About 10% of women and 3% of men older than 60

Transcription

1 Aals of Iteral Medicie Review Subcliical Thyroid Dysfuctio ad the Risk for Fractures A Systematic Review ad Meta-aalysis Christia D. Wirth, MD; Mauel R. Blum, MD; Bruo R. da Costa, PhD; Christie Baumgarter, MD; Tih-Hai Collet, MD; Marco Medici, MD, MSc; Robi P. Peeters, MD, PhD; Drahomir Aujesky, MD, MSc; Douglas C. Bauer, MD; ad Nicolas Rododi, MD, MAS Backgroud: Data o the associatio betwee subcliical thyroid dysfuctio ad fractures coflict. Purpose: To assess the risk for hip ad ospie fractures associated with subcliical thyroid dysfuctio amog prospective cohorts. Data Sources: Search of MEDLINE ad EMBASE (1946 to 16 March 2014) ad referece lists of retrieved articles without laguage restrictio. Study Selectio: Two physicias screeed ad idetified prospective cohorts that measured thyroid fuctio ad followed participats to assess fracture outcomes. Data Extractio: Oe reviewer extracted data usig a stadardized protocol, ad aother verified data. Both reviewers idepedetly assessed methodological quality of the studies. Data Sythesis: The 7 populatio-based cohorts of heterogeeous quality icluded participats with 1966 hip ad 3281 ospie fractures. I radom-effects models that icluded the 5 higher-quality studies, the pooled adjusted hazard ratios (HRs) of participats with subcliical hyperthyroidism versus euthyrodism were 1.38 (95% CI, 0.92 to 2.07) for hip fractures ad 1.20 (CI, 0.83 to 1.72) for ospie fractures without statistical heterogeeity (P 0.82 ad 0.52, respectively; I 2 0%). Pooled estimates for the 7 cohorts were 1.26 (CI, 0.96 to 1.65) for hip fractures ad 1.16 (CI, 0.95 to 1.42) for ospie fractures. Whe thyroxie recipiets were excluded, the HRs for participats with subcliical hyperthyroidism were 2.16 (CI, 0.87 to 5.37) for hip fractures ad 1.43 (CI, 0.73 to 2.78) for ospie fractures. For participats with subcliical hypothyroidism, HRs from higher-quality studies were 1.12 (CI, 0.83 to 1.51) for hip fractures ad 1.04 (CI, 0.76 to 1.42) for ospie fractures (P for heterogeeity 0.69 ad 0.88, respectively; I 2 0%). Limitatios: Selective reportig caot be excluded. Adjustmet for potetial commo cofouders varied ad was ot adequately doe across all studies. Coclusio: Subcliical hyperthyroidism might be associated with a icreased risk for hip ad ospie fractures, but additioal large, high-quality studies are eeded. Primary Fudig Source: Swiss Natioal Sciece Foudatio. A Iter Med. 2014;161: doi: /m For author affiliatios, see ed of text. About 10% of wome ad 3% of me older tha 60 years have subcliical hypothyroidism (1 3), ad prevalece icreases with age. Subcliical hypothyroidism is defied as elevated thyroid-stimulatig hormoe (TSH) ad ormal free thyroxie (FT 4 ) levels (4). Subcliical hyperthyroidism, defied as decreased TSH ad ormal FT 4 ad triiodothyroie (T 3 ) levels (4), is less commo ad affects about 1.5% of wome ad 1% of me older tha 60 years. Subcliical thyroid dysfuctio has previously bee associated with a icreased risk for coroary heart disease ad heart failure evets (5 7). Thyroid hormoes ifluece the homeostasis ad remodelig of boe (8). Overt hyperthyroidism is a risk factor for fractures (9). A few observatioal studies have also foud a icreased risk for fracture i persos with overt hypothyroidism (10, 11). The associatio betwee subcliical thyroid dysfuctio ad fractures remais uclear. A prospective cohort study of 3567 elderly participats foud a icreased risk for hip fractures i me with edogeous subcliical hyperthyroidism ad a similar tred i wome, whereas subcliical hypothyroidism was associated with a icreased risk for hip fracture i me oly (12). Coversely, a case cohort study of 1526 ambulatory me older tha 65 years foud o sigificat relatioship betwee subcliical hyperthyroidism ad fractures, but low-ormal TSH levels were sigificatly associated with a icreased risk for hip fractures (13). Other prospective studies (14) did ot adjust for commo relevat potetial cofouders betwee subcliical thyroid dysfuctio ad fractures, such as age, sex, body mass idex, smokig, ad corticosteroid use (15 24). Two meta-aalyses of postmeopausal wome with exogeous subcliical hyperthyroidism due to thyroxie substitutio showed a reductio i boe mieral desity (BMD), which is a surrogate marker for osteoporosis (25, 26). To our kowledge, o meta-aalysis has bee doe o the risk for fractures related with subcliical thyroid dysfuctio. Therefore, we did a meta-aalysis to determie whether subcliical thyroid dysfuctio ad TSH levels were associated with a icreased risk for fractures i prospective cohort studies. METHODS Data Sources ad Searches We followed a stadardized protocol to do this metaaalysis. Similar to our previous study (27), we coducted a systematic literature search for articles i ay laguage o the associatio betwee subcliical thyroid dysfuctio (both subcliical hypothyroidism ad hyperthyroidism) ad fractures published betwee 1946 ad 16 March 2014 i the MEDLINE ad EMBASE databases. I Ovid MEDLINE, we used the followig broadly defied Medical Subject Headigs: thyroid diseases, hypothyroidism, 2014 America College of Physicias 189

