1 / 67

dr. Stefano Calabro

BPCO: Documenti e linee guida a confronto. Mogliano Veneto (TV ) 3 1 gennaio 2014. Le Comorbilità. dr. Stefano Calabro. Dr. Stefano Calabro REGIONE VENETO – AZIENDA U.L.S.S. n.3 Ospedale S. Bassiano - Bassano del Grappa Dipartimento di Medicina Struttura Complessa di Pneumologia.

kennedy-lee
Download Presentation

dr. Stefano Calabro

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. BPCO: Documenti e linee guida a confronto Mogliano Veneto (TV) 31 gennaio 2014 Le Comorbilità dr. Stefano Calabro Dr. Stefano Calabro REGIONE VENETO – AZIENDA U.L.S.S. n.3Ospedale S. Bassiano - Bassano del GrappaDipartimento di MedicinaStruttura Complessa di Pneumologia Dr. Rolando Negrin REGIONE VENETO – AZIENDA U.L.S.S. n.6Ospedale S. Bortolo - VicenzaDipartimento di Area Medica IIUnità Operativa Complessa di Pneumologia Ultima revisione 28.01.2014.

  2. Un caso di instabilità terminologica nel vocabolario medico: comorbidità, comorbilità, comorbosità Comorbidità e comorbilitàsono due forme lessicali – entrambe attestate negli usi linguistici medico-scientifici italiani, a volte anche in grafia non univerbata (cioè con il trattino) – usate dagli specialisti in maniera intercambiabile: negli stessi contesti, con gli stessi significati, per indicare quindi uno stesso concetto o grappolo di concetti. Questa oscillazione fra comorbidità e comorbilitànegli usi specialistici si spiega, più che in termini di sinonimia, come compresenza nel vocabolario medico italiano attuale di forme alternative e concorrenti, in competizione fra di loro per designare sostanzialmente la stessa cosa. Si tratta, dunque, di un caso di instabilità terminologica, accentuata dall’alternanza con una terza forma, comorbosità, che, sebbene meno frequente – e probabilmente per questo non menzionata nelle domande – è tuttavia attestata e registrata.

  3. Definizione di comorbidità “The existence or occurrenceofanydistinctadditionalentityduring the Clinicalcourseof a patientwhohas the indexdisease under study”. “l’esistenza o la presenza di ogni entità patologica distinta addizionale durante il decorso clinico di una patologia oggetto di studio”.

  4. Comorbidityconstructs Valderas JM, Starfield B, Sibbald B, et al. Defining Comorbidity: Implications for Understanding Health and Health Services. AnnFamMed 2009;7:357-363. doi:10.1370/afm.983.

  5. BroncoPneumopatia Cronica Ostruttiva Complicanze Comorbilità

  6. Malattie croniche Number of chronic disorders by age-group Barnett K, Mercer SW, Norbury M, et al. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Published online May 10, 2012 DOI:10.1016/S0140-6736(12)60240-2.

  7. Malattie croniche Invecchiamento (modificazioni strutturali organo-specifiche, sistemiche e immunologiche in senso proinfiammatorio) fattori di rischio (es. fumo, inquinamento, iperdislipidemia, obesità) Invecchiamento, infiammazione sistemica e malattie croniche complesse Franceschi C, Pauletto P, Incalzi RA, Fabbri LM Invecchiamento, infiammazione sistemica e malattie cliniche complesse Italian Journal of Medicine 2011;5S: S3—S13.

  8. The guideline with the highest coverage of comorbidities was that of the Global Initiative for Chronic Obstructive Lung Disease (GOLD).

  9. Comorbidity Prevalence in COPD (%) Patel AR, Hurst JR. Extrapulmonarycomorbidities in chronic obstructive pulmonary disease: state of the art. Expert RevRespirMed. 2011; 5:647-62.

  10. Diagnosi fattori di rischio sintomi spirometria Valutazione della gravità gravità dei sintomi grado di ostruzione bronchiale rischio di riacutizzazioni numero e gravità delle comorbidità

  11. Relation between lung function and death due to cardiovascular disease, lung cancer, and respiratory failure Sin DD, Anthonisen NR, Soriano JB, et al. Mortalityin COPD: roleof comorbidities. EurRespir J 2006; 28: 1245–57.

  12. Cardiovasculardiseases (CVD) Vascular and heart diseases are among the most important comorbidities observed in COPD, because they have a direct impact on patient survival. The pathophysiological mechanisms underlying the vascular alterations observed in COPD appear to be mainly mediated by endothelial dysfunction and coagulopathy.

  13. Relationship Between Reduced Lung Function and Cardiovascular Mortality There is strong epidemiologic evidence to indicate that reduced FEV1 is a marker for cardiovascular mortality independent of age, gender, and smoking history.

  14. Risk for cardiovascular disease in COPD patients and matched controls Prevalence of all cardiovascular diseases was higher in the COPD group than in the comparison group. * *P<0.05 for between-group difference MI = myocardial infarction CHF = congestive heart failure CVD = cardiovascular disease * * * * * * Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Am J Epidemiol. 2006;16:63-70.

  15. Cardiovascular disease in COPD patients 1200 COPD patients 300 control subjects COPD Compared with the control group, the COPD group showed a significantly higher prevalence of ischemic heart disease, cerebrovascular disease, and peripheral vascular disease In the univariate risk analysis, COPD, hypertension, diabetes, obesity, and dyslipidemia were risk factors for ischemic heart disease In the multivariate analysis adjusted for the remaining factors, COPD was still an independent risk factor (odds ratio: 2.23; 95% confidence interval: 1.18–4.24; P = 0.014) COPD patients show a high prevalence of cardiovascular disease, higher than expected given their age and the coexistence of classic cardiovascular risk factors de Lucas-Ramos P, Izquierdo-Alonso JL, Moro JM, et al. Chronic obstructive pulmonary disease as a cardiovascular risk factor. Results of a case–control study (CONSISTE study) Int J ChronObstructPulmonDis. 2012;7:679-686.

  16. The mechanistic links between COPD and cardiovascular disease are complex, multifactorial, and not entirelyunderstood Decramer M, Janssens W. Chronic obstructive pulmonary disease and comorbidities. LancetRespirMed. 2013;1:73-83.

  17. Cardiovasculardiseases (CVD) Systemic venous thromboembolism During COPD exacerbations, VTE is found in 3–29% of cases GunenH, Gulbas G, In E, et al. Venousthromboemboli and exacerbations of COPD. EurRespir J 2010; 35: 1243–1248. Pulmonary artery disease : pulmonary hypertension Coronary heart disease Heartfailure Heartarrhythmia

  18. Prevention of VTE in Nonsurgical Patients Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-BasedClinicalPracticeGuidelines 2012 Prevention of Thrombosis For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulantthromboprophylaxis with low-molecular-weightheparin [LMWH], low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux(Grade 1B). For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis(Grade 1B). In acutely ill hospitalized medical patients who receive an initial course of thromboprophylaxis, we suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B). In chronically immobilized persons residing at home or at a nursing home, we suggest against the routine use of thromboprophylaxis(Grade 2C).

  19. Prevention of VTE in Nonsurgical Patients Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-BasedClinicalPracticeGuidelines 2012 Increasedrisk of thrombosis Risk Factors for VTE in Hospitalized MedicalPatients In the Padua Prediction Score risk assessment model, high risk of VTE is defined by a cumulative score 4 points.

