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(Chest. 2006;129:140-146.)
© 2006 American College of Chest Physicians

Osteoporosis in Diffuse Parenchymal Lung Disease*

Caralee E. Caplan-Shaw, MD; Selim M. Arcasoy, MD, FCCP; Elizabeth Shane, MD; David J. Lederer, MD; Jessie S. Wilt, MD; Mitchell K. O’Shea, RRT; Vicki Addesso, BS; Joshua R. Sonett, MD and Steven M. Kawut, MD, MS, FCCP

* From the Departments of Medicine (Drs. Caplan-Shaw, Arcasoy, Shane, Kawut, Lederer, and Wilt, and Ms. Addesso) and Surgery (Dr. Sonett), College of Physicians and Surgeons, and the Department of Medicine (Mr. O’Shea), Mount Sinai School of Medicine, New York, NY.

Correspondence to: Steven Kawut, MD, MS, FCCP, Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University College of Physicians and Surgeons, 622 W 168th St, PH 8E, Room 101, New York, NY 10032; e-mail: sk2097{at}columbia.edu

Abstract

Study objectives: There are no studies focused on skeletal status in patients with diffuse parenchymal lung disease (DPLD). We hypothesized that patients with DPLD referred for lung transplantation would have a high prevalence of osteoporosis related to corticosteroid use or reduced pulmonary function and exercise capacity.

Design: Retrospective cohort study.

Setting: Tertiary care center.

Patients: Eighty-six patients with DPLD referred to our center for lung transplantation evaluation between March 1999 and April 2004.

Measurements and results: Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) at the lumbar spine, femoral neck, total hip, and radius at the time of referral. Criteria developed by the World Health Organization were used to define osteopenia and osteoporosis. Fifty-five patients (64%) had usual interstitial pneumonia-pattern lung disease, 14 patients (16%) had nonspecific interstitial pneumonia-pattern lung disease, and 17 patients (20%) had other forms of DPLD. Sixty-four patients (74%) were receiving corticosteroids, and 43 patients (50%) were receiving preventive therapy for osteoporosis. Eleven patients (13%; 95% confidence interval [CI], 7 to 22%) met criteria for osteoporosis at any site, and 49 patients (57%; 95% CI, 46 to 68%) had osteopenia. Lower body mass index (BMI) [adjusted odds ratio (OR), 1.3; 95% CI, 1.1 to 1.6; p = 0.007] and Hispanic ethnicity (adjusted OR, 9.7; 95% CI, 1.8 to 52; p = 0.008) were independently associated with an increased risk of osteoporosis. Linear regression analysis confirmed that BMD at the femoral neck and hip was directly associated with BMI (p < 0.002). These findings were not affected by adjustment for the use of corticosteroids or osteoporosis prophylaxis, pulmonary function, or exercise performance.

Conclusions: Reduced BMD was common in patients with DPLD who were referred for lung transplantation. Lower BMD was associated with lower BMI, whereas there was no association with other clinical factors in our cohort. Hispanic patients with DPLD had a higher risk of osteoporosis than non-Hispanic patients, independent of other variables. Given their increased risk of bone loss, patients with DPLD should undergo screening for osteoporosis and receive prophylaxis and treatment according to published guidelines.

Key Words: idiopathic pulmonary fibrosis • interstitial lung diseases • lung transplantation • osteoporosis

Low bone mineral density (BMD) and fractures are common in patients with COPD, cystic fibrosis, and lymphangioleiomyomatosis.123456789 Advanced age, hypogonadism, limited physical activity, poor nutritional status, cigarette smoking, long-term corticosteroid use, and systemic inflammation may contribute to the increased risk of low BMD in these patients. Progressive bone loss is almost universal after lung transplantation, potentially compounding the problem of low pretransplant BMD in candidates for this procedure. Not surprisingly, posttransplant osteoporosis results in an increased risk of fractures, which may significantly impact quality of life.710

Diffuse parenchymal lung disease (DPLD) incorporates a variety of disorders characterized by pulmonary inflammation and fibrosis. Indeed, patients with DPLD have many of the same risk factors for osteoporosis as patients with other chronic lung diseases. However, the prevalence of and risk factors for osteoporosis in patients with DPLD are unknown.11 We aimed to determine the prevalence and predictors of osteoporosis in patients with DPLD. We hypothesized that low body mass index (BMI), corticosteroid use, poor pulmonary function, and low exercise capacity would be associated with an increased risk of osteoporosis.

