Inhaled corticosteroids & fracture
risk: disease or drugs
• Frank de Vries
• Utrecht Institute for Pharmaceutical Sciences...
Conflict of Interest
• The dept of Pharmacoepidemiology &
pharmacotherapy, Universiteit Utrecht has
received an unconditio...
History
• Late ’60s: first studies with inhaled
corticosteroids in asthmatic children to
avoid severe corticosteroid-induc...
16 yr old girl
Asthma since 18
months old
On systemic steroids
for 11 year
Before (left) & after
(right) 5 months on
ICS
+...
History
• Late ’90s: well accepted treatment for
reductions of airway hyperresponsiveness,
asthma symptoms & lung function...
History
• Early 2000s: long acting beta-2 agonists,
leukotriene receptor antagonists:
alternatives.
 increased attention...
Evidence from RCTs: BMD
Source: Richy F et al Osteop. Int. May 2003
Evidence from RCTs (’99-’07):
ICS use & risk of any fracture
Mantel Haenzel OR 1.16 (0.94-1.44)
Sources: Torch Trial, NEJM...
Epi studies
• Inhaled corticosteroids have been
associated with
• low bone mineral density [1]
• increased risk of hip fra...
Objective
• Does severity of obstructive airway
disease confounds the relationship
between inhaled corticosteroids and ris...
Study population
UIPS Utrecht Institute fo r
Pharmaceutical Sciences
• Case-control study
• General Practice Research Data...
Adjustment for Indicators of Severity of
Obstructive Airway Disease
• Adjustment for:
• Specific indicators of severity of...
0
1
2
3
4
5
6
7
1-400
ug
401-800
ug
801-1600
ug>1600
ug
1-400
ug
401-800
ug
801-1600
ug
>1600
ug
1-400
ug
401-800
ug
801-1...
0
1
2
3
4
5
6
7
1-400
ug
401-800
ug
801-1600
ug>1600
ug
1-400
ug
401-800
ug
801-1600
ug
>1600
ug
1-400
ug
401-800
ug
801-1...
Discussion
• Severity of obstructive airway disease confounds
the relationship between inhaled corticosteroids and risk
of...
Source: de Vries et al. Pharmacol
Drug Saf 2007 2007;16:612-9.
Source: de Vries et al. Pharmacol
Drug Saf 2007 2007;16:612-9.
Epi studies: ICS & fracture risk
• Observational studies, stratified by extensive
adjustment of respiratory disease severi...
Limitations
• RCTs (fracture risk): limited no. of highly
selected patients
• Epi studies (fracture risk)
– Respiratory di...
Clinical implications
• Discontinuation of ICS in patients using
high (>800 ug/ becl. Eq. day) dosages of
ICS is probably ...
Hartelijk dank voor uw aandacht
• Frank de Vries
• Universiteit Utrecht
• f.devries@uu.nl
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Seminar 09-04-2008 -inhaled corticosteroids & fracture risk

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Seminar 09-04-2008 -inhaled corticosteroids & fracture risk

  1. 1. Inhaled corticosteroids & fracture risk: disease or drugs • Frank de Vries • Utrecht Institute for Pharmaceutical Sciences – (Bert Leufkens, Tjeerd van Staa) • MRC Epidemiology Resource Centre, Southampton General Hospital, Southampton – (Cyrus Cooper) • General Practice Research Database, MHRA, London UK
  2. 2. Conflict of Interest • The dept of Pharmacoepidemiology & pharmacotherapy, Universiteit Utrecht has received an unconditional educational grant for the conduct of pharmaco- epidemiological research from GSK • Dr de Vries & Van Staa conduct commissioned studies using GPRD for several pharmaceutical companies
  3. 3. History • Late ’60s: first studies with inhaled corticosteroids in asthmatic children to avoid severe corticosteroid-induced side effects • Mid ’80s: 400 – 600 ug beclomethasone equivalents / day
  4. 4. 16 yr old girl Asthma since 18 months old On systemic steroids for 11 year Before (left) & after (right) 5 months on ICS + Less depressed + 11 kg weight loss + 1.3 cm length gain Source: Morrow Brown, BMJ 1973, 3 161-164
  5. 5. History • Late ’90s: well accepted treatment for reductions of airway hyperresponsiveness, asthma symptoms & lung function • ’90 – ’97: ICS use doubled in UK & Netherlands • Start high, go low approach (800-1000 ug/day) • 1998: est. 60% of COPD patients used ICS in the Netherlands
  6. 6. History • Early 2000s: long acting beta-2 agonists, leukotriene receptor antagonists: alternatives.  increased attention for potential side effects of ICS, including cataract & osteoporosis.
