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Smokers with emphysema and small airway disease on computed tomography have lower bone density

Osteoporosis is more common in patients with COPD and in smokers. The aim of this study was to assess whether measures of emphysema and airway disease on computed tomography (CT) were associated with lower bone density or vertebral fractures in smokers with and without COPD. For this purpose, we included participants from the NELSON lung cancer screening trial. Bone density was measured as Hounsfield Units in the first lumbar vertebra, and vertebral fractures were assessed semiquantitatively. The 15th percentile method (Perc15) was used to assess emphysema, and the airway lumen perimeter (Pi10) was used for airway wall thickness. Expiratory/inspiratory-ratiomean lung density (E/I-ratioMLD) was used as a measure for air trapping and tracheal index to assess tracheal deformity. Linear regression models and logistic regression models were used to assess associations between CT biomarkers, bone density, and presence of fractures. Exactly 1,093 male participants were eligible for analysis. Lower Perc15 and higher E/I-ratioMLD were significantly associated with lower bone density (b=−1.27, P=0.02 and b=−0.37, P=0.02, respectively). Pi10 and tracheal index were not associated with bone density changes. CT-derived biomarkers were not associated with fracture prevalence. Bone density is lower with increasing extent of emphysema and small airway disease but is not associated with large airway disease and tracheal deformity. This may indicate the necessity to measure bone density early in smokers with emphysema and air trapping to prevent vertebral fractures.


Introduction
Systemic consequences of COPD, such as cachexia, skeletal muscle wasting, and anemia, significantly contribute to the burden of disease. 1,2 The high prevalence of osteoporosis in COPD patients is especially problematic because fractures can lead to substantial disability. [3][4][5] Although the exact pathophysiological relationship between osteoporosis and COPD remains largely unknown, studies have shown similarities between emphysema and osteoporosis in loss of extracellular matrix and associations with inflammatory mediators such as tumor necrosis factor-α. 6,7 Also, Ohara et al 8 showed that a relationship exists between emphysema and low bone mineral density (BMD) on dual X-ray absorptiometry. However, less is known on the relationship between bone density and airway disease. Computed tomography (CT) is increasingly used to identify biomarkers to classify COPD patients, and it could be helpful in studying the association between morphologic abnormalities underlying COPD and osteoporosis. 9 Next to smoking-related lung changes on CT, bone density measurements based on Hounsfield Dovepress Dovepress 1208 Pompe et al unit (HU) could provide a measure for osteoporosis and are increasingly being investigated as a diagnostic aid. 10,11 A recent study showed that bone density measured with CT could be used to identify patients with osteoporosis. 12 We hypothesized that lower bone density and vertebral fractures could be found more often in COPD patients with an emphysema-dominant phenotype, compared to COPD patients in whom chronic bronchitis is more evident. This is in line with the hypothesis of an overall wasting COPD phenotype, although these pulmonary and skeletal changes might already be present before COPD is diagnosed. 13 Therefore, the purpose of this study was to assess the association of bone density (as a proxy for osteoporosis) and vertebral fractures with several CT quantification measures for lung abnormalities in smokers with and without COPD.

Methods Participants
The included participants were part of the Dutch and Belgium Lung Cancer Screening Trial (NELSON trial). 14 After gaining information on smoking history, which was derived from questionnaires sent to the general population aged between 50 years and 75 years, participants were invited to participate in the study. 15 The NELSON trial included current and former smokers aged between 50 years and 75 years, with a smoking history of at least 16.5 pack-years. Former smokers should not have quit more than 10 years prior to inclusion. Participants were excluded based on self-reported poor health status or if they were unable to climb two flights of stairs, had a recent chest CT scan, had a history of cancer, or a body weight of more than 140 kg. The Ministry of Health of the Netherlands and the institutional ethical review board approved the NELSON trial. The NELSON trial is registered at www.trialregister.nl with trial number ISRCTN63545820 (Institutional Review Board approval number 03/040). Written informed consent was obtained from all participants. A random subset of participants selected from the University Medical Center Utrecht underwent additional lung function tests and expiratory CT and were included in the present study. 16 Because of logistical reasons, not all participants underwent lung function testing.

