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A nemi a and osteoporosis in chronic lung diseases

A nemi a and osteoporosis in chronic lung diseases. Prof Dr Berrin Ceyhan Marmara University School of Medicine. Definition of anemia. WHO (World health organisation) describes anemia as Hgb< 1 3 g/dl or Htc<39% in males Hgb<1 2 g/dl or Htc<36% in females. Anemia. Disability

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A nemi a and osteoporosis in chronic lung diseases

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  1. Anemia and osteoporosis in chronic lung diseases Prof Dr Berrin Ceyhan Marmara University School of Medicine

  2. Definition of anemia • WHO (World health organisation) describes anemia as • Hgb< 13g/dl or Htc<39% in males • Hgb<12 g/dl or Htc<36% in females

  3. Anemia • Disability • Impaired physical performance • Lower muscle strength • Increased mortality • Fatigue • Cachexia • Impaired mood • Lower cognitive function • Quality of life

  4. Anemia in COPD It can be the result of • Systemic inflammation • Nutritional disorders • Occult blood loss • Drugs (theopylline, ACE, Phenoterol via direct, RAAS, and EPO secretion) • Oxygen therapy • Decreased renal flow (EPO is sytnthesized in kidney) • Hypogonadism in COPD (androgens stimulates erythropoiesis via direct stimulation or RAAS )

  5. Chronic disease anemia • Chronic infections • Chronic inflammation • Neoplasms • Heart failure

  6. Mechanisms of chronic disease anemia • IL-6 • Interferon gamma • Shortened RBC survival (IL-1 and TNF) • Slight increase RBC production • Impaired proliferationof erythroid precursors (IFN-gamma, free radicals)

  7. Bone marrow can not respond to increased demand and relative erthropoietin resistance (IL-1, TNF-alpha, and IFN- gamma) • Impaired RES iron stores, sequestration of iron in macrophages, dysregulation of iron homeostasis, impaired iron utilisation and mobilisation (IL-1 and INF-gamma)

  8. Alterations in hematopoiesis in COPD Increase in mean corpuscular volume (MCV) • 29%-37% in COPD (MCV>94 fL) • No correlation between MCV and PaO2mmHg • Renin angiotensin aldosterone system (RAAS) activation • Increased EPO with renin or aldosterone in animal models • ACEI decreseases EPO and hematocrit • In this group of COPD patients renin aldosteron level 3 times higher when compared hypoxemic COPD patients

  9. Anemia and cystic fibrosis • Inflammatory mediators IL-1, Il-8 and TNF-alpha • Nutritional factors • Iron kinetics are lower

  10. Anemia and pulmonary fibrosis • Inflammatory cytokines TNF-alpha, IL-6, IL-8 levels are high • Erythroid colony forming unit is inhibited • Ineffective erythropoiesis • Lower hgb and EPO levels than COPD • Tsantes A Med Sci Monit 2005

  11. Anemia and pulmonary fibrosis • N=9 • Hgb and serum EPO did not differ from controls • TNF-alpha, IL-6 and IL-8 significantly raised • Proliferating capacity of RBCs higher • Rate of differentiation of RBCs slower • Tsantes A Chest 2003

  12. Epidemiology of COPD and anemia • 7337 COPD patients between 1996-2003 23.1 % anemia (%23.3 % in heart failure patients) • John M Int J Cardiol 2006

  13. 177 COPD patients • 31% anemic • 58% normochrom normocytemic • 41% chronic disease anemia • 25 iron deficiency anemia • 34% other causes Portillo K Rev Clin Esp 2007

  14. Stable COPD outpatients N=683 • Anemia 17%Polycytemia 6% 10.6% of prevalance among community dwelling elderly Anemic patients have Higher dyspnea score Shorter 6MWD Lower median survival Lower functional capacity Polycytemic patients have higher BMI Cote C et al Eur Respir J 2007;29:923