2 Review Subcliical Thyroid Dysfuctio ad the Risk for Fractures Table 1. Descriptio ad Results of Icluded Studies for the Effect of Subcliical Thyroid Dysfuctio o the Risk for Fractures Study, Year (Referece) Populatio, Mea Age, y Subcliical Hypothyroidism, TSH Cutoff Level* Subcliical Hyperthyroidism, MrOS, 2013 (13) Me, miu/l, miu/l, 37 Rotterdam, 2008 (44) ad Both sexes, 1473 (wome, 59.3%) miu/l, miu/l, (45) CHS, 2010 (12) Both sexes, 3567 (wome, 61.5%) miu/l, miu/l, 171 HUNT2, 2013 (36) Both sexes, (wome, 65.9%) miu/l, miu/l, 558 SOF, 2001 (35) Wome, 428 (hip fractures) ad 352 (ospie fractures) miu/l, miu/l, 23 (hip fractures) ad 20 (ospie fractures) 0.1 miu/l, 22 (hip fractures) ad 12 (ospie fractures) miu/l, miu/l, miu/l, 1070 TEARS, 2010 (14) Both sexes, all receivig thyroxie, (wome, 85.9%) Sheffield, 2008 (46) Wome, miu/l, miu/l, 11 CHS Cardiovascular Health Study; FT 4 free thyroxie; HR hazard ratio; HUNT2 Nord Trødelag Health Study 2; MrOS Osteoporotic Fractures i Me Study; ot reported; SOF Study of Osteoporotic Fractures; TEARS Thyroid Epidemiology Audit ad Research Study; TSH thyroid-stimulatig hormoe. * For the defiitio of subcliical thyroid dysfuctio. Most adjusted HRs available. Data from me ad wome combied (if available). Upublished data, icludig HRs, provided by the authors. Radom sample of the overall cohort. Data with exclusio of thyroxie recipiets available. Data available for me ad wome separately. ** Estimates reported were stratified by sex, so the authors used fixed effects to combie them before coductig the meta-aalysis to avoid double coutig a study i the radom-effects models. The FT 4 level was measured if the TSH level was 0.2 miu/l or 4.0 miu/l, but participats with biochemically overt thyroid dysfuctio were ot excluded. Nested sample of the overall cohort. The authors provided HRs with adjustmet for additioal cofouders, which had ot bee measured i all wome ad therefore reduced. Hip fractures were ot icluded i ospie fractures. Lower levels used oly for sesitivity aalyses. Oe hip fracture occurrig after a ospie fracture could ot be tracked. Crude data to prevet overfittig (oly 1 hip fracture). hyperthyroidism, thyroid hormoes, thyrotropi, subcliical hyperthyroidism, subcliical hypothyroidism, subcliical dysthyroidism, subcliical thyroid, ad fractures or osteoporosis. These headigs were combied with the filter desiged by British Medical Joural kowledge iformatio specialists to idetify radomized, cotrolled trials; cohorts; ad case cotrol studies without year limitatio or exclusio of commets, editorials, meta-aalyses, practice guidelies, reviews, letters, joural correspodeces, books, coferece papers, or aimal studies (28). We used a similar procedure i EMBASE. We also searched the bibliographies of key articles i the field ad those icluded i this review, ad we cotacted authors for upublished studies. Study Selectio Similar to our previous study (27), 2 authors idepedetly screeed the abstracts ad titles of the search results ad retaied articles o prospective cohorts studyig the associatio betwee thyroid dysfuctio ad osteoporotic fractures. The same reviewers idepedetly assessed the remaiig full-text articles for eligibility o the basis of predefied criteria. Ay disagreemet was resolved by discussio with a third author. Because some prospective studies that measured thyroid fuctio ad assessed multiple outcomes may ot have reported fracture outcomes i the abstract, we also assessed the full text ad tables for reported fracture data i these studies. We icluded oly studies that fulfilled the followig a priori defied criteria: measuremet of thyroid fuctio, prospective follow-up of participats, assessmet of fracture outcomes, compariso group with euthyroidism, ad provisio of hazard ratios (HRs) or sufficiet data to calculate them. We excluded studies that examied oly persos with a history of overt thyroid dysfuctio or thyroid cacer. We cosidered ospie, hip, ad ay fractures, but we excluded spie fractures because vertebral fracture age is difficult to assess without serial radiographs ad the accuracy of self-report is poor (29). Agreemet amog reviewers was 97.9% for the first screeig of titles ad abstracts ( 0.69) ad 100% for full-text screeig ( 1.0). Data Extractio ad Quality Assessmet We used a stadardized data abstractio form to extract iformatio about participat characteristics, the criteria used to defie subcliical thyroid dysfuctio, ad fractures. We evaluated study quality usig slightly updated criteria (27, 30), addig iclusio of testig for the assumptio of proportioal hazards. Oe physicia reviewer extracted data, ad aother checked data. We assessed key idicators for the quality of the cohort studies August 2014 Aals of Iteral Medicie Volume 161 Number 3

