters, journal correspondences, books, conference papers, or animal studies (28). We used a similar procedure in EMBASE. We also searched the bibliographies of key articles in the field and those included in this review, and we contacted authors for unpublished studies. Study Selection Similar to our previous study (27), 2 authors independently screened the abstracts and titles of the search results and retained articles on prospective cohorts studying the association between thyroid dysfunction and osteoporotic fractures. The same reviewers independently assessed the remaining full-text articles for eligibility on the basis of predefined criteria. Any disagreement was resolved by discussion with a third author. Because some prospective studies that measured thyroid function and assessed multiple outcomes may not have reported fracture outcomes in the abstract, we also assessed the full text and tables for reported fracture data in these studies. We included only studies that fulfilled the following a prioridefined criteria: measurement of thyroid function, prospective follow-up of participants, assessment of fracture outcomes, comparison group with euthyroidism, and provision of hazard ratios (HRs) or sufficient data to calculate them. We excluded studies that examined only persons with a history of overt thyroid dysfunction or thyroid cancer. We considered nonspine, hip, and any fractures, but we excluded spine fractures because vertebral fracture age is difficult to assess without serial radiographs and the accuracy of self-report is poor (29). Agreement among reviewers was 97.9% for the first screening of titles and abstracts (= 0.69) and 100% for full-text screening (= 1.0). Data Extraction and Quality Assessment We used a standardized data abstraction form to extract information about participant characteristics, the criteria used to define subclinical thyroid dysfunction, and fractures. We evaluated study quality using slightly updated criteria (27, 30), adding inclusion of testing for the assumption of proportional hazards. One physician reviewer extracted data, and another checked data. We assessed key indicators for the quality of the cohort studies (31, 32): the population studied (convenience sample vs. population-based, which was defined as a random sample of the general population) and methods of fracture ascertainment and adjudication (considered adequate if done by an expert panel blinded to thyroid status using a clear outcome definition); assessment of the proportional hazard assumption; completeness of follow-up; and adjustment for potential confounders. We defined age, sex, body mass index, smoking, and corticosteroid use (1524) as common relevant potential confounders for the relationship between subclinical thyroid dysfunction and fractures based on a literature search considering their prevalence and strength of association with fractures and thyroid dysfunction. We required adjustment for most of these risk factors and lack of violation of the proportional hazard assumption for a study to be rated as higher quality. If an article did not clearly mention one of these criteria, we considered that it had not been done. Two reviewers independently rated all studies for quality, and disagreement was resolved with a third reviewer. We contacted the authors of all cohorts to request more detailed data on the association between subclinical thyroid dysfunction and fractures. We used the most adjusted HRs and 95% CIs available. Data Synthesis and Statistical Analysis We used TSH cutoff levels as reported by each cohort. If not otherwise specified by a cohort, we used a common definition of subclinical thyroid disease based on expert reviews (4, 33) and the definition used in the Cardiovascular Health Study (12, 34), as done in previous articles (57). Subclinical hypothyroidism was defined as a TSH level greater than 4.5 to 20.0 mIU/L and an FT4 level in the reference range. Subclinical hyperthyroidism was defined as a TSH level less than 0.45 mIU/L and an FT4 level in the reference range. Euthyroidism was defined as a TSH cutoff level from 0.45 to 4.5 mIU/L. For FT4, we used study-specific cutoff levels because these measurements show greater intermethod variation than TSH. Three studies (14, 35, 36) did not include FT4 in their definition of subclinical thyroid dysfunction. Two of these studies (35, 36) were included in the main analysis of the higher-quality studies, but we did a sensitivity analysis excluding studies without FT4 measurement or with abnormal FT4 because some participants may have overt thyroid dysfunction. Two of these studies differentiated between low and suppressed TSH levels (14, 35). We used data from the group with low but not suppressed TSH levels because, according to unpublished data in our previous individual- participant data analysis (7), about one fourth of persons with a TSH level less than 0.1 mIU/L had overt hyperthyroidism, but only about 5% of those with a TSH level greater than 0.1 mIU/L had overt hyperthyroidism. We qualitatively synthesized data and assessed which participants were included, the definition of thyroid dysfunction, and which types of fractures were studied. First, for the higher-quality studies, we calculated pooled estimates and 95% CIs of the risk for subclinical hyperthyroidism and hypothyroidism on hip and nonspine fractures using random-effects models based on the KnappHartung approach (37) to account for the uncertainty associated with statistical heterogeneity (tau-square estimation) and the small number of studies included (38). Second, we assessed overall pooled estimates for all studies using the same approach. Because the Cardiovascular Health Study only reported estimates stratified by sex, we used fixed effects to combine these estimates before pooling them with other cohorts (12). To assess heterogeneity among studies, we quantified the Q statistic with a conservative P value of 0.10 (39) and used the I 2 statistic, which describes the total variation across studies attributable to heterogeneity rather than chance (I 2> 50%, indicating at least moderate statistical heterogeneity) (40). To explore sources of heterogeneity, we did several predefined sensitivity analyses from all included studies using random-effects models. We also did analyses stratified by age and sex. Stratified analysis were accompanied by interaction tests based on Z scores, which are defined as the difference in effect estimates between strata divided by the SE of the difference. We used an adjusted rank correlation test to assess for publication bias (41). However, graphical and statistical methods may not be reliable because of their limited power due to the small number of studies include

