Complex Co-morbidities of COPD - Osteoporosis -

2. Complex Co-morbidities of COPD - Osteoporosis -

3. Bone is a unique tissue

4. Normal Bone Remodeling

7. Clinical Consequences of Osteoporosis

9. Patterns of co-morbidities in newly diagnosed COPD and Asthma in Primary Care Speaker notes Analysis of the relative risk for systemic disease in patients with and without COPD indicated that those with COPD were at increased risk for glaucoma, angina, fractures, myocardial infarction, osteoporosis, and respiratory infections. Additional Information Patient data from the United Kingdom General Practice Research Database were analyzed to quantify baseline rates of comorbidities in 2,699 patients with COPD (46% were current smokers) compared with age-, sex-, practice- and time-matched controls (21% were current smokers). Angina, cataracts, and osteoporosis all had a frequency >1% within the first year after COPD diagnosis. Furthermore, compared with controls, COPD patients had a significantly increased risk of comorbidities and other medical events. The authors concluded that COPD is associated with many comorbidities, particularly those related to cardiovascular-, bone- and other smoking-related conditions, that previously had not been systematically documented. References Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell AL. Patterns of comorbidities in newly diagnosed COPD and asthma in primary care. Chest. 2005;128:2099-2107. Soriano, 2005, pSpeaker notes Analysis of the relative risk for systemic disease in patients with and without COPD indicated that those with COPD were at increased risk for glaucoma, angina, fractures, myocardial infarction, osteoporosis, and respiratory infections. Additional Information Patient data from the United Kingdom General Practice Research Database were analyzed to quantify baseline rates of comorbidities in 2,699 patients with COPD (46% were current smokers) compared with age-, sex-, practice- and time-matched controls (21% were current smokers). Angina, cataracts, and osteoporosis all had a frequency >1% within the first year after COPD diagnosis. Furthermore, compared with controls, COPD patients had a significantly increased risk of comorbidities and other medical events. The authors concluded that COPD is associated with many comorbidities, particularly those related to cardiovascular-, bone- and other smoking-related conditions, that previously had not been systematically documented. References Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell AL. Patterns of comorbidities in newly diagnosed COPD and asthma in primary care. Chest. 2005;128:2099-2107. Soriano, 2005, p

10. The risk of osteoporosis in Caucasian men and women with obstructive airways disease Speaker notes Data from subjects (N = 9,502) in the Third National Health and Nutrition Examination Survey, conducted in the US between 1988 and 1994, were used along with total bone mineral density (BMD) measurements to determine whether osteoporosis (defined as total BMD values ?2.5 SD below the corresponding mean values from young, healthy participants) was associated with COPD. Airflow obstruction was classified as none (FEV1/FCV ?0.7), versus mild (FEV1 ?80% predicted), moderate (FEV1 50% to 80% predicted), and severe (FEV1 <50% predicted). Overall, airflow obstruction was associated with increased odds of osteoporosis compared with without airflow obstruction (Odds Ratio [OR] 1.9; 95% CI 1.4 to 2.5). Participants with severe airflow obstruction were at especially increased risk (OR 2.4; 95% CI 1.3 to 4.4). Moderate, but not mild, airflow obstruction was also associated with osteoporosis. For women and men evaluated separately, the trends for increased prevalence of osteoporosis with increased severity of airflow obstruction were statistically significant (P<0.005 for both). Reference Sin DD, Man JP, Man SF. The risk of osteoporosis in Caucasian men and women with obstructive airways disease. Am J Med. 2003;114:10-14. Sin, 2003, p10-12 Speaker notes Data from subjects (N = 9,502) in the Third National Health and Nutrition Examination Survey, conducted in the US between 1988 and 1994, were used along with total bone mineral density (BMD) measurements to determine whether osteoporosis (defined as total BMD values ?2.5 SD below the corresponding mean values from young, healthy participants) was associated with COPD. Airflow obstruction was classified as none (FEV1/FCV ?0.7), versus mild (FEV1 ?80% predicted), moderate (FEV1 50% to 80% predicted), and severe (FEV1 <50% predicted). Overall, airflow obstruction was associated with increased odds of osteoporosis compared with without airflow obstruction (Odds Ratio [OR] 1.9; 95% CI 1.4 to 2.5). Participants with severe airflow obstruction were at especially increased risk (OR 2.4; 95% CI 1.3 to 4.4). Moderate, but not mild, airflow obstruction was also associated with osteoporosis. For women and men evaluated separately, the trends for increased prevalence of osteoporosis with increased severity of airflow obstruction were statistically significant (P<0.005 for both). Reference Sin DD, Man JP, Man SF. The risk of osteoporosis in Caucasian men and women with obstructive airways disease. Am J Med. 2003;114:10-14. Sin, 2003, p10-12