3 Subcliical Thyroid Dysfuctio ad the Risk for Fractures Review Table 1 Cotiued Was FT 4 Level Measured ad Normal? Were Recipiets of Thyroid Hormoe Excluded? Follow-up, y Fractures (Overall Number of Fractures/Subcliical Hypothyroid; Euthyroid; Subcliical Hyperthyroid Subgroup) Subcliical Hypothyroidism HR (95% CI) Subcliical Hyperthyroidism Yes No (7.4% treated) 5.3 (mea) Hip fractures (48/6; 40; 2) 1.29 ( ) 2.41 ( ) Nospie fractures (106/10; 92; 4) 0.89 ( ) 1.58 ( ) Yes Yes 9.4 (mea) Hip fractures (53/4; 45; 4) 1.81 ( ) 1.61 ( ) Nospie fractures (249/12; 224; 13) 0.97 ( ) 1.36 ( ) Yes No (9.2% treated) 13 (media) Hip fractures (331/54; 256; 21) 1.23 ( ) ** 1.71 ( ) ** No Yes 12.5 (media) Hip fractures (1006/99; 876; 31) 1.05 ( ) 1.22 ( ) Hip ad forearm fractures (2212/204; 1948; 60) 1.05 ( ) 1.09 ( ) No No (11% treated) 3.7 (mea) Hip fractures (139/0; 114; 11 for a TSH level of 1.36 ( ) miu/l ad 14 for a TSH level 0.1 miu/l) Nospie fractures (93/0; 80; 8 for TSH level of 1.95 ( ) miu/l, 5 for TSH level 0.1 miu/l) No No (100% treated) 4.5 (media) Hip fractures (384/) 1.70 ( ) 1.08 ( ) Nospie fractures (540/) 1.81 ( ) 1.11 ( ) Yes No (1.7% treated) 10 (media) Hip fractures (5/) ( ) Nospie fractures (81/) 2.04 ( ) 1.89 ( ) (31, 32): the populatio studied (coveiece sample vs. populatio-based, which was defied as a radom sample of the geeral populatio) ad methods of fracture ascertaimet ad adjudicatio (cosidered adequate if doe by a expert pael blided to thyroid status usig a clear outcome defiitio); assessmet of the proportioal hazard assumptio; completeess of follow-up; ad adjustmet for potetial cofouders. We defied age, sex, body mass idex, smokig, ad corticosteroid use (15 24) as commo relevat potetial cofouders for the relatioship betwee subcliical thyroid dysfuctio ad fractures based o a literature search cosiderig their prevalece ad stregth of associatio with fractures ad thyroid dysfuctio. We required adjustmet for most of these risk factors ad lack of violatio of the proportioal hazard assumptio for a study to be rated as higher quality. If a article did ot clearly metio oe of these criteria, we cosidered that it had ot bee doe. Two reviewers idepedetly rated all studies for quality, ad disagreemet was resolved with a third reviewer. We cotacted the authors of all cohorts to request more detailed data o the associatio betwee subcliical thyroid dysfuctio ad fractures. We used the most adjusted HRs ad 95% CIs available. Data Sythesis ad Statistical Aalysis We used TSH cutoff levels as reported by each cohort. If ot otherwise specified by a cohort, we used a commo defiitio of subcliical thyroid disease based o expert reviews (4, 33) ad the defiitio used i the Cardiovascular Health Study (12, 34), as doe i previous articles (5 7). Subcliical hypothyroidism was defied as a TSH level greater tha 4.5 to 20.0 miu/l ad a FT 4 level i the referece rage. Subcliical hyperthyroidism was defied as a TSH level less tha 0.45 miu/l ad a FT 4 level i the referece rage. Euthyroidism was defied as a TSH cutoff level from 0.45 to 4.5 miu/l. For FT 4, we used study-specific cutoff levels because these measuremets show greater itermethod variatio tha TSH. Three studies (14, 35, 36) did ot iclude FT 4 i their defiitio of subcliical thyroid dysfuctio. Two of these studies (35, 36) were icluded i the mai aalysis of the higherquality studies, but we did a sesitivity aalysis excludig studies without FT 4 measuremet or with abormal FT 4 because some participats may have overt thyroid dysfuctio. Two of these studies differetiated betwee low ad suppressed TSH levels (14, 35). We used data from the group with low but ot suppressed TSH levels because, accordig to upublished data i our previous idividualparticipat data aalysis (7), about oe fourth of persos with a TSH level less tha 0.1 miu/l had overt hyperthyroidism, but oly about 5% of those with a TSH level greater tha 0.1 miu/l had overt hyperthyroidism. We qualitatively sythesized data ad assessed which participats were icluded, the defiitio of thyroid dysfuctio, ad which types of fractures were studied. First, for the higher-quality studies, we calculated pooled estimates ad 95% CIs of the risk for subcliical hyperthyroidism ad hypothyroidism o hip ad ospie fractures usig radom-effects models based o the Kapp Hartug approach (37) to accout for the ucertaity associated with statistical heterogeeity (tau-square estimatio) ad the small umber of studies icluded (38). Secod, we assessed overall pooled estimates for all studies usig the same approach. Because the Cardiovascular Health Study oly reported estimates stratified by sex, we used fixed effects to combie these estimates before poolig them with other cohorts (12). To assess heterogeeity amog studies, we quatified the Q statistic with a coservative P value of 0.10 (39) ad used the I 2 statistic, which describes the total variatio across studies attributable to heterogeeity rather tha chace (I 2 50%, idicatig at least moderate statistical 5 August 2014 Aals of Iteral Medicie Volume 161 Number 3 191