  20. Pulmonaryhypertension (PH) Haemodynamicdefinitions of pulmonaryhypertension a All values measured at rest. c High CO can be present in cases of hyperkinetic conditions such as systemic-to-pulmonary shunts (only in the pulmonary circulation),anaemia, hyperthyroidism, etc. CO = cardiac output; PAP = pulmonary arterial pressure; PH = pulmonary hypertension; PWP = pulmonary wedge pressure; TPG = transpulmonary pressure gradient (mean PAP – mean PWP). ECS/ERS Guidelines 2009

  21. Pulmonaryhypertension (PH) Moststudieshaveindicatedthat COPD tends to produce relativelymodesthemodynamicalterationsatrest, relative to otherforms of PH, suchasidiopathicpulmonaryarterialhypertension or PH associated with connectivetissuediseases. Typicalhemodynamicalterations include mildelevations in mPAP, right atrial pressure (RAP), and pulmonaryvascularresistance (PVR). PH in COPD typicallyoccurs in patients with more advanced compromise in respiratoryfunction (FEV1 < 30% predicted) and low PaO2. Pulmonary hypertension in COPD: a review of the literature Minai OA www.pvrireview.org

  22. PulmonaryHypertension in COPD PH ismild to moderate butitmay be severe and could be observedwithout major airflowlimitation Thislatterconditionhasbeentermed‘‘out-of- proportion’’ PH (may be defined by mPAP > 35–40 mmHg and a mild-to- moderate airflowlimitation) Meanpulmonaryartery pressure in a hospital-basedcohort of 998 COPD patients with a mild to very severe airflowlimitation Chaouat A, Bugnet AS, Kadaoui N, et al. Severe pulmonaryhypertension and chronicobstructivepulmonarydisease AmJ RespirCrit Care Med 2005; 172: 189–194

  23. Prognostic impact of PH in patients with COPD Chronicobstructivepulmonarydiseasepatients with a mPAP> 25 mmHg (– – – –) at the beginning of long-termoxygentherapyhave a significantly (p < 0.001) shorter life expectancycompared with patients with mPAP < 25 mmHg (––––) Oswald-Mammosser M, Weitzenblum E, Quoix E, et al Prognosticfactors in COPD patientsreceiving long-term oxygentherapy. Importance of pulmonaryartery pressure Chest1995; 107: 1193–1198

  24. CHF & COPD Heart failure is a complex clinical syndrome with many features in common with COPD, particularly the cardinal symptoms of dyspnea and fatigue. Prevalence of COPD ranges from 20-32% in CHF Risk ratio of developing CHF is 4.5 in COPD Rutten FH, Cramer MM, Lammers JJ, et al. Heart failure and chronic obstructive pulmonary disease: an ignored combination. Eur J Heart Fail 2006;8:706-711. O'Connor CM, Stough WG, Gallup DS, et al. Demographics, clinical characteristics, and outcomes of patients hospitalized for decompensated heart failure: observations from the IMPACT-HF registry. J Card Fail 2005;11:200-205. Gustafsson F, Torp-Pedersen C, Burchardt H, et al. Female sex is associated with a better longterm survival in patients hospitalized with congestive heart failure. Eur Heart J. 2004;25:129-315.

  25. BPCO e Scompenso cardiaco – mortalità 1.0 • primary care patients with COPD ≥ 65 • years (n=404) • follow up for a mean duration of 4.2 • (SD 1.4) years. • HF doubles mortality of patients with • COPD: adjusted HR 2.1 (1.2–3.6 C.I.) 0.9 0.8 Survival 0.7 COPD COPD GOLD COPD + Heart failure 0.6 COPD GOLD + Heart Failure 0.5 0 12 24 36 48 60 72 Boudestein LC, Rutten FH, Cramer MJ, et al. The impact of concurrent heart failure on prognosis in patients with chronic obstructive pulmonary disease. Eur J Heart Fail 2009;11:1182–1188. Time (Months)

  26. Heartfailure (HF) The combinationofheartfailure and chronicobstructivepulmonarydiseasepresentsmanytherapeuticchallenges. The cornerstonesoftherapy are beta-blockers and beta-agonists, respectively. Theirpharmacologicaleffects are diametricallyopposed, and eachispurportedto adverselyaffect the alternative condition.

