Prevalence and predictors of vertebral fracture in patients with chronic obstructive pulmonary disease

Open ArchivePublished:October 15, 2009DOI:https://doi.org/10.1016/j.rmed.2009.09.013

      Summary

      Objectives

      Patients with COPD are at risk for osteoporosis-related vertebral compression fractures (VCF) which predispose to more fractures and worsening pulmonary function. Our objectives were to: 1 document VCF prevalence in COPD patients; and 2 determine the independent correlates of VCF.

      Methods

      From 2004–2006, we prospectively recruited consecutive consenting COPD patients presenting with acute exacerbation at three Canadian Emergency Departments (ED). We collected clinical and pulmonary function data. Primary outcome was radiologist documented VCF on chest radiograph. Multivariable logistic regression was used for all adjusted analyses.

      Results

      Overall, 245 patients were studied; 37% were ≥75 years and 44% were women. Prevalence of VCF documented by chest radiograph was 22 of 245 (9%; 95%CI 6–13%). Almost half (10 of 22 [43%]) of VCF patients were not treated for osteoporosis and all 10 received oral steroids. Compared to patients without fractures, those with VCF were older (p=0.014), had COPD of longer duration (p=0.09) and greater severity (mean FEV1 0.9 vs 1.1 L; p=0.05), and had lower body mass index [BMI] (median 26 vs 28; p=0.01). Across BMI quartiles (from heaviest [median 37] to lightest [median 21]) the prevalence of VCF progressively increased (2%, 8%, 10%, 21%; p<0.001). In analyses adjusted for age, sex, and COPD duration, the only independent correlate of VCF was BMI: VCF increased as BMI decreased from heaviest (OR=1) to lightest (OR=11.0) quartiles (p=0.025).

      Conclusions

      Almost one-tenth of COPD patients presenting with acute exacerbation have chest radiographs documenting VCF. About half of patients with VCF were not treated for osteoporosis, but all were started on oral steroids. Our findings suggest chest radiograph reports may represent an important case-finding tool for VCF, particularly in underweight patients with COPD.