4 Review Subcliical Thyroid Dysfuctio ad the Risk for Fractures Table 2. Quality Assessmet of Icluded Studies* Study, Year (Referece) Desig Coutry Settig, Formal Adjudicatio Procedures for Fractures MrOS, 2013 (13) Radom sample of a prospective cohort Uited States Cliical ceter, 6 Yes Rotterdam, 2008 (44) ad 2013 (45) Prospective cohort study The Netherlads District, 1 Yes CHS, 2010 (12) Prospective cohort study Uited States Commuity, 4 No HUNT2, 2013 (36) Prospective cohort study Norway Regio, 1 Yes SOF, 2001 (35) Nested case cohort study Uited States Cliical ceter, 4 Yes TEARS, 2010 (14) Prospective cohort study Scotlad Regio, 1 Sheffield, 2008 (46) Prospective cohort study Uited Kigdom Tow, 1 BMI body mass idex; CHS Cardiovascular Health Study; HUNT2 Nord Trødelag Health Study 2; ICD-9 Iteratioal Classificatio of Diseases, Nith Revisio; ICD-10 Iteratioal Classificatio of Diseases, Teth Revisio; MrOS Osteoporotic Fractures i Me Study; NCSP Nomesco Classificatio of Surgical Procedures; ot reported; SIFF-95 third versio of the atioal classificatio of surgical procedures; SOF Study of Osteoporotic Fractures; TEARS Thyroid Epidemiology Audit ad Research Study. * If a article did ot clearly metio oe of the quality measures (e.g., formal adjudicatio procedures, adjudicatio without kowledge of thyroid status, lost to follow-up, or adjustmets made), we cosidered that it had ot bee doe. All studies listed were populatio-based, which was defied as a radom sample of the geeral populatio. Defied as havig clear criteria for the outcome that was reviewed by experts for each potetial case. The sample was chose radomly at the baselie cliic visit from the 5994 participats icluded i the MrOS cohort. Commuicated by the ivestigator. 214 participats died. ** 3 participats were missig fracture outcomes amog those who did ot die. Tested usig log log survival plots. Idetificatio of outcomes by review of hospital records. Missig outcome data caot formally be excluded because fractures treated i other hospitals might be missig. Refers to 1 hip fracture occurrig after a ospie fracture that could ot be tracked. Assessed by graphical methods (log log graphs) ad the Schoefeld test. heterogeeity) (40). To explore sources of heterogeeity, we did several predefied sesitivity aalyses from all icluded studies usig radom-effects models. We also did aalyses stratified by age ad sex. Stratified aalysis were accompaied by iteractio tests based o Z scores, which are defied as the differece i effect estimates betwee strata divided by the SE of the differece. We used a adjusted rak correlatio test to assess for publicatio bias (41). However, graphical ad statistical methods may ot be reliable because of their limited power due to the small umber of studies icluded i our metaaalysis (42). All aalyses were doe by usig Stata, versio 12.1 (StataCorp, College Statio, Texas). Role of the Fudig Source The fudig source had o role i defiig questios, abstractig data, sythesizig results, or preparig or decidig to submit the mauscript for publicatio. RESULTS Study Selectio Of the 1185 reports iitially idetified, 1132 were excluded o the basis of their title ad abstract because they were urelated to the associatio betwee subcliical thyroid dysfuctio ad fractures or were ot prospective studies with measuremet of thyroid hormoes (Appedix Figure 1, available at After full-text review of the 53 selected articles, we excluded 46 studies that did ot meet the iclusio criteria (Appedix Table, available at Seve studies met all eligibility criteria ad were icluded i the aalyses. Study Characteristics Table 1 shows the study characteristics of icluded studies i our meta-aalysis ad the HRs for the associatios betwee subcliical thyroid dysfuctio ad hip ad ospie fractures. These 7 studies icluded par August 2014 Aals of Iteral Medicie Volume 161 Number 3

5 Subcliical Thyroid Dysfuctio ad the Risk for Fractures Review Table 2 Cotiued Methods for Fracture Ascertaimet Cotact by mail; cetral adjudicatio by physicia review of radiology reports or radiographs Records from geeral practitioers ad the Dutch Natioal Hospital Registratio system; review of all coded evets by a medical expert Telephoe iterview or cliical visit; hospital records coded with ICD-9 Hospital records (patiet admiistratio system), diagoses coded with ICD-9, ICD-10, SIFF-95, or NCSP, ad x-ray descriptios; validatio by physicias, health secretaries, ad urses Cotact by mail; cofirmatio by review of radiographs or writte radiology reports Hospital records; diagoses coded with ICD-9 or ICD-10 Questioaire, geeral practitioer s otes, ad request forms; cofirmatio by radiologist s report or orthopedist s otes Adjudicatio Without Kowledge of Thyroid Status Lost to Follow-up, % Missig Outcome Data, % Proportioal Hazard Assumptio Adjustmets Yes Not violated Age, cliic site, race, BMI, physical activity score, alcohol itake, smokig, ad corticosteroid or thyroid hormoe use Yes ** Not violated Age, BMI, ad sex 0 0 Not violated Age, race, self-reported health status, frailty status, smokig, alcohol use, height, weight, calcium