  27. Terapia dell’insufficienza cardiaca OBIETTIVI A BREVE TERMINE Riduzione sintomatologia DIURETICI VASODILATATORI DIGITALE Prolungamento sopravvivenza OBIETTIVI A LUNGO TERMINE I b – bloccanti migliorano in modo marcato la sintomatologia e la sopravvivenza dei pazienti con scompenso ACE- INIBITORI b – BLOCCANTI INIBITORI RECETTORIALI A II ANTIALDOSTERONICI INIBITORI NEURO-UMORALI

  28. Differenze farmacologiche dei β-bloccanti approvati per lo scompenso cardiaco • BloccoBloccoBlocco ISA ß1ß2 α1 Carvedilolo +++ +++ +++ - Metoprololo +++ - - - Bisoprololo +++ - - - Nebivololo +++ - - - ISA attività simpaticomimetica intrinseca

  29. Heartdisease - COPD Le linee guida della Società Europea di Cardiologia dicono che la BPCO non rappresenta una controindicazione all'utilizzo dei beta-bloccanti. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronicheartfailure 2008: the Task Force for the Diagnosis and Treatment of Acute and ChronicHeartFailure 2008 of the European Society of Cardiology. EurHeart J 2008;29:2388-442

  30. Beta-bloccanti – BPCO/scompenso cardiaco I beta-bloccanti migliorano in maniera altamente significativa i sintomi e la sopravvivenza nei pazienti con scompenso cardiaco. La BPCO (anche se moderata o grave) non costituisce una controindicazione per i beta-bloccanti. Va raccomandato un inizio a basso dosaggio e incrementi progressivi graduali. Un aspetto fondamentale è la cardioselettività: sono permessi nella BPCO metoprololo, bisoprololo e nebivololo.

  31. Beta bloccanti e BPCO What this study adds β blockers (predominantly cardioselective) reduced mortality and COPD exacerbations when added to stepwise inhaled therapy for COPD (including long acting β agonists and antimuscarinics) in addition to the benefits attributable to addressing cardiovascular risk. The benefits observed occurred without adverse effects on pulmonary function. These data support the use of β blockers in patients with COPD. Kaplan-Meier estimate of probability of survival among patients with COPD by use of β blockers Adjusted hazard ratios for all cause mortality among patients with COPD in reference to the control group (who received only inhaled therapy with short acting β agonists or antimuscarinics) Short PM, Lipworth, SIW, Elder DHJ, et al. Effect of β blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ 2011;342:bmj.d2549

  32. Heart failure (HF) Are beta2-agonists responsible for increased mortality in heart failure? Bermingham M, O'Callaghan E, Dawkins I, et al. Eur J Heart Fail 2011; 13: 885-891. Data were available for 1294 patients (age 70.6 ± 11.5 years) of whom 64% were male and 22.2% were taking B2As. β2-Agonist users were older, more likely to be male, to have smoked, to have chronic obstructive pulmonary disease (COPD) and asthma. When adjusted for age, sex, medication, co-morbidity, smoking, COPD, and BNP differences, overall mortality rates were similar [HR 1.043, 95% CI (0.771–1.412), P= 0.783]. Unlike previous reports, this retrospective evaluation of β2-agonist therapy in HF patients shows no relationship with long-term mortality when adjusted for population differences including BNP.  Large, prospective studies are required to define the risk/benefit ratio of β2-agonists in patients with heart failure.

  33. Broncodilatatori – BPCO/scompenso cardiaco Anche se trial clinici randomizzati e controllati hanno stabilito la sicurezza dei beta-agonisti a lunga durata d'azione nei pazienti con BPCO, restano zone d'ombra riguardo la sicurezza nei pazienti con asma. Nessuno studio prospettico ha valutato la sicurezza dei beta-agonisti a lunga durata d'azione nei pazienti con BPCO e asma concomitante. Un broncodilatatore anticolinergico a lunga durata d'azione (tiotropio) si è dimostrato efficace sia nella BPCO che nell'asma; per tale agente è stata evidenziata una sicurezza cardiovascolare. . I pazienti con SC e BPCO concomitante che hanno bisogno di un'assunzione regolare di broncodilatatori per via inalatoria a lunga durata d'azione potrebbero iniziare con un agente anticolinergico piuttosto che con un beta-agonista a lunga durata d'azione. Hawkins NM, Petrie MC, MacDonald MR, et al. Heart Failure and Chronic Obstructive Pulmonary Disease: The Quandary of Beta-Blockers and Beta-Agonists. J Am Coll Cardiol.2011; 57: 2127-2138. Chowdhury BA, Dal PG. The FDA and safe use of long-acting betaagonists in the treatment of asthma. N Engl J Med 2010;362:1169-71.

