Bone stiffness and failure load are related with clinical parameters in men with chronic obstructive pulmonary disease

Authors

  • Elisabeth APM Romme,

    Corresponding author
    1. Department of Respiratory Medicine, Catharina Hospital, Eindhoven, The Netherlands
    2. Department of Respiratory Medicine, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
    • Address correspondence to: Elisabeth APM Romme, MD, Maastricht University Medical Centre+, Department of Respiratory Medicine, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: lisette.romme@catharinaziekenhuis.nl

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  • Erica PA Rutten,

    1. Program Development Centre, Centre of Expertise for Chronic Organ Failure (CIRO+), Horn, The Netherlands
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  • Piet Geusens,

    1. Department of Internal Medicine, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
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  • Joost JA de Jong,

    1. Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
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  • Bert van Rietbergen,

    1. Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
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  • Frank WJM Smeenk,

    1. Department of Respiratory Medicine, Catharina Hospital, Eindhoven, The Netherlands
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  • Emiel FM Wouters,

    1. Department of Respiratory Medicine, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
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  • Joop PW van den Bergh

    1. Department of Internal Medicine, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
    2. Department of Internal Medicine, VieCuri Medical Centre, Venlo, The Netherlands
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ABSTRACT

Osteoporosis is frequently seen in patients with chronic obstructive pulmonary disease (COPD). Because research on bone structure and bone strength in COPD patients is limited, the objectives of this pilot study were as follows: (1) to compare bone structure, stiffness, and failure load, measured at the peripheral skeleton, between men with and without COPD after stratification for areal bone mineral density (aBMD); and (2) to relate clinical parameters with bone stiffness and failure load in men with COPD. We included 30 men with COPD (normal aBMD, n = 18; osteoporosis, n = 12) and 17 men without COPD (normal aBMD, n = 9; osteoporosis, n = 8). We assessed pack-years of smoking, body mass index (BMI), fat free mass index (FFMI), pulmonary function (forced expiratory volume in 1 second [FEV1], FEV1/forced vital capacity [FVC], diffusion capacity for carbon monoxide [DLCO], and transfer coefficient for carbon monoxide [KCO]), and extent of emphysema. Bone structure of the distal radius and tibia was assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone stiffness and failure load of the distal radius and tibia were estimated from micro finite element analysis (µFEA). After stratification for aBMD and COPD, men with osteoporosis showed abnormal bone structure (p < 0.01), lower bone stiffness (p < 0.01), and lower failure load (p < 0.01) compared with men with normal aBMD, and men with COPD had comparable bone structure, stiffness, and failure load compared with men without COPD. In men with COPD, lower FFMI was related with lower bone stiffness, and failure load of the radius and tibia and lower DLCO and KCO were related with lower bone stiffness and failure load of the tibia after normalization with respect to femoral neck aBMD. Thus, this pilot study could not detect differences in bone structure, stiffness, and failure load between men with and without COPD after stratification for aBMD. FFMI and gas transfer capacity of the lung were significantly related with bone stiffness and failure load in men with COPD after normalization with respect to femoral neck aBMD. © 2013 American Society for Bone and Mineral Research.

Introduction

Osteoporosis and vertebral fractures are frequently seen in patients with chronic obstructive pulmonary disease (COPD) and are related with the severity of airflow obstruction.[1-3] The relationship between COPD and osteoporosis is assumed to be due to common risk factors, such as older age and cigarette smoking, or to COPD-specific mechanisms, such as systemic inflammation,[4] the use of corticosteroids,[5] and vitamin D deficiency.[6]

The current gold standard for diagnosing osteoporosis is areal bone mineral density (aBMD) on dual-energy X-ray absorptiometry (DXA).[7] Although low aBMD is a well-established risk factor of fragility fractures,[8] COPD subjects with a normal aBMD can have vertebral fractures,[9] suggesting that other factors are involved. Indeed, in addition to aBMD, bone strength is influenced by several structural and material properties of bone.[10]

Recently, high-resolution peripheral quantitative computed tomography (HR-pQCT) has been introduced to assess structural parameters of bone.[11] In addition, HR-pQCT images can be used to estimate mechanical parameters of bone, such as bone stiffness and failure load, from micro finite element analysis (µFEA).[12, 13] Previous data have shown that structural parameters assessed on HR-pQCT and mechanical parameters estimated from µFEA are related with fragility fractures.[11] Vilayphiou and colleagues[14] showed that bone structure, stiffness, and failure load were associated with all types of fractures in postmenopausal women, and Graeff and colleagues[15] demonstrated that structural and mechanical parameters of bone were superior to aBMD in discriminating men with and without vertebral fractures.