supplemetatio, ad the use of atiosteoporosis ad thyroid-alterig medicatio durig follow-up Not violated Age, sex, BMI, ad smokig status Yes 1 1 Not violated Thyroid hormoe or oral estroge use, previous hyperthyroidism, age, self-rated health, smokig, ad BMI Not violated Age, sex, history of hyperthyroidism, history of osteoporotic fracture, ad diabetic status 2 1 Not violated Age ticipats with 1966 hip ad 3281 ospie fractures. Four cohorts icluded me ad wome, 2 cohorts icluded oly wome, ad 1 cohort icluded oly me. Follow-up raged from 3.7 to 13 years. Oe cohort icluded oly participats treated with thyroid hormoe, ad 2 cohorts excluded all treated participats. Most cohorts assessed subcliical hyperthyroidism ad hypothyroidism, ad 1 cohort assessed oly subcliical hyperthyroidism. All studies used a secod- or third-geeratio TSH assay. Descriptio of Study Quality The quality of icluded studies was heterogeeous. All studies were populatio-based (Table 2). Four used a formal adjudicatio procedure for fracture ascertaimet, ad 3 reported adjudicatio of fractures without kowledge of thyroid status. Five cohorts provided iformatio o loss to follow-up, which was 2% or less. All cohorts reported oviolatio of the proportioal hazard assumptio. Table 2 idicates the cofouders that were adjusted for by the differet studies by usig appropriate multivariate aalyses. Five of the studies reported HRs with adjustmet for most of the aforemetioed commo relevat cofouders, but 2 studies lacked such adjustmet (14, 46). O the basis of the quality assessmet i Table 2, with the request of the adjustmet for most of these cofouders ad lack of violatio of the proportioal hazard assumptio, 5 studies were rated higher quality ad thus were icluded i the mai pooled aalysis (12, 13, 35, 36, 44). Subcliical Hyperthyroidism ad Hip Fractures All studies foud a icreased risk for hip fractures associated with subcliical hyperthyroidism, ad the Sheffield cohort had a statistically sigificat icreased risk (Figure, top) (46). Amog the higher-quality studies, 3 studies showed a HR greater tha 1.5; the 2 largest studies foud a lower HR, although TEARS (Thyroid Epidemiology Audit ad Research Study) was ot icluded i the aalysis of the higher-quality studies because of iadequate adjustmet for commo relevat cofouders ad erollmet of oly participats receivig log-term thyroxie medicatio. I a radom-effects model with the 5 higher-quality studies, the pooled HR of subcliical hyperthyroidism ad hip fractures was 1.38 (95% CI, 0.92 to 2.07) without evidece of heterogeeity (P for heterogeeity 0.82; I 2 0%) (Table 3). Poolig estimates from all 7 icluded studies yielded similar results (Table 3). Icludig oly studies that used a TSH cutoff level less tha 0.45 miu/l yielded a HR of 1.46 (CI, 0.62 to 3.45) for hip fractures. Pooled estimates for a TSH cutoff level of 0.1 miu/l or less yielded a HR of 2.03 (CI, 0.27 to 15.00) with large CIs because oly 2 studies reported such data. Results excludig all thyroid hormoe recipiets ad thereby limitig the aalysis to participats with edogeous subcliical hyperthyroidism idicated a icreased risk for hip fracture (HR, 2.16 [CI, 0.87 to 5.37]). Predefied sesitivity aalyses excludig studies that did ot iclude FT 4 i their defiitio of subcliical thyroid dys- 5 August 2014 Aals of Iteral Medicie Volume 161 Number 3 193

6 Review Subcliical Thyroid Dysfuctio ad the Risk for Fractures Figure. Forest plots for subcliical hyperthyroidism. Study, Year (Referece) Subcliical Hyperthyroid Group Hip Fracture Evets, Participats, Hip Fracture Evets, Euthyroid Group Participats, Hazard Ratio (95% CI) MrOS, 2013 (13) ( ) Rotterdam, 2008 (44) ad 2013 (45) ( ) CHS, 2010 (12) ( ) HUNT2, 2013 (36) ( ) SOF, 2001 (35) ( ) TEARS, 2010 (14) ( ) Sheffield, 2008 (46) ( ) Lower Risk Higher Risk Study, Year (Referece) Subcliical Hyperthyroid Group Nospie Fracture Evets, Participats, Nospie Fracture Evets, Euthyroid Group Participats, Hazard Ratio (95% CI) MrOS, 2013 (13) ( ) Rotterdam, 2008 (44) ad 2013 (45) ( ) HUNT2, 2013 (36) ( ) SOF, 2001 (35) ( ) TEARS, 2010 (14) ( ) Sheffield, 2008 (46) ( ) Lower Risk Higher Risk CHS Cardiovascular Health Study; HUNT2 Nord Trødelag Health Study 2; MrOS Osteoporotic Fractures i Me Study; ot reported; SOF Study of Osteoporotic Fractures; TEARS Thyroid Epidemiology Audit ad Research Study. Top. Risk for hip fractures. Bottom. Risk for ospie fractures. fuctio, with the potetial erollmet of participats with overt thyroid disease, yielded a slightly higher fracture risk. Stratified aalyses by sex ad age did ot show statistical sigificace for iteractio. A sesitivity aalysis cosiderig our predefied quality measures showed similar results for iclusio of studies usig formal adjudicatio procedures. Results remaied similar after excludig 1 study with a case cohort desig. After excludig a study that lacked FT 4 measuremets, icluded oly thyroxietreated patiets, ad therefore compared overtreated participats with those i whom euthyroidism was achieved (14), the HR for hip