12. With estrogen deficiency, osteoclasts erode deeper than normal cavities, creating a biomechanically weakened structure. If they break through the trabeculae, the surface on which new bone would be formed is lost. Modified Masson stain, original magnification ×100. With estrogen deficiency, osteoclasts erode deeper than normal cavities, creating a biomechanically weakened structure. If they break through the trabeculae, the surface on which new bone would be formed is lost. Modified Masson stain, original magnification ×100.

13. The Osteoclast

14. Osteoclastogenesis

16. Role of Osteoprotegerin (OPG) in controlling osteoclastogenesis

17. A healthy skeleton depends on a balanced RANK Ligand/OPG ratio

18. The OPG/RANK/RANKL system and Osteoclastogenesis: Role of Inflammation

19. Evidence for Systemic Inflammation in COPD - Increased C-reactive protein and TNF-? levels - Speaker notes A systematic review identified 14 studies which reported on the relationship between COPD, FEV1 or FVC, and levels of systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, TNF-a, and IL-6 and -8. Overall, the standardized mean difference in the CRP level between COPD and control subjects was 0.53 units (95% CI 0.34 to 0.72). Additional Information The finding of elevated CRP is consistent with the presence of systemic inflammation in patients with stable COPD, and may explain, at least in part, the high prevalence of systemic complications such as cachexia, osteoporosis, and cardiovascular diseases among patients with COPD. Reference Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59:574-580. Gan, 2004, p574. 575, 578, 579 Speaker notes A systematic review identified 14 studies which reported on the relationship between COPD, FEV1 or FVC, and levels of systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, TNF-a, and IL-6 and -8. Overall, the standardized mean difference in the CRP level between COPD and control subjects was 0.53 units (95% CI 0.34 to 0.72). Additional Information The finding of elevated CRP is consistent with the presence of systemic inflammation in patients with stable COPD, and may explain, at least in part, the high prevalence of systemic complications such as cachexia, osteoporosis, and cardiovascular diseases among patients with COPD. Reference Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59:574-580. Gan, 2004, p574. 575, 578, 579

20. Parameters of systemic inflammation increase parallel with increases in severity of COPD Speaker notes Review of clinical study databases was conducted to determine how existing clinical and laboratory measures change with COPD severity and to identify disease markers that can serve as better endpoints for diagnosis and assessment of COPD progression and treatment effect. A meta-analysis of 652 studies comprising 146,255 enrollees showed trends in serum TNF-? and CRP toward separation between COPD stages. Additional Information Serum concentrations of CRP showed no statistical differences between the healthy subjects and those for individuals at each of the COPD stages but showed an upward trend with increasing disease severity. For serum TNF-a, there was a similar trend for increasing level with increasing level of COPD severity, but there were no statistically significant differences between the healthy subjects and any of the COPD stages. Reference Franciosi LG, Page CP, Celli BR, et al. Markers of disease severity in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2006;19:189-199. Franciosi, 2006, p189, 192-194 Speaker notes Review of clinical study databases was conducted to determine how existing clinical and laboratory measures change with COPD severity and to identify disease markers that can serve as better endpoints for diagnosis and assessment of COPD progression and treatment effect. A meta-analysis of 652 studies comprising 146,255 enrollees showed trends in serum TNF-? and CRP toward separation between COPD stages. Additional Information Serum concentrations of CRP showed no statistical differences between the healthy subjects and those for individuals at each of the COPD stages but showed an upward trend with increasing disease severity. For serum TNF-a, there was a similar trend for increasing level with increasing level of COPD severity, but there were no statistically significant differences between the healthy subjects and any of the COPD stages. Reference Franciosi LG, Page CP, Celli BR, et al. Markers of disease severity in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2006;19:189-199. Franciosi, 2006, p189, 192-194

21. Bone mineral density at the lumbar spine and hip regions in patients according to lung function and compared with healthy subjects. Data are shown as means with 95% confidence intervals. Open columns, healthy; solid columns, patients with FEV1 greater than 50% predicted; gray columns, patients with FEV1 less than 50% predicted. *Significant difference (p < 0.05). Bone mineral density at the lumbar spine and hip regions in patients according to lung function and compared with healthy subjects. Data are shown as means with 95% confidence intervals. Open columns, healthy; solid columns, patients with FEV1 greater than 50% predicted; gray columns, patients with FEV1 less than 50% predicted. *Significant difference (p < 0.05).