      Keywords

      Introduction

      Both chronic obstructive pulmonary disease (COPD) and osteoporosis are common, affecting an estimated 10 million
      • Mannino D.M.
      COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity.
      and 44 million Americans
      • Reginster J.
      • Burlet N.
      Osteoporosis: a still increasing prevalence.
      respectively. With the population aging, the prevalence of both diseases is on the rise,
      • Reginster J.
      • Burlet N.
      Osteoporosis: a still increasing prevalence.
      • O'Donnel D.E.
      • Aaron S.
      • Bourbeau J.
      • Hernandex P.
      • Marchiniuk D.D.
      • et al.
      Canadian thoracic society recommendations for management of chronic obstructive pulmonary disease-2007 update.
      and COPD patients are at particular risk of developing osteoporosis.
      • Jorgensen N.R.
      • Schwarz P.
      Osteoporosis in chronic obstructive pulmonary disease.
      • Gross N.J.
      Extrapulmonary effects of chronic obstructive pulmonary disease.
      Indeed, COPD and osteoporosis share several risk factors including older age and smoking.
      • Mannino D.M.
      COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity.
      • O'Donnel D.E.
      • Aaron S.
      • Bourbeau J.
      • Hernandex P.
      • Marchiniuk D.D.
      • et al.
      Canadian thoracic society recommendations for management of chronic obstructive pulmonary disease-2007 update.
      • Scientific Advisory Council
      Osteoporosis society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada.
      Furthermore, advanced COPD is associated with regular systemic corticosteroid use, chronic inflammation and low body weight, all of which predispose to osteoporosis.
      • Jorgensen N.R.
      • Schwarz P.
      Osteoporosis in chronic obstructive pulmonary disease.
      • Gan W.Z.
      • Man S.F.P.
      • Senthilselvan A.
      • Sin D.D.
      Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis.
      • Gluck O.
      • Colic G.
      Recognizing and treating glucocorticoid induced osteoporosis in patients with pulmonary disease.
      • Antonelli Incalzi R.
      • Caradonna P.
      • Ranieri P.
      • Basso S.
      • Fuso L.
      • et al.
      Correlates of osteoporosis in chronic obstructive pulmonary disease.
      The only clinical sequela of osteoporosis is fracture, the most common of which is the vertebral compression fracture.
      • Papaioannou A.
      • Watts N.B.
      • Kendler D.L.
      • Yuen C.K.
      • Adachi J.D.
      • Ferko N.
      Diagnosis and management of vertebral fractures in elderly adults.
      In addition to pain and height loss, osteoporosis-related vertebral compression fractures (VCFs) can lead to kyphosis that directly impairs pulmonary function – both in terms of reduced vital capacity (9% decrease in vital capacity per fracture) and perhaps even increased airflow obstruction.
      • Harrison R.A.
      • Siminoski K.
      • Vethanayagam D.
      • Majumdar S.R.
      Osteoporosis-related kyphosis and impairments in pulmonary function: A systematic review.
      This is concerning in patients with COPD who often already have compromised pulmonary status.
      Regrettably, VCFs are rarely diagnosed as 60–70% are asymptomatic and thus escape clinical detection.
      • Cooper C.
      • Melton III, L.J.
      Vertebral fractures: how large is the silent epidemic?.
      Nevertheless, patients with osteoporosis-related VCFs have at least a 5-fold increased risk of another vertebral fracture and a 3-fold increased risk of hip fracture.
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      As a result, it is important to target patients with VCFs because appropriate treatment with a number of approved agents reduces the risk of future fracture by about 50%.
      • MacLean C.
      • Newberry S.
      • Maglione M.
      • MmMhon M.
      • Ranganath V.
      • et al.
      Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis.
      Although population-screening for osteoporosis-related VCF is not recommended,
      • Scientific Advisory Council
      Osteoporosis society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada.
      a potentially valuable case-finding tool in patients with COPD might be recognition of “incidental” vertebral deformities documented by chest radiographs undertaken during an acute exacerbation. Because most VCF involve the mid-thoracic (T7-T8) spine and the thoraco-lumbar junction (T12-L1), and because these regions can be quite adequately visualized with standard chest radiographs, about 80–90% of VCF could potentially be identified.
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      In fact, this is one of the reasons that the chest radiograph is such a well validated method to identify previously unrecognized VCFs.
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      Studies performed at our center have demonstrated that at least 60% of clinically important vertebral fractures are recognized and reported on chest radiographs and that board-certified radiologists have a specificity for documenting fractures of 100%.
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      Since most patients with COPD will, by necessity, receive multiple chest radiographs over time, these radiographs might be useful for detecting VCFs. The potential yield of this approach has not been well-described.
      Previous reports suggest that 10–30% of COPD patients have clinically important moderate-to-severe grade VCFs found using various radiographic imaging modalities.
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      • Carter J.D.
      • Patel S.
      • Sultan F.L.
      • Thompson Z.J.
      • Margaux H.
      • et al.
      The recognition and treatment of vertebral fractures in males with chronic obstructive pulmonary disease.
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      • Jorgensen N.R.
      • Schwarz P.
      • Holme I.
      • Henriksen B.M.
      • Petersen L.J.
      The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease-a cross sectional study.
      • Angeli A.
      • Guglielmi G.
      • Dovoi A.
      • Capelli G.
      • de Fe D.
      • et al.
      High prevalence of asymptomatic vertebral fractures in post menopausal women receiving chronic glucocorticoid therapy:a cross sectional study.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      These previous studies, however, are limited by small sample size,
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      • Jorgensen N.R.
      • Schwarz P.
      • Holme I.
      • Henriksen B.M.
      • Petersen L.J.
      The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease-a cross sectional study.
      • Angeli A.
      • Guglielmi G.
      • Dovoi A.
      • Capelli G.
      • de Fe D.
      • et al.
      High prevalence of asymptomatic vertebral fractures in post menopausal women receiving chronic glucocorticoid therapy:a cross sectional study.
      lack of clinical data,
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      poor or inadequately documented reliability of vertebral fracture identification,
      • Carter J.D.
      • Patel S.
      • Sultan F.L.
      • Thompson Z.J.
      • Margaux H.
      • et al.
      The recognition and treatment of vertebral fractures in males with chronic obstructive pulmonary disease.
      or analyses of populations with limited generalizability.
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • Carter J.D.
      • Patel S.
      • Sultan F.L.
      • Thompson Z.J.
      • Margaux H.
      • et al.
      The recognition and treatment of vertebral fractures in males with chronic obstructive pulmonary disease.
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      • Angeli A.
      • Guglielmi G.
      • Dovoi A.
      • Capelli G.
      • de Fe D.
      • et al.
      High prevalence of asymptomatic vertebral fractures in post menopausal women receiving chronic glucocorticoid therapy:a cross sectional study.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      Therefore, we undertook a prospective cohort study of consecutive patients with COPD exacerbation visiting the Emergency Department (ED) with two main objectives: 1 to describe the prevalence of chest radiograph documented VCFs; and 2 to determine the independent correlates of vertebral fracture, with attention to easily measured historical (i.e., COPD duration, corticosteroid use) and clinical (i.e., weight, spirometry) data.

      Methods

       Subjects and setting

      From 2004 to 2006, we conducted a 3-site prospective cohort study of consecutive consenting patients with acute exacerbation of COPD seen in the ED in Edmonton, Alberta, Canada. We previously established the accuracy and reliability of vertebral fracture documentation on chest radiograph of our 3 site's radiologists.
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      The study EDs represent about half the emergency care capacity for the region which has about 1000 primary care physicians and provides care for one million people with universal health care coverage. Inclusion criteria were: age greater than 35 years; physician-diagnosis of chronic bronchitis, emphysema, or COPD; treated in the ED for an acute COPD exacerbation that met at least one of three validated criteria
      • Anthonisen N.
      • Manfreda J.
      • Warren P.
      • Hershfield E.
      • Harding G.
      • Nelson N.
      Antibiotic therapy in exacerbation of chronic obstructive pulmonary disease.
      ; 15 or more pack-years of smoking; ability to communicate in English; and provision of written informed consent. We screened 1095 potentially eligible patients at our three study EDs, and excluded 161 patients because they did not meet all inclusion criteria, and excluded another 468 patients because they had reasons for acute presentation that were not related to COPD (i.e., asthma, bronchiectasis, pulmonary fibrosis or radiographic evidence of pneumonia or heart failure). The 245 study patients were cared for by board-certified Emergency Medicine specialists, interviewed by research personnel (registered nurses), underwent spirometry, and had a standard posteroanterior and lateral chest radiographs interpreted by a board-certified radiologist. The study received ethics approval from the University of Alberta.