fractures was 1.43 (CI, 0.99 to 2.06) ad the duratio of overtreatmet was ot reported. Subcliical Hyperthyroidism ad Nospie Fractures All icluded studies had a patter of a icreased risk for ospie fractures associated with subcliical hyperthyroidism, although it was ot statistically sigificat (Figure, bottom). The pooled HR, icludig estimates from the 4 higher-quality studies, was 1.20 (CI, 0.83 to 1.72), with weak evidece for statistical heterogeeity (P for heterogeeity 0.52; I 2 0%). Poolig estimates from all studies ad sesitivity aalyses yielded similar results (Table 3) to those for the associatio betwee subcliical hyperthyroidism ad hip fractures. Subcliical Hypothyroidism ad Fractures Most idividual studies showed a statistically osigificat patter of a icreased risk for hip fractures associated with subcliical hypothyroidism (Appedix Figure 2, available at Pooled HRs from the higher-quality studies were 1.12 (CI, 0.83 to 1.51) for hip fractures ad 1.04 (CI, 0.76 to 1.42) for ospie fractures, both without evidece for heterogeeity across stud August 2014 Aals of Iteral Medicie Volume 161 Number 3

7 Subcliical Thyroid Dysfuctio ad the Risk for Fractures Review ies (P 0.69 ad 0.88, respectively; I 2 0%) (Appedix Figure 2 ad Table 4). Pooled estimates from studies with FT 4 measuremets, which have excluded possibly erolled participats with overt hypothyroidism, as well as from studies excludig thyroxie recipiets, yielded similar results. Evaluatio of Potetial Publicatio Bias The rak correlatio tests idicated little evidece of publicatio bias (P 0.05) for all associatios, although these tests are ot sesitive due to the small umber of studies (42). DISCUSSION I this meta-aalysis of 7 populatio-based, prospective cohort studies, pooled results from the 5 higher-quality studies idicated that subcliical hyperthyroidism might be associated with a icreased risk for hip fractures (HR, 1.38 [CI, 0.92 to 2.07]) ad ospie fractures (HR, 1.20 [CI, 0.83 to 1.72]). Whe thyroxie recipiets were excluded, the HRs for participats with subcliical hyperthyroidism were 2.16 (CI, 0.87 to 5.37) for hip fractures ad 1.43 (CI, 0.73 to 2.78) for ospie fractures. The relatioship betwee subcliical hyperthyroidism ad fractures seemed to be stroger amog adults with a TSH cutoff level of 0.1 miu/l or less, which idicated a possible dose respose relatioship; however, CIs were large because oly 2 studies provided such data. I subcliical hypothyroidism, the risk for fractures did ot seem to be icreased amog the higher-quality studies. To our kowledge, our study is the first systematic review ad meta-aalysis to examie the associatio betwee subcliical thyroid dysfuctio ad fracture risk. Our fidigs are supported by 2 previous meta-aalyses of TSH-suppressive thyroxie therapy (25, 26), which foud that i postmeopausal wome, exogeous subcliical hyperthyroidism was sigificatly associated with a 0.91% aual decrease i boe mass (25). I additio, itervetioal studies o edogeous subcliical hyperthyroidism due to odular goiter showed a 2% aual lower BMD tha i postmeopausal wome treated with a atithyroid drug or radioiodie (47, 48). I overt hyperthyroidism, a meta-aalysis of 5 cohort or case cotrol studies showed that the risk for fractures ormalized after 1 year of atithyroid therapy (9). A recet systematic review o the Table 3. Stratified ad Sesitivity Aalyses of the Associatio of Subcliical Hyperthyroidism ad the Risk for Fractures Variable Hip Fractures Nospie Fractures Pooled HR (95% CI) Studies, P for Heterogeeity* Pooled HR (95% CI) Studies, Higher-quality studies Radom effects 1.38 ( ) ( ) Fixed effects 1.38 ( ) ( ) 4 Estimates with all studies Radom effects 1.26 ( ) ( ) Fixed effects 1.22 ( ) ( ) 6 Stratified ad sesitivity aalyses Defiitio of subcliical hyperthyroidism TSH cutoff level 0.45 miu/l 1.46 ( ) ( ) TSH cutoff level 0.1 miu/l 2.03 ( ) ( ) Exclusio of recipiets of thyroxie 2.16 ( ) ( ) Measuremet of FT 4 level ad ormal FT 4 level 1.90 ( ) ( ) Stratified by sex Wome 1.22 ( ) ( ) Me 1.35 ( ) ( ) Stratified by mea age at erollmet i the cohorts 65 y 1.21 ( ) ( ) y 1.67 ( ) ( ) Characteristics of study quality Formal fracture adjudicatio procedures ad adjudicatio 1.31 ( ) ( ) without kowledge of thyroid status Studies excluded HUNT2 (36), icluded oly hip ad forearm fractures 1.40 ( ) ( ) as ospie fractures TEARS (14), icluded oly recipiets of thyroxie 1.43 ( ) ( ) SOF (35), used case cohort desig 1.30 ( ) ( ) P for Heterogeeity* FT 4 free thyroxie; HUNT2 Nord Trødelag Health Study 2; HR hazard ratio; SOF Study of Osteoporotic Fractures; TEARS Thyroid Epidemiology Audit ad Research Study; TSH thyroid-stimulatig hormoe. * P 0.10; ratios are homogeeous. Did ot measure FT 4 or triiodothyroie. P for iteractio (sex) 0.82 (hip fractures) ad 0.69 (ospie fractures). P for iteractio (age) 0.63 (hip fractures) ad 0.53 (ospie fractures). 5 August 2014 Aals of Iteral Medicie Volume 161 Number 3 195

