Severity of obstructive airway disease and risk of osteoporotic fracture

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1 Eur Respir J 2005; 25: DOI: / CopyrightßERS Jourals Ltd 2005 Severity of obstructive airway disease ad risk of osteoporotic fracture F. de Vries*, T.P. va Staa*,#,", M.S.G.M. Bracke*,+, C. Cooper #, H.G.M. Leufkes* ad J-W.J. Lammers + ABSTRACT: The use of ihaled corticosteroids has bee associated with a dose-related icreased risk of fracture. This may be related to systemic absorptio. However, several studies have foud that patiets with more severe reductios i pulmoary fuctio had reduced boe mieral desity, idepedet of ihaled corticosteroids. The objective of this study was to evaluate the relatioship betwee disease severity ad fracture risk. A large case cotrol study (108,754 cases) was coducted usig data from the UK Geeral Practice Research Database. It was foud that higher doses of ihaled corticosteroids were associated with greater risks of fracture. The crude odds ratio of fracture amog patiets exposed to.1,600 mg beclomethasoe equivalets per day was 1.95 (95% cofidece iterval (CI) ). Whe adjustmets were made for disease severity ad use of brochodilators, the iitial dose respose relatioship betwee ihaled corticosteroids ad fracture risk disappeared (adjusted odds ratio of 1.19 (95% CI )). I coclusio, patiets with severe obstructive airway disease are at risk of fracture. However, adequate adjustmet for disease severity is essetial whe the associatio betwee the use of ihaled corticosteroids ad risk of osteoporotic fracture is studied i observatioal research. KEYWORDS: Ati-iflammatory agets, brochodilator agets, hip fractures, obstructive lug diseases, spial fractures AFFILIATIONS *Dept of Pharmacoepidemiology ad Pharmacotherapy, Utrecht Istitute for Pharmaceutical Scieces, Uiversity of Utrecht, ad + Dept of Pulmoary Diseases, Utrecht Medical Ceter, Utrecht, The Netherlads. # Medical Research Coucil Evirometal Epidemiology Uit, Uiversity of Southampto, Southampto Geeral Hospital, Southampto, ad " Procter ad Gamble Pharmaceuticals, Egham, UK. CORRESPONDENCE H.G.M. Leufkes Sorboelaa CA Utrecht The Netherlads Fax: secrfef@pharm.uu.l Ihaled corticosteroids are frequetly prescribed to patiets with obstructive airway disease (OAD) [1]. Although admiistered locally, ihaled corticosteroids udergo systemic absorptio ad may iduce a suppressio of plasma cortisol, especially at higher doses [2]. Patiets usig oral corticosteroids have a icreased risk of osteoporosis ad fractures [3]. For users of ihaled corticosteroids, a associatio betwee daily dose ad icreased risk of fractures has bee reported [4 7]. However, adjustmet for uderlyig disease severity was limited i these studies. I the largest case cotrol study, adjustmet for uderlyig disease severity was restricted to prior use of oral corticosteroids [5]. The importace of cotrollig for severity of uderlyig disease i this type of research has recetly bee emphasised [8, 9]. Also, it has bee reported that there was o icreased risk of fracture i patiets usig ihaled corticosteroids after adjustmet for the presece of OAD [10] or use of brochodilators [11]. Patiets with OAD have bee foud to have a reduced boe mieral desity (BMD), idepedet of the use of respiratory medicatio [12 14]. Therefore, the objective of this study was to evaluate the relatioship betwee disease severity of OAD ad the risk of fracture. METHODS Study populatio A case cotrol study was coducted usig data obtaied from the Geeral Practice Research Database (GPRD) [15]. This database comprises the etire computerised medical records of a sample of geeral practitioers i the UK. Several idepedet validatio studies have cofirmed a high level of completeess ad validity of the GPRD with regard to the recordig