       Outcomes

      Our dependent binary variable of interest was the presence or absence of a recognized and board-certified radiologist documented VCF on chest radiograph.
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      A fracture was considered to be present if there was any mention of vertebral fracture, deformity, compression, wedging, or loss of height reported in the body or summary of the official radiograph report.
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      VCFs present when these terms are used for reporting fall into the grade 2 (moderate) or grade 3 (severe) category,
      • Genant H.K.
      • Wu C.Y.
      • Van Kuijk C.
      Vertebral fracture assessment using a semiquantitative technique.
      and are widely considered to be “clinically important”
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      • Genant H.K.
      • Wu C.Y.
      • Van Kuijk C.
      Vertebral fracture assessment using a semiquantitative technique.
      The reliability and validity of this method of fracture recognition on chest radiograph, compared with both a reference standard osteoporosis expert radiologist using semi-quantitative methods as well as automated quantitative digital morphometry, has been extensively documented at our sites.
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      In summary, the true positive rate of reporting by our radiologists is 60% (95%CI 48–71) with moderate inter-rater agreement (kappa=0.64, 95%CI 0.53–0.75); however, specificity for reporting of moderate-to-severe VCFs is 100%.
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.

       Other measurements

      We prospectively collected general information on socio-demographic (e.g., age, sex, education) and clinical (e.g., smoking status, self-reported comorbidities, medications) characteristics. Single item health status (in the week prior to illness) was asked of each patient. In terms of COPD, we ascertained disease duration, current and past inhaled and oral treatments, and collected physical measures that included height, weight, and pulmonary function tests determined using MicroLoop Spirometers (Spida 5 software, MicroMedical®). For the latter, we report the last (post-bronchodilator) measurements of FEV1, FVC, and PEF obtained in the ED before discharge home or admission to hospital. All data were obtained through structured interviews and medical record abstraction by research personnel masked to all osteoporosis-related hypotheses.

       Analysis

      Data are presented as numbers and proportions (%), means with standard deviations (SD), or medians with interquartile ranges (IQR), as appropriate. For univariable analyses we used chi-square tests, t-tests or Mann-Whitney U tests. Because of relatively few outcomes (n=22), multivariable logistic regression modeling strategies were undertaken both purposefully and parsimoniously – acknowledging that we could not assess more than four or five potentially independent variables if we wanted to avoid over-fitting. We forced age and sex into our models, and then considered for inclusion covariates based on a review of the literature, biologic plausibility, association (p<0.2) with the presence of a vertebral fracture on univariable analysis, or if confounding (10% or greater change in beta-estimates of any included parameter) was present. All first-order interaction terms were tested; none were statistically significant (p<0.1) and so none are included in the final models. We report adjusted odds ratios (OR) with their 95% confidence intervals (CI), and describe the overall model goodness of fit using the c-statistic (a measure akin to the area under the curve). All analyses were performed using Stata Statistical Software, Release 10 (College Station, TX: Stata Corporation).

      Results

      Overall, 37% of patients were 75 years of age or older, 44% were women, and 7% were non-white. About half (54%) reported fair or poor health and the majority (69%) had one or more comorbidities unrelated to COPD (Table 1). In terms of COPD, 30% had a 10 year or longer duration of disease, 23% had very severe disease (defined by a FEV1<30% predicted), 37% required admission to hospital, and 86% were already treated with oral corticosteroids (Table 2). The overall prevalence of one or more VCFs documented by chest radiograph was 22 of 245 (9%, 95%CI 6–13%).
      Table 1Description of 245 Patients Treated in the Emergency Department for an Acute Exacerbation of COPD, According to the Presence or Absence of Documented Moderate-to-Severe Vertebral Fractures.
      CharacteristicsWith moderate-to-severe vertebral fracture (N=22)Without vertebral fracture (N=223)P-value
      Socio-demographic
      Age, median years (IQR)76 (68–73)70 (61–77)0.014
      Age>75 years12 (55)78 (35)0.094
      Female8 (36)100 (45)0.4
      White22 (100)207 (93)0.2
      Married9 (41)106 (48)0.6
      High school completed3 (14)46 (21)0.6
      Self-Reported Health
      Fair or Poor13 (59)119 (53)0.8
      Comorbidities
      Hypertension10 (45)105 (47)0.9
      Coronary disease6 (27)54 (24)0.8
      Heart failure4 (18)28 (13)0.5
      Diabetes3 (14)35 (16)1.0
      Osteoporosis13 (59)42 (19)<0.001
      No other comorbidities6 (27)70 (31)0.9
      Medications
      Diuretics (loop or thiazide)11 (50)57 (26)0.015
      Thyroid replacement3 (14)28 (13)0.8
      Anticonvulsants03 (1)
      Estrogen replacement09 (4)
      Bisphosphonates12 (57)27 (12)<0.001
      Calcium supplements6 (27)24 (11)0.024
      Vitamin-D supplements6 (27)13 (6)<0.001
      No other medications6 (27)118 (53)0.028
      IQR, denotes interquartile range; COPD, chronic obstructive pulmonary disease.
      Table 2Clinical and Pulmonary Function Measures of COPD Severity According to Presence or Absence of Documented Moderate-to-Severe Vertebral Fracture.
      CharacteristicsWith moderate-to-severe vertebral fracture (N=22)Without vertebral fracture (N=223)P-value
      General
      COPD, median years (IQR)12 (5–16)6 (3–12)0.16
      COPD duration>10 years10 (45)63 (28)0.093
      Current Smoker4 (19)92 (42)0.060
      Pack-years, median (IQR)35 (22–51)40 (25–55)0.6
      Weight, median kg (IQR)67 (60–88)80 (68–95)0.033
      Body mass index, median kg/m2 (IQR)26 (21–29)28 (24–33)0.010
      COPD Management
      Discharged on oral steroids20 (91)191 (86)0.5
      Treatments at presentation
       Oral steroids14 (64)139 (62)0.8
       Inhaled steroids5 (23)65 (29)0.6
       Short-acting beta-agonist17 (77)161 (72)0.7
       Long-acting beta-agonist13 (59)100 (48)0.14
       Inhaled anticholinergic17 (77)122 (55)0.019
       Theophylline5 (23)24 (11)0.077
      Admitted to hospital12 (55)79 (35)0.077
      Pulmonary Function Tests+
      FEV1, mean L (SD)0.9 (0.4)1.1 (0.6)0.055
      FEV1, % predicted (SD)38 (15)44 (20)0.11
      FEV1/FVC, ratio (SD)50 (14)57 (19)0.061
      PEF, mean L/min (SD)124 (74)170 (102)0.042
      PEF, % predicted (SD)31 (16)43 (21)0.016
      Very severe (FEV1<30%)6 (27)50 (22)0.6
      +Last post-bronchodilator measurement performed in the Emergency Department. COPD, denotes chronic obstructive pulmonary disease; IQR, interquartile range; FEV1, Forced expiratory volume at first second; FVC, forced vital capacity; FEV1/FVC, Forced expiratory volume first second/forced vital capacity; PEF, peak expiratory flow.