8 Review Subcliical Thyroid Dysfuctio ad the Risk for Fractures Table 4. Stratified ad Sesitivity Aalyses of the Associatio of Subcliical Hypothyroidism ad the Risk for Fractures Variable Hip Fractures Nospie Fractures Pooled HR (95% CI) Studies, P for Heterogeeity* Pooled HR (95% CI) Studies, Higher-quality studies Radom effects 1.12 ( ) ( ) Fixed effects 1.12 ( ) ( ) 3 Estimates with all studies Radom effects 1.30 ( ) ( ) Fixed effects 1.25 ( ) ( ) 5 Stratified ad sesitivity aalyses Defiitio of subcliical hypothyroidism Exclusio of recipiets of thyroxie 1.10 ( ) ( ) Measuremet of FT 4 level ad ormal FT 4 level 1.28 ( ) ( ) Stratified by sex Wome 1.29 ( ) ( ) Me 1.31 ( ) ( ) Stratified by mea age at erollmet i the cohorts 65 y 1.32 ( ) ( ) y 1.28 ( ) ( ) Characteristics of study quality Formal fracture adjudicatio procedures ad adjudicatio 1.08 ( ) ( ) without kowledge of thyroid status Studies excluded HUNT2 (36), icluded oly hip ad forearm 1.49 ( ) ( ) fractures as ospie fractures TEARS (14), icluded oly recipiets of thyroxie 1.12 ( ) ( ) FT 4 free thyroxie; HUNT2 Nord Trødelag Health Study 2; HR hazard ratio; TEARS Thyroid Epidemiology Audit ad Research Study. * P 0.10; ratios are homogeeous. P for iteractio (sex) 0.98 (hip fractures) ad 0.50 (ospie fractures). P for iteractio (age) 0.98 (hip fractures) ad 0.77 (ospie fractures). P for Heterogeeity* cliical cosequeces of variatios i thyroid hormoes withi the euthyroid referece rage foud good evidece for icreased fracture risk associated with lower euthyroid TSH levels (49). Differet hypotheses have bee made about the mechaisms of the associatio betwee subcliical hyperthyroidism ad fractures. Subcliical hyperthyroidism has bee associated with decreased BMD (25, 26) ad may cotribute to osteoporosis (50), which icreases vulerability to fractures (51). A study showed that thigh muscle stregth decreases i subcliical hyperthyroidism ad possibly leads to a icreased risk for fall-related fractures (52, 53), although data o a direct associatio betwee subcliical hyperthyroidism ad falls are lackig. The duratio of subcliical hyperthyroidism may also play a importat role i fracture developmet (47, 48, 51); however, this is difficult to assess, especially for edogeous subcliical hyperthyroidism (54). The observed lower risk for fractures whe combiig patiets with exogeous ad edogeous subcliical hyperthyroidism may be due to a presumably lower risk for fractures i patiets with exogeous subcliical hyperthyroidism who may receive a reduced dosig of thyroid hormoes, which limits the duratio of the dysfuctio. We foud o evidece of a risk differece for fractures i wome compared with me, despite the fact that wome especially postmeopausal wome have a icreased risk for osteoporosis. I Americas aged 80 years, the 10-year probability of a hip fracture was 14% for wome ad 6% for me (55). Because all studies but 1 (35) did ot have HRs adjusted for BMD, our aalysis did ot iclude BMD. Whe the Study of Osteoporotic Fractures (35) accouted for BMD, results did ot substatially chage the associatio betwee subcliical hyperthyroidism ad fractures. However, the extet to which boe mass mediates the adverse effect of low TSH levels o fracture risk remais ucertai. Prospective data o the associatio betwee subcliical hypothyroidism ad fractures are scarce, ad studies maily ivestigate treated patiets. A small radomized study showed a 1.3% reductio i lumbar BMD after 48 weeks of thyroxie treatmet for subcliical hypothyroidism compared with placebo (56), ad a large registry study i Demark foud a icreased fracture risk for participats with overt hypothyroidism up to 4 years after iitiatio of thyroxie substitutio (57). I our meta-aalysis, we did ot fid a icreased risk for fractures amog participats with subcliical hypothyroidism. However, isufficiet data preveted us from doig a sesitivity aalysis to assess fracture risk amog participats with subcliical hypothyroidism receivig thyroxie (compared with utreated participats). Overall, we did ot fid a effect of subcliical hypothyroidism o fractures, but the actual ef August 2014 Aals of Iteral Medicie Volume 161 Number 3

9 Subcliical Thyroid Dysfuctio ad the Risk for Fractures Review fect of thyroxie therapy o subcliical hypothyroidism caot be assessed with the preset study data. Our meta-aalysis of subcliical thyroid dysfuctio ad fractures has importat stregths. First, by poolig the data of all available studies, we aalyzed a total of 1966 hip ad 3281 ospie fractures i more tha participats, which icreased power to detect a associatio (58). Secod, oly populatio-based prospective studies were icluded. Third, by cotactig all pricipal ivestigators or coauthors of these 7 studies, we received additioal data that allowed us to derive more uiform subgroup ad sesitivity aalyses. Our study also has limitatios. First, because it is a meta-aalysis of observatioal studies, results have to be iterpreted with cautio, ad potetial biases, cofoudig, ad heterogeeity must be carefully ivestigated (31, 59). The quality of the studies was heterogeeous. Some studies did ot adequately adjust