CT acquisition
All participants underwent a low-dose paired inspiratory and expiratory volumetric CT scan, which was acquired with 16×0.75 mm collimation (Brilliance 16P; Philips Healthcare, Best, the Netherlands). Scans were made without intravenous contrast injection. For the inspiratory CT, participants weighing 80 kg or less were scanned with 120 kVp at 30 mA, and participants weighing 80 kg were scanned with 140 kVp at 30 mA (estimated effective dose of 1.40 mSv). For the expiratory CT, participants were scanned at 90 kVp (80 kg) or 120 kVp (80 kg) at 20 mA (estimated effective dose of 0.65 mSv). Axial images with a slice thickness of 1.0 mm were reconstructed at 0.7 mm increment using a smooth reconstruction filter (B-filter; Philips Healthcare).
CT assessment of emphysema, airway wall thickness, air trapping, and tracheal index The quantification of emphysema and airway wall thickness has been reported before. 17,18 All quantifications were performed with CIRRUS Lung 12.03 (Cirrus, Diagnostic Image Analysis Group, Radboud University Medical Center, Nijmegen, the Netherlands; Fraunhofer MEVIS, Bremen, Germany). The lungs were segmented, and large airways were excluded. Severity of emphysema was assessed with the 15th percentile (Perc15) technique. This technique acquires the HU point below which 15% of the voxels are distributed. 19 The closer the Perc15 is to −1,000 HU, the more emphysema is present.
For analysis of large airway disease, the airway lumen was automatically segmented as previously described. 20 Airway wall thickness was calculated by the square root of wall area for a theoretical airway with an internal perimeter of 10 mm (Pi10). Airway wall borders were visually inspected to verify correct segmentation. 21 CT air trapping was defined as the expiratory to inspiratory ratio of mean lung density (expiratory/inspiratoryratio mean lung density [E/I-ratio MLD ]) and was used as a measure of small airway dysfunction. 22 Tracheal index (TI) was measured on inspiratory scans at every slice from 2.5 cm above the bifurcation of the main bronchi to the top of the trachea. 23,24 TI was defined by the ratio of coronal and sagittal length of the trachea on the axial plane. Figures 1 and 2 illustrate all CT-derived measurements.

Bone density and fracture assessment
Bone density measurements and fracture assessment have been reported before. 25 Bone density measurements were performed in the first lumbar vertebra (L1). If L1 was fractured or not visualized, bone density was measured in a visible adjacent normal vertebra. A region of interest was placed in axial view in the upper part of the vertebra between the endplate and the entrance of the vessels at the anterior midportion, in a homogeneous area of trabecular bone  Figure 3). Regions of interest were as large as possible, and focal heterogeneous areas were avoided. All measurements were taken by a research student (WJ) under the supervision of a chest radiologist (PJ). Vertebral fracture assessment was conducted in a sagittal plane. Height loss of 20% was considered a vertebral facture, compared to an adjacent, nonfractured vertebra. Fracture assessment was executed using semiquantitative method of Genant et al. 26 Pulmonary function testing All participants underwent prebronchodilator pulmonary function tests according to the European Respiratory Society/ American Thoracic Society guidelines with ZAN equipment (ZAN Messgeräte GmbH, Oberthulba, Germany). 27 Forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity were measured. COPD was defined according to the Global Strategy for the Diagnosis, Management, and Prevention of COPD (Global Initiative for Chronic Obstructive Lung Disease). 1

statistical analysis
Mean and standard deviation (SD) values were calculated for normally distributed data and median and interquartile range for non-normally distributed data. Univariate analyses were used to assess the association of bone density with CT-related COPD measures (Perc15, Pi10, E/I-ratio MLD , and TI) and demographic characteristics (age, body mass index [BMI], smoking status, pack-years, FEV 1 % predicted, and COPD status [absent/present]). Biomarkers with a P-value of 0.20 were included in a multivariate linear regression model.
To compare Pi10, Perc15, E/I-ratio MLD , and TI between participants with and without a fracture, a Student's t-test was performed. Logistic regression was used to study the association    Table 1. Mean values of Perc15, Pi10, E/I-ratio MLD , and TI are shown in Table 2.

