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 f.devries@uu.nl

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.

Hartelijk dank voor uw aandacht

• Frank de Vries

• Universiteit Utrecht

• f.devries@uu.nl