       Potential correlates of vertebral fracture

      In general, patients with VCF were older, sicker, and more likely to have a diagnosis of osteoporosis (57% vs 12% of those without fracture, p<0.001). Ten of 22 (43%) patients with COPD and documented VCF were not treated for osteoporosis and all 10 of these patients were discharged from the ED with oral corticosteroid therapy. Table 1 provides general patient characteristics stratified by the presence or absence of VCF. In terms of their COPD, patients with VCF tended to have more severe disease based on history or spirometry. For example, 45% had 10 or more years of disease compared with 28% of patients without a fracture (p=0.093). Also, results of all pulmonary function tests tended to be worse among patients with VCF; for instance, mean FEV1 was 0.9 (SD 0.4) L vs 1.1 (SD 0.6) L for those without fracture (p=0.055). Table 2 provides measures of COPD severity and treatments stratified by presence of VCF.
      There was a particularly noteworthy relationship seen between weight and VCF. Patients with fracture weighed less, whether considering their weight (median 67 kg vs 80 kg, p=0.033) or body mass index [BMI] (median 26 vs 28, p=0.010). To explore this association in further detail, we grouped patients into quartiles according to their BMI and arranged the data from heaviest quartile (median BMI=37) vs BMI=30 vs BMI=26 vs BMI=21 (lightest quartile). The Fig. 1 illustrates the strong and graded increased risk for VCF with decreasing levels of BMI (p<0.001 for trend).
      Figure thumbnail gr1
      Figure 1Prevalence of Moderate-to-Severe Vertebral Fractures in Patients with COPD According to Body Mass Index.

       Multivariable analysis

      In models adjusted for age, sex, and duration of COPD, the only independent correlate of the presence of a documented VCF was BMI (Table 3). None of the measures of pulmonary function, such as FEV1 or PEF, remained significant in models that were adjusted for age, sex, and COPD duration nor did they confound the association between fracture and BMI (data not shown). Compared with the heaviest quartile of patients, those who were most underweight (lightest quartile, median BMI=21) had a significant 11-fold increased risk of VCF (2% vs 16% prevalence, adjusted odds ratio 11.0, 95%CI 1.3–90.7, p=0.025). The c-statistic for our final multivariable model was 0.71. The relationship between weight and VCF was present regardless of how it was classified. For example, simply considering BMI as a dichotomous variable (below vs above the average of 28) demonstrated the same relationship: those below average BMI had an adjusted odds ratio for VCF of 8.6 (95%CI 1.8–41.6, p=0.007). Even considering weight as a continuous measure, the adjusted odds ratio for VCF was 0.96 (95%CI 0.94–0.99, p=0.012) per kg, roughly a 4% reduction in fracture for each additional kg of weight.
      Table 3Independent Correlates of the Presence of a Moderate-to-Severe Vertebral Fracture in Patients with COPD Exacerbation (Multivariable Logistic Regression).
      VariableAdjusted odds ratio (95% Confidence Interval)P-value
      Age>75 years1.5 (0–3.9)0.4
      Female1.1 (0.4–3.1)0.8
      COPD duration>10 years1.9 (0.7–5.2)0.2
      Quartiles of Body Mass Index
       1 (median BMI=37)1.0 (reference group)
       2 (median BMI=30)4.6 (0.5–41.2)0.17
       3 (median BMI=26)5.6 (0.6–48.9)0.12
       4 (median BMI=21)11.0 (1.3–90.7)0.025