Although previous studies have shown that lung function parameters and radiographic emphysema are related with aBMD and vertebral fractures,[16-18] research on structural and mechanical parameters of bone in COPD patients is sparse. A previous study using histomorphometry and micro–computed tomography (µCT) showed that structural parameters of bone in bone biopsies were different in postmenopausal women with COPD compared with control subjects.[19] However, the COPD and control groups were not matched for aBMD.

Because research on structural and mechanical parameters of bone in COPD patients is limited, the objectives of this pilot study were as follows: (1) to compare bone structure, stiffness, and failure load, measured at the peripheral skeleton, between men with and without COPD after stratification for aBMD; and (2) to relate clinical parameters with bone stiffness and failure load in men with COPD.

Subjects and Methods

Subjects

This study included men with moderate to very severe COPD and men without COPD matched for age, who were enrolled in a clinical trial at the Catharina hospital (Eindhoven, the Netherlands) between February 2010 and September 2011. The inclusion and exclusion criteria of this clinical trial have been published.[20] Women were excluded from our analysis, because their number was relatively small and previous data showed differences in bone structure between men and women.[21]

The study was approved by the medical ethical committee of the Catharina hospital (M09-1971) and registered at ClinicalTrials.gov (http://clinicaltrials.gov/show/NCT01067248, “Chronic Obstructive Pulmonary Disease (COPD) and Osteoporosis”). All subjects gave written informed consent.

Clinical parameters

At study entry, structured interviews were used to document the subjects' self-reported smoking history, medications (e.g., use of oral or inhaled corticosteroids), and coexisting medical conditions. Total body weight and height were measured to calculate body mass index (BMI). Fat free mass (FFM) was assessed by bioimpedance analysis (Bodystat 1500; Bodystat Ltd., Onchan, Isle of Man) and FFM index (FFMI) was calculated as FFM divided by height[2].

Pulmonary function was measured with standardized equipment (MasterScreen Body; Carefusion, San Diego, CA, USA) according to the guidelines of the American Thoracic Society (ATS)/European Respiratory Society (ERS).[22] Measurements included forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), vital capacity (VC), total lung capacity (TLC), residual volume (RV), inspiratory capacity (IC), and expiratory reserve volume (ERV). Following the ERS recommendations, the single-breath technique was used to determine the diffusion capacity for carbon monoxide (DLCO) and transfer coefficient for carbon monoxide (KCO).[23]

Chest CT examinations were performed using a single-energy 256 multidetector row scanner (Philips Brilliance Intelligent CT; Philips Healthcare, Eindhoven, The Netherlands) with technical parameters of 120 kVp, 350-mm field of view, 2.5-mm slice thickness and electrocardiograph (ECG) gated. The scanner was calibrated daily to ensure accurate CT attenuation numbers. All subjects were scanned in supine position, during deep inspiration, and without administration of contrast. Emphysema was quantified by in-house software using the 15th percentile point of the frequency distribution of lung density and pixel index for −950 (PI-950) Hounsfield units, as described.[24-27]

Bone density, structure, stiffness, and failure load

aBMD of the lumbar spine (L1–L4), femoral neck, and total hip were measured using a Delphi upgraded to a discovery W (S/N70991) DXA scanner (Tromp Medical Engineering BV, Castricum, The Netherlands). Diagnosis of osteoporosis was based on the lowest T-score of the lumbar spine, femoral neck, and total hip, and defined according to the criteria of the World Health Organization (WHO) (osteoporosis: T-score ≤ −2.5; osteopenia: T-score < −1.0 and > −2.5; and normal aBMD: T-score ≥ −1.0).[7]

HR-pQCT images of the nondominant (or nonfractured) distal radius and tibia were taken using a HR-pQCT device (XtremeCT; Scanco Medical AG, Brüttisellen, Switzerland) with standard in vivo parameters of 60 kVp, 900 µA, and 100 ms integration time. Each measurement took approximately 3 minutes and resulted in a 9.02-mm-thick stack of parallel images (110 slices, voxel size of 82 µm). Quality control was performed by daily scans of a phantom containing rods of hydroxyapatite (HA) embedded in a soft-tissue equivalent resin (QRM, Moehrendorf, Germany).