of fractures [16, 17]. I this study, cases were patiets aged o18 yrs with a first record durig GPRD followup (Jauary 1987 to July 1999) of a osteoporotic fracture (defied as a fracture of the radius/ula, femur/hip, ribs, humerus, vertebrae or clavicle) [18]. The date of the first fracture was defied as the idex date. For each case, oe cotrol patiet without a history of a fracture was matched to a case by age, sex, medical practice ad caledar time. A history of OAD before the idex date was examied i both cases ad cotrols. The defiitios for asthma ad chroic obstructive Received: May Accepted after revisio: Jauary SUPPORT STATEMENT This study was supported by Procter & Gamble Pharmaceuticals, Egham, UK. Europea Respiratory Joural Prit ISSN Olie ISSN c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 5 879

2 DISEASE SEVERITY AND FRACTURE RISK F. DE VRIES ET AL. pulmoary disease (COPD) were the same as those used i a previous GPRD validatio study [19]. TABLE 1 Baselie characteristics Defiitios of variables Use of medicatio for the treatmet of OAD was examied, icludig brochodilators (British Natioal Formulary (BNF) chapter 3.1 or 3.3) ad ihaled corticosteroids (BNF chapter 3.2) [20]. Curret users were patiets who had received at least oe prescriptio i the 6 moths before the idex date. Past users had received their last prescriptio.6 moths prior to the idex date. For each curret user, the average daily dose of brochodilators or ihaled corticosteroids was estimated by dividig the total amout of respiratory medicatio by the treatmet time (the time betwee the first ad last prescriptio of respiratory medicatio). Dose equivaleces were expressed as beclomethasoe diproprioate equivalets (ihaled corticosteroids) or salbutamol equivalets (brochodilators). Equivalets of differet compouds were calculated with defied daily doses [21]. Idicators of more severe OAD icluded records of OAD exacerbatios ad oxyge use i the 12 moths before the idex date, respiratory problems (bacterial respiratory tract ifectios, coughig, presece of sputum, haemoptysis, dyspoea, tachypoea, shortess of breath, acute brochitis or wheezig), use of oral corticosteroids i the 6 moths before the idex date ad a body mass idex (BMI),20. Next, the curret authors cotrolled for various geeral risk factors of fracture, icludig history of diabetes mellitus, rheumatoid arthritis, hyperthyroidism, cogestive heart failure, seizures, aaemia, demetia, depressio, psychotic disorder ad cerebrovascular accidet. Moreover, prescriptios i the 6 moths before the idex date for aticovulsats, osteroidal atiiflammatory drugs, methotrexate, hormoe-replacemet therapy, thiazide diuretics, axiolytics/hypotics, atipsychotics, atidepressats ad ati-parkiso s drugs were also cosidered as potetial cofoudig variables. BMI ad smokig status (curret or ex-smoker, osmoker or ukow) were icluded if etered i the database. Statistical aalyses Odds ratios (ORs) of fracture were estimated usig coditioal logistic regressio. Fial regressio models were determied by backward elimiatio usig a sigificace level of The ORs of these models were compared with the ORs of the models icludig all variables to idetify cofoudig by a elimiated variable, with iclusio of this variable i cases of cofoudig. Curret users of ihaled corticosteroids or brochodilators with a history of OAD before the idex date were compared with patiets who had ever bee exposed to ihaled corticosteroids or brochodilators ad who did ot have a diagosis of OAD. RESULTS The study populatio icluded 108,754 adult patiets who sustaied a osteoporotic fracture (44,201 radius/ula, 22,250 femur/hip, 16,189 rib, 14,646 humerus, 8,712 vertebral ad 3,908 clavicle fractures). Baselie characteristics are listed i table 1. The media time of erolmet before the idex date was 