COPD: Bone Density (2008)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
The purpose of the study was to examine the long-term effects of inhaled corticosteroids on bone metabolism, via serum osteocalcin and bone mineral density measurements, in subjects with COPD.
Inclusion Criteria:
Participants in the Lung Health Study II.
Exclusion Criteria:
  • Recent oral or systemic glucocorticoid use
  • Inhaled glucocorticoid use in past six months from baseline
  • Known osteoporosis
  • Known disorders of calcium metabolism
  • Other unspecified conditions that would interfere with study
Description of Study Protocol:

Recruitment 

Participants from the Lung Health Study II cohort

Design

Longitudinal randomized control trial with intervention versus placebo

Blinding used (if applicable)

Blinding was used for osteocalcin measurements

Intervention (if applicable)

Inhaled triamcinolone acetonide (Azmacort) 6 puffs daily, 1200 micrograms/day or placebo

Statistical Analysis

Bivariate analysis for categorical and continuous variables included chi-square and unpaired t-tests, respectively.  Multivariate linear regression using SAS PROC GLM procedure was used for controlled comparisons. Change scores for bone mineral density between baseline and year 1 and year 3 and between year 1 and year 3 were also compared.

Data Collection Summary:

Timing of Measurements

  • Bone mineral density - baseline and 1 and 3 years of treatment
  • Osteocalcin - baseline, 3, 12, and 36 months of treatment

Dependent Variables

  • Bone mineral density (BMD) of the hip and spine measured by dual energy X-ray absorptiometry
  • Serum osteocalcin was measured with radioimmunoassay

Independent Variables

  • Inhaled triamcinolone acetonide (Azmacort) 6 puffs daily, 1200 micrograms/day or placebo
  • Adherence was measured by weighing inhaler canisters at 3 month visits. Adherence was good for 46.6%, satisfactory for 21.2%, less than satisfactory for 13.2%, poor for 8.3%, and very poor for 10.7% corresponding to at least 9, 6-8.99, 3-5.99, 1-2.99, and less than 1 puffs/day average over 3 year, respectively.

Control Variables

  • Sex
  • Age
  • Cigarettes
  • Calcium supplement use
  • Vitamin D supplement use
  • Multivitamin use

 

Description of Actual Data Sample:

Initial N: 412 participants from Lung Health Study II cohort of 1116 with:

Males:  N=107 ICS, N=109 Placebo

Females: N=94 ICS, N=102 Placebo

Attrition (final N):

Age: 40-69 years old, median age 56 years, ICS group slightly younger than placebo group

Ethnicity:  2-4.6% non-white across groups

Other relevant demographics: 83.5-90.4% current smokers across groups

Anthropometrics: ICS group had higher FEV1 pre and post treatment and fewer reported taking calcium supplements than placebo group.

Location: 7 centers in North America

 

Summary of Results:
  • Serum osteocalcin levels were not significantly different at baseline and dropped in both groups over the course of treatment.
  • The inhaled corticosteroid group had significantly lower osteocalcin levels at 3 months (p=0.002) and at Year 1 (p=0.031), but the difference between groups had disappeared by Year 3 (p=0.675).
  • There were no significant differences in Baseline the inhaled corticosteroid versus placebo groups in femoral neck or lumbar spine BMD considering all subjects, men, and women.
  • There were no significant differences in Baseline to Year 1 % changes between inhaled corticosteroid and placebo groups in femoral neck or lumbar spine BMD considering all subjects, men, and women.
  • There were significant differences in Baseline to Year 3 and Year 1 to Year 3  % changes between inhaled corticosteroid and placebo groups in femoral neck or lumbar spine BMD considering all subjects, men, and women.

Variable

Inhaled Corticosteroids

Placebo

Significance level

% Change Baseline to Year 3
(Year 1 to Year 3)
Femoral Neck
All subjects
-2.00±4.67
(-1.66±4.40)
-0.22±4.36
(0.10±4.01)
p<0.001
(p<0.001)
% Change Baseline to Year 3
(Year 1 to Year 3)
Femoral Neck
Men

-2.22±4.08
(-1.74±4.26)

0.003±4.37
(0.05±3.84)

p<0.001
(p=0.005)
% Change Baseline to Year 3
(Year 1 to Year 3)
Femoral Neck
Women

-1.73±5.31
(-1.57±4.59)

-0.45±4.36
(0.26±4.19)


p=0.087
(p=0.008)

  % Change Baseline to Year 3
(Year 1 to Year 3)
Lumbar Spine
All subjects
 -0.35±4.19
(-0.30±3.49)
0.98±4.67
(1.52±4.15) 
p<0.007
(p<0.001)
% Change Baseline to Year 3
(Year 1 to Year 3)
Lumbar Spine
Men
 0.23±4.12
(0.13±3.47)
 1.43±4.81
(1.77±4.05)
p=0.082
(p=0.005)
 % Change Baseline to Year 3
(Year 1 to Year 3)
Lumbar Spine
Women
 -1.04±4.19
(-0.81±3.48)
 0.52±4.50
(1.26±4.26)
 p=0.027
(p=0.001)

Other Findings

There were no significant differences in clinical indicators of osteoporosis including loss in height, fractures of spine, hip, or any bone and diagnosis of osteoporosis between the inhaled corticosteroid and placebo groups.

Age of greater than 56 years was a significant predictor of BMD loss at the femoral neck, while sex, baseline femoral BMD, cigarette smoking, and calcium, vitamin D, and multivitamin supplements were not.  

Continued cigarette smoking was a significant predictor of BMD loss at the lumbar spine.

Author Conclusion:
Persons with mild to moderate COPD who have taken moderate to high cumulative dose of inhaled corticosteroids (triamcinolone) over 3 years have accelerated loss of femoral and spinal bone mineral density, although clinical indicators of osteoporosis were not increased compared to placebo over the same period.

Risks of potential for osteoporosis and benefits of improvement of COPD with inhaled corticosteroid therapy should be weighed carefully and other means of monitoring and reducing risk of osteoporosis employed with and without ICS therapy.
Funding Source:
Reviewer Comments:
Slight but significant differences between groups at baseline - these were accounted for in statistical analysis.
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? ???
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  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.) Yes
  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? ???
  4.4. Were reasons for withdrawals similar across groups? ???
  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? ???
  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? Yes
  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? Yes
  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? Yes
  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)? ???
  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? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? ???
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? ???