There are disputes whether inhaled corticosteroids (ICS) increase the incidence of fracture or osteoporosis among patients with COPD. The aim of this meta-analysis was to assess the effect of ICS treatment on the risk of fracture and osteoporosis in subjects with COPD.
METHODS:
This study included parallel-group randomized controlled trials (RCTs) comparing ICS and control (non-ICS) therapy for subjects with COPD that reported adverse events including fractures or osteoporosis. Studies were found using MEDLINE/PubMed, Embase, and Cochrane Library databases between 1998–September 2022. Pooled risk ratios (RRs) and 95% CIs were calculated for primary outcomes.
RESULTS:
A total of 61,380 participants from 26 RCTs were included in the meta-analysis. Exposure to ICS did not increase the risk of fracture (RR 1.10 [95% CI 0.98–1.23], P = .10) or osteoporosis risk (RR 0.93 [95% CI 0.49–1.79], P = .84) in subjects with COPD.
CONCLUSIONS:
ICS use did not increase the incidence of fracture or osteoporosis in subjects with COPD.
SandelowskyH, WeinreichUM, AarliBB, SundhJ, HøinesK, StratelisG, et al. COPD - do the right thing. BMC Fam Pract, 2021; 22(1):244.
2.
ManSF, SinDD. Inhaled corticosteroids in chronic obstructive pulmonary disease: is there a clinical benefit?. Drugs, 2005; 65(5):579-591.
3.
SinghD, AgustiA, AnzuetoA, BarnesPJ, BourbeauJ, CelliBR, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report 2019. Eur Respir J, 2019; 53(5):1900164.
4.
AgustiA, FabbriLM, SinghD, VestboJ, CelliB, FranssenFME, et al. Inhaled corticosteroids in COPD: friend or foe?. Eur Respir J, 2018; 52(6):1801219.
5.
CasasA, Montes de OcaM, MenezesAM, WehrmeisterFC, Lopez VarelaMV, MendozaL, et al. Respiratory medication used in COPD patients from seven Latin American countries: the LASSYC study. Int J Chron Obstruct Pulmon Dis, 2018; 13:1545-1556.
6.
BarrechegurenM, MonteagudoM, FerrerJ, BorrellE, LlorC, EsquinasC, et al. Treatment patterns in COPD patients newly diagnosed in primary care. A population-based study. Respir Med, 2016; 111:47-53.
7.
LokeYK, CavallazziR, SinghS. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomized controlled trials and observational studies. Thorax, 2011; 66(8):699-708.
8.
MaltaisF, SchenkenbergerI, WieldersP, Ortiz de SarachoJ, ChinskyK, WatkinsM, et al. Effect of once-daily fluticasone furoate/vilanterol versus vilanterol alone on bone mineral density in patients with COPD: a randomized controlled trial. Ther Adv Respir Dis, 2020; 14:1753466620965145.
9.
KerwinEM, FergusonGT, MoM, DeAngelisK, DorinskyP. Bone mineral density and ocular safety after 52 weeks’ treatment with budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler (BGF MDI) using co-suspension delivery technology in COPD. Am J Respir Crit Care Med, 2019(9):A3319-A3319.
10.
RabeKF, MartinezFJ, FergusonGT, WangC, SinghD, WedzichaJA, et al. ETHOS Investigators. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. N Engl J Med, 2020; 383(1):35-48.
11.
LipsonDA, BarnhartF, BrealeyN, BrooksJ, CrinerGJ, DayNC, et al. IMPACT Investigators. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med, 2018; 378(18):1671-1680.
12.
Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ, 2016; 354:i4086.
13.
CumpstonM, LiT, PageMJ, ChandlerJ, WelchVA, HigginsJP, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev, 2019; 10:Ed000142.
14.
BalshemH, HelfandM, SchünemannHJ, OxmanAD, KunzR, BrozekJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol, 2011; 64(4):401-406.
15.
AnzuetoA, FergusonGT, FeldmanG, ChinskyK, SeibertA, EmmettA, et al. Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD, 2009; 6(5):320-329.
16.
BhattSP, DransfieldMT, CockcroftJR, Wang-JairajJ, MidwinterDA, RubinDB, et al. A randomized trial of once-daily fluticasone furoate/vilanterol or vilanterol versus placebo to determine effects on arterial stiffness in COPD. Int J Chron Obstruct Pulmon Dis, 2017; 12:351-365.
17.
BurgePS, CalverleyPM, JonesPW, SpencerS, AndersonJA, MaslenTK. Randomized, double-blind, placebo-controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ, 2000; 320(7245):1297-1303.
18.
CalverleyP, PauwelsR, VestboJ, JonesP, PrideN, GulsvikA, et al. TRial of Inhaled STeroids ANd long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet, 2003; 361(9356):449-456.
19.
CalverleyPM, AndersonJA, CelliB, FergusonGT, JenkinsC, JonesPW, et al. TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med, 2007; 356(8):775-789.
20.
FergusonGT, AnzuetoA, FeiR, EmmettA, KnobilK, KalbergC. Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Respir Med, 2008; 102(8):1099-1108.