  7. 7. Evidence from RCTs: BMD Source: Richy F et al Osteop. Int. May 2003
  8. 8. Evidence from RCTs (’99-’07): ICS use & risk of any fracture Mantel Haenzel OR 1.16 (0.94-1.44) Sources: Torch Trial, NEJM Jan 2007, Euroscop NEJM Jun 1999
  9. 9. Epi studies • Inhaled corticosteroids have been associated with • low bone mineral density [1] • increased risk of hip fracture [2] • Severity of OAD is associated with • low bone mineral density [3,4] UIPS Utrecht Institute fo r Pharmaceutical Sciences [1] Israel et al. NEJM 1999 [2] Hubbard et al. Am. J. Resp. Crit. Care 2002 [3] Van Staa et al. Am J Respir Crit Care Med. 2003 [4] Sin et al. Am. J. Med. 2003
  10. 10. Objective • Does severity of obstructive airway disease confounds the relationship between inhaled corticosteroids and risk of osteoporotic fracture? UIPS Utrecht Institute fo r Pharmaceutical SciencesSource: de Vries et al. Eur Respir J May 2005
  11. 11. Study population UIPS Utrecht Institute fo r Pharmaceutical Sciences • Case-control study • General Practice Research Database (GPRD) • 6% of the UK population • 1987 – July 1999 • Age: 18 and older Source: de Vries et al. Eur Respir J May 2005
  12. 12. Adjustment for Indicators of Severity of Obstructive Airway Disease • Adjustment for: • Specific indicators of severity of obstructive airway disease 6 or 12 months prior: • Average daily dose of bronchodilators • Use of oral corticosteroids • Exacerbations • Use of oxygen • Body mass index • Respiratory symptoms (i.e.chest infections) UIPS Utrecht Institute fo r Pharmaceutical Sciences Source: de Vries et al. Eur Respir J May 2005
  13. 13. 0 1 2 3 4 5 6 7 1-400 ug 401-800 ug 801-1600 ug>1600 ug 1-400 ug 401-800 ug 801-1600 ug >1600 ug 1-400 ug 401-800 ug 801-1600 ug >1600 ug Osteoporotic Hip Vertebral n=108,754 n=14,388 n=8,712 oddsratio Inhaled corticosteroid dose Inhaled corticosteroid use and fracture risk -------- Diamonds: crude analysis Source: de Vries et al. Eur Respir J May
  14. 14. 0 1 2 3 4 5 6 7 1-400 ug 401-800 ug 801-1600 ug>1600 ug 1-400 ug 401-800 ug 801-1600 ug >1600 ug 1-400 ug 401-800 ug 801-1600 ug >1600 ug oddsratio Inhaled corticosteroid dose Inhaled corticosteroid use and fracture risk -------- Diamonds: crude analysis -------- Squares: adjustment for general risk factors, disease severity indicators and bronchodilator exposure NOT significantly increased (p<0.05) Osteoporotic Hip Vertebral n=108,754 n=14,388 n=8,712 Source: de Vries et al. Eur Respir J May
  15. 15. Discussion • Severity of obstructive airway disease confounds the relationship between inhaled corticosteroids and risk of osteoporotic fracture. • Limitations: • No lung function measurements available • Mechanism of severity and fracture risk unclear • Strengths: • First study that quantified bronchodilator exposure concisely • First study that adjusts for a wide range of indicators of severity UIPS Utrecht Institute fo r Pharmaceutical Sciences
  16. 16. Source: de Vries et al. Pharmacol Drug Saf 2007 2007;16:612-9.
  17. 17. Source: de Vries et al. Pharmacol Drug Saf 2007 2007;16:612-9.
  18. 18. Epi studies: ICS & fracture risk • Observational studies, stratified by extensive adjustment of respiratory disease severity – No, or only limited adjustments: positive association ICS use & fracture risk. – Adjustment for disease severity: no significantly increased association between ICS use & fracture risk Source: de Vries et al. Universiteit Utrecht 2007, PhD thesis general discussion f.devries@uu.nl
  19. 19. Limitations • RCTs (fracture risk): limited no. of highly selected patients • Epi studies (fracture risk) – Respiratory disease severity: black box – Epi studies: limited data on smoking, BMI, muscle strengths – Methodological issue: overadjustment may have masked a true positive association – No data available on e.g. lifetime corticosteroid exposure (alternative explanation for positive association)
  20. 20. Clinical implications • Discontinuation of ICS in patients using high (>800 ug/ becl. Eq. day) dosages of ICS is probably not indicated • Fracture risk assessment may be indicated among patients using high daily dosages of ICS, e.g. 1600 ug becl. Eq. & higher.
  21. 21. Hartelijk dank voor uw aandacht • Frank de Vries • Universiteit Utrecht • f.devries@uu.nl
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