  15. COPD pts n=683 Cote C ERJ 2007

  16. COPD pts n=683 Cote C ERJ 2007

  17. 2524 COPD patients receiving LTOT (ANTADIR) Anemia is seen 12.6% of males and 8.2% of females Polycythaemiahtc>54% (8.4% of patients) Anemia is associated with • Survival rate • Hospital admission rate • Longer duration of hospital stay Polycythemia is associated with higher survival rates If Htc>55% , 3 year survival rate is 70% If Htc <35%, 3 year survival rate is 24% Chambellan A et al Chest 2005

  18. Htc was the strongest predictor of mortality Htc was inversely correlated with the hospital admission rate and duration of hospitalisation Negative correlation with PaCO2 level Other survival predictors • Age • Htc • BMI • PaO2 • Sex • FEV1 Chambellan A et al Chest 2005

  19. Markers of COPD severity • BMI • Airflow obstruction • Dyspnea • Exercise capacity BODE index Predictor of mortality due to respiratory or all other causes Htc 42+/_5% for survivers Htc 39+/_5% for those who died Celli Br NEJM 2004

  20. Negative correlation between rate of hospitalisation and anemia John M Int J Cardiol 2006 • NETT Study .Increased mortality in anemic patients Other mortality predictors: Age,oxygen use, higher residual volume, higher BODE index Martinez et al Am J Respir Crit Care Med 2006

  21. n=101 • Stable COPD patients ( FEV1 37+/-2% predic) • Anemia subgroup 13% • Increased EPO level • Inversed correlation between hgb and EPO (resistance to EPO hormone) • Decreased apetite • No correlation between anemia and nutritional abnormalities (weight loss and cachexia) • No change of lung function test • No change of COPD severity • No change of age, height and drug therapy • CRP significantly increased • IL-6, IL-8,IL-10 not changed • John M et al Chest 2005

  22. Clinical relevance of anemia of COPD Blood cell transfusion leades to • Reduction in minute ventilation • Reduction of work of breathing • Improved pulmonary gas exchange • Improved exercise capacity • Ventilator dependent COPD pts after transfusion (hgb>12 g/dl) weaned in 1-4 days Schoneofer B Anesthesia 1998

  23. Anemia and economic implications • 2404 COPD patients 33% had anemia • Annual costs 17240$ versus 6492 $ Shorr AF Curr ed Rev Opin 2008 • 132. 424 COPD patients • 21% had anemia • mortality rate 262 vs 133 death/1000 person-year • Annual medicare payment 1466 $ vs 649$ • Halpern MT Cost Eff Resour Alloc 2006

  24. Osteoporosis and COPD Etiology • Inflammatory lung disease • Reduced physical activity • Reduced skeletal muscle mass • Systemic inflammation • Treatment (steroids ) • Ageing (hypogonadism, reduced muscle mass, inactivity)

  25. Diagnosis Dual energy X-Ray absorptiometry (DXA) • T score; a standart deviation compared to a young adult sex matched control population • Z score ; a standard deviation compared to an age and sex matched control population

  26. Epidemiology • 15 pre-transplantation COPD pts 45% had bone Z scores of >2SD Pre transplantation cystic fibrosis pts 75% Other pulmonary disease pts 15% Aris RM Chest 1996 29% vertebral fractures in pre-transplantation COPD patients Shane E Am J Med 1996

  27. Epidemiology • 44 elderly female patients (ICS treatment) • 20 pts with COPD 50%(correlated with BMI) • 24 pts with asthma 21% have osteoporosis (288 vs 743 miligram ICS) • Total cumulative BDP dose did not correlate with BMD • BMD is high even higher BDP dose in asthma • Katsura H Chest 2002

  28. Epidemiology • 412 COPD patients, 1200 mcg taking triamcinolone • Greater lumbar spine and femoral neck osteoporosis in triamcinalone group in 3 years, no increased fracture risk • LHSR NEJM 2000 • 102 smoker COPD patients with mild COPD, taking budesonide • A modest reduction at the trochanteric site BMD in 3 years (13.4% versus 11.5% vertebral fracture) • Pauwels RA NEJM 1999