Methods and Materials

Study Population
We included patients with a diagnosis of either DPLD of known cause or idiopathic interstitial pneumonia evaluated in the New York Presbyterian Hospital Lung Transplant Program between March 1999 and April 2004. We excluded patients with sarcoidosis, lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, or eosinophilic pneumonia. The study was approved by the Columbia University Institutional Review Board.

Data Collection
Demographic data, anthropometric measurements, insurance status, smoking history, and details of corticosteroid use and osteoporosis prophylaxis were collected from patient records. A patient was considered to have a history of significant corticosteroid use if he/she had ever received the equivalent of prednisone, ≥ 10 mg, for > 3 months. Two pulmonologists (J.S.W. and S.M.K.) independently assigned lung disease diagnoses according to American Thoracic Society (ATS) guidelines, which incorporate diagnostic criteria with and without lung biopsy.11 Disagreements were resolved by a third pulmonologist (C.E.C.). The median household income, educational status (percentage of residents with a high school education), and percentage of families below poverty level in the neighborhood (census tract) in which each patient lived were obtained from the 2000 United States Census.

Patients evaluated for lung transplantation in our program undergo bone mineral densitometry, pulmonary function testing, cardiopulmonary exercise testing, and right-heart catheterization. BMD of the lumbar spine (L1 to L4), right femoral neck, right total hip, and left distal radius was measured by dual energy X-ray absorptiometry (QDR-4000; Hologic; Bedford, MA). BMD was expressed as absolute values (grams per centimeter squared), T scores (the number of SDs from mean peak bone mass of normal individuals of the same gender), and Z scores (the number of SDs from mean bone mass of age-and gender-matched reference values). BMD values were classified according to World Health Organization guidelines established for postmenopausal white women: normal BMD, T score > – 1; osteopenia, T score between – 1 and – 2.5 inclusive; and osteoporosis, T score < – 2.5. Lung volumes, flow rates, and diffusion capacity of the lung for carbon monoxide (DLCO) were measured according to ATS standards.12

Cardiopulmonary exercise testing was performed on a single bicycle ergometer (Ergometrics 800; SensorMedics; Yorba Linda, CA) with a metabolic cart (SensorMedics Vmax 229; SensorMedics) according to ATS guidelines, as previously described.13 Patients receiving supplemental home oxygen therapy or who had room air oxygen saturation < 90% (n = 67) exercised with 30% fractional oxygen via mouthpiece. Six-minute walk testing was performed as recommended by ATS guidelines14; the distance walked was expressed using normative values.15

Statistical Methods
Continuous variables were summarized by the mean ± SD or median (interquartile range). Categorical variables were summarized by the frequency (95% confidence interval [CI]). Unpaired Student t test, Wilcoxon rank-sum tests, {chi}2 tests, and (Fisher Exact Tests) were used, as appropriate.

Multivariate logistic regression incorporated skeletal status (presence of osteoporosis at any site) as the dependent variable. Factors from bivariate analyses with p values < 0.20 or with a biological basis for an association with skeletal status were assessed as independent variables. We used linear regression to determine predictors of T score using a similar procedure. All p values < 0.05 were considered statistically significant. Statistical software (SAS version 9.1.3; SAS Institute; Cary, NC) was used for all analyses.

Results

Ninety-nine patients with DPLD were evaluated between March 1999 and April 2004. Eighty-six patients (87%) with complete dual energy X-ray absorptiometry data from the lumbar spine, right femoral neck, and right total hip were included in the study. The mean age was 53 ± 9 years, and 43% were women. Fifty-five patients (64%) had usual interstitial pneumonia-pattern lung disease, 14 patients (16%) had nonspecific interstitial pneumonia-pattern lung disease, 3 patients (3.5%) had asbestosis, 3 patients (3.5%) had hypersensitivity pneumonitis, 1 patient (1%) had desquamative interstitial pneumonia-pattern lung disease, 1 patient (1%) had Hermansky-Pudlak syndrome, and 9 patients (10.5%) had unclassified interstitial pneumonia. Sixty-one patients (71%) underwent lung biopsy. Nineteen patients (22%) had collagen vascular disease. Among patients with a history of significant corticosteroid use (n = 62), 40% were treated with supplemental calcium, 29% with a bisphosphonate, and 40% with 400 IU of vitamin D. Patients with missing BMD data did not differ significantly from those in the final study group in terms of age, gender, or diagnosis (data not shown).