      Discussion

      In our study of patients presenting to the ED with an acute exacerbation of COPD, we found almost one in ten had a clinically important moderate-to-severe VCF documented on their official chest radiograph report. About half (43%) of the patients with VCF were not receiving treatment for osteoporosis but all of these patients received oral corticosteroids in the ED. Patients with VCFs were older, had more comorbidity, and seemed to have more severe COPD (based on history or spirometry) than those without fracture. Of note, patients with fracture weighed significantly less than patients without fracture, and BMI was the only independent correlate of VCF in multivariable analyses – compared to the heaviest quartile of patients, those in the lightest quartile (median BMI 21) had an adjusted 11-fold increased risk.
      Our reported 9% prevalence of vertebral fracture in patients with COPD exacerbation is in keeping with previous reports that suggest a prevalence of clinically important VCF ranging from 10–30%.
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      • Carter J.D.
      • Patel S.
      • Sultan F.L.
      • Thompson Z.J.
      • Margaux H.
      • et al.
      The recognition and treatment of vertebral fractures in males with chronic obstructive pulmonary disease.
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      • Jorgensen N.R.
      • Schwarz P.
      • Holme I.
      • Henriksen B.M.
      • Petersen L.J.
      The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease-a cross sectional study.
      • Angeli A.
      • Guglielmi G.
      • Dovoi A.
      • Capelli G.
      • de Fe D.
      • et al.
      High prevalence of asymptomatic vertebral fractures in post menopausal women receiving chronic glucocorticoid therapy:a cross sectional study.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      Vertebral fracture prevalences at the lower end of this range were reported in studies that considered male COPD outpatients who had never used large doses of oral corticosteroids
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      while prevalences at the higher end of this range included post-menopausal women and patients exposed to large cumulative doses of corticosteroids.
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      • Angeli A.
      • Guglielmi G.
      • Dovoi A.
      • Capelli G.
      • de Fe D.
      • et al.
      High prevalence of asymptomatic vertebral fractures in post menopausal women receiving chronic glucocorticoid therapy:a cross sectional study.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      In addition, we identified VCFs using the official chest radiograph report while several previous studies used study radiologists or automated digital morphometry to independently re-review and then identify fractures of all degrees (i.e., mild, moderate, and severe)
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      • Carter J.D.
      • Patel S.
      • Sultan F.L.
      • Thompson Z.J.
      • Margaux H.
      • et al.
      The recognition and treatment of vertebral fractures in males with chronic obstructive pulmonary disease.
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      • Jorgensen N.R.
      • Schwarz P.
      • Holme I.
      • Henriksen B.M.
      • Petersen L.J.
      The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease-a cross sectional study.
      • Angeli A.
      • Guglielmi G.
      • Dovoi A.
      • Capelli G.
      • de Fe D.
      • et al.
      High prevalence of asymptomatic vertebral fractures in post menopausal women receiving chronic glucocorticoid therapy:a cross sectional study.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      ; these latter methods consistently demonstrate higher fracture prevalence because of inclusion of much less severe fractures and better recognition of moderate and severe fractures and confirm systematic under-reporting in routine chest radiograph reports.
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      • Carter J.D.
      • Patel S.
      • Sultan F.L.
      • Thompson Z.J.
      • Margaux H.
      • et al.
      The recognition and treatment of vertebral fractures in males with chronic obstructive pulmonary disease.
      Using the previously documented 100% specificity and 40% false-negative reporting rate at our center,
      • Kim N.
      • Rowe B.H.
      • Raymond G.
      • Jen H.
      • Colman I.
      • et al.
      Under-reporting of vertebral fractures on routine chest radiography.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      we estimate that the prevalence of clinically important VCFs in our cohort of COPD patients is approximately 15% – thereby bringing our results in line with previous estimates.
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • Majumdar S.R.
      • Kim N.
      • Colman I.
      • Chahal A.M.
      • Raymond G.
      • et al.
      Incidental vertebral fractures discovered with chest radiography in the emergency department.
      • Carter J.D.
      • Patel S.
      • Sultan F.L.
      • Thompson Z.J.
      • Margaux H.
      • et al.
      The recognition and treatment of vertebral fractures in males with chronic obstructive pulmonary disease.
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      • Jorgensen N.R.
      • Schwarz P.
      • Holme I.
      • Henriksen B.M.
      • Petersen L.J.
      The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease-a cross sectional study.
      • Angeli A.
      • Guglielmi G.
      • Dovoi A.
      • Capelli G.
      • de Fe D.
      • et al.
      High prevalence of asymptomatic vertebral fractures in post menopausal women receiving chronic glucocorticoid therapy:a cross sectional study.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      The other noteworthy finding in our study was the striking association between low body weight and vertebral fractures. There are two plausible explanations. First, low body weight in and of itself is a well-established risk factor for low bone mineral density.
      • Antonelli Incalzi R.
      • Caradonna P.
      • Ranieri P.
      • Basso S.
      • Fuso L.
      • et al.
      Correlates of osteoporosis in chronic obstructive pulmonary disease.
      • Roy D.K.
      • O'Neill T.W.
      • Finn J.D.
      • Lunt M.
      • Silman A.J.
      • et al.
      Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS).
      • Papaioannou A.
      • Kennedy C.C.
      • Cranney A.
      • Hawker G.
      • Brown J.P.
      • Kaiser S.M.
      • et al.
      Risk factors for low BMD in healthy men age 50 years or older: a systematic review.
      • Morin S.
      • Tsang J.F.
      • Leslie W.D.
      Weight and body mass index predict bone mineral density and fractures in women aged 40–59 years.
      • Iqbal F.
      • Michaelson J.
      • Thaler L.
      • Rubin J.
      • Roman J.
      • et al.
      Declining bone mass in men with chronic pulmonary disease; contribution of glucocorticoid treatment, body mass index and gonadal function.
      Patients with COPD are predisposed to low body weight for a variety of reasons including malnutrition, depression and hyper-catabolism related to increased energy costs of breathing, tissue hypoxia, use of beta-agonists, and chronic systemic inflammation.
      • Gross N.J.
      Extrapulmonary effects of chronic obstructive pulmonary disease.
      • Gan W.Z.
      • Man S.F.P.
      • Senthilselvan A.
      • Sin D.D.
      Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis.
      • Agusti A.
      • Sorian J.B.
      COPD as a systemic disease.
