COPD: Bone Density (2008)

Citation:
 
Study Design:
Class:
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Quality Rating:
Research Purpose:
The purpose of this study was to determine the effects of inhaled glucocorticoid treatments on bone mineral density and related biochemical indices in COPD patients.
Inclusion Criteria:
  • Two types of COPD patients living in the Rotterdam Netherlands area were included in the study, those requiring steroid treatment and those not requiring steroid treatment.
  • All subjects could perform daily activities without assistance.
Exclusion Criteria:
  • Preexisting bone disease
  • Disorders of calcium metabolism
  • Use of bone-affecting drugs including Vitamin D, estrogens, calcitonin, bisphosphonates, or fluoride. 
Description of Study Protocol:

Recruitment 

Between February 1, 1991 and January 31, 1992 39 COPD patients in the Rotterdam, Netherlands area were recruited through unspecified means.

Design

Randomized Controlled Trial.  Patients were randomized to 1 of 3 groups.

Blinding used (if applicable)

Bone density scans were completed by a technician blinded to the treatment condition of the subjects.  Further blinding in other analyses was not mentioned by the authors.

Intervention (if applicable)

  • Group A:  200 micrograms, 4X daily inhaled bethomeclosone for 1 year
  • Group B:  200 micrograms, 4X daily inhaled budesonide for 1 year
  • Group C:  No inhaled glucocorticoids for 1 year

Statistical Analysis

One sample t-test for between group changes, with 95% confidence interval, p<0.05 considered for statistical significance.

Data Collection Summary:

Timing of Measurements

Baseline, 3 months, 6 months, 9 months, 12 months.

Dependent Variables

  • Lumbar Vertebral Bone Mineral Density (L1-L4) measured by Dual Energy X-ray Absorptiometry (DEXA)
  • Hip Bone Mineral Density measured by DEXA
  • Serum Calcium measured by Autoanalyzer
  • Serum Alkaline Phosphatase measured by Autoanalyzer
  • Pro-peptide of Type 1 Collagen measured by Radioimmunoassay (RIA)
  • Cross-linked carboxy terminal telopeptide of Type 1 Collagen measured by RIA
  • Osteocalcin measured by RIA

Independent Variables

  • Group A:  200 micrograms, 4X daily inhaled bethomeclosone for 1 year
  • Group B:  200 micrograms, 4X daily inhaled budesonide for 1 year
  • Group C:  No inhaled glucocorticoids for 1 year

Control Variables

 

Description of Actual Data Sample:

Initial N: 39 subjects total

Attrition (final N): 33 subjects total with group and gender distribution as follows:

  • Group A (bethomeclosone): 8 men, 4 women
  • Group B (budesonide): 6 men, 5 women
  • Group C (no glucocorticoid): 6 men, 4 women

Age:

  • Group A (bethomeclosone): 36-76 years, mean = 46 years
  • Group B (budesonide): 34-79 years, mean = 49 years
  • Group C (no glucocorticoid): 28-81 years, mean = 50 years

Ethnicity: Not specified

Other relevant demographics: There was 1 post-menopausal woman in each of groups A and B and 2 post-menopausal women in group C.

Anthropometrics:  Although the age ranges and means of each group were similar, insufficient detail of age matching with consideration to gender was provided.

Location:  Rotterdam, Netherlands

 

Summary of Results:
  • There were no significant differences in serum calcium concentrations at baseline, 3, 6, 9 or 12 months within or among any of the groups.
  • Osteoblastic markers alkaline phosphatase, osteocalcin, and PICP decreased similarly and significantly in the beclomethosone and budesonide groups and remained unchanged in the control group.
  • Osteoclastic marker ICTP increased significantly only in the beclomethasone group.
  • There were no significant differences in lumbar or hip bone mineral density among the groups and mean bone mineral density decreased similarly over 12 months in all groups.
  • The beclomethosone group, however, did exhibit a statistically significant percent decrease in lumbar and hip bone mineral density.

 

Variable

GROUP A
Bethomeclosone
Mean ± Standard Deviation

GROUP B
Budesonide
Mean ± Standard Deviation

GROUP C
No glucocorticoid
Mean ± Standard Deviation

BMD lumbar (g Ca/cm2)

Before

1.101±0.019

1.096±0.018

1.101±0.019

6 months

1.092±0.020

1.091±0.016

1.092±0.020

12 months

1.089±0.014

1.090±0.018

1.089±0.014

 

 

 

 

BMD total hip(g Ca/cm2)

Before

0.884±0.015

0.875±0.018

0.869±0.020

6 months

0.874±0.018

0.872±0.021

0.873±0.018

12 months

0.869±0.014

0.875±0.018

0.867±0.016

 

 

 

 

% change alkaline phosphatase at 12 months

-15.6

-17.2

+3.2

% change osteocalcin at 12 months

-12.6

-10.4

+0.7

% change PICP

-30.9

-28.7

+2.0

% change ICTP

+13.3

+3.4

+3.6

Other Findings

Beclomethosone and budesonide were both well tolerated with no side effects that resulted discontinuation with the study.

Mobility was reported to be similar in all subjects, but it was not clear how mobility was assessed in order to reach that conclusion.


 

Author Conclusion:
Inhaled glucocorticoids decrease bone formation and increase bone formation as indicated by decreased osteoblastic markers and increased osteoclastic marker, respectively.

Of the inhaled glucocorticoids studied, beclomethasone had a more pronounced effect on indirect and direct measures of bone mineral density reduction compared with budesonide, which the authors attributed to less bioactivity and faster metabolism of the latter.  

Both inhaled glucocorticoids had less (approximately 1-2% reduction depending on measurement site) bone mineral density reduction than that (8%) in previous studies with oral glucocorticoid administration.

Small numbers in and short length of study were recognized as limitations of the study.  Authors recommend larger prospective study with longer follow up.
Funding Source:
Reviewer Comments:

Small sample size and differences between groups not statistically analyzed.

It is not clear to me if the statistics used for this study were appropriate to analyze the repeated measures, as use of one sample t-tests was the only method mentioned.  Also, specific values or statistical significance identification was not provided for % change in bone mineral density data (Figure 1).

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? No
  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? ???
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) ???
  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? 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? No
  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? ???
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? ???
  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? N/A
  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? ???
  7.6. Were other factors accounted for (measured) that could affect outcomes? ???
  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? No
  8.1. Were statistical analyses adequately described and the results reported appropriately? No
  8.2. Were correct statistical tests used and assumptions of test not violated? No
  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)? ???
  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? No
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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes