Osteoporosis and COPD

E.F.M. Wouters Department of Respiratory Medicine

Maastricht University

E.F.M. Wouters

Disclosures

•  Member Scientific Committee Eclipse (GSK)

•  Lectures: Almirall, AstraZeneca, Chiesi, Danone, GSK, Novartis

•  Advisory board: AstraZeneca, Boehringer Ingelheim, GSK, Pfizer

•  Research grants: AstraZeneca, Boehringer Ingelheim, Danone, GSK

E.F.M. Wouters

Definition of COPD

Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic

inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall

severity in individual patients Vestbo et al, Am J Respir Crit Care Med 2013

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Background

Osteoporosis

Hypertension Depressive disorder

COPD

Cardiovascular disease

Muscle weakness

Wouters EFM et al, Systemic effects in COPD. Chest 2002;121(5 Suppl):127S-30S. Barnes PJ et al, Systemic manifestations and comorbidities of COPD. ERJ 2009;33(5):1165-85.

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Number of objectively identified comorbidities

7.0

17.819.2

24.9

17.8

8.0

2.30.5

2.3

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8No. of comorbidities per patient

Freq

uenc

y (%

)

Vanfleteren et al, Am J Respir Crit Care Med 2013

E.F.M. Wouters

Frequencies of objectively identified comorbidities

5 9

14 16 21 22 23

28 31 36

48 53 54

0 10 20 30 40 50 60

Freq

uenc

y (%

)

Vanfleteren et al, Am J Respir Crit Care Med 2013

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Lehouck et al, Chest 2011

Pathogenesis of osteoporosis in COPD

Low  body  weight  Smoking  Age  Gender  Inac7vity    Systemic  inflamma7on    Systemic  Cor7costeroids    Vitamin  D  deficiency  

Osteoporosis  

Rib  cage  fractures  

Risk  for  fractures  ↑  

Vertebral  fractures  

Exacerba7ons    ↑  

Morbidity  and  Mortality  ↑  

Decline  of  FEV1  

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Prevalence of osteoporosis in COPD

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Prevalence of osteoporosis in COPD

Osteoporosis:  Tscores  –2.5  

Sin et al, Am J Med 2003

0  5  10  15  20  25  30  35  

no   mild   moderate   severe  

male  female  

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Osteoporosis in COPD

Sin et al, Am J Med 2003

Odds  ra7o  

Normal            Reference  Mild  obstruc7on          1.3  Moderate  obstruc7on        2.1  Severe  obstruc7on        2.4  

Airflow  obstruc7on,  independent  of  age,  body  mass  index  and  medica7ons  including  recent  use  of  cor7costeroids,  increased  the  risk  of  osteoporosis  in  a  severity-­‐dependent  fashion.  

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Osteoporosis in COPD

0%

20%

40%

60%

80%

100%

low BMI-lowFFMI n=16

normal BMI-lowFFMI n=17

normal BMI-normal FFMI

n=44

Healthy subjectsn=38

Perc

enta

ge o

f sub

ject

gro

up

osteoporosisosteopeniano bone loss

50

5

50

18

47

41

12

50

32

13

32

55

Bolton C et al, AJRCCM 2004

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Prevalence of osteoporosis in COPD

Graat-Verboom et al, ERJ 2009

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Prevalence of osteoporosis in COPD

Graat-Verboom et al, ERJ 2009

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Prevalence of osteoporosis in COPD

Schnell et al, BMC Pulmonary Medicine 2012

0  

2  

4  

6  

8  

10  

12  

14  

16  

18  

without  COPD   with  COPD  n=  14,828   n=  995  

P<0.001  

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Prevalence of osteoporosis in COPD