      Alternately, it may just be that low body weight is an excellent proxy measure for severity of COPD. Studies have shown a direct association between low bone mineral density and severity of COPD as defined by spirometry,
      • Bolton C.E.
      • Ionescu A.A.
      • Shiels K.M.
      • Pettit R.J.
      • Edwards P.H.
      Associated loss of fat-free mass and bone mineral density in chronic obstructive pulmonary disease.
      • Sin D.D.
      • Man J.P.
      • Man S.F.P.
      The risk of osteoporosis in Caucasian men and women with obstructive airways disease.
      • Vrieze A.
      • de Greef M.H.G.
      • Wykstra P.J.
      Low bone mineral density in COPD patients related to worse lung function, low weight and decreased fat free mass.
      • Kjensli A.
      • Mowinchel P.
      • Ryg R.S.
      • Falch J.A.
      Low bone mineral density is related to severity of chronic obstructive pulmonary disease.
      but none of these examined the relationship between vertebral fracture and disease severity.
      The few studies that have examined the association between vertebral fracture and severity of COPD have had conflicting results.
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      • Jorgensen N.R.
      • Schwarz P.
      • Holme I.
      • Henriksen B.M.
      • Petersen L.J.
      The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease-a cross sectional study.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      • de Vries F.
      • van Staa T.P.
      • Bracke M.S.G.M.
      • Cooper C.
      • Leufkens H.G.M.
      • et al.
      Severity of obstructive airway disease and risk of osteoporotic fracture.
      This may be in part related to how “severity” is defined.
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      • Jorgensen N.R.
      • Schwarz P.
      • Holme I.
      • Henriksen B.M.
      • Petersen L.J.
      The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease-a cross sectional study.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      For example, patients' measured heights are often used to calculate the percent predicted values for pulmonary function tests, and use of measured heights will systematically under-estimate COPD severity in patients with vertebral fractures, height loss, and kyphosis.
      • Harrison R.A.
      • Siminoski K.
      • Vethanayagam D.
      • Majumdar S.R.
      Osteoporosis-related kyphosis and impairments in pulmonary function: A systematic review.
      Using arm span corrects this bias and has been recommended.
      • Harrison R.A.
      • Siminoski K.
      • Vethanayagam D.
      • Majumdar S.R.
      Osteoporosis-related kyphosis and impairments in pulmonary function: A systematic review.
      If we (and others
      • Papaionnou A.
      • Parkinson W.
      • Ferko N.
      • Probyn L.
      • Ioannidis G.
      • et al.
      Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
      • McEvoy C.E.
      • Ensrud K.E.
      • Bender E.
      • Genant H.K.
      • Yu W.
      Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
      • Jorgensen N.R.
      • Schwarz P.
      • Holme I.
      • Henriksen B.M.
      • Petersen L.J.
      The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease-a cross sectional study.
      • Nuti R.
      • Siviero P.
      • Maggi S.
      • Guglielmi G.
      • Cafarelli C.
      • Crepaldi G.
      • et al.
      Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
      ) had used arm span for determining predicted values, a stronger and more robust association between COPD severity and vertebral fractures might have been detected. In addition, our measures of pulmonary function were obtained soon after management of an acute exacerbation, and may not reflect a true “baseline” of COPD severity. For our purposes, the mechanism for the association between low body weight and COPD severity and fracture is perhaps less important than the fact that it is robust and can be applied in the clinical setting.
      This study has several limitations that merit consideration. First, we did not undertake dedicated spinal radiographs or re-review chest radiographs to determine the prevalence of vertebral fracture. However, it should be acknowledged our objective was to examine the issue using the data that are already available to any physician that is managing COPD. Thus our use of chest radiograph reports might instead be considered a strength.
      Second, we had no measures of bone mineral density. Nevertheless, more than 90–95% of patients over the age of 60 years with a VCF have low bone mass
      • Melton 3rd, L.J.
      • Thamer M.
      • Ray N.F.
      • Chan J.K.
      • Chesnut 3rd, C.H.
      • et al.
      Fractures attributable to osteoporosis: report from the national osteoporosis foundation.
      and current guidelines suggest that osteoporosis treatment could be initiated without measurement of bone mineral density.
      • Scientific Advisory Council
      Osteoporosis society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada.
      That said, bone mineral density testing near the time that treatment is started may still be useful to document the severity of osteoporosis, to monitor response to treatment over time, and even to ensure medication adherence.
      Third, concerns about the absence of bone mineral density measurements do not acknowledge the fact that the COPD patients with documented fracture in our study were almost universally started on moderate-to-high doses of oral corticosteroids (the standard regimen at our center is 50 mg of prednisone per exacerbation for 10–14 days, for a total dose >0.5 g). It is a weakness of our study that we had no way of determining the total or lifetime cumulative dose of corticosteroids received prior to presentation, another risk factor for osteoporosis.
      Fourth, we did not collect some specific osteoporosis-related data, such as remote use of bone-sparing agents like the bisphosphonates, past history of non-vertebral fractures, vitamin-D sufficiency, hypogonadism, family history, or measures of physical activity. One could imagine how several of these risk factors might co-exist and lead to very heightened risk for osteoporosis. For example, consider a 65-year old, white, underweight, post-menopausal woman with COPD who still smokes and has very limited exercise capacity – not an uncommon scenario in clinic, but an almost incalculable risk for osteoporosis-related fracture.
      Finally, in terms of wider applicability of our results, we note that our patients were selected at the time of COPD exacerbation and were volunteers willing to participate in an observational study suggesting they might be somewhat “healthier” than the general population seeking care in the ED, thus under-estimating the prevalence of VCF in patients with COPD.
      Accepting the limitations of our work, the findings may still have important potential implications for practicing clinicians. First, physicians who regularly treat patients with COPD exacerbations should keep in mind the results of chest radiographs and the need for osteoporosis management when considering the decision to prescribe oral corticosteroids. Second, since other fractures have been successfully targeted in the ED and had interventions directed at them in the community to improve screening and treatment of osteoporosis,
      • Majumdar S.R.
      • Johnson J.A.
      • McAlister F.A.
      • Bellerose D.
      • Russell A.S.
      • et al.
      Multifaceted intervention to improve osteoporosis diagnosis and treatment in patients with recent wrist fracture: a randomized controlled trial.
      perhaps interventions could be developed and tested to address the problem of unrecognized and untreated VCF in COPD patients.