22. Severity of obstructive airway disease and risk of osteoporotic fracture de Vries et al, Eur Respir J 2005; 25:879-884 Crude odds ratios (95% confidence interval) for fracture among patients with obstructive airway disease. #: respiratory symptoms include bacterial respiratory tract infections, coughing, presence of sputum, haemoptysis, dyspnoea, tachypnoea, shortness of breath, acute bronchitis and wheezing. Crude odds ratios (95% confidence interval) for fracture among patients with obstructive airway disease. #: respiratory symptoms include bacterial respiratory tract infections, coughing, presence of sputum, haemoptysis, dyspnoea, tachypnoea, shortness of breath, acute bronchitis and wheezing.

23. Chronic obstructive pulmonary disease, inflammation and co-morbidity – a common inflammatory phenotype? The central role of TNF-a in co-morbidity associated with COPD. TNF-a appears to play a central role in the pathogenesis of COPD and other conditions that are increasingly being recognised as systemic inflammatory diseases. Certain TNF-a receptor polymorphisms are associated with increased severity of disease [85,86] and this may be due to enhanced TNF-a effects. CRP levels can be increased directly by TNF-a and other cytokines. Elevated CRP levels appear to be particularly crucial in the pathogenesis of cardiovascular disease. ROS released as a result of COPD may enhance the likelihood of developing cardiovascular disease, diabetes and osteoporosis. TNF-a – tumour necrosis factor – alpha CRP – C reactive protein ROS – reactive oxygen speciesThe central role of TNF-a in co-morbidity associated with COPD. TNF-a appears to play a central role in the pathogenesis of COPD and other conditions that are increasingly being recognised as systemic inflammatory diseases. Certain TNF-a receptor polymorphisms are associated with increased severity of disease [85,86] and this may be due to enhanced TNF-a effects. CRP levels can be increased directly by TNF-a and other cytokines. Elevated CRP levels appear to be particularly crucial in the pathogenesis of cardiovascular disease. ROS released as a result of COPD may enhance the likelihood of developing cardiovascular disease, diabetes and osteoporosis. TNF-a – tumour necrosis factor – alpha CRP – C reactive protein ROS – reactive oxygen species

24. Role of Systemic Inflammation as Risk Factor for Osteoporosis in COPD COPD is an inflammatory condition Pro-inflammatory cytokines, in particular TNF-?, may be the driving force behind the disease process Inflammation and actions of pro-inflammatory cytokines may extend beyond the lungs and play a part in the development of osteoporosis as systemic COPD co-morbidity. Speaker notes COPD is an inflammatory condition. Pro-inflammatory cytokines, in particular TNF-?, may be the driving force behind the disease process. Inflammation and actions of pro-inflammatory cytokines may extend beyond the lungs and play a part in systemic COPD comorbidities. As effective anti-inflammatory therapy becomes available for COPD, it will be important to monitor the effects on lungs and associated co-morbidities. Reference Sevenoaks MJ, Stockley RA. Chronic Obstructive Pulmonary Disease, inflammation and co-morbidity--a common inflammatory phenotype? Respiratory Res. 2006;7:70-78.   Sevenoaks, 2006, p70 Speaker notes COPD is an inflammatory condition. Pro-inflammatory cytokines, in particular TNF-?, may be the driving force behind the disease process. Inflammation and actions of pro-inflammatory cytokines may extend beyond the lungs and play a part in systemic COPD comorbidities. As effective anti-inflammatory therapy becomes available for COPD, it will be important to monitor the effects on lungs and associated co-morbidities. Reference Sevenoaks MJ, Stockley RA. Chronic Obstructive Pulmonary Disease, inflammation and co-morbidity--a common inflammatory phenotype? Respiratory Res. 2006;7:70-78.   Sevenoaks, 2006, p70