The HR-pQCT images were evaluated using standard software of the manufacturer to assess total bone density (Dtot), trabecular density (Dtrab), relative bone volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), cortical density (Dcort), and cortical thickness (Ct.Th), as described.[28, 29] In addition, µFEA was performed to calculate bone stiffness in kiloNewtons per millimeter (kN/mm) and failure load in kiloNewtons (kN), as described.[13, 29] Bone stiffness is the resistance against deformation, and failure load is the estimated load at which bone failure will occur.

Statistical analysis

Subjects were classified into: COPD subjects with normal aBMD; COPD subjects with osteoporosis; control subjects with normal aBMD; and control subjects with osteoporosis. Comparisons among groups were made using Mann-Whitney U and chi-square analyses. Bonferroni correction was used to adjust for multiple comparisons. Two-sided p values ≤0.0125 (0.05/4) were considered statistically significant.

Standard simple and multiple regression models were used to assess relationships between clinical parameters and bone stiffness and failure load. Preliminary analyses were conducted to ensure no violation of the assumptions of normality, linearity, multicollinearity, and homoscedasticity. Since the study group is relatively small en femoral neck aBMD is a strong predictor of osteoporosis-related fractures,[30] multiple regression models were adjusted for femoral neck aBMD only.

All statistical analyses were performed in SPSS version 17.0 (SPSS Inc., Chicago, IL, USA).

Results

We included 30 men with COPD (normal aBMD, n = 18; osteoporosis, n = 12) and 17 men without COPD (normal aBMD, n = 9; osteoporosis, n = 8). Table 1 shows the clinical characteristics. COPD subjects with osteoporosis had lower BMI (p = 0.007), FFMI (p = 0.01), FEV1 (p = 0.008), FEV1/FVC (p = 0.005), DLCO (p = 0.001), and KCO (p < 0.001) compared with COPD subjects with normal aBMD, and control subjects with osteoporosis had similar clinical characteristics compared with control subjects with normal aBMD. No differences were found in the use of corticosteroids between COPD subjects with and without osteoporosis.

