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
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
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
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
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
History
• Early 2000s: long acting beta-2 agonists, leukotriene receptor antagonists: alternatives.
increased attention for potential side effects of ICS, including cataract & osteoporosis.
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 Jan 2007, Euroscop NEJM Jun 1999
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]
UIPSUtrecht Institute for 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
Objective
• Does severity of obstructive airway disease confounds the relationship between inhaled corticosteroids and risk of osteoporotic fracture?
UIPSUtrecht Institute for Pharmaceutical SciencesSource: de Vries et al. Eur Respir J May 2005
Study population
UIPSUtrecht Institute for 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
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)
UIPSUtrecht Institute for Pharmaceutical Sciences
Source: de Vries et al. Eur Respir J May 2005
0
1
2
3
4
5
6
7 Osteoporotic Hip Vertebral
n=108,754 n=14,388 n=8,712
od
ds
rati
o
Inhaled corticosteroid dose
Inhaled corticosteroid use and fracture risk
-------- Diamonds:
crude analysis
Source: de Vries et al. Eur Respir J May 2005
0
1
2
3
4
5
6
7
od
ds
rati
o
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 2005
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
UIPSUtrecht Institute for Pharmaceutical Sciences
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 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 [email protected]
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)
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.
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