Bone density and CT-related COPD measures
The majority of bone density measurements were performed in L1 (n=938, 85.8%). Because of inhomogeneities and/or fractures in L1 or nonvisualization of L1, 140 measurements were performed in the 12th thoracic vertebra (12.8%), 13 in the eleventh thoracic vertebra (1.2%), and one in the second lumbar vertebra (0.1%). Overall mean (SD) bone density was 105.9 (33.3) HU.
Univariate results are shown in Table 3. Age, pack-years, smoking status, FEV 1 % predicted, COPD status, Perc15, and E/I-ratio MLD were included in the multivariate model. BMI, Pi10, and TI were not associated with bone density in univariate analyses. In Table S1, the results of the first multiple linear regression model with bone density as outcome are shown. In this model, pack-years, FEV 1 % predicted, and COPD status did not associate independently with bone density. The second and final model included age, smoking status, Perc15, and E/I-ratio MLD (Table 4).
With every year of aging, bone density lowers by 1.75 HU (P0.001). Current smokers have an 8.89 HU lower bone density (P0.001). When Perc15 lowers by 10 HU, the bone density lowers by 1.27 HU (P=0.02), and when E/I-ratio MLD increases by 1%, the bone density lowers by 0.37 HU (P=0.02).
When comparing the effects of Perc15 and E/I-ratio MLD on bone density by standardization of the effect of one SD change, Perc15 resulted in a 2.42 HU lower bone density and E/I-ratio MLD resulted in a 2.29 HU lower bone density. As an example, Figure 4 includes images of a participant with normal Perc15 and normal bone density and a participant with low Perc15 and low bone density.

Fracture prevalence and CT-related COPD measures
Of 1,093 participants, 95 had a vertebral fracture (8.7%). Participants with a fracture had a 1.4 HU lower Perc15 (P=0.02). Pi10, E/I-ratio MLD , and TI were not significantly different in participants with a fracture, compared to those without (P=0.43, P=0.43, and P=0.24, respectively) ( Table 2). Table 5 shows the outcomes of the logistic regression analysis. None of the CT-related COPD measures were associated with the presence of a fracture. Only bone density (P0.01) and smoking status (P=0.03) were associated with the presence of a fracture. For the complete model (Table S2).

Discussion
The purpose of this study was to assess the association between bone density and morphologic lung changes on CT in heavy smokers. Our data showed that patients with emphysema and air trapping have lower bone density. We did not find an association between airway wall thickness or trachea deformity and bone density. Also, the presence of COPD was not associated with bone density or fracture presence. Thus, low bone density is not disease-specific for COPD, but rather phenotype-specific (emphysema or small

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Pompe et al airway disease), and could therefore provide relevant prognostic information in a specific group of smokers. With CT, we are able to directly measure the presence of airway wall thickening from large and medium airways (2-2.5 mm) by using Pi10 and indirectly measure the presence of air trapping (ie, small airway disease; airways 2 mm) by using E/I-ratio MLD . 28 Therefore, Pi10 and E/I-ratio MLD are thought to represent different anatomical parts of the airway tree. In this study, we showed that bone density was associated with emphysema and small airway disease, but airway wall thickening of the larger airway walls was not. The discrepancy between the association of E/I-ratio MLD , Pi10, and bone density might be explained by a difference in underlying systemic processes in small and large airway disease. 29 There are several studies that evaluated bone density in participants with COPD. Ohara et al 8 used CT measurements to evaluate 65 COPD patients with emphysema and showed that pulmonary emphysema was associated with reduced bone density. Our study confirmed these results in a larger study population, but we also included current and former smoking participants without COPD and evaluated other smoking-related changes such as small airway Abbreviations: B, unstandardized coefficient; BMI, body mass index; E/I-ratio MlD , expiration to inspiration ratio of mean lung density; FeV 1 , forced expiratory volume in 1 second; Perc15, emphysema score as 15th percentile of attenuation distribution curve on inspiratory scan; Pi10, airway wall thickness at an internal perimeter of 10 mm; se, standard error; TI, tracheal index. Abbreviations: CI, confidence interval; E/I-ratio MlD , expiration to inspiration ratio of mean lung density; HU, Hounsfield Unit; Perc15, emphysema score as 15th percentile of attenuation distribution curve on inspiratory scan. disease, large airway disease, and trachea deformity, next to emphysema. In this way, the impact of COPD and different characteristics of COPD on bone density could be evaluated. Bon et al 30 showed there was a strong and independent association between emphysema and low bone density as well, but they only used visual emphysema scores. Rutten et al 13 demonstrated that fat-free mass index, as a measure of muscle wasting, decreases as the level of emphysema increases in participants with COPD. This relationship was independent of airway wall thickness. Our study complemented these findings by showing an independent association between emphysema and bone density. Moreover, we added E/I-ratio MLD as a measure for air trapping and TI for trachea deformity.
When interpreting the results of the study by Rutten et al combined with the results of our present study, there is an indication that an emphysema phenotype does not only involve destruction of alveolar walls, but also systemic processes that result in destruction of soft tissue and bone. 31 While the pathophysiological relationship between tissue inflammation and destruction in the lungs and in the whole body is not confirmed yet, it is hypothesized that an inflammatory response resulting in protease antiprotease imbalance could lead to tissue destruction in both lungs and the whole body. 32 A vertebral fracture in COPD patients may interfere with these patients' already compromised pulmonary function. 5 Therefore, early recognition of low bone density in this patient group is of great importance in order to prevent a fracture. Several factors have been reported to contribute to reduced bone density in COPD patients, such as BMI, FEV 1 , smoking, inactivity, and corticosteroid therapy. 33,34 Our results show that smokers with emphysema and air trapping are more at risk for lower bone density than smokers with large airway disease. With this, a specific patient group could be examined and possibly be selected for preventive care.
Our study has limitations. First, our cohort consisted of only male participants with mild emphysema. However, it has been shown that osteoporosis affects men with severe COPD to a similar degree as females, which highlights the International Journal of COPD 2016:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 1213 smokers and lower bone density correlation study available for E/I-ratio MLD as a measure of air trapping. However, several studies have shown that E/I-ratio MLD is the most suitable criterion for assessing small airway disease. 21,23,39 Lastly, we only included emphysema, air trapping, and airway wall thickening as CT measures of lung disease but did not include signs of interstitial lung disease, which has been shown to be associated with BMD as well. 40,41

Conclusion
This study showed that bone density is significantly lower in smokers with emphysema and small airway disease on CT. It is, however, not associated with large airway wall thickening or trachea deformity. These extrapulmonary skeletal impairments in patients with emphysema and small airway disease support the thought on the existence of a importance of early screening in men as well. 35 Second, we did not measure fat-free mass or the use of corticosteroid drugs, while both are associated with bone density. 36,37 Although fat-free mass could be a better method to evaluate soft tissue loss, BMI has been shown to be correlated with low BMD in patients with COPD. 38 Because our population was considered to be relatively healthy, the impact of the use of corticosteroids could be limited. Third, unlike emphysema and airway wall thickening, there is no pathological

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Submit your manuscript here: http://www.dovepress.com/international-journal-of-chronic-obstructive-pulmonary-disease-journal The International Journal of COPD is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in COPD. Special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols.
This journal is indexed on PubMed Central, MedLine and CAS. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.  Abbreviations: B, unstandardized coefficient; COPD, chronic obstructive pulmonary disease; E/I-ratio MlD , expiration to inspiration ratio of mean lung density; FeV 1 , forced expiratory volume in 1 second; Perc15, emphysema score as 15th percentile of attenuation distribution curve on inspiratory scan; se, standard error.