      Conclusions

      Almost one-tenth of patients with COPD exacerbation have VCF recognized and documented by chest radiograph. About half of these patients were not receiving treatment for osteoporosis, and yet all of these patients were prescribed oral corticosteroids putting them at risk for more fractures and perhaps additional compromise of pulmonary function. Our findings suggest that the chest radiograph may be an important case-finding tool for vertebral compression fractures, particularly for those COPD patients who are underweight.

      Conflicts of interest

      Dr. Majumdar receives salary support from the Alberta Heritage Foundation for Medical Research (Health Scholar). Dr. Rowe's research is supported by the 21st Century Canada Research Chairs Program through the Government of Canada (Ottawa, Ontario). All authors declare no known or potential conflicts of interest.

      Acknowledgements

      The authors would like to thank the Canadian Association of Emergency Physicians (CAEP) Research Consortium who provided support and funding for this study and the Department of Emergency Medicine Research Group (EMeRG®) at the University of Alberta for their in-kind support of this project. The research team would like to thank the site PIs at the three EDs and express their gratitude to the research staff at each of the study sites.

      References

        • Mannino D.M.
        COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity.
        Chest. 2002; 121: 121S-126S
        • Reginster J.
        • Burlet N.
        Osteoporosis: a still increasing prevalence.
        Bone. 2005; 38: S4-S9
        • O'Donnel D.E.
        • Aaron S.
        • Bourbeau J.
        • Hernandex P.
        • Marchiniuk D.D.
        • et al.
        Canadian thoracic society recommendations for management of chronic obstructive pulmonary disease-2007 update.
        Can Respir J. 2007; 14: 5B-32B
        • Jorgensen N.R.
        • Schwarz P.
        Osteoporosis in chronic obstructive pulmonary disease.
        Curr Opin Pulm Med. 2008; 14: 84-92
        • Gross N.J.
        Extrapulmonary effects of chronic obstructive pulmonary disease.
        Curr Opin Pulm Med. 2001; 7: 122-127
        • Scientific Advisory Council
        Osteoporosis society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada.
        CMAJ. 2002; 167: S1-S34
        • Gan W.Z.
        • Man S.F.P.
        • Senthilselvan A.
        • Sin D.D.
        Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis.
        Thorax. 2004; 59: 574-580
        • Gluck O.
        • Colic G.
        Recognizing and treating glucocorticoid induced osteoporosis in patients with pulmonary disease.
        Chest. 2004; 125: 1859-1876
        • Antonelli Incalzi R.
        • Caradonna P.
        • Ranieri P.
        • Basso S.
        • Fuso L.
        • et al.
        Correlates of osteoporosis in chronic obstructive pulmonary disease.
        Resp Med. 2000; 94: 1079-1084
        • Papaioannou A.
        • Watts N.B.
        • Kendler D.L.
        • Yuen C.K.
        • Adachi J.D.
        • Ferko N.
        Diagnosis and management of vertebral fractures in elderly adults.
        Am J Med. 2002; 113: 220-228
        • Harrison R.A.
        • Siminoski K.
        • Vethanayagam D.
        • Majumdar S.R.
        Osteoporosis-related kyphosis and impairments in pulmonary function: A systematic review.
        J Bone Miner Res. 2007; 22 (247–457)
        • Cooper C.
        • Melton III, L.J.
        Vertebral fractures: how large is the silent epidemic?.
        BMJ. 1992; 304: 793-794
        • Papaionnou A.
        • Parkinson W.
        • Ferko N.
        • Probyn L.
        • Ioannidis G.
        • et al.
        Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
        Osteoporos Int. 2003; 14: 913-917
        • MacLean C.
        • Newberry S.
        • Maglione M.
        • MmMhon M.
        • Ranganath V.
        • et al.
        Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis.
        Ann Intern Med. 2008; 148: 197-213
        • Kim N.
        • Rowe B.H.
        • Raymond G.
        • Jen H.
        • Colman I.
        • et al.
        Under-reporting of vertebral fractures on routine chest radiography.
        AJR Am J Roentgenol. 2004; 182: 297-300
        • Majumdar S.R.
        • Kim N.
        • Colman I.
        • Chahal A.M.
        • Raymond G.
        • et al.
        Incidental vertebral fractures discovered with chest radiography in the emergency department.
        Arch Intern Med. 2005; 165: 905-909
