The Risk of Nonvertebral Fracture Related to Inhaled Corticosteroid Exposure Among Adults With Chronic Respiratory Disease

doi:10.1378/chest.127.1.89

Chest

Volume 127, Issue 1, January 2005, Pages 89-97

https://doi.org/10.1378/chest.127.1.89 Get rights and content

Objective

To examine nonvertebral fracture risk in relation to inhaled corticosteroid (ICS) exposure among adults with respiratory disease.

Design and patients

Nested case-control study within a cohort of 89,877 UnitedHealthcare members aged ≥ 40 years with physician insurance claims for COPD or asthma, enrolled for ≥ 1 year from January 1, 1997 to June 30, 2001.

Methods

Cases (n = 1,722) represented patients with a first treated nonvertebral fracture (the index date is the first fracture claim). Control subjects (n = 17,220) were randomly selected from the person-time and assigned a random index date. ICS exposure was ascertained 1 month, 3 months, 6 months, and 12 months before the index date, with estimated cumulative dose through 0 to 6 months, 7 to 12 months, and 0 to 12 months. Covariates included demographics, oral corticosteroid and other medication exposure, comorbidities, and indicators of respiratory disease severity. Odds ratios (ORs) adjusted for all covariates were estimated by logistic regression.

Results

No increased fracture risk with ICS exposure as a class or with fluticasone propionate alone was detected. ORs for exposure in the preceding 30 days were 1.05 (95% confidence interval [CI], 0.89 to 1.24), 1.13 (95% CI, 0.90 to 1.40), and 0.97 (95% CI, 0.78 to 1.21) for all ICS, fluticasone propionate, and other ICS, respectively. No dose-response effect was present. Among patients with COPD only (n = 6,932), no increased risk was found for recent ICS exposure (OR, 0.86; 95% CI, 0.59 to 1.25).

Conclusions

Concern about nonvertebral fracture risk should not strongly influence the decision to use recommended doses of ICS for adult patients with asthma or COPD in managed-care settings in the United States. This study could not evaluate very-high ICS dose, long-term ICS exposure, or vertebral fracture risk.

Section snippets

Source Population

Ingenix Epidemiology (Auburndale, MA) maintains a research database of UnitedHealthcare members who have both medical and prescription benefit coverage. For the time of this study, the research database included complete health services utilization information (eg, claims for all dispensations, inpatient and outpatient services, and procedures including the associated diagnoses and costs) on approximately 5 million persons in 17 states in the United States. Health insurance claims data are an

Results

The respiratory cohort totaled of 89,877 people. Approximately 40% of the cohort had insurance claims evidence of COPD, while 56% had asthma, and approximately 4% had both at cohort entry. Just over three fourths of the cohort members were 40 to 59 years old, while 14% were 60 to 64 years old, and 10% were ≥ 65 years old. We identified 1,722 persons with a treated nonvertebral fracture: 609 among 36,190 persons with COPD only, 1,033 among 50,313 persons with asthma only, and 80 among 3,374

Discussion

This study showed elevations in the incidence of nonvertebral fractures in association with the previously reported risk factors of older age, female sex, chronic medical conditions associated with osteoporosis, depression, and anticonvulsant use,⁴⁰⁴¹⁴² but did not find a detrimental effect of ICS. A number of indicators of medical care utilization for respiratory disease were related to increased fracture risk, consistent with prior research showing that chronic respiratory disease is an

References (42)