  34. Treatment of chronic obstructive pulmonary disease and its comorbidities Treatmentsfor COPD may positively affect morbidity and mortality linked to comorbidities of COPD Treatments for comorbidities may positively affect morbidity and mortality linked to COPD Luppi F, Franco F, Beghé B, et al. Treatment of chronic obstructive pulmonary disease and its comorbidities Proc Am Thorac Soc 2008;5:848-856.

  35. Predictors of Early and Late Mortality in Hospitalized Patients with Acute Exacerbation of COPD Adaptedfrom Singanayagam A, Schembri S, Chalmers JD. Predictors of mortality in hospitalized adults with acute exacerbation of chronic obstructive pulmonary disease. Ann Am Thoracic Soc 2013, 10:81–89.

  36. Changing paradigms in cardiovascular risk management Volpe M, Erhardt LR, Williams B. Managing cardiovascular risk: the need for change. J Hum Hypertens 2008; 22: 154–157.

  37. Valutazione del rischio cardiovascolare nel paziente BPCO Età Sesso (prima della menopausa) Familiarità per coronaropatia o morte improvvisa: positiva se coronaropatia o morte improvvisa Attività fisica: livello di attività sia al lavoro che extra Fumo: 1) numero di sigarette fumate al giorno e durata della abitudine al fumo 2) se ex fumatore, da quando ha smesso e per quanto tempo ha fumato 3) esposizione passiva Peso corporeo e distribuzione del grasso: 1) anamnesi familiare/personale 2) peso, altezza con calcolo dell’IMC( > 25 Kg/m2 sovrappeso, > 30 Kg/m2 obesità) 3) circonferenza vita (adiposità addominale > 102cm per uomo, > 88cm per donna, adiposità addominale borderline > 94 cm per uomo e > 80 cm per donna) Pressione arteriosa Sindrome metabolica, intolleranza glucidica, diabete, Lipidi plasmatici (colesterolo, HDL colesterolo, LDL colesterolo, trigliceridi) Sindrome delle apnee ostruttive nel sonno Malattie renali croniche Valutazione dei fattori di rischio

  38. Effects of statins on the cholesterol biosynthesis pathway De Loecker I and Preiser J-C Statins in the critically ill Annals of Intensive Care 2012, 2:19.

  39. Pleiotropiceffectsofstatins De Loecker I and Preiser J-C Statins in the critically ill Annals of Intensive Care 2012, 2:19.

  40. Effect of statinson mortality and exacerbation in COPD 1,687 patients (mean age 70.6 years) 596 statin users - 1,091 non-users Hazard ratios calculated for statin users versus statin non-users for all-cause mortality over follow-up of up to 4 years. Statin use is associated with a 30% reduction in all-cause mortality at 3-4 years after first admission for COPD, irrespective of a past history of cardiovascular disease and diabetes. Lawes CM, Thornley S, Young R,et al. Statin use in COPD patients is associated with a reduction in mortality: a national cohort study. Prim Care Respir J 2012, 21:35–40. Mortensen EM, Copeland LA, Pugh MJ, et al. Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respiratory Research 2009, 10:45 doi:10.1186/1465-9921-10-45 Proportion of surviving patients hospitalized with COPD exacerbation by use of statin versus non-use (p < 0.0001).