Table 1. Clinical Characteristics
 Group 1: COPD subjects, normal aBMD (n = 18)Group 2: COPD subjects, osteoporotic aBMD (n = 12)Group 3: control subjects, normal aBMD (n = 9)Group 4: control subjects, osteoporotic aBMD (n = 8)1 versus 2: p3 versus 4: p1 versus 3: p2 versus 4: p
  1. Results are presented as median (range) unless otherwise indicated. After Bonferroni correction, two-sided p values ≤0.0125 (0.05/4) are considered statistically significant.
  2. COPD = chronic obstructive pulmonary disease; aBMD = areal bone mineral density; BMI = body mass index; FFMI = fat free mass index; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; DLCO = diffusion capacity for carbon monoxide; KCO = transfer coefficient for carbon monoxide.
Age, years64.0 (28.0)64.5 (16.0)65.0 (17.0)68.0 (13.0)0.820.210.700.14
BMI, kg/m226.7 (19.2)23.3 (14.6)27.5 (9.9)25.2 (7.5)0.0070.270.800.14
FFMI, kg/m218.6 (8.8)17.3 (7.1)19.3 (4.5)18.0 (2.7)0.010.410.610.19
Pack-years, n37.0 (105.5)37.2 (100.0)11.3 (37.5)6.8 (90.0)0.770.710.0010.08
Oral corticosteroids
n (%)8 (44)6 (50)0 (0)0 (0)0.771.000.020.02
Dose, mg0 (4500)150 (3650)0 (0)0 (0)0.591.000.020.02
Inhaled corticosteroids
n (%)9 (50)8 (67)0 (0)0 (0)0.371.000.0090.003
Dose, mg46 (7862)326 (2920)0 (0)0 (0)0.451.000.010.005
FEV1, L2.01 (1.50)1.35 (2.33)3.47 (1.66)3.34 (2.06)0.0080.16<0.001<0.001
FEV1, % pred67.5 (36.0)51.5 (52.0)108.0 (29.0)114.5 (59.0)0.010.74<0.001<0.001
FVC, L3.66 (4.37)3.18 (3.89)4.73 (2.58)4.49 (2.59)0.110.210.0040.01
FVC, % pred93.1 (88.0)91.0 (67.0)114.0 (36.0)117.0 (60.0)0.670.920.0010.004
FEV1/FVC ratio56.0 (30.8)41.9 (32.7)74.7 (5.6)74.6 (13.1)0.0050.92<0.001<0.001
DLCO, mmol/min/kPa6.78 (5.56)3.80 (5.43)8.98 (5.61)7.86 (2.52)0.0010.040.0010.001
DLCO, % pred78.0 (59.0)46.0 (42.0)98.0 (27.0)88.5 (18.0)<0.0010.19<0.001<0.001
KCO, mmol/min/kPa/L1.23 (1.00)0.78 (0.48)1.38 (0.55)1.24 (0.45)<0.0010.150.009<0.001
KCO, % pred94.5 (67.0)58.0 (36.0)104 (32.0)97.0 (32.0)<0.0010.210.003<0.001
T-score
Femoral neck−0.8 (2.1)−2.5 (2.5)−0.4 (1.4)−1.9 (2.1)<0.0010.0010.220.02
Total hip0.9 (2.2)−1.6 (3.1)1.4 (2.4)−1.0 (2.7)<0.0010.0060.900.26
L1–L41.0 (3.0)−2.7 (4.2)0.3 (3.9)−2.5 (2.2)<0.0010.0010.110.97

Table 2 shows the structural and mechanical parameters of bone after stratification for COPD and aBMD. COPD subjects and control subjects with osteoporosis had lower total bone density, lower trabecular density, lower relative bone volume, lower trabecular number, higher trabecular separation, lower cortical thickness, lower bone stiffness, and lower failure load compared with COPD subjects and control subjects with normal aBMD, respectively. In addition, COPD subjects had comparable bone structure, stiffness, and failure load compared with control subjects after stratification for aBMD.