for all commo potetial cofouders, which left a risk for residual cofoudig, ad loss to follow-up ad missig data were ot reported i all studies. To address these limitatios, we reported this study accordig to accepted guidelies for a meta-aalysis of observatioal studies ad did sesitivity aalyses whe appropriate (59). Furthermore, we excluded studies with major limitatios from our mai aalysis ad pooled oly the 5 higher-quality studies. Secod, selectio bias may be preset. To reduce this possibility, we used broad iclusio criteria ad did sesitivity aalyses stratified by desig characteristics (59). Third, selective reportig caot be excluded because tests ad graphical assessmet for publicatio bias are ot sesitive eough owig to the small umber of studies icluded i our meta-aalysis (42). Fourth, our aalysis icluded oly Europea or U.S. cohorts, which limits the geeralizability to other settigs. Fifth, 6 of the 7 studies measured thyroid fuctio at baselie oly. Abormal TSH levels ca spotaeously ormalize i 20% to 40% of persos after a mea follow-up of 2 to 4 years (60, 61), which may have decreased the potetial associatios. Sixth, oly 4 of the 7 cohorts icluded the FT 4 level ad o study icluded the T 3 level i its defiitio of subcliical thyroid disease. However, excludig studies (14, 35, 36) i a sesitivity aalysis that did ot iclude the FT 4 level yielded similar results with slightly higher poit estimates. Fially, we coducted aalyses stratified by age ad sex usig aggregate data at study level, but we might have missed a sigificat relatioship because of ecological bias (62). What are the cliical ad research implicatios of these fidigs? Recet guidelies recommed treatmet of subcliical hyperthyroidism i all persos older tha 65 years (63), ad our fidigs of a possibly icreased fracture risk associated with subcliical hyperthyroidism are cosistet with these guidelies, although there are o studies i which treatmet resulted i a reduced fracture risk. Give the high prevalece of both osteoporosis ad subcliical thyroid dysfuctio i our agig populatios, our fidigs may have public health implicatios. However, because this is a meta-aalysis of observatioal studies, we caot rule out that our fidigs are due to reasos other tha subcliical thyroid dysfuctio. A meta-aalysis of idividual-participat data that does ot have potetial aggregatio bias could provide more isight through uiform TSH cutoff levels, stadardized adjustmet for potetial cofoudig factors, ad a thorough aalysis of subgroups. To prove causality, large radomized, cotrolled trials are ecessary to assess the efficacy of ormalizig TSH levels i subcliical thyroid dysfuctio associated with fracture risk (64). For subcliical hyperthyroidism, its low prevalece ad the requiremet for log follow-up make such trials a challege. But for subcliical hypothyroidism, the ogoig TRUST (Thyroid Hormoe Replacemet for Subcliical Hypothyroidism) trial (CliicalTrials.gov: NCT ) will clarify this issue (65). I summary, our systematic review idicates that subcliical hyperthyroidism might be associated with a icreased risk for hip ad ospie fractures, but additioal large, high-quality studies are eeded. From Uiversity of Ber, Ber, Switzerlad; Uiversity Hospital of Lausae, Lausae, Switzerlad; Erasmus Medical Ceter, Rotterdam, the Netherlads; ad Uiversity of Califoria, Sa Fracisco, Sa Fracisco, Califoria. Ackowledgmet: The authors thak Professor Richard Eastell ad Dr. Judith Fiiga (Uiversity of Sheffield, Sheffield, Uited Kigdom); Dr. Avatika Warig (Uiversity of Califoria, Sa Fracisco, Sa Fracisco, Califoria); Dr. Stephaie Litwack-Harriso (Sa Fracisco Coordiatig Ceter, Califoria Pacific Medical Ceter Research Istitute, Sa Fracisco, Califoria); Professor Graham Leese ad Dr. Robert W. Fly (Niewells Hospital ad Medical School, Dudee, Scotlad, Uited Kigdom); Dr. Aders Svare (Faculty of Medicie, Norwegia Uiversity of Sciece ad Techology, Trodheim, Norway); Professor Howard Fik (Geriatric Research Educatio ad Cliical Ceter, Mieapolis Veteras Affairs Medical Ceter, ad Departmet of Medicie, Uiversity of Miesota School of Medicie, Mieapolis, Miesota); ad Professor Ae R. Cappola (Perelma School of Medicie, Uiversity of Pesylvaia, Philadelphia, Pesylvaia) for supplyig additioal data from their studies. Fiacial Support: By the Swiss Natioal Sciece Foudatio (grat SNSF [Dr. Rododi]; salary support [Drs. Wirth, Blum, ad Baumgarter]; ad grat PBLAP for salary support [Dr. Collet]) ad i part by the Swiss Heart Foudatio (Dr. Rododi). Disclosures: Disclosures ca be viewed at /icmje/coflictofiterestforms.do?msnum M Requests for Sigle Reprits: Nicolas Rododi, MD, MAS, Departmet of Geeral Iteral Medicie, Iselspital, Ber Uiversity Hospital, 3010 Ber, Switzerlad; , Nicolas.Rododi@isel.ch. Curret author addresses ad author cotributios are available at August 2014 Aals of Iteral Medicie Volume 161 Number 3 197

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Effects of serum TSH ad FT4 levels ad the TSHR August 2014 Aals of Iteral Medicie Volume 161 Number 3