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. 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. 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. 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. 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. History
• Early 2000s: long acting beta-2 agonists,
leukotriene receptor antagonists:
alternatives.
 increased attention for potential side
effects of ICS, including cataract &
osteoporosis.

7. Evidence from RCTs: BMD
Source: Richy F et al Osteop. Int. May 2003

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. 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. 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. 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. 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. 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. 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. 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. Source: de Vries et al. Pharmacol
Drug Saf 2007 2007;16:612-9.

17. Source: de Vries et al. Pharmacol
Drug Saf 2007 2007;16:612-9.

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. 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. 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. Hartelijk dank voor uw aandacht
• Frank de Vries
• Universiteit Utrecht
• f.devries@uu.nl