Table 2. Bone Structure, Stiffness, and Strength of the Radius and Tibia
 Group 1: COPD subjects, normal aBMD (n = 18)Group 2: COPD subjects, osteoporotic aBMD (n = 12)Group 3: control subjects, normal aBMD (n = 9)Group 4: control subjects, osteoporotic aBMD (n = 8)1 versus 2: p3 versus 4: p1 versus 3: p2 versus 4: p
  1. Results are presented as median (range) unless otherwise indicated. After Bonferroni correction, two-sided p values ≤0.0125 (0.05/4) are considered statistically significant.
  2. COPD = chronic obstructive pulmonary disease; aBMD = areal bone mineral density; Dtot = total density; Dtrab = trabecular density; BV/TV = relative bone volume; Tb.N = trabecular number; Tb.Th = trabecular thickness; Tb.Sp = trabecular separation; Dcort = cortical density; Ct.Th = cortical thickness.
Radius
Dtot, mg HA/cm3346.0 (268.2)247.2 (127.3)363.6 (146.2)287.6 (154.9)0.0040.040.360.12
Dtrab, mg HA/cm3184.4 (157.8)142.0 (124.4)199.7 (90.4)137.9 (38.2)0.0020.0010.610.82
BV/TV, %15.4 (13.2)11.8 (10.3)16.6 (7.6)11.5 (3.2)0.0020.0010.610.82
Tb.N, mm−12.27 (1.34)1.86 (1.24)2.12 (0.71)1.86 (0.46)0.0010.0070.270.94
Tb.Th, mm0.070 (0.040)0.063 (0.036)0.082 (0.030)0.063 (0.033)0.130.020.110.97
Tb.Sp, mm0.366 (0.379)0.471 (0.572)0.388 (0.181)0.479 (0.137)0.0010.0070.570.94
Dcort, mg HA/cm3859.6 (274.0)788.7 (161.1)861.4 (118.9)830.3 (259.0)0.070.530.760.19
Ct.Th, mm0.950 (0.870)0.595 (0.470)1.110 (0.550)0.785 (0.680)0.020.090.680.18
Stiffness, kN/mm120.3 (84.1)87.1 (73.3)132.6 (81.9)97.2 (23.1)0.0030.0090.300.49
Failure load, kN5.69 (4.00)4.14 (3.27)6.27 (3.72)4.62 (0.87)0.0030.0070.330.44
Tibia
Dtot, mg HA/cm3299.4 (140.4)227.5 (88.9)337.7 (148.6)227.4 (148.3)<0.0010.0030.240.64
Dtrab, mg HA/cm3184.8 (122.8)129.2 (112.9)214.0 (137.3)134.5 (37.0)<0.0010.0050.210.46
BV/TV, %15.4 (10.3)10.8 (9.5)17.8 (11.5)11.3 (3.1)<0.0010.0050.210.46
Tb.N, mm-12.11 (1.18)1.55 (0.97)2.16 (0.85)1.50 (0.66)<0.0010.0020.840.94
Tb.Th, mm0.074 (0.044)0.070 (0.031)0.084 (0.047)0.074 (0.029)0.160.360.320.28
Tb.Sp, mm0.409 (0.318)0.579 (0.519)0.378 (0.218)0.595 (0.285)<0.0010.0010.590.94
Dcort, mg HA/cm3863.0 (215.6)807.7 (143.3)853.6 (102.9)799.1 (199.6)0.030.150.680.88
Ct.Th, mm1.325 (0.610)0.890 (0.630)1.450 (0.850)1.030 (0.900)<0.0010.0090.050.59
Stiffness, kN/mm278.8 (126.1)206.3 (118.9)313.1 (176.0)211.9 (51.6)<0.0010.0010.170.54
Failure load, kN13.1 (6.21)9.83 (6.01)14.73 (7.98)10.15 (2.48)<0.0010.0010.150.54

In the total cohort, BMI, FFMI, FVC, VC, DLCO, KCO, PI-950, 15th percentile, and aBMD were significantly related with bone stiffness and failure load of the radius and tibia, and FEV1, TLC, and IC were significantly related with bone stiffness and failure load of the radius or tibia (Supporting Tables 1 and 2). In the COPD subjects, BMI, FFMI, DLCO, KCO, PI-950, 15th percentile, and aBMD were significantly related with bone stiffness and failure load of the radius and tibia, and FEV1 and FEV1/FVC were significantly related with bone stiffness and failure load of the radius or tibia (Supporting Tables 3 and 4). In the COPD subjects, lower FFMI was significantly related with lower bone stiffness and failure load of the radius and tibia and DLCO and KCO were significantly related with lower bone stiffness and failure load of the tibia, after adjustment for femoral neck aBMD (Table 3). Figure 1 shows the relationship between DLCO and failure load of the tibia in the COPD subjects after adjustment for femoral neck aBMD.