25. Role of Glucocorticoids in the pathogenesis of OP

27. Association between corticosteroid use and vertebral fractures in older men with COPD Speaker notes In a cross-sectional study, the association between steroid use and vertebral fractures was evaluated in 312 men, 50 years of age or older, with COPD. Subjects were evaluated according to their corticosteroid use. The prevalence of one or more vertebral fractures was 48.7% in the group that had never used steroids, 57.1% in the ICS group, and 63.3% in the group that had used systemic corticosteroids (SCS). Compared with non-users, steroid users were more than twice as likely to have one or more vertebral fractures: multivariate-OR = 2.16 (95% CI 1.14-4.11). This relationship was primarily due to a strong association between continuous systemic steroid use and vertebral fractures: multivariate-adjusted OR = 2.99 (95% CI 1.38-6.49. Weaker relationships existed between vertebral fractures and ICS use (adjusted OR verses non-users = 1.35 [95% CI 0.77-2.56] and intermittent SSC use (OR =1.55 [95% CI 0.72-3.32]). Additional Information These data indicate that vertebral fractures are common in older men with COPD; the likelihood of these fractures is greatest in those men using continuous systemic steroids. Reference McEvoy CE, Ensrud KE, Bender E, et al. Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease. Am J Resp Crit Care Med. 1998;157:704-709. McEvoy, 1998, p707, 704 Speaker notes In a cross-sectional study, the association between steroid use and vertebral fractures was evaluated in 312 men, 50 years of age or older, with COPD. Subjects were evaluated according to their corticosteroid use. The prevalence of one or more vertebral fractures was 48.7% in the group that had never used steroids, 57.1% in the ICS group, and 63.3% in the group that had used systemic corticosteroids (SCS). Compared with non-users, steroid users were more than twice as likely to have one or more vertebral fractures: multivariate-OR = 2.16 (95% CI 1.14-4.11). This relationship was primarily due to a strong association between continuous systemic steroid use and vertebral fractures: multivariate-adjusted OR = 2.99 (95% CI 1.38-6.49. Weaker relationships existed between vertebral fractures and ICS use (adjusted OR verses non-users = 1.35 [95% CI 0.77-2.56] and intermittent SSC use (OR =1.55 [95% CI 0.72-3.32]). Additional Information These data indicate that vertebral fractures are common in older men with COPD; the likelihood of these fractures is greatest in those men using continuous systemic steroids. Reference McEvoy CE, Ensrud KE, Bender E, et al. Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease. Am J Resp Crit Care Med. 1998;157:704-709. McEvoy, 1998, p707, 704

29. Glucocorticoid Use and RR for Vertebral Fractures according to underlying disease RR (95% CI) IBD 1.0 COPD 2.92 (1.09, 7.80) Vasculitides 6.07 (1.15, 32.11) Adjusted for gender, age, menopausal status and FN-BMD

31. Risk Factors for Osteoporosis in COPD Underlying disease pathology chronic systemic inflammation Corticosteroid use Disease co-morbidities: Skeletal muscle dysfunction Low BMI / cachexia Low vitamin D levels General factors Menopausal status Increased alcohol intake Speaker notes Increased risk for osteoporosis may be due to the lifestyle, genetics, treatment with corticosteroids, endocrine abnormalities, or the impairment of the body composition and peripheral skeletal muscles. Some specifically identified risk factors for osteoporosis in patients with COPD are: Smoking Increased alcohol intake Reduced vitamin D levels Genetic factors Treatment with corticosteroids Reduced skeletal muscle mass and strength Low BMI and changes in body composition Hypogonadism Reduced levels of insulin-like growth factors (IGFs) Chronic systemic inflammation Reference Ionescu AA, Schoon E. Osteoporosis in chronic obstructive pulmonary disease. Eur Respir J. 2003;22 (Suppl 46):64s-75s. Ionescu, 2003, p64s, 65s Speaker notes Increased risk for osteoporosis may be due to the lifestyle, genetics, treatment with corticosteroids, endocrine abnormalities, or the impairment of the body composition and peripheral skeletal muscles. Some specifically identified risk factors for osteoporosis in patients with COPD are: Smoking Increased alcohol intake Reduced vitamin D levels Genetic factors Treatment with corticosteroids Reduced skeletal muscle mass and strength Low BMI and changes in body composition Hypogonadism Reduced levels of insulin-like growth factors (IGFs) Chronic systemic inflammation Reference Ionescu AA, Schoon E. Osteoporosis in chronic obstructive pulmonary disease. Eur Respir J. 2003;22 (Suppl 46):64s-75s. Ionescu, 2003, p64s, 65s

33. Osteoporosis is a significant component of the complex chronic co-morbidities of COPD