  29. Osteoporosis risk factors • Smoking ( lunglow attenuation area correlated with reduced bone density) Olvara T Chest 2008 • Increased alcohol intake (RR: 2.4) • Low Vitamin D level (It regulates the absorption of calcium, PTH, bone resorption) • Genetic factors(COLIA1 gene polymorphism encodes type I Collagen)

  30. Osteoporosis risk factors • Treatment with corticosteroids • Reduces the absorption of calcium in the gut • Increases the renal excretion of calcium • Stimulates the bone resorption (through the effect of parathormone) • Inhibits the osteoblastic line • Especially in trabecular bone(proximal femur, Ward’s triangle) and cortical rim of the vertebral bodies Mecran K Am J Respir Crit Care Med 1995

  31. A reduction of osteocalcin after first week (42% of pts with oral steroid and 17% of pts with beclamethasoneMecran K Am J RespirCrit Care Med 1995 • Mild to moderate COPD 1.2 mg/day triamcinolone for 40 months. BMD reduction in lumbar spine and femoral neck Scanlon PD Am J RespCrit Care Med 2004

  32. Mild COPD pts 800 ug budesonide 3 years no reduction in BMD • 800 ug beclomethasone and budesonide and 750 ug flixotide had limited effects on bone metabolism LHSRG NEJM 2000,Goldstein MF Chest 1999, Pauwels RA NEJM 1999

  33. Osteoporosis risk factors • Reduced skeletal muscle mass and strength which is related to BMD The greater the stress on a bone area, the greater the bone mass In COPD, • Reduced mobility due to shortness of breath • steroid myopathy • metabolic factors may cause osteoporosis BMD at femoral neck was up to 10% greater in those who exercised regularly Valimaki MJ BMJ 1994

  34. Osteoporosis risk factors • Weight loss and Low BMI are predictors of mortality FFM( fat free mass) is associated with exacerbations and hospital admission rate FFM are related to bone density Load of soft tissue preserves the bone mass Mostert R Respir Med 2000

  35. Osteoporosis risk factors • Hypogonadism and reduced IGF Oestrogen regulates bone resorption and formation Testesterone regulates bone formation Ageing causes low eostrogen and testerone levels Steroid treatment decreases LH and circulating oestrogen and testerone levels IGF-1 stimulate the differentiation and proliferation of osteoblasts

  36. Osteoporosis risk factors • Chronic systemic inflammation • IL-1 alpha and TNF-alpha stimulate bone resorption • IL-6 stimulates the formation of osteoclasts Raisz LG NEJM 1988

  37. Consequences of osteoporosis in COPD • Steroid treatment increases the risk of fractures RR: 1.33-1.61 Risk disappeared within 1 year after stopped Van Staa TP J Bone Miner Res 2001

  38. Consequences of osteoporosis in COPD 312 male COPD pts , prevalance of at least one vertebral fracture • 48.7% pts never used steroid • 57.1% pts received inh. steroids • 63.3% pts receiving systemic steroids McEvoy CE Crit Care Med 1998

  39. Consequences of osteoporosis in COPD Thoracic vertebral fracture and hyperkyphosis causes • 10% reduction FVC in lung function • Mortality after hip fracture is 20% in first year • Morbidity; 19% requires residential care • High economic burden

  40. UK, 108745 patients (9100 asthma and 5500 COPD) OR; • Asthma 1.28 • COPD 1.61 • 1500 microgm BDP increases fracture risk 1.95(hip 1.77 and vertebra 3.78) • OCS risk 1.75 • Smoking 1.57-1.79 • Fracture risk disappeared after adjustment was made for disease severity in pts using ICS (1.47-1.48 F De Vries ERJ 2005

  41. Severity of obstructive airway disease and risk of osteoporotic fracture F De Vries ERJ 2005

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