  41. Simvastatin Therapy for Moderate and Severe COPD (STATCOPE) To determine the effect of daily administration of 40 mg simvastatin taken for at least 12 months (range 12-36 months) on the frequency of exacerbations of chronic obstructive lung disease (COPD) in patients with moderate to severe COPD who are prone to exacerbations and do not have other indications for statin treatment. Estimated Study Completion Date: January 2014 Simvastatin therapy for moderate and severe COPD (STSTCOPE).: United States National Institute of Health; http://clinicaltrials.gov/ct2/show/NCT01061671

  42. BPCO e Diabete mellito . Kannel WB and McGee DL Diabetes and cardiovascular disease.TheFramingham study Jama1979, 241:2035-2038 Large population studies show that there is an increased prevalence of diabetes among COPD patients (relative risk 1.5– 1.8), even in patients with mild disease. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension, and cardiovascular disease in chronic obstructive pulmonary disease EurRespir J 2008; 32: 962–269.

  43. BPCO e Diabete mellito Mortality in COPD PtsDischargedfrom Hospital (AECOPD) - RoleofComorbidity 416 patients Follow-up 24 months 122 (29.3%) of the 416 patients died Kaplan-Meier survival curve in patients with and without diabetes Patients with diabetes had an increased mortality rate [HR = 2.25 (1.28–3.95)] Gudmundsson G, Gislason T, Lindberg E, et al. Mortality in COPD patients discharged from hospital: the role of treatment and co-morbidity RespiratoryResearch 2006, 7:109.

  44. Corticosteroidi inalatori Effetti collaterali Inhaled corticosteroids and the risk of diabetes Current use of inhaled corticosteroids was associated with a 34% increase in the rate of diabetes (rate ratio [RR] 1.34; 95% confidence interval [CI], 1.29-1.39) and in the rate of diabetes progression (RR 1.34; 95% CI, 1.17-1.53). The risk increases were greatest with the highest inhaled corticosteroid doses, equivalent to fluticasone 1000 μg per day or more (RR 1.64; 95% CI, 1.52-1.76 and RR 1.54; 95% CI, 1.18-2.02; respectively). *Individuals who entered the cohort after the age of 55 years and without mention of asthma during a hospitalization. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression Am J Med 2010;123:41001-1006.

  45. Corticosteroidi inalatori Effetti collaterali Inhaled corticosteroids and the risk of diabetes 388,584 patients 30,167 had diabetes onset during 5.5 years of follow-up (incidence rate 14.2/1000/year), and 2099 subsequently progressed from oral hypoglycemic treatment to insulin (incidence rate 19.8/1000/year). Adjusted rate ratio of diabetes incidence associated with inhaled corticosteroid use, as a function of the current dose converted to fluticasone equivalents (in g), along with the corresponding 95% confidence limits for the fitted dose-response curve. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and Progression Am J Med 2010;123:41001-1006.

  46. Ionescu AA, Schoon E. Osteoporosis in chronicobstructivepulmonarydisease. Eur Respir J Suppl. 2003;46:64s-75s.

  47. Osteoporosis - COPD Osteoporosis is highly prevalent in patients with COPD, irrespective of gender. Langhammer A, Forsmo S, and Syversen U. Long-term therapy in COPD: any evidence of adverse effect on bone? Int J Chron Obstruct Pulmon Dis. 2009; 4: 365–380.

  48. Osteoporosis – Fractures – ICS - COPD Inhaledcorticosteroiduse is associated with a modest but statistically significant increase in the risk of fractures in patients with COPD. Meta-analysis of inhaled corticosteroids versus controls for fractures in observationalstudies Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax 2011;66:699-708.

  49. Osteoporosis - Prednisolone Adjusted odds ratio for fracture risk at different sites by daily dose of prednisolone in UK General Practice Research Database (GPRD) and Danish large register studies. Langhammer A, Forsmo S, and Syversen U. L ong-term therapy in COPD: any evidence of adverse effect on bone? Int J Chron Obstruct Pulmon Dis. 2009; 4: 365–380.

More Related