HurdS et al.
Global initiative for chronic obstructive pulmonary disease
Pulm Pharmacol Ther
(2002)
BaltzanMA et al.
Hip fracture attributable to corticosteroid use [letter]
Lancet
(1999)
KellyHW et al.
Potential adverse effects of the inhaled corticosteroids
J Allergy Clin Immunol
(2003)
LauE et al.
Inhaled or systemic corticosteroids and the risk of hospitalization for hip fracture among elderly women
Am J Med
(2003)
IqbalF et al.
Declining bone mass in men with chronic pulmonary disease
Chest
(1999)
SinDD et al.
The risk of osteoporosis in Caucasian men and women with obstructive airways disease
Am J Med
(2003)
BiskobingDM
COPD and osteoporosis
Chest
(2002)
RayWA et al.
Identification of fractures from computerized Medicare files
J Clin Epidemiol
(1992)
Guidelines for the diagnosis and management of asthma: expert panel report II
(1997)
BonayM et al.
Benefits and risks of inhaled corticosteroids in chronic obstructive pulmonary disease
Drug Safety
(2002)

PauwelsRA et al.

Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking

N Engl J Med

(1999)

Effect of triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease

N Engl J Med

(2000)

BurgePS et al.

Randomised, double blind placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial

BMJ

(2000)

Global initiative for chronic obstructive pulmonary disease: global strategy for the diagnosis

Standards for the diagnosis and management of patients with COPD

van StaaTP et al.

Use of oral corticosteroids and risk of fractures

J Bone Miner Res

(2000)

AdachiJD

Corticosteroid-induced osteoporosis

Int J Fertil Womens Med

(2001)

NaganthanV et al.

Vertebral fracture risk with long-term corticosteroid therapy

Arch Intern Med

(2000)

van StaaTP et al.

Oral corticosteroids and fracture risk: relationship to daily and cumulative doses

Rheumatology

(2000)

ReidR

Glucocorticoid-induced osteoporosis

Baillières Clin Endocrinol Metab

(2000)

BarnesPJ et al.

Efficacy and safety of inhaled corticosteroids: new developments

Am J Respir Crit Care Med

(1998)

Cited by (26)