2.2 yrs. I the overall study populatio, higher BMI (.25) was associated with a reduced risk of a hip fracture (crude OR 0.61; 95% cofidece iterval (CI) ), compared with Characteristics Cases Cotrols Subjects Age yrs Mea Media Females (66) (66) Disease history before the idex date Asthma 9172 (8.4) 6737 (6.2) COPD 5537 (5.1) 3463 (3.2) Acute brochitis 3190 (2.9) 2237 (2.1) Heart failure 7586 (7.0) 6339 (5.8) Symptoms 1 yr before the idex date Exacerbatios 1174 (1.1) 605 (0.6) Difficulty with breathig 3326 (3.1) 2517 (2.3) Wheezig 1018 (0.9) 822 (0.8) Coughig 8417 (7.7) 6554 (6.0) Respiratory ifectio 1200 (1.1) 956 (0.9) Drug use 6 moths before the idex date Oe or more brochodilators 8213 (7.6) 5745 (5.3) Short-actig b 2 -agoists 6694 (6.2) 4626 (4.3) Atimuscariics 1439 (1.3) 829 (0.8) Xathies 1863 (1.7) 1237 (1.1) Log-actig b 2 -agoists 585 (0.5) 335 (0.3) Ihaled corticosteroids 5960 (5.5) 4107 (3.8) Oral corticosteroids 5405 (5.0) 2989 (2.7) Body mass idex, (6.2) 4875 (4.5) (26.7) (23.9) (26.1) (27.2) Not determied (41.0) (44.5) Data are preseted as ad (%). COPD: chroic obstructive pulmoary disease. patiets with a BMI ragig For patiets with low BMI (,20), the reverse was observed (crude OR 1.78; 95% CI ). Oral corticosteroid use was also associated with a icreased risk of hip fracture (crude OR 1.75; 95% CI ). Of the cases with curret oral corticosteroid use, 54% received five or more oral corticosteroid prescriptios i the previous year (for cotrols, this was 43%). The percetage of patiets with cotiuous oral corticosteroid use for.6 moths was 44% amog the cases ad 36% amog the cotrols (cotiuous use was defied as receivig a repeat oral corticosteroid prescriptio withi 3 moths of the previous prescriptio). The risk of osteoporotic fracture was icreased i patiets with asthma (crude OR 1.28; 95% CI ), i patiets with COPD (crude OR 1.61; 95% CI ), ad i patiets who had both diagoses recorded (crude OR 1.72; 95% CI ). Patiets with a idicator of more severe OAD geerally had icreased risks of fracture (fig. 1) compared with patiets without the idicator who did ot have a history of OAD. For example, the risk of osteoporotic fracture amog patiets with OAD exacerbatios was 2.02 (95% CI ) ad 2.54 (95% CI ) amog patiets with a BMI,20. Patiets with OAD who also smoked had a icreased risk of osteoporotic 880 VOLUME 25 NUMBER 5 EUROPEAN RESPIRATORY JOURNAL

3 F. DE VRIES ET AL. DISEASE SEVERITY AND FRACTURE RISK a) Respiratory symptoms b) c) 6 moths prior # Oral-steroid use 6 moths prior Exacerbatio(s) 12 moths prior Oxyge use 12 moths prior Body mass idex < Osteoporotic fractures Hip fractures Vertebral fractures FIGURE 1. Crude odds ratios (95% cofidece iterval) for fracture amog patiets with obstructive airway disease. # : respiratory symptoms iclude bacterial respiratory tract ifectios, coughig, presece of sputum, haemoptysis, dyspoea, tachypoea, shortess of breath, acute brochitis ad wheezig. fracture (crude OR 1.57; 95% CI ). Those who smoked,20 cigarettes?day -1 had a crude OR of 1.57 (95% CI ) compared with a OR of 1.79 (95% CI ) i patiets with OAD who smoked.20 cigarettes?day -1. Amog patiets with a history of OAD, the risk of osteoporotic fracture was icreased i both curret (crude OR 1.53; 95% CI ) ad past users (crude OR 1.36; 95% CI ) of ihaled corticosteroids, compared with those who had ever used ihaled corticosteroids ad were ot diagosed with OAD. Amog the curret users, the risk of fracture icreased with daily dose (table 2). Patiets exposed to brochodilators also had a icreased risk of fracture. Whe the curret authors adjusted for geeral risk factors, brochodilator use ad idicators of disease severity, curret use of ihaled corticosteroids was o loger associated with a icreased risk of osteoporotic fracture (adjusted OR 1.04; 95% CI ). Furthermore, the dose respose with ihaled corticosteroids observed i the crude aalysis was o loger statistically sigificat. Curret users of beclomethasoe, budesoide or fluticasoe had a comparable risk of fracture. TABLE 2 Crude ad adjusted odds ratios (OR) for fracture ad use of ihaled corticosteroids ad brochodilators 6 moths before the idex date Fracture type ad average daily dose Ihaled corticosteroids Brochodilators Cases Cotrols Crude OR (95% CI) Adjusted OR (95% CI) Cases Cotrols Crude OR (95% CI) Adjusted OR (95% CI) Referet Osteoporotic mg ( ) 1.04 ( ) ( ) 1.20 ( ) mg ( ) 1.03 ( ) ( ) 1.45 ( ) mg ( ) 1.15 ( ) ( ) 1.28 ( ).1600 mg ( ) 1.19 ( ) ( ) 1.35 ( ) Hip mg ( ) 1.01 ( ) ( ) 1.20 ( ) mg ( ) 0.97 ( ) ( ) 1.58 ( ) mg ( ) 1.09 ( ) ( ) 1.17 ( ).1600 mg ( ) 1.18 ( ) ( ) 1.37 ( ) Vertebral mg ( ) 1.60 ( ) ( ) 1.03 ( ) mg ( ) 1.33 ( ) ( ) 1.32 ( ) mg ( ) 1.21 ( ) ( ) 1.43 ( ).1600 mg ( ) 1.85 ( ) ( ) 1.62 ( ) CI: cofidece iterval; referet crude OR: subjects who were ever exposed to ihaled corticosteroids ad who did ot have a history of obstructive airway disease (OAD); referet adjusted OR: subjects who were ever exposed to ihaled corticosteroids ad brochodilators, ad who did ot have a history of OAD; adjusted: adjustmets were made for geeral risk factors, smokig status, body mass idex, duratio of erolmet i the Geeral Practice Research Database, idicators of OAD severity, ad exposure to brochodilators (ihaled corticosteroid group) or ihaled corticosteroids (brochodilator group). c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 5 881

4 DISEASE SEVERITY AND FRACTURE RISK F. DE VRIES ET AL. Most curret users of ihaled corticosteroids were also cocomitatly exposed to brochodilators (76% for cases ad 72% for cotrols). No statistically sigificat differeces could be foud betwee the use of both drugs at the same time ad sigle use. I the high-dose group (.1,600 mg beclomethasoe equivalets per day), approximately half had ot bee exposed to oral corticosteroids i the previous 6 moths. These patiets did ot have a icreased risk of osteoporotic fracture (adjusted OR 1.19; 95% CI ). The risk of fracture was icreased i patiets who were exposed to both oral corticosteroids ad high-dose ihaled corticosteroids. For osteoporotic fracture, the adjusted OR was 1.79 (95% CI ), for hip fracture 1.77 (95% CI ), ad 3.78 (95% CI ) for vertebral fracture. The media umber of prior oral corticosteroid prescriptios was 14 i these patiets. As show i table 3, patiets with more severe OAD had higher risks of fracture, ad these risks were comparable betwee users ad ousers of ihaled corticosteroids. The adjusted OR for osteoporotic fracture was 1.47 (95% CI ) i ousers ad 1.48 (95% CI ) i users of ihaled corticosteroids with more severe OAD. DISCUSSION I the curret study, the associatio betwee exposure to high doses of ihaled corticosteroids ad the risk of osteoporotic fracture was cofirmed. Nevertheless, it was also foud that the risk of fracture was related to idicators of severe OAD, ad that patiets usig higher doses of brochodilators also had icreased risks of fracture. After adjustmet for disease severity ad use of brochodilators, the iitial associatio betwee use of ihaled corticosteroids ad risk of osteoporotic fracture almost disappeared. Two other studies, oe usig a case cotrol desig ad the other a cohort desig, evaluated the risk of fracture of patiets usig ihaled corticosteroids i GPRD [4, 5]. Both these studies foud a dose-depedet icrease i fracture risk, but they differed i their iterpretatio o the aetiology of this icreased risk. The curret authors were able to cofirm the results of the case cotrol study [5] whe the same defiitios were applied (i.e. timig of prior use of ihaled corticosteroids was igored by combiig curret ad past users, ad