Eleven patients (13%; 95% CI, 7 to 22%) had osteoporosis at any site, and 49 patients (57%; 95% CI, 46 to 68%) had osteopenia (Table 1 ). The mean T score of the most severely affected site in patients with osteoporosis was – 2.9 ± 0.3; this site was the lumbar spine for nine patients and the femoral neck in two patients. In the subset of patients with idiopathic pulmonary fibrosis (n = 45), 11% (95% CI, 4 to 24%) had osteoporosis and 62% (95% CI, 47 to 76%) had osteopenia at any site.


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  		Table 1.. BMD in Patients With DPLD

 
There were no differences in age or gender between patients with osteoporosis and others (Table 2 ). Patients with osteoporosis were more likely to be Hispanic or Asian (p = 0.02) and had a significantly lower BMI (p = 0.007) than patients with normal bone density or osteopenia. There were no differences in insurance status or neighborhood income, educational achievement, or poverty level between the groups (data not shown). Linear regression analysis showed a direct association between BMI and BMD at the femoral neck and total hip (Fig 1 ).


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  		Table 2.. Patient Characteristics by BMD*

 

Figure 1
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  		Figure 1.. Linear regression of (top, A) femoral neck T score and (bottom, B) total hip T score by BMI.

 
There was a history of significant steroid use in 55% of patients with osteoporosis and 75% of patients without osteoporosis (p = 0.28). There were no associations between skeletal status and cumulative exposure to corticosteroids, duration of corticosteroid use, or average daily dose of prednisone (Table 3 ). There were no differences between groups in the use of osteoporosis prophylaxis. Forty percent of women with osteoporosis were receiving hormone replacement therapy, compared to 19% of women without osteoporosis (p = 0.29).


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  		Table 3.. Medication Use by BMD*

 
There were no significant differences in spirometry or total lung capacity between patients with and without osteoporosis (Table 4 ). DLCO was somewhat lower in patients with osteoporosis, but this finding was not statistically significant. However, peak work rate, unloaded oxygen saturation, and peak oxygen pulse were significantly lower in patients with osteoporosis compared to others. Mean pulmonary artery pressure was similar between the groups (osteoporosis, 24 ± 6 mm Hg, vs no osteoporosis, 22 ± 8 mm Hg; p = 0.43; n = 75).


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  		Table 4.. Pulmonary Function and Exercise Parameters by BMD*

 
Multivariate logistic regression showed that low BMI (adjusted odds ratio [OR], 1.3; 95% CI, 1.1 to 1.6; p = 0.007) and Hispanic ethnicity (adjusted OR, 9.7; 95% CI, 1.8 to 52; p = 0.008) were independent risk factors for osteoporosis at any site. Adjustment for the use of bisphosphonates (adjusted OR, 0.89; 95% CI, 0.15 to 5; p = 0.89), any osteoporosis prophylaxis (adjusted OR, 1.4; 95% CI, 0.34 to 6; p = 0.61), or other clinical variables did not change these results.

Discussion

We have shown that patients with DPLD evaluated for lung transplantation frequently have significant bone loss. Only one third had normal BMD at all sites evaluated, and 13% had osteoporosis. The prevalence of osteoporosis in Americans aged ≥ 50 years was 13 to 18% for women and 3 to 6% for men in the third National Health and Nutrition Examination Survey.16 Given the age and gender distribution of our cohort compared to those of the third National Health and Nutrition Examination Survey,16 our data therefore suggest an increased risk of osteoporosis in DPLD.

Osteoporotic fractures not only cause pain and deformity that affect quality of life but are also associated with respiratory morbidity and mortality.1718192021 Osteoporosis appears to be somewhat less common in patients with DPLD (13%) than in patients with other forms of chronic lung diseases such as COPD, cystic fibrosis, and lymphangioleiomyomatosis (with estimates ranging from 23 to 61%).123456789 The loss of fat-free mass and a systemic inflammatory state may account for the greater risk in obstructive lung disease. Patients with cystic fibrosis are also characterized by pancreatic insufficiency, inadequate vitamin D and calcium absorption, reduced sex hormone production, and increased serum levels of catabolic cytokines, impacting on bone and mineral homeostasis. In addition, cystic fibrosis is present from birth, adversely affecting bone acquisition during adolescence and resulting in lower peak bone mass and smaller skeletal size. Lastly, the use of osteoporosis prophylaxis in our cohort appears to have exceeded that in previous studies of patients with lung disease, perhaps resulting in greater maintenance of BMD. For example, a previous study6 at our center of lung transplant candidates who were receiving corticosteroids showed that only 20% were receiving oral calcium supplements, 5% were receiving the recommended daily allowance of vitamin D, and none were receiving bisphosphonates.