Miller et al, Respir Med 2013

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Comorbidity in COPD

Stage II Stage III Stage IV p-value Heart trouble 26% 25% 25% 0.992 Heart attack 10% 8% 8% 0.457 Stroke 4% 3% 3% 0.327 Heart failure 7% 6% 9% 0.287 Arrhythmia 12% 12% 10% 0.721 Osteoporosis 13% 14% 12% 0.785 Diabetes 11% 9% 11% 0.118 Inflamm. Bowel Dis. 6% 3% 6% 0.045 Peptic ulcer 11% 11% 8% 0.206 Reflux/heartburn 31% 23% 21% <0.001 Depression requring tx. 16% 17% 15% 0.516

Agusti A et al, Respir Res 2010

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Prevalence of osteoporosis in COPD

Graat et al, J Bone Miner Res 2011

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

GOLD I GOLD II GOLD III GOLD IV

DXA-scan

Normal BMD Osteopenia Osteoporosis

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Underweight: BMI < 21 kg·m-2 (Celli et al., N Engl J Med 2004) Muscle wasting: FFMI < 16 kg·m-2 for men or < 15 kg·m-2 for

women (Schols et al., Am J Clin Nutr 2005) Obesity: BMI ≥ 30 kg·m-2 (WHO) Renal failure: eGFR (Cockroft and Gault) < 60 ml·min-1

(KDOQI, Am J Kidney Dis 2007)

Osteoporosis: T-score < -2,5 on the local sites hip and lumbal spine or whole body (Graat-Verboom et al., J. Osteoporos 2010)

Anemia: Hemoglobin level <13 g·dL-1 (8,1 mmol/L) in men and <12 g·dL-1 (7,5 mmol/L) in women (WHO)

Definitions of 13 comorbidities

Vanfleteren et al, Am J Respir Crit Care Med 2013

E.F.M. Wouters

Frequencies of objectively identified comorbidities

5 9

14 16 21 22 23

28 31 36

48 53 54

0 10 20 30 40 50 60

Freq

uenc

y (%

)

Vanfleteren et al, Am J Respir Crit Care Med 2013

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Identification of five comorbidity clusters

Vanfleteren et al, Am J Respir Crit Care Med 2013

Less comorbidity

Cardiovascular

Cachectic

Psychological

Metabolic

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Clinical characteristics CLUSTER 1 ‘less comorbidity’

CLUSTER 2 ‘cardiovascular’

CLUSTER 3 ‘cachectic’

CLUSTER 4 ‘metabolic’

CLUSTER 5 ‘psychologic’

n 67 49 44 33 20 No. of comorbidiites 2.5 ± 1.4 3.8 ± 1.7 4.2 ± 1.4 4.4 ± 1.1 4.1 ± 1.8 Renal impairment 16 24 45 9 5 Anaemia, % 9 4 2 3 5 Hypertension, % 3 98 43 100 5 Obesity, % 30 14 0 61 15 Underweight, % 0 0 66 3 0 Muscle wasting, % 12 10 98 0 20 Hyperglycaemia, % 52 14 43 91 60 Dyslipidaemia, % 42 16 25 67 40 Osteoporosis, % 27 37 52 0 35 Anxiety, % 5 28 26 0 84 Depression, % 6 23 7 6 68 Atherosclerosis, % 56 67 12 81 53 Myocardial infarction, % 2 11 7 13 32

Characteristics of comorbidity clusters

Vanfleteren et al, Am J Respir Crit Care Med 2013

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Osteoporosis in COPD

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Ohara et al, Chest 2008

Pulmonary emphysema and osteoporosis in COPD

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Risk factors for osteoporosis in COPD

Emphysema

Corticosteroids: inhaled

Vit D deficiency

Systemic inflammation

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Den Uyl et al, Curr Rheumatol Rep 2011

Pathophysiology of glucocorticoid-induced effects on bone cells

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Inhaled steroids and osteoporosis