21.
FergusonGT, TashkinDP, SkärbyT, JorupC, SandinK, GreenwoodM, et al. Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: the 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study. Respir Med, 2017; 132:31-41.
22.
HananiaNA, DarkenP, HorstmanD, ReisnerC, LeeB, DavisS, et al. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest, 2003; 124(3):834-843.
23.
JohnellO, PauwelsR, LöfdahlCG, LaitinenLA, PostmaDS, PrideNB, et al. Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler. Eur Respir J, 2002; 19(6):1058-1063.
24.
KardosP, WenckerM, GlaabT, VogelmeierC. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2007; 175(2):144-149.
25.
KerwinEM, FergusonGT, MoM, DeAngelisK, DorinskyP. Bone and ocular safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a 52-week randomized study. Respir Res, 2019; 20(1):167.
26.
KerwinEM, Scott-WilsonC, SanfordL, RennardS, AgustiA, BarnesN, CrimC. A randomized trial of fluticasone furoate/vilanterol (50/25 mug; 100/25 mug) on lung function in COPD. Respir Med, 2013; 107(4):560-569.
27.
MahlerDA, WireP, HorstmanD, ChangC-N, YatesJ, FischerT, ShahT. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2002; 166(8):1084-1091.
28.
MartinezFJ, BosciaJ, FeldmanG, Scott-WilsonC, KilbrideS, FabbriL, et al. Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomized trial. Respir Med, 2013; 107(4):550-559.
29.
PaggiaroPL, DahleR, BakranI, FrithL, HollingworthK, EfthimiouJ. Multi-center randomized placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group. Lancet, 1998; 351(9105):773-780.
30.
PauwelsRA, LöfdahlCG, LaitinenLA, SchoutenJP, PostmaDS, PrideNB, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med, 1999; 340(25):1948-1953.
31.
ScanlonPD, ConnettJE, WiseRA, TashkinDP, MadhokT, SkeansM, et al. Lung Health Study Research Group. Loss of bone density with inhaled triamcinolone in Lung Health Study II. Am J Respir Crit Care Med, 2004; 170(12):1302-1309.
32.
SilerTM, NagaiA, Scott-WilsonCA, MidwinterDA, CrimCA. Randomized, phase 3 trial of once-daily fluticasone furoate/vilanterol 100/25 μg versus once-daily vilanterol 25 μg to evaluate the contribution on lung function of fluticasone furoate in the combination in patients with COPD. Respir Med, 2017; 123:8-17.
33.
TashkinDP, DohertyDE, KerwinE, Matiz-BuenoCE, KnorrB, ShekarT, et al. Efficacy and safety of a fixed-dose combination of mometasone furoate and formoterol fumarate in subjects with moderate to very severe COPD: results from a 52-week phase 3 trial. Int J Chron Obstruct Pulmon Dis, 2012; 7:43-55.
34.
VestboJ, AndersonJA, BrookRD, CalverleyPM, CelliBR, CrimC, et al. SUMMIT Investigators. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomized controlled trial. Lancet, 2016; 387(10030):1817-1826.
35.
VestboJ, LeatherD, BakerlyND, NewJ, Martin GibsonJ, McCorkindaleS, et al. Salford Lung Study Investigators. Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J Med, 2016; 375(13):1253-1260.
36.
WangC, YangT, KangJ, ChenR, ZhaoL, HeH, et al. Efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler in Chinese patients with COPD: a subgroup analysis of KRONOS. Adv Ther, 2020; 37(4):1591-1607.
37.
WoutersEF, PostmaDS, FokkensB, HopWC, PrinsJ. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomized controlled trial. Revista Portuguesa de Pneumologia, 2005; 11(6):587-589.
38.
EtminanM, SadatsafaviM, Ganjizadeh ZavarehS, TakkoucheB, FitzGeraldJM. Inhaled corticosteroids and the risk of fractures in older adults: a systematic review and meta-analysis. Drug Saf, 2008; 31(5):409-414.
39.
DrummondMB, DasenbrookEC, PitzMW, MurphyDJ, FanE. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA, 2008; 300(20):2407-2416.
40.
DerendorfH. Pharmacokinetic and pharmacodynamic properties of inhaled corticosteroids in relation to efficacy and safety. Respir Med, 1997; 91 Suppl A:22-28.
41.
WeatherallM, JamesK, ClayJ, PerrinK, MasoliM, WijesingheM, et al. Dose-response relationship for risk of non-vertebral fracture with inhaled corticosteroids. Clin Exp Allergy, 2008; 38(9):1451-1458.
42.
FergusonGT, CalverleyPMA, AndersonJA, JenkinsCR, JonesPW, WillitsLR, et al. Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study. Chest, 2009; 136(6):1456-1465.
43.
ChiuKL, LeeCC, ChenCY. Evaluating the association of osteoporosis with inhaled corticosteroid use in chronic obstructive pulmonary disease in Taiwan. Sci Rep, 2021; 11(1):724.