        • Carter J.D.
        • Patel S.
        • Sultan F.L.
        • Thompson Z.J.
        • Margaux H.
        • et al.
        The recognition and treatment of vertebral fractures in males with chronic obstructive pulmonary disease.
        Respir Med. 2008; 102: 1165-1172
        • McEvoy C.E.
        • Ensrud K.E.
        • Bender E.
        • Genant H.K.
        • Yu W.
        Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 1998; 157: 704-709
        • Jorgensen N.R.
        • Schwarz P.
        • Holme I.
        • Henriksen B.M.
        • Petersen L.J.
        The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease-a cross sectional study.
        Resp Med. 2007; 101: 177-185
        • Angeli A.
        • Guglielmi G.
        • Dovoi A.
        • Capelli G.
        • de Fe D.
        • et al.
        High prevalence of asymptomatic vertebral fractures in post menopausal women receiving chronic glucocorticoid therapy:a cross sectional study.
        Bone. 2006; 39: 253-259
        • Nuti R.
        • Siviero P.
        • Maggi S.
        • Guglielmi G.
        • Cafarelli C.
        • Crepaldi G.
        • et al.
        Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study.
        Osteoporos Int. 2009; 20: 989-998
        • Anthonisen N.
        • Manfreda J.
        • Warren P.
        • Hershfield E.
        • Harding G.
        • Nelson N.
        Antibiotic therapy in exacerbation of chronic obstructive pulmonary disease.
        Ann Intern Med. 1987; 106: 196-204
        • Genant H.K.
        • Wu C.Y.
        • Van Kuijk C.
        Vertebral fracture assessment using a semiquantitative technique.
        J Bone Miner Res. 1993; 8: 1137-1148
        • Roy D.K.
        • O'Neill T.W.
        • Finn J.D.
        • Lunt M.
        • Silman A.J.
        • et al.
        Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS).
        Osteoporos Int. 2003; 14: 19-26
        • Papaioannou A.
        • Kennedy C.C.
        • Cranney A.
        • Hawker G.
        • Brown J.P.
        • Kaiser S.M.
        • et al.
        Risk factors for low BMD in healthy men age 50 years or older: a systematic review.
        Osteoporos Int. 2009; 20: 507-518
        • Morin S.
        • Tsang J.F.
        • Leslie W.D.
        Weight and body mass index predict bone mineral density and fractures in women aged 40–59 years.
        Osteoporos Int. 2009; 20: 363-370
        • Iqbal F.
        • Michaelson J.
        • Thaler L.
        • Rubin J.
        • Roman J.
        • et al.
        Declining bone mass in men with chronic pulmonary disease; contribution of glucocorticoid treatment, body mass index and gonadal function.
        Chest. 1999; 116: 1616-1624
        • Agusti A.
        • Sorian J.B.
        COPD as a systemic disease.
        COPD. 2008; 5: 133-138
        • Bolton C.E.
        • Ionescu A.A.
        • Shiels K.M.
        • Pettit R.J.
        • Edwards P.H.
        Associated loss of fat-free mass and bone mineral density in chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2004; 170: 1286-1293
        • Sin D.D.
        • Man J.P.
        • Man S.F.P.
        The risk of osteoporosis in Caucasian men and women with obstructive airways disease.
        Am J Med. 2003; 114: 10-14
        • Vrieze A.
        • de Greef M.H.G.
        • Wykstra P.J.
        Low bone mineral density in COPD patients related to worse lung function, low weight and decreased fat free mass.
        Osteoporos Int. 2007; 18: 1197-1202
        • Kjensli A.
        • Mowinchel P.
        • Ryg R.S.
        • Falch J.A.
        Low bone mineral density is related to severity of chronic obstructive pulmonary disease.
        Bone. 2007; 40: 493-497
        • de Vries F.
        • van Staa T.P.
        • Bracke M.S.G.M.
        • Cooper C.
        • Leufkens H.G.M.
        • et al.
        Severity of obstructive airway disease and risk of osteoporotic fracture.
        Eur Respir J. 2005; 25: 879-884
        • Melton 3rd, L.J.
        • Thamer M.
        • Ray N.F.
        • Chan J.K.
        • Chesnut 3rd, C.H.
        • et al.
        Fractures attributable to osteoporosis: report from the national osteoporosis foundation.
        J Bone Miner Res. 1997; 12: 16-23
        • Majumdar S.R.
        • Johnson J.A.
        • McAlister F.A.
        • Bellerose D.
        • Russell A.S.
        • et al.
        Multifaceted intervention to improve osteoporosis diagnosis and treatment in patients with recent wrist fracture: a randomized controlled trial.
        CMAJ. 2008; 178: 569-575