Corticosteroids and bone health in people with asthma: A systematic review and meta-analysis
2021, Respiratory Medicine
Citation Excerpt :
Tables 2 and 3 summarise the details of the nine studies [25,26,39,40,42,44–47] reporting fracture risk. One was cross-sectional [40], five case-controls [25,26,42,45,47], and three cohort [39,44,46]. There was a predominance of females in all of the studies and the mean age was between 28.2 and 63 yrs.
Understanding the potential deleterious effects of corticosteroids on bone health in people with asthma is important when making treatment decisions. There is a need for clearer evidence to better quantify the risk and effect size.
Databases were systematically searched to identify studies reporting on bone mineral density (BMD) measurement and risk of osteoporosis or fracture, comparing people with asthma exposed to inhaled (ICS) or oral (OCS) corticosteroids, with nonexposed people with asthma and healthy controls. Data were narratively synthesized, and a series of meta-analyses were performed using the random-effects inverse variance method.
This review consists of 28 studies (six randomized control trials and 22 observational). There was no effect of ICS on bone loss both at spine and femoral neck in asthma. People with asthma receiving OCS were at greater risk of osteoporosis than nonexposed people with asthma (pooled HR = 1.76; 95%CI: 1.48 to 2.09; $I^{2} = 68 %$ ). Similarly, higher ICS exposure was associated with higher risk of osteoporosis (OR = 1.63; 95%CI: 1.33 to 1.99) and fracture (pooled OR = 1.19; 95%CI: 1.05 to 1.35; $I^{2} = 0 %$ ) when comparing people with asthma receiving ICS and not.
Patients with asthma exposed to OCS or high ICS doses become more susceptible to bone comorbidities. Striking the right balance between efficacy and safety of steroids in asthma is important to improve patients’ quality of life.
Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture
2018, Chest
It is uncertain whether long-term use of inhaled corticosteroids (ICSs), widely used to treat COPD, increases the risk of fracture, particularly in women, in view of the postmenopausal risks. We assessed whether long-term ICS use in patients with COPD increases the risk of hip or upper extremity fractures, and examined sex-related differences.
The Quebec health-care databases were used to form a cohort of patients with COPD over 1990 to 2005, followed until 2007 for the first hip or upper extremity fracture. In a nested case-control analysis, each case of fracture was matched with 20 control subjects on age, sex, and follow-up time. The adjusted rate ratio (RR) of fracture with ICS use, by duration and dose, was estimated using conditional logistic regression, with an interaction term to compare the risk in men and women.
In the cohort of 240,110 subjects, 19,396 sustained a fracture during a mean 5.3 years (rate, 15.2 per 1,000 per year). Any use of ICSs was not associated with an increased rate of fracture (RR, 1.00; 95% CI, 0.97-1.03). The fracture rate was increased with > 4 years of ICS use at daily doses ≥ 1,000 μg in fluticasone equivalents (RR, 1.10; 95% CI, 1.02-1.19). This risk increase did not differ between men and women.
Long-term ICS use at high doses is associated with a modest increase in the risk of hip and upper extremity fractures in patients with COPD. This dose-duration risk increase does not appear to be higher for women.
Prevalence and progression of osteoporosis in patients with COPD: Results from the towards a revolution in COPD health study
2009, Chest
Osteoporosis is common in patients with COPD, but its prevalence and progression are not well characterized. Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids (ICSs) on bone density in this population. Here, we investigated the long-term effects of therapy with fluticasone propionate (FP) alone, salmeterol (SAL) alone, and a SAL/FP combination (SFC) on bone mineral density (BMD) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health (TORCH) study.
A randomized, double-blind, parallel-group, placebo-controlled study conducted at 88 US centers involving 658 patients (a subset of 6,184 international subjects in TORCH). Therapy with placebo, SAL (50 μg), FP (500 μg), or SFC (SAL 50 μg/FP 500 μg) twice daily was administered for 3 years. Baseline and yearly measurements of BMD at the hip and lumbar spine were performed. The incidence of traumatic and nontraumatic bone fractures was recorded.
At baseline, 18% of men and 30% of women had osteoporosis, and 42% of men and 41% of women had osteopenia based on BMD assessments. Forty-three percent of subjects completed all testing. The changes in BMD at the hip and lumbar spine over 3 years were small. No significant differences were observed between treatment arms (adjusted mean percent change from baseline at hip was −3.1% for placebo, −1.7% for SAL, −2.9% for FP, and −3.2% for SFC therapy, respectively; while, the corresponding changes for the lumbar spine were 0, 1.5%, −0.3%, and −0.3% for placebo, respectively, SAL, FP, and SFC therapy). The incidence of fractures was low and was similar for all treatments (5.1% to 6.3%).
Osteoporosis is highly prevalent in patients with COPD, irrespective of gender. In the TORCH study, no significant effect on BMD was detected for ICS therapy compared with placebo.
ClinicalTrials.gov Identifier: NTC00268216
The Association of Inhaled Corticosteroid Use with Serum Glucose Concentration in a Large Cohort
2009, American Journal of Medicine
Citation Excerpt :
For example, among subjects with self-reported diabetes, applying our described association to the dose of ICS used in a recent study (500 μg of fluticasone twice daily, equal to 4000 TAC equivalents),25,30 we would estimate that ICS use may potentially contribute to an increase of serum glucose concentration of 72.8 mg/dL (95% CI, 19.5-126.2). Our results are consistent with studies showing an association between ICS use and bone density, fractures, skin changes, myocardial infarctions, and markers of inflammation,8-14,31-33 as well as the relationship between systemic corticosteroids and glucose control.16 Among subjects without diabetes, a previous study demonstrated that ICS use was associated with higher glucose concentrations after an oral glucose test compared with pretreatment values for subjects with COPD, perhaps related to a decrease in insulin sensitivity.34
Inhaled corticosteroids (ICSs) are widely used in the treatment of obstructive lung disease. ICSs have been shown to be systemically absorbed. The association between ICS and serum glucose concentration is unknown.
To explore the association of ICS dosing with serum glucose concentration, we used a prospective cohort study of US veterans enrolled in 7 primary care clinics between December 1996 and May 2001 with 1 or more glucose measurements while at least 80% adherent to ICS dosing. The association between ICS dose from pharmacy records standardized to daily triamcinolone equivalents and serum glucose concentration was examined with generalized estimating equations controlling for confounders, including systemic corticosteroid use.
Of the 1698 subjects who met inclusion criteria, 19% had self-reported diabetes. The mean daily dose of ICS in triamcinolone equivalents was 621 μg (standard deviation 555) and 610 μg (standard deviation 553) for subjects with and without diabetes, respectively. After controlling for systemic corticosteroid use and other potential confounders, no association between ICS and serum glucose was found for subjects without diabetes. However, among subjects with self-reported diabetes, every additional 100 μg of ICS dose was associated with an increased glucose concentration of 1.82 mg/dL (P value .007; 95% confidence interval [CI], 0.49-3.15). Subjects prescribed antiglycemic medications had an increase in serum glucose of 2.65 mg/dL (P value .003; 95% CI, 0.88-4.43) for every additional 100 μg ICS dose.
Among diabetic patients, ICS use is associated with an increased serum glucose concentration in a dose-response manner.
ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE
2008, Pharmacology and Therapeutics: Principles to Practice
Effective management of COPD in primary care - the role of long-acting beta agonist/inhaled corticosteroid combination therapy
2006, Primary Care Respiratory Journal
Chronic obstructive pulmonary disease (COPD) is the internationally preferred term for chronic, progressive lung disorders which are characterised by airflow limitation that is not fully reversible. The symptoms of COPD – including breathlessness, cough, excessive sputum production and reduced muscle tone and muscle wasting – reflect the complex pathophysiology of the disease. In order to address these symptoms, treatment regimens should take into account the multiple components that contribute to COPD. Clinical evidence has emerged indicating that, especially in patients with severe COPD, long-acting beta₂-agonists (LABAs) and inhaled corticosteroids (ICS) result in improvements in symptoms, reduce the frequency and severity of exacerbations, and improve health-related quality of life. This review evaluates the clinical evidence for the potential of LABA/ICS treatment to address the symptoms of COPD and whether combination therapy of this nature adds significant benefit to patients.