o adjustmet was made for geeral risk factors, prior use of brochodilators or disease-severity idicators, with the exceptio of oral corticosteroid use). However, whe adjustig for disease-severity idicators, the hip-fracture risk i patiets usig ihaled corticosteroids was statistically comparable with ousers, eve at the higher doses. The preset fidigs suggest a importat role of the uderlyig respiratory disease i the aetiology of icreased fracture risk. There have bee several studies that have evaluated the risk of fracture i users of ihaled corticosteroids. A case cotrol study coducted i Demark foud a osigificat tred betwee use of high-dose ihaled ad itraasal corticosteroids ad risk of hip fracture, but the authors did ot adjust for comedicatio ad severity idicators [7]. I a ested case cotrol study amog elderly America veteras with COPD, a dose respose relatioship betwee short-term use of ihaled corticosteroids ad overtebral fracture risk was foud. Adjustmet for disease severity was limited to use of oral corticosteroids, the umber of hospitalisatios ad the umber of outpatiet visits [6]. The importace of adjustmet for the uderlyig disease severity was cofirmed i a ested case cotrol study coducted i a Caadia populatio. Hipfracture risk was ot associated with exposure to high-dose ihaled corticosteroids over a 4-yr period. The aalysis was adjusted for the umber of dispesigs of brochodilators [11]. I a cohort study cosistig of Caadia females, exposure to ihaled corticosteroids was ot associated with a icreased risk of hip fracture. Results were adjusted for a wide rage of uderlyig diseases, icludig a history of COPD [10]. The relatioship betwee the use of ihaled corticosteroids ad BMD was aalysed i two meta-aalyses, with icosistet results. A Cochrae review of radomised cliical trials foud o evidece for a effect of ihaled-corticosteroid exposure o BMD; however, the patiet populatio icluded i the radomised trials had relatively mild respiratory disease ad TABLE 3 Associatio betwee obstructive airway disease (OAD) ad risk of osteoporotic fracture stratified by presece of idicators of disease severity ad use of ihaled corticosteroids 6 moths before the idex date Patiets with OAD Osteoporotic Hip Vertebral Severe OAD # Use of ihaled corticosteroids Crude OR Adjusted OR " 95% CI Crude OR Adjusted OR " 95% CI Crude OR Adjusted OR " 95% CI No No ( ) ( ) ( ) No Yes ( ) ( ) ( ) Yes No ( ) ( ) ( ) Yes Yes ( ) ( ) ( ) Referet crude odds ratio (OR): subjects who were ever exposed to ihaled corticosteroids ad who did ot have a history of OAD; referet adjusted OR: subjects who had ever bee exposed to ihaled corticosteroids ad brochodilators ad who did ot have a history of OAD; CI: cofidece iterval. # : severe disease was defied as the presece of oe or more disease-severity idicators (exacerbatio of OAD, use of oxyge i the previous 12 moths, use of oral corticosteroids, body mass idex,20, bacterial respiratory tract ifectios, coughig, presece of sputum, haemoptysis, dyspoea, tachypoea, shortess of breath, acute brochitis ad wheezig i the previous 6 moths; " : adjusted for geeral risk factors, smokig status, duratio of erolmet i the Geeral Practice Research Database ad exposure to brochodilators. 882 VOLUME 25 NUMBER 5 EUROPEAN RESPIRATORY JOURNAL