Table 3. Clinical Parameters Related With Bone Stiffness and Failure Load in COPD Subjects After Adjustment for Femoral Neck aBMD (g/cm2)
 RadiusTibia
Stiffness, kN/mmFailure load, kNStiffness, kN/mmFailure load, kN
B (SE)95% CIpB (SE)95% CIpB (SE)95% CIpB (SE)95% CIp
  1. Two-sided p values ≤0.05 are considered statistically significant.
  2. COPD = chronic obstructive pulmonary disease; aBMD = areal bone mineral density; B = unstandardized regression coefficient; SE = standard error; CI = confidence interval; BMI = body mass index; FFMI = fat free mass index; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; DLCO = diffusion capacity for carbon monoxide; KCO = transfer coefficient for carbon monoxide; PI-950 = pixel index for −950 Hounsfield units; HU = Hounsfield units.
BMI, kg/m21.33 (0.85)−0.41, 3.070.130.06 (0.04)−0.02, 0.140.152.43 (1.24)−0.12, 4.970.060.11 (0.06)−0.01, 0.230.07
FFMI, kg/m24.04 (1.92)0.10, 7.990.050.19 (0.09)0.01, 0.370.046.81 (2.81)1.03, 12.60.020.33 (0.13)0.06, 0.600.02
FEV1, L1.65 (8.06)−14.9, 18.20.840.17 (0.37)−0.60, 0.940.655.67 (12.0)−19.0, 30.30.640.35 (0.57)−0.81, 1.520.54
FEV1/FVC ratio−0.13 (0.44)−1.04, 0.780.780.00 (0.02)−0.05, 0.040.870.26 (0.66)−1.10, 1.610.700.01 (0.03)−0.05, 0.080.74
DLCO, mmol/min/kPa4.01 (2.75)−1.64, 9.650.160.21 (0.13)−0.05, 0.470.118.15 (3.98)−0.01, 16.30.050.40 (0.19)0.02, 0.780.04
KCO, mmol/min/kPa/L21.3 (18.1)−15.9, 58.40.251.04 (0.84)−0.68, 2.760.2355.9 (25.6)3.35, 1080.042.56 (1.22)0.05, 5.060.05
PI-950, %−0.59 (0.76)−2.18, 1.000.45−0.03 (0.04)−0.10, 0.040.38−1.45 (1.06)−3.65, 0.750.18−0.07 (0.05)−0.18, 0.030.18
15th percentile, HU0.32 (0.25)−0.20, 0.850.220.02 (0.01)−0.01, 0.040.200.49 (0.36)−0.25, 1.240.180.02 (0.02)−0.01, 0.060.19
Figure 1.

Diffusion capacity for carbon monoxide related with failure load of the distal tibia in COPD subjects after adjustment for femoral neck aBMD (g/cm2). aBMD = areal bone mineral density; DLCO = diffusion capacity for carbon monoxide.

Discussion

This study could not detect differences in bone structure, stiffness, and failure load, measured at the peripheral skeleton, between men with and without COPD after stratification for aBMD. FFMI and gas transfer capacity of the lung were significantly related with bone stiffness and failure load in men with COPD after normalization with respect to femoral neck aBMD.

Our data showed that men with osteoporosis had impaired bone structure and lower bone stiffness and failure load compared with men with normal aBMD. These findings are in line with previous data demonstrating associations between aBMD, bone structure, stiffness, and failure load.[14, 28, 31] In addition, previous data have shown that structural and mechanical parameters of bone are even better predictors of vertebral fractures than aBMD,[15, 28] suggesting that structural and mechanical parameters of bone might improve the prediction of vertebral fractures.

After stratification for COPD and aBMD, men with COPD had comparable bone structure, stiffness, and failure load compared with men without COPD. To the best of our knowledge, only one previous study has investigated differences in bone structure between subjects with and without COPD.[19] This study showed that postmenopausal women with COPD had abnormal bone structure compared with control subjects.[19] However, the COPD and control groups were not matched for aBMD. These findings suggest that structural parameters of bone are more impaired in COPD patients than in control subjects, whereas structural and mechanical parameters of bone are similar in COPD patients and control subjects after matching for aBMD.

Several pulmonary parameters, including FEV1, FVC, VC, TLC, IC, DLCO, KCO, 15th percentile, and PI-950, were significantly related with bone stiffness and failure load. Although research on associations between pulmonary function and mechanical parameters of bone is lacking, previous studies have shown associations between pulmonary function and bone density or fragility fractures.[18, 32] In 85 subjects with moderate to very severe COPD, lower VC and DLCO, and more severe emphysema were associated with osteoporosis defined as a T-score < −2.5, whereas lower VC and FEV1 were associated with vertebral fractures.[17] In addition, a longitudinal study in 70 subjects with emphysema showed that lung volume reduction surgery improved pulmonary function and aBMD, compared with respiratory rehabilitation therapy.[33] These findings suggest associations between the pulmonary and skeletal system.