Subclinical Thyroid Dysfunction and Depressive Symptoms among the Elderly: A Prospective Cohort Study

Background: Subclinical hypothyroidism has been associated with depressive symptoms in cross-sectional studies, but prospective data and data on subclinical hyperthyroidism are scarce. Methods: In the Leiden substudy of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), thyroid-stimulating hormone and free T4 levels were measured at baseline and repeated after 6 months in adults aged 70-82 years with preexisting cardiovascular disease or known cardiovascular risk factors to define persistent thyroid functional status. Main outcome measures were depressive symptoms, assessed with the Geriatric Depression Scale 15 (GDS-15) at baseline and after 3 years. All analyses were adjusted for age, gender and education. Results: In 606 participants (41% women; mean age 75 years) without antidepressant medication, GDS-15 scores at baseline did not differ for participants with subclinical hypothyroidism (n = 47; GDS-15 score 1.75, 95% CI 1.29-2.20, p = 0.53) or subclinical hyperthyroidism (n = 13; GDS-15 score 1.64, 95% CI 0.78-2.51, p = 0.96) compared to euthyroid participants (n = 546; mean GDS-15 score 1.60, 95% CI 1.46-1.73). After 3 years, compared to the euthyroid participants, changes in GDS-15 scores did not differ for participants with subclinical hypothyroidism (ΔGDS-15 score -0.03, 95% CI -0.50 to 0.44, p = 0.83), while subclinical hyperthyroidism was associated with an increase in GDS scores (ΔGDS-15 score 1.13, 95% CI 0.32-1.93, p = 0.04). All results were similar for persistent subclinical thyroid dysfunction. Conclusions: In this largest prospective study on the association of persistent subclinical thyroid dysfunction and depression, subclinical hypothyroidism was not associated with increased depressive symptoms among older adults at high cardiovascular risk. Persistent subclinical hyperthyroidism might be associated with increased depressive symptoms, which requires confirmation in a larger prospective study.

Low statin use in adults hospitalized with acute coronary syndrome

OBJECTIVE To assess recommended and actual use of statins in primary prevention of cardiovascular disease (CVD) based on clinical prediction scores in adults who develop their first acute coronary syndrome (ACS). METHOD Cross-sectional study of 3172 adults without previous CVD hospitalized with ACS at 4 university centers in Switzerland. The number of participants eligible for statins before hospitalization was estimated based on the European Society of Cardiology (ESC) guidelines and compared to the observed number of participants on statins at hospital entry. RESULTS Overall, 1171 (37%) participants were classified as high-risk (10-year risk of cardiovascular mortality ≥5% or diabetes); 1025 (32%) as intermediate risk (10-year risk <5% but ≥1%); and 976 (31%) as low risk (10-year risk <1%). Before hospitalization, 516 (16%) were on statins; among high-risk participants, only 236 of 1171 (20%) were on statins. If ESC primary prevention guidelines had been fully implemented, an additional 845 high-risk adults (27% of the whole sample) would have been eligible for statins before hospitalization. CONCLUSION Although statins are recommended for primary prevention in high-risk adults, only one-fifth of them are on statins when hospitalized for a first ACS.

