EAL

COPD: Bone Density (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate the hypotheses that:

inhaled corticosteroids would decrease the rate of decline of pulmonary function
inhaled corticosteroids would reduce symptoms, morbidity, and airway reactivity without systemic adverse effects

Inclusion Criteria:

Persons with COPD aged 40 - 69 years with airflow obstruction
FEV1 was 30 - 90% of predicted value
Ratio of FEV1 to FVC of less than 0.70
All were current smokers or had quit within previous 2 years

Exclusion Criteria:

Medical conditions such as cancer, recent myocardial infarction, alcoholism, heart failure, insulin-dependent diabetes mellitus, and neuropsychiatric disorders
Had used bronchodilators or oral or inhaled corticosteroids in previous year

Description of Study Protocol:

Recruitment

Patients were recruited from those who had previously participated in or been screened for the Lung Health Study, a trial of smoking cessation and use of inhaled bronchodilators in 5887 smokers with airflow obstruction between November 1986 and May 1994. The enrollment period for the current study was from November 1994 to November 1995.

Design: Randomized Placebo-Controlled Trial. Randomization occurred during second baseline visit to 1 of 2 treatment groups with stratification by clinical center and smoking status.

Blinding used (if applicable): not mentioned, assumed for laboratory measures

Intervention (if applicable)

Inhaled triamcinolone acetonide (600 µg twice daily) or placebo for 3 years

Statistical Analysis

Target enrollment of 1100 participants was designed to enable the study to detect a mean difference of 12.5 ml per year between treatment groups. FEV1 analyzed according to intention-to-treat principle. Rates of health care use, respiratory symptoms, dyspnea and wheezing scales and airway reactivity in response to methacholine were compared by Wilcoxon rank-sum test. Comparisons of overall and cause-specific mortality were performed with use of life-table methods and log-rank test.

Data Collection Summary:

Timing of Measurements

Participants returned every 3 months to obtain new inhalers and report respiratory symptoms or potential side effects. Spirometry and medical care interviews conducted every 6 months. Methacholine testing repeated at 9 and 33 months. Bone density measured at baseline and 1 and 3 years of treatment.

Dependent Variables

FEV1 measured with spirometry
Respiratory symptoms assessed with American Thoracic Society Division of Lung Diseases questionnaire
Cause-specific morbidity and mortality through medical records
Use of health care services through medical records
Airway reactivity in response to methacholine
Health-related quality of life assessed with 36-item Medical Outcomes Study Short-Form General Health Survey (SF-36)
Bone density measured using DEXA in subset of 412 participants at lumbar spine and femur

Independent Variables

Inhaled triamcinolone acetonide (600 µg twice daily) or placebo for 3 years
Adherence measured at each 3-month visit by questioning participants and weighing returned canisters
Satisfactory adherence defined as the use of 6 or more puffs per day averaged

Control Variables

Sex
Age
Smoking status
Baseline lung function
Baseline bronchodilator response

Description of Actual Data Sample:

Initial N: 1347 candidates completed initial screening. 1116 persons with COPD were enrolled, 559 in the triamcinolone group and 557 in the placebo group

Attrition (final N): 66 subjects (38 in placebo, 28 in triamcinolone) permanently discontinued the study

Age: mean age 56 years at entry

Ethnicity: not mentioned

Other relevant demographics:

Anthropometrics: Triamcinolone group had slightly better baseline lung function, FVC was significantly different between groups at baseline (P = 0.03).

Location: 10 centers in the United States

Summary of Results:

Bone Mineral Density Measurements

Variables	Triamcinolone Group	Placebo Group	P Value
Lumbar Spine - baseline (g/cm2)	0.988 ± 0.013	0.979 ± 0.013	0.60
Lumbar Spine - 12 months (g/cm2)	0.988 ± 0.013	0.973 ± 0.013	0.43
Lumbar Spine - 36 months (g/cm2)	0.985 ± 0.013	0.988 ± 0.014	0.89
Lumbar Spine (% change)	-0.35 ± 0.33	0.98 ± 0.36	0.007
Femoral Neck - baseline (g/cm2)	0.762 ± 0.010	0.754 ± 0.010	0.54
Femoral Neck - 12 months (g/cm2)	0.760 ± 0.010	0.751 ± 0.010	0.53
Femoral Neck - 36 months (g/cm2)	0.747 ± 0.010	0.752 ± 0.010	0.73
Femoral Neck (% change)	-2.00 ± 0.35	-0.22 ± 0.32	<0.001

Other Findings

Mean duration of follow-up was 40 months.

Rate of satisfactory adherence was 68.9% for placebo group, 69.4% for triamcinolone group.

Rate of decline of FEV1 was similar in both groups (44.2 ± 2.9 in the triamcinolone group and 47.0 ± 3.0 ml per year in the placebo group, P = 0.50).

The triamcinolone group had fewer respiratory symptoms during the course of the study (21.1 per 100 person-years vs 28.2 per 100 person-years, P = 0.005) and had fewer visits to a physician due to respiratory illness (1.2 per 100 person-years vs 2.1 per 100 person-years, P = 0.03).

Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months (P = 0.02 for both).

After 3 years, the bone density of the lumbar spine (P = 0.007) and the femur (P < 0.001) was significantly lower in the triamcinolone group.

Author Conclusion:

In summary, we found that inhaled triamcinolone does not reduce the decline in FEV1 in patients with COPD but is associated with less severe airway reactivity and reduced respiratory symptoms. Triamcinolone use is also associated with loss of bone mineral density and increased skin bruising. In patients with COPD, therefore, the symptomatic benefits of inhaled corticosteroids must be weighed against the potential long term adverse effects. We observed no effect on the long-term progression of the disease.

Funding Source:

Reviewer Comments:

Groups had statistically significant differences at baseline. Bone mineral density only measured in subset. Other factors affecting bone density not measured.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		No
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	No
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	No
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	???
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		???
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		???
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes