Low bone mineral density (BMD) has been linked to chronic obstructive pulmonary disease (COPD) independent of traditional osteoporosis risk factors including steroid use, cachexia, and decreased physical activity. Although the increased prevalence of osteoporosis contributes to morbidity and mortality in COPD patients, little is known regarding indications for BMD assessment or osteoporosis mechanisms in this susceptible population. The rate of BMD loss is an independent risk factor for fracture. Yet, cross-sectional dual x-ray absorptiometry (DXA) assessment of BMD provides no information about rate of BMD decline. Immunologic alterations contribute to the pathogenesis of both COPD and osteoporosis but the role of autoimmunity in COPD-related osteoporosis has not been studied. An independent association between emphysema and low BMD has been supported by the literature, but the mechanism for this association is also unknown. This project's overall goal is to study how specific autoimmune processes relate to concurrent emphysema progression and accelerated BMD decline in male and female smokers with lung disease. This goal will be accomplished through extension to six years of an already established longitudinal cohort with pre- existing baseline and two-year assessments of BMD, radiographic emphysema, pulmonary function, and autoimmune biomarker levels. The association of an autoimmune biomarker, anti-glucose regulated protein 78 (GRP78) IgG, with emphysema progression, measured by quantitative CT scan, and BMD loss, measured by serial DXA, over the six-year time interval will be studied in smokers with emphysema or airflow obstruction. A series of in vitro osteoclast studies will be performed to assess the effect of autoantibodies to GRP78, an endoplasmic reticulum (ER) chaperone protein intimately involved in the ER stress response, on osteoclast formation, proliferation, and activity. The findings from this project will identify criteria for smokers at risk of accelerated BMD loss in whom early and serial measurements of BMD may be warranted, provide insight into pathogenic mechanisms linking emphysema and osteoporosis, and provide novel targets for osteoporosis prevention and treatment strategies in patients with COPD.

Public Health Relevance

Although the increased incidence of osteoporotic fractures contributes to unnecessary morbidity and mortality in patients with COPD, little is known regarding indications for bone mineral density assessment and disease mechanisms in this susceptible population. This project will assess the ability of a novel immunologic biomarker to predict accelerated bone mineral density loss and emphysema progression in male and female current and former smokers with smoking-related lung disease. This project will also investigate the mechanisms linking COPD and osteoporosis that may serve as possible targets for future therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Neurological, Aging and Musculoskeletal Epidemiology (NAME)
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Punturieri, Antonello
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Bon, Jessica; Zhang, Yingze; Leader, Joseph K et al. (2018) Radiographic Emphysema, Circulating Bone Biomarkers, and Progressive Bone Mineral Density Loss in Smokers. Ann Am Thorac Soc 15:615-621
Grace, Jon; Leader, Joseph K; Nouraie, Seyed M et al. (2017) Mediastinal and Subcutaneous Chest Fat Are Differentially Associated with Emphysema Progression and Clinical Outcomes in Smokers. Respiration 94:501-509