5 F. DE VRIES ET AL. DISEASE SEVERITY AND FRACTURE RISK was youg [22]. A meta-aalysis, which also icluded observatioal studies, foud that ihaled-corticosteroid users had, o average, a lower BMD tha expected for their age ad sex. To address the effect of cofoudig by uderlyig disease severity, RICHY et al. [23] classified studies o the basis of the type of cotrols to the ihaled-corticosteroid users: healthy populatio cotrols or cotrols with lug disease. It was foud that ihaled-corticosteroid users had lower BMD i both sets of study populatios ad that these results were statistically similar. Nevertheless, the umber of patiets i the studies with healthy cotrols was quite small. Moreover, the largest differeces betwee ihaled-corticosteroid users ad cotrols were see i the studies with healthy cotrols, although this was ot statistically sigificat. I coclusio, this tred is cosistet with the curret hypothesis that uderlyig disease severity is importat i the aetiology of reduced BMD i patiets usig ihaled corticosteroids [23]. The severity of pulmoary disease iversely correlated with BMD i three studies. A aalysis of the Third Natioal Health ad Nutritio Examiatio Survey (NHANES) revealed that the risk of osteoporosis amog males ad females was iversely correlated with the degree of their airway obstructio. Adjustmet for age, smokig, BMI, physical activity ad differet types of medicatio (amog others, ihaled or oral corticosteroids, brochodilators ad oestroges) did ot chage these results [13]. I a group of elderly Japaese females with COPD who were ot exposed to oral corticosteroids, the prevalece of osteoporosis was 50%, twice as high as a compariso group cosistig of females of the same age with asthma [24]. A cross-sectioal study i a geeral-practice settig amog British females aged yrs also showed a iverse relatioship betwee forced expiratory volume i oe secod ad BMD at the hip, which remaied after adjustmet for body weight ad legth. Although use of ihaled corticosteroids was ot measured, the results remaied similar after exclusio of patiets who had a history of respiratory disease [12]. Several mechaisms have bee suggested for this possible relatioship betwee OAD ad icreased risk of fracture or osteoporosis. They iclude lack of physical activity [25, 26], low BMI amog patiets with COPD [27], smokig [28], a decreased exposure to sulight [13], decreased testosteroe levels [29], hypercapia [30], ad chroic iflammatio. Cytokies that are expressed i iflammatory diseases, such as asthma ad/or COPD, iclude tumour ecrosis factor (TNF)-a, trasformig growth factor-b, iterleuki (IL)-1b, IL-4 ad IL-8. These cytokies have bee show to affect boe remodellig i vivo ad i vitro [31 37]. However, it is ucertai whether these cytokie levels are also icreased i the osteoblasts ad osteoclasts at the basic multicellular uit [38] i humas with respiratory disease. I a study amog 68 post-meopausal females with osteoporosis, a correlatio betwee levels of plasma IL-8 or TNF-a ad BMD was ot foud [39]. May patiets with OAD use b 2 -agoists. The adreergic pathway may play a role i the regulatio of boe formatio i ovariectomised mice [40]. The curret authors stratified the brochodilator group to b 2 -agoists, atimuscariics, xathies, cromoes ad adreoceptor agoists (e.g. ephedrie), ad were uable to fid a clear relatioship betwee ay class of drugs ad risk of fractures. A iterestig fidig i the preset study was a icreased risk of fracture amog past users of ihaled corticosteroids. This might be related to a history of cocomitat oral-steroid use or a history of OAD. This study has several limitatios. Data o physical activity ad smokig were limited. It is ot obligatory for participatig practices to record smokig status. The curret data o smokig were icomplete, ad the preset results o the relatioship betwee smokig ad risk of fracture were lower tha those recetly reported i a meta-aalysis [41]. There were o data o the loss of fat-free mass. Loss of fat-free mass has bee associated with reduced BMD ad more severe COPD, ad might be a more cocise marker of severity of OAD compared with BMI [42, 43]. Although the curret authors did ot have data o BMI for all patiets, the preset fidig of a iverse relatioship betwee BMI ad fracture risk was cosistet with those previously reported [44, 