View all citing articles on Scopus

The work was performed at Ingenix Epidemiology, supported by a research contract with GlaxoSmithKline.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]).

View full text

Chest

Clinical InvestigationsThe Risk of Nonvertebral Fracture Related to Inhaled Corticosteroid Exposure Among Adults With Chronic Respiratory Disease

Objective

Design and patients

Methods

Results

Conclusions

Section snippets

Source Population

Results

Discussion

Pulm Pharmacol Ther

Lancet

J Allergy Clin Immunol

Am J Med

Chest

Am J Med

Chest

J Clin Epidemiol

Guidelines for the diagnosis and management of asthma: expert panel report II

Benefits and risks of inhaled corticosteroids in chronic obstructive pulmonary disease

Drug Safety

Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking

N Engl J Med

Effect of triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease

N Engl J Med

Randomised, double blind placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial

BMJ

Global initiative for chronic obstructive pulmonary disease: global strategy for the diagnosis

Standards for the diagnosis and management of patients with COPD

Use of oral corticosteroids and risk of fractures

J Bone Miner Res

Corticosteroid-induced osteoporosis

Int J Fertil Womens Med

Vertebral fracture risk with long-term corticosteroid therapy

Arch Intern Med

Oral corticosteroids and fracture risk: relationship to daily and cumulative doses

Rheumatology

Glucocorticoid-induced osteoporosis

Baillières Clin Endocrinol Metab

Efficacy and safety of inhaled corticosteroids: new developments

Am J Respir Crit Care Med

Clinical Investigations
The Risk of Nonvertebral Fracture Related to Inhaled Corticosteroid Exposure Among Adults With Chronic Respiratory Disease