COPD: Bone Density (2008)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To compare the effects of the inhaled corticosteroid budesonide and placebo in patients with COPD who continued to smoke through the study on bone mineral density and vertebral fracture rates.
Inclusion Criteria:
  • Mild COPD  
Exclusion Criteria:
  • History of asthma, allergic rhinitis or allergic eczema
  • Those who had received oral corticosteroids for >4 weeks during the preceding 6 months
Description of Study Protocol:

Recruitment

Methods not described, 9 centers involved.

Design:  Randomized Controlled Trial

Blinding used (if applicable):  Double blind

Intervention (if applicable)

Randomized to receive budesonide (400 ug) or placebo twice daily via Turbuhaler for 3 years.

Statistical Analysis

Changes in bone mineral density analyzed by ANOVA, with treatment, center and sex as factors in the model.  Age at the start of the study and baseline BMD were covariates.  Proportion of patients in each group with new vertebral fractures on spinal radiography was compared by Fisher's exact test.  Homogeneity of the corresponding odds ratios for males and females was evaluated by means of the Breslow-Day test.  Serum osteocalcin data were expressed as the area under the concentration-time curve. 

Data Collection Summary:

Timing of Measurements

Venous blood samples collected and DEXA measurements made at baseline and after 6, 12, 24 and 36 months.  Radiographs obtained at baseline and at end of treatment. 

Dependent Variables

  • Bone mineral density measured at the L2-L4 vertebrae and the femoral neck, trochanter and Ward's triangle by DEXA, completed in 161 patients 
  • Radiographs of the thoracic and lumbar spine, completed in 653 patients, one center changed radiographical equipment during the study and 16 patients had to be excluded
  • Venous blood samples analyzed for serum osteocalcin 

Independent Variables

  • Randomized to receive budesonide (400 ug) or placebo twice daily via Turbuhaler for 3 years.

Control Variables

  • Treatment
  • Center
  • Sex
  • Age at the start of the study
  • Baseline BMD
Description of Actual Data Sample:

Initial N: original enrollment unclear

Attrition (final N):  912 completed 3 years of treatment, not all measurements made in all subjects

Age: mean age 52 years

Ethnicity: not mentioned

Other relevant demographics: Mean FEV1 77% of predicted

Anthropometrics:  Both radiography and DEXA populations were comparable with overall study population in terms of demographics

Location: 39 centers in 9 European countries:  Belgium, Denmark, Norway, Finland, Italy, the Netherlands, Sweden, Spain and the United Kingdom

 

Summary of Results:

Bone Mineral Density at Baseline and at End of Study

Variables

Budesonide -Baseline (n=82)

Budesonide- 3 years (n=78)

Placebo - Baseline (n=79)

Placebo - 3 Years (n=71)

Femoral Neck (g/cm2)

0.89 +/- 0.15 (0.59 - 1.26) 0.88 +/- 0.15 (0.57 - 1.27) 0.85 +/- 0.16 (0.57 - 1.33) 0.85 +/- 0.15 (0.54 - 1.29)

Femoral Trochanter (g/cm2)

0.79 +/- 0.16 (0.38 - 1.21)

0.78 +/- 0.16 (0.33 - 1.19)

0.77 +/- 0.17 (0.45 - 1.22)

0.77 +/- 0.17 (0.48 - 1.22)

Femoral Ward's Triangle (g/cm2)

0.69 +/- 0.19 (0.35 - 1.14)

0.68 +/- 0.18 (0.30 - 1.12)

0.66 +/- 0.20 (0.31 - 1.27)

0.66 +/- 0.18 (0.34 - 1.20)
L2-L4 (g/cm2) 1.09 +/- 0.17 (0.58 - 1.59) 1.09 +/- 0.19 (0.56 - 1.68) 1.06 +/- 0.19 (0.67 - 1.60) 1.06 +/- 0.19 (0.70 - 1.61)

Other Findings

Previous fractures were present at baseline in 43 budesonide-treated patients (13.4%) and 38 placebo-treated patients (11.5%).

New fractures occurred in 5 budesonide-treated patients compared with 3 in the placebo group (p = 0.50).

There were no significant changes in BMD at any site in the budesonide-treated patients, compared with the placebo group, during the course of the study.

Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin. 

Author Conclusion:
In conclusion, the results of the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease show that a long-term treatment with inhaled budesonide at a dose of 800 ug/day has no significant effect on bone mineral density or fracture rate in patients with chronic obstructive pulmonary disease.
Funding Source:
Reviewer Comments:
Original enrollment unclear.  Not all measurements made in all patients.  Compliance to inhaled corticosteroids not addressed.
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? ???
  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? ???
3. Were study groups comparable? Yes
  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? Yes
  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? ???
  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? Yes
  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? ???
  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? ???
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  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? 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)? N/A
  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? 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