FFMI was significantly related with bone stiffness and failure load of the radius and tibia and DLCO and KCO were significantly related with bone stiffness and failure load of the tibia, after normalization with respect to femoral neck aBMD. These data suggest that FFMI and gas transfer capacity of the lung are related with properties of bone that are only partially related with aBMD, such as bone structure, micro damage burden, collagen type, and cross-linking.[10]

FFMI might interact with properties of bone via physical activity. Reduced physical activity has been related with bone loss and osteoporosis-related fractures,[34, 35] whereas, on the other hand, exercise interventions have been shown to increase aBMD[36] and reduce the number of fractures.[37] In addition to physical activity, decreased mechanical loading might influence bone strength.

In addition to FFMI, gas transfer capacity of the lung might interact with properties of bone. The gas transfer capacity of the lung is associated with several factors that have already been related with properties of bone. First, a lower gas transfer capacity of the lung is associated with emphysema,[23] which has been related with osteoporosis.[18] The relationship between emphysema and osteoporosis might be due to a common mechanism, such as impaired Wnt/β-catenin signaling.[38] Second, a lower gas transfer capacity of the lung is associated with anemia,[23] which has been related with osteoporosis and vertebral fractures.[39, 40] Animal studies have demonstrated that anemia-induced hypoxia might be responsible for the effects on bone remodeling.[41] However, additional research is needed to further elucidate the interaction between hypoxia and bone remodeling. Third, a lower gas transfer capacity of the lung is associated with thoracic deformity,[23] which has been related with vertebral fractures.[42] These data suggest a mechanical relationship between lung function and osteoporosis. Fourth, a higher gas transfer capacity of the lung is associated with obesity,[23] which has been shown to be protective against osteoporosis.[16] Previous research has indeed shown beneficial effects of adipose tissue on bone density.[43, 44] Although several potential mechanisms have been described, additional research is warranted to further investigate the relationship between gas transfer capacity of the lung and mechanical parameters of bone.

Some limitations should be mentioned. First, no causal relationship could be established due to the cross-sectional design of the study. Second, a relatively small number of men was included. Third, subjects with osteopenia were excluded, as described.[20] Fourth, our bone analyses were limited to the peripheral skeleton, because high-resolution CT is only possible at peripheral sites. Acknowledging these limitations, our study is the first to show that disease-specific parameters, such as FFMI and gas transfer capacity of the lung, are related with structural and mechanical parameters of bone in COPD subjects.

Because FFMI and gas transfer capacity of the lung were related with bone stiffness and failure load independent of aBMD, we suggest that FFMI and gas transfer capacity of the lung can improve risk stratification of fragility fractures in COPD patients. A combination of clinical features and structural and mechanical parameters of bone is likely to be a better predictor of fragility fractures than aBMD alone.[45] Longitudinal studies are needed to investigate which clinical features and structural and mechanical parameters of bone are related with future fractures.

This pilot study could not detect differences in bone structure, stiffness, and failure load between men with and without COPD after stratification for aBMD. FFMI and gas transfer capacity of the lung were related with bone stiffness and failure load in men with COPD after normalization with respect to femoral neck aBMD. These data suggest that FFMI and gas transfer capacity of the lung might interact with structural and mechanical parameters of bone. Longitudinal studies are needed to further investigate associations between clinical features and structural and mechanical parameters of bone in COPD patients.

Disclosures

BvR is a consultant for Scanco Medical AG. All other authors state that they have no conflicts of interest.

Acknowledgments

This study was funded by the Weijerhorst Foundation. We thank M. Groenen, Centre of expertise for chronic organ failure (CIRO+), for assistance with statistical analysis.

Authors' roles: Study design: EAR, EPR, BvR, and JvdB. Study conduct: EAR, EPR, JdJ, and JvdB. Data collection: EAR and JdJ. Data analysis: EAR, EPR, and JvdB. Data interpretation: EAR, EPR, PG, JdJ, BvR, FS, EW, and JvdB. Drafting manuscript: EAR, EPR, and JvdB. Revising manuscript content: EAR, EPR, PG, JdJ, BvR, FS, EW, and JvdB. Approving final version of manuscript: EAR, EPR, PG, JdJ, BvR, FS, EW, and JvdB. EAR takes responsibility for the integrity of the data analysis.

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