Lower BMI was independently associated with an increased risk of osteoporosis in our cohort. Although BMI is an established predictor of osteoporosis in the general population and in patients with advanced lung disease,1389 this finding has not been documented previously in DPLD. Malnutrition, vitamin D deficiency, and abnormal skeletal loading likely explain this consistent association.3 Hispanic ethnicity was also associated with an increased risk of osteoporosis in our study, and this association was not explained by differences in insurance or socioeconomic status, BMI, or therapy for osteoporosis. A recent study22 of healthy women showed similar findings, which may be related to specific diet or activity patterns in certain ethnic groups. While possible, biological differences are a less plausible explanation for this finding, considering the independence of ethnicity and race, and considering the substantial genetic variability that exists within racial/ethnic groups.

Corticosteroids have several adverse effects on bone formation and resorption. Indeed, most studies14567910 of BMD in advanced lung disease have found corticosteroid use to be an independent risk factor for osteoporosis. In contrast, we found no association between corticosteroid use and BMD in patients with DPLD. Our distinct findings might be explained by the relatively low doses and durations of corticosteroid use, higher rates of prophylaxis with calcium, vitamin D, hormone replacement therapy and bisphosphonates, or misclassification of steroid use in our cohort. Of note, the pattern of bone loss (ie, more severe at the lumbar spine compared to other sites) is consistent with steroid-induced bone loss, suggesting that corticosteroid exposure could still play a role.

Some studies489 have also suggested a correlation between lung function and BMD, which was not seen in our cohort. The absence of an association may be explained by the limited range of disease severity seen in a cohort of lung transplant candidates. We did find that work rate at maximum exercise and oxygen saturation with unloaded exercise were lower in patients with osteoporosis, perhaps reflecting differences in conditioning or subtle distinctions in parenchymal or vascular lung disease not reflected in traditional measures of lung function.

Finally, we did not find an association between the use of osteoporosis prophylaxis and the prevalence of osteoporosis. It is important to note that this does not disprove a beneficial effect of prophylaxis on skeletal status in these patients. In an observational study such as ours, various factors that predict the risk of developing osteoporosis may also affect the clinician’s decision to prescribe prophylaxis, potentially resulting in confounding by indication. Only randomized clinical trials can therefore prove the clinical efficacy of osteoporosis prophylaxis in patients with DPLD. As such trials do not exist (and might be difficult to conduct due to lack of clinical equipoise), we must presume that supplemental calcium, vitamin D, and bisphosphonate use are as effective in preventing bone loss in patients with DPLD as they are in other populations.

There are other limitations to our study. Our study population included patients with DPLD who were referred for lung transplantation, representing a small, selected group; however, our sample size rivals those of other observational studies of DPLD. A lack of sufficient power may have accounted for the absence of associations between certain variables and the presence of osteoporosis. There were some missing data, but the final cohort with complete data appeared similar to those excluded for this reason. Some patients were receiving calcium or bisphosphonates for osteoporosis prophylaxis, potentially resulting in an underestimation of the true incidence of osteoporosis in this population. Despite the frequent use of corticosteroids in our study group, however, only a minority of patients were receiving osteoporosis prophylaxis.

We have shown that most patients with DPLD evaluated for lung transplantation have abnormal BMD. Despite the frequent use of corticosteroids in these patients, they rarely receive adequate prophylaxis for osteoporosis, despite rates of preventive therapy that are higher than those seen in prior studies.6 Low BMI and Hispanic ethnicity were independent risk factors for osteoporosis in this population, characterizing particularly high-risk patients. Based on our findings, we recommend that patients with DPLD undergo periodic measurement of BMD. Treatment with calcium and vitamin D supplements as well as antiresorptive or anabolic therapy should be initiated in accordance with published guidelines.

Footnotes

Abbreviations: ATS = American Thoracic Society; BMD = bone mineral density; BMI = body mass index; CI = confidence interval; DLCO = diffusion capacity of the lung for carbon monoxide; DPLD = diffuse parenchymal lung disease; OR = odds ratio

Supported in part by National Institutes of Health grant HL67771, the Martin and Ellen Strahl Research Fund, and the Jean Muir-Katz Research Fund.

Received for publication August 11, 2005. Accepted for publication October 11, 2005.

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