Ferguson et al, Chest 2009

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Ferguson et al, Chest 2009

Inhaled steroids and osteoporosis: Change in hip BMD

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Ferguson et al, Chest 2009

Inhaled steroids and osteoporosis: spine BMD

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Ferguson et al, Chest 2009

Bone fractures in COPD

17  

18  

19  

20  

21  

22  

Placebo  Group   SAL  Group   FP  Group   SFC  Group  

Rate  of  fracture  per  1,000  treatment  years  

n=1,544   n=1,542   n=1,546  n=1,552  

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Ferguson et al, Chest 2009

Bone fractures in COPD

0  

1  

2  

3  

4  

5  

6  

7  

Placebo  Group   SAL  Group   FP  Group   SFC  Group  

Probability  of  fracture  by  3  yr,  %  

n=1,544   n=1,542   n=1,546  n=1,552  

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Risk factors for osteoporosis in COPD

Emphysema

Corticosteroids: inhaled

Vit D deficiency

Systemic inflammation

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Vitamin D metabolism

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Vitamin D synthesis pathways

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Janssens et al, Thorax 2010

Vit D deficiency in COPD

25-­‐OHD  levels  >  30  ng/ml  

25-­‐OHD  levels  20  -­‐  30  ng/ml  

25-­‐OHD  levels  <  20  ng/ml  

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Romme et al, Ann Med 2013

Vit D status in COPD

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Berg et al, Respir Med 2013

Vit D and lung function in COPD

25-­‐OHD  levels  <  30  ng/ml:  69  %  25-­‐OHD  levels  <  20  ng/ml:  39  %  25-­‐OHD  levels  <  10  ng/ml:  8.7  %  

r  =  0.116  p  <  0.01  

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Berg et al, Respir Med 2013

Vit D and lung structure in COPD

r  =  0.141  p  <  0.01  

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Vit D and GOLD severity

Berg et al, Respir Med 2013

<  

>  

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Graat-Verboom, Bone 2012

Risk factors for osteoporosis in COPD

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Romme et al, Ann Med 2013

Bone mineral density and Vit D

R2=0.22  

Age    

BMI  

25  (OH)D    

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Vitamin D beyond bones in COPD

Janssens et al, AJRCCM 2009

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Risk factors for osteoporosis in COPD

Emphysema

Corticosteroids: inhaled

Vit D deficiency

Systemic inflammation

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Lehouck et al, Chest 2011

Pathogenesis of osteoporosis in COPD

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OPG/RANK/RANKL system in COPD with osteoporosis

Zhang et al, COPD 2013

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OPG/RANK/RANKL system in COPD with osteoporosis

Zhang et al, COPD 2013

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OPG/RANK/RANKL pathway in COPD with osteoporosis

Bai et al, Respir Research 2011

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OPG/RANK/RANKL pathway in COPD with osteoporosis

Bai et al, Respir Research 2011

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OPG/RANK/RANKL pathway in COPD with osteoporosis

Bai et al, Respir Research 2011

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Inflammation data and osteoporosis in COPD

Miller J et al, Respir Med 2013

Inflammatory  markers   YES   NO   P-­‐value  

N   283   1730  

CRP,  mg/L   2.6  +  5   3.3  +  6   0.035  

Fibrogen,  mg/dL   462  +  135   446  +  126.5   0.310  

IL-­‐6,  pg/mL   1.4  +  2   1.5  +  2   0.371  

IL-­‐8,  pg/mL   5.4  +  8.3   7.3  +  10.2   0.272  

TNF-­‐alpha,  pg/mL   2.4  +  4   2.4  +  10   0.994  

SPD,  ng/mL   117  +  89   119  +  87   0.971  

CCL-­‐18,  ng/mL   108  +  57   105  +  53   0.954  

CC-­‐16,  ng/mL   4.8  +  3.6   5.0  +  3.5   0.947  

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Agus7  et  al,  Plos  One  2012  

Biomarkers  in  COPD  

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Conclusions

1.  Osteoporosis is highly prevalent in COPD

2.  The pathogenesis of bone abnormalities in COPD is multifactorial

3.  Growing evidence of a link between emphysema and osteoporosis: The implosive COPD phenotype?

E.F.M. Wouters