45]. Cotrollig for severity of the uderlyig disease could also be improved with spirometry data, which were ot available i this study. Lastly, amog the patiets who used.1,600 mg beclomethasoe equivalets per day, a large umber (46%) were usig oral corticosteroids (media umber of oral-corticosteroid prescriptios was 14). Therefore, it may be difficult i this patiet group to separate the effects of oral ad ihaled corticosteroids. I coclusio, patiets usig higher doses of ihaled corticosteroids have a icreased risk of osteoporotic fracture. However, patiets usig brochodilators ad those with more severe obstructive airway disease also have a icreased risk of fracture, ad the dose respose relatioship betwee ihaled corticosteroids ad fracture risk almost disappears after adjustmet for disease severity. Cosequetly, adequate adjustmet for disease severity is essetial whe the associatio betwee use of ihaled corticosteroids ad risk of fracture is studied i observatioal research. REFERENCES 1 Laes SF, Garcia Rodriguez LA, Huerta C. Respiratory medicatios ad risk of asthma death. Thorax 2002; 57: Marti RJ, Szefler SJ, Chichilli VM, et al. Systemic effect comparisos of six ihaled corticosteroid preparatios. Am J Respir Crit Care Med 2002; 165: Va Staa TP, Leufkes HG, Abehaim L, Zhag B, Cooper C. Use of oral corticosteroids ad risk of fractures. J Boe Mier Res 2000; 15: Va Staa TP, Leufkes HG, Cooper C. Use of ihaled corticosteroids ad risk of fractures. J Boe Mier Res 2001; 16: Hubbard RB, Smith CJ, Smeeth L, Harriso TW, Tattersfield AE. Ihaled corticosteroids ad hip fracture: a populatio-based case-cotrol study. Am J Respir Crit Care Med 2002; 166: Lee TA, Weiss KB. Fracture risk associated with ihaled corticosteroid use i chroic obstructive pulmoary disease. Am J Respir Crit Care Med 2004; 169: Vestergaard P, Olse ML, Paaske Johse S, Rejmark L, Sorese HT, Mosekilde L. Corticosteroid use ad risk of hip fracture: a populatio-based case-cotrol study i Demark. J Iter Med 2003; 254: c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 5 883

6 DISEASE SEVERITY AND FRACTURE RISK F. DE VRIES ET AL. 8 Suissa S. Possible sources of bias i observatioal studies of the effectiveess of ihaled corticosteroids i COPD. Eur Respir J 2003; 22: Suppl. 43, 9s 12s. 9 va Staa TP, Leufkes B, Cooper C. Boe loss ad ihaled glucocorticoids. N Egl J Med 2002; 346: Lau E, Mamdai M, Tu K. Ihaled or systemic corticosteroids ad the risk of hospitalizatio for hip fracture amog elderly wome. Am J Med 2003; 114: Suissa S, Baltza M, Kremer R, Erst P. Ihaled ad asal corticosteroid use ad the risk of fracture. Am J Respir Crit Care Med 2004; 169: Lekamwasam S, Trivedi DP, Khaw KT. A associatio betwee respiratory fuctio ad boe mieral desity i wome from the geeral commuity: a cross sectioal study. Osteoporos It 2002; 13: Si DD, Ma JP, Ma SF. The risk of osteoporosis i Caucasia me ad wome with obstructive airways disease. Am J Med 2003; 114: va Staa TP, Leufkes HG, Cooper C. Ihaled corticosteroids ad hip fracture: disease or drugs? Am J Respir Crit Care Med 2003; 168: Walley T, Matgai A. The UK Geeral Practice Research Database. Lacet 1997; 350: va Staa TP, Abehaim L, Cooper C, et al. The use of a large pharmacoepidemiological database to study exposure to oral corticosteroids ad risk of fractures: validatio of study populatio ad results. Pharmacoepidemiol Drug Saf 2000; 9: Hollowell J. Geeral Practice Research Database (GPRD): Scope ad Quality of Data. Lodo, Office of Populatio Cesuses ad Statistics, va Staa TP, Wegma S, de Vries F, Leufkes B, Cooper C. Use of statis ad risk of fractures. JAMA 2001; 285: Soriao JB, Maier WC, Visick G, Pride NB. Validatio of geeral practitioer-diagosed COPD i the UK Geeral Practice Research Database. Eur J Epidemiol 2001; 17: British Natioal