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts

Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear.

Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts

Context Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design Individual participant data analysis. Setting Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants Adults with baseline TSH 0.45 to 4.49 mIU/L. Main Outcome Measures Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses. Conclusions Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.

The lower quality of preventive care among forced migrants in a country with universal healthcare coverage

OBJECTIVE To assess the association between socio-demographic factors and the quality of preventive care and chronic care of cardiovascular (CV) risk factors in a country with universal health care coverage. METHODS Our retrospective cohort assessed a random sample of 966 patients aged 50-80years followed over 2years (2005-2006) in 4 Swiss university primary care settings (Basel/Geneva/Lausanne/Zürich). We used RANDs Quality Assessment Tools indicators and examined recommended preventive care among different socio-demographic subgroups. RESULTS Overall patients received 69.6% of recommended preventive care. Preventive care indicators were more likely to be met among men (72.8% vs. 65.4%; p<0.001), younger patients (from 71.0% at 50-59years to 66.7% at 70-80years, p for trend=0.03) and Swiss patients (71.1% vs. 62.7% in forced migrants; p=0.001). This latter difference remained in multivariate analysis adjusted for gender, age, civil status and occupation (OR 0.68; 95% CI 0.54-0.86). Forced migrants had lower scores for physical examination and breast and colon cancer screening (all p≤0.02). No major differences were seen for chronic care of CV risk factors. CONCLUSION Despite universal healthcare coverage, forced migrants receive less preventive care than Swiss patients in university primary care settings. Greater attention should be paid to forced migrants for preventive care.

Prevalence of potentially inappropriate prescribing in a subpopulation of older European clinical trial participants: a cross-sectional study.

Objectives To estimate and compare the prevalence and type of potentially inappropriate prescribing (PIP) and potential prescribing omissions (PPOs) among community-dwelling older adults (≥65 years) enrolled to a clinical trial in three European countries. Design A secondary analysis of the Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial dataset. Participants A subset of 48/80 PIP and 22/34 PPOs indicators from the Screening Tool of Older Persons Prescriptions/Screening Tool to Alert doctors to Right Treatment (STOPP/START) V2 criteria were applied to prescribed medication data for 532/737 trial participants in Ireland, Switzerland and the Netherlands. Results The overall prevalence of PIP was lower in the Irish participants (8.7%) compared with the Swiss (16.7%) and Dutch (12.5%) participants (P=0.15) and was not statistically significant. The overall prevalence of PPOs was approximately one-quarter in the Swiss (25.3%) and Dutch (24%) participants and lower in the Irish (14%) participants (P=0.04) and the difference was statistically significant. The hypnotic Z-drugs were the most frequent PIP in Irish participants, (3.5%, n=4), while it was non-steroidal anti-inflammatory drug and oral anticoagulant combination, sulfonylureas with a long duration of action, and benzodiazepines (all 4.3%, n=7) in Swiss, and benzodiazepines (7.1%, n=18) in Dutch participants. The most frequent PPOs in Irish participants were vitamin D and calcium in osteoporosis (3.5%, n=4). In the Swiss and Dutch participants, they were bone antiresorptive/anabolic therapy in osteoporosis (9.9%, n=16, 8.6%, n=22) respectively. The odds of any PIP after adjusting for age, sex, multimorbidity and polypharmacy were (adjusted OR (aOR)) 3.04 (95% CI 1.33 to 6.95, P<0.01) for Swiss participants and aOR 1.74 (95% CI 0.79 to 3.85, P=0.17) for Dutch participants compared with Irish participants. The odds of any PPOs were aOR 2.48 (95% CI 1.27 to 4.85, P<0.01) for Swiss participants and aOR 2.10 (95% CI 1.11 to 3.96, P=0.02) for Dutch participants compared with Irish participants. Conclusions This study has estimated and compared the prevalence and type of PIP and PPOs among this cohort of community-dwelling older people. It demonstrated a significant difference in the prevalence of PPOs between the three populations. Further research is urgently needed into the impact of system level factors as this has important implications for patient safety, healthcare provision and economic costs.