Formulary. Vol. 37. Lodo, British Medical Associatio, Aoymous. ATC classificatio idex with DDDs Nydale, WHO Collaboratig Cetre for Drug Statistics Methodology, Norwegia Istitute of Public Health, Joes A, Fay JK, Burr M, Stoe M, Hood K, Roberts G. Ihaled corticosteroid effects o boe metabolism i asthma ad mild chroic obstructive pulmoary disease. Cochrae Database Syst Rev 2002; 1: CD Richy F, Bousquet J, Ehrlich GE, et al. Ihaled corticosteroids effects o boe i asthmatic ad COPD patiets: a quatitative systematic review. Osteoporos It 2003; 14: Katsura H, Kida K. A compariso of boe mieral desity i elderly female patiets with COPD ad brochial asthma. Chest 2002; 122: Malkia E, Impivaara O. Itesity of physical activity ad respiratory fuctio i subjects with ad without brochial asthma. Scad J Med Sci Sports 1998; 8: Ford ES, Heath GW, Maio DM, Redd SC. Leisure-time physical activity patters amog US adults with asthma. Chest 2003; 124: Icalzi RA, Caradoa P, Raieri P, et al. Correlates of osteoporosis i chroic obstructive pulmoary disease. Respir Med 2000; 94: Ward KD, Klesges RC. A meta-aalysis of the effects of cigarette smokig o boe mieral desity. Calcif Tissue It 2001; 68: Kamischke A, Kemper DE, Castel MA, et al. Testosteroe levels i me with chroic obstructive pulmoary disease with or without glucocorticoid therapy. Eur Respir J 1998; 11: Dimai HP, Domej W, Leb G, Lau KH. Boe loss i patiets with utreated chroic obstructive pulmoary disease is mediated by a icrease i boe resorptio associated with hypercapia. J Boe Mier Res 2001; 16: Lam J, Takeshita S, Barker JE, Kaagawa O, Ross FP, Teitelbaum SL. TNF-alpha iduces osteoclastogeesis by direct stimulatio of macrophages exposed to permissive levels of RANK ligad. J Cli Ivest 2000; 106: Jilka RL, Weistei RS, Bellido T, Parfitt AM, Maolagas SC. Osteoblast programmed cell death (apoptosis): modulatio by growth factors ad cytokies. J Boe Mier Res 1998; 13: Hock JM, Krisha V, Oyia JE, Bidwell JP, Milas J, Staislaus D. Osteoblast apoptosis ad boe turover. J Boe Mier Res 2001; 16: Boyle WJ, Simoet WS, Lacey DL. Osteoclast differetiatio ad activatio. Nature 2003; 423: Chug K. Cytokies. I: Bares P, Draze J, Reard S, Thompso N, eds. Asthma ad COPD. Basic mechaisms ad cliical maagemet. Lodo, Academic Press, Okada Y, Morimoto I, Ura K, et al. Short-term treatmet of recombiat murie iterleuki-4 rapidly ihibits boe formatio i ormal ad ovariectomized mice. Boe 1998; 22: Bedre MS, Motague DC, Peery T, Akel NS, Gaddy D, Suva LJ. Iterleuki-8 stimulatio of osteoclastogeesis ad boe resorptio is a mechaism for the icreased osteolysis of metastatic boe disease. Boe 2003; 33: Frost HM. Tetracyclie-based histological aalysis of boe remodelig. Calcif Tissue Res 1969; 3: Sahi G, Ozturk C, Bagis S, Cime OB, Erdoga C. Correlatio of serum cytokie levels with axial boe mieral desity. Sigapore Med J 2002; 43: Takeda S, Elefteriou F, Levasseur R, et al. Lepti regulates boe formatio via the sympathetic ervous system. Cell 2002; 111: Kais JA, Johell O, Ode A, et al. Smokig ad fracture risk: a meta-aalysis. Osteoporos It 2005; 16: Ioescu AA, Evas WD, Pettit RJ, Nixo LS, Stoe MD, Shale DJ. Hidde depletio of fat-free mass ad boe mieral desity i adults with cystic fibrosis. Chest 2003; 124: Bolto CE, Ioescu AA, Shiels KM, et al. Associated loss of fat free mass ad boe mieral desity i chroic obstructive pulmoary disease. Am J Respir Crit Care Med 2004; 170: Johell O, Gullberg B, Kais JA, et al. Risk factors for hip fracture i Europea wome: the MEDOS Study. Mediterraea Osteoporosis Study. J Boe Mier Res 1995; 10: Roy DK, O Neill TW, Fi JD, et al. Determiats of icidet vertebral fracture i me ad wome: results from the Europea Prospective Osteoporosis Study (EPOS). Osteoporos It 2003; 14: VOLUME 25 NUMBER 5 EUROPEAN RESPIRATORY JOURNAL