COPD: Bone Density (2008)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
The purpose of this study was to evaluate the relationship between disease severity of obstructive airway disease (OAD) and the risk of fracture.
Inclusion Criteria:
Patients age > 18 with a first record of an osteoporotic fracture (defined as a fracture of the radius/ulna, femur/hip, ribs, humerus, vertebrae or clavicle) from January 1987 to July 1999 in the General Practice Research Database (which comprises the entire computerized medical records of a sample of general practitioners in the United Kingdom.)
Exclusion Criteria:
See above.
Description of Study Protocol:

Recruitment

Patients from January 1987 to July 1999 in the General Practice Research Database (which comprises the entire computerized medical records of a sample of general practitioners in the United Kingdom.)  

Design

The date of the first fracture was defined as the index date. For each case, one control patient without a history of a fracture was matched to a case by age, sex, medical practice and calendar time. A history of OAD before the index date was examined in both cases and controls.

Blinding used (if applicable): None

Intervention (if applicable)

Use of medication for the treatment of OAD was examined, using bronchodilators and inhaled corticosteroids. Current users were patients who had received at least one prescription in the 6 months before the index date. Past users had received their last prescription > 6 months prior to the index date.

Indicators of more severe OAD included records of OAD exacerbations and oxygen use in the 12 months before the index date, respiratory problems (bacterial respiratory tract infections, coughing, presence of sputum, hemoptysis, dyspnea, tachypnea, shortness of breath, acute bronchitis or wheezing), use of oral corticosteroids in the 6 months before the index date and a body mass index (BMI) <20.

Statistical Analysis

Odds ratio (ORs) of fracture were estimated using conditional logistic regression. Final regression models were determined by backward elimination using a significance level of 0.05. The ORs of these models were compared with the ORs of the models including all variables to identify confounding by an eliminated variable, with inclusion of this variable in cases of confounding.

Data Collection Summary:

Timing of Measurements

Median time of enrollment before the index date was 2.2 years.

Dependent Variables

  • Rate/location of osteoporotic fracture

Independent Variables

  • Use of inhaled corticosteroids
  • Use of bronchodialators
  • Number of OAD exacerbations
  • Oxygen use in the previous 12 months
  • Respiratory problems
  • Body mass index < 20

Control Variables

General risk factors of fracture:

  • History of diabetes mellitus, rheumatoid arthritis, hyperthyroidism, congestive heart failure, seizures, anemia, dementia, depression, psychotic diorder and cerebrovascular accident
  • Prescriptions in the 6 months  (anticonvulsants, nonsteroidal antiinflammatory drugs, methotrexate, hormone-replacement therapy, thiazide diuretics, anxiolytics/hypnotics, antispsychotics, antidepressants and anti-Parkinson's drugs) prior to the index date were also considered confounding variables
Description of Actual Data Sample:

Initial N: 108,754 cases (44,201 radius/ulna, 22,250 femur/hip, 16,189 rib, 14,646 humerus, 8,712 vertebral and3,908 clavicular fractures). Controls were 108,754

Attrition (final N): As above

Age: Subjects Age mean 62.3 years; Controls age mean 62.3 years

Ethnicity: Not stated

Other relevant demographics: Not stated

Anthropometrics:  41% of the cases and 44.5% of the controls had no BMI available

Location: The United Kingdom

 

Summary of Results:

                                                  

Inhaled corticosteroids

       Bronchodilators    
  Cases Controls Crude OR (95% CI) Adjusted OR (95% CI) Cases Controls Crude OR (95%) CI Adjusted OR (95% CI)  
Referent     1.00 1.00   1.00 1.00 1.00  
Osteoporotic 108754 108754              
 1–400 µg 1747 1211    1.41 (1.31–1.53) 1.04 (0.95–1.14) 1650 1183 1.37 (1.27–1.48) 1.20 (1.09–1.31)  
 401–800 µg 1571 1050    1.49 (1.37–1.62) 1.03 (0.93–1.14) 1606 976 1.70 (1.57–1.85) 1.45 (1.32–1.60)  
 801–1600 µg 1367 788     1.77 (1.61–1.93) 1.15 (1.03–1.29) 1642 1091 1.57 (1.45–1.70) 1.28 (1.16–1.41)  
 >1600 µg 512 281     1.95 (1.68–2.27) 1.19 (1.01–1.41) 1375 817 1.81 (1.66–1.98) 1.35 (1.21–1.51)  
 Hip 14388 14388              
  1–400 µg 188 139     1.36 (1.08–1.71) 1.01 (0.76–1.34) 203 157 1.29 (1.04–1.61) 1.20 (0.94–1.55)  
  401–800 µg 212 164     1.29 (1.04–1.59) 0.97 (0.74–1.28) 257 153 1.75 (1.42–2.16) 1.58 (1.22–2.04)  
  801–1600 µg 190 120    1.55 (1.22–1.97) 1.09 (0.81–1.48) 247 211 1.27 (1.05–1.53) 1.17 (0.91–1.50)  
  >1600 µg 73 45    1.78 (1.21–2.62) 1.18 (0.75–1.85) 214 133 1.72 (1.37–2.16) 1.37 (1.01–1.86)  
 Vertebral 8712 8712              
  1–400 µg 205 84     2.61 (2.00–3.39) 1.60 (1.14–2.24) 168 101 1.80 (1.39–2.32) 1.03 (0.75–1.43)  
  401–800 µg 209 85     2.71 (2.07–3.55) 1.33 (0.93–1.90) 199 84 2.72 (2.08–3.57) 1.32 (0.94–1.86)  
  801–1600 µg 209 87    2.88 (2.21–3.77) 1.21 (0.83–1.75) 228 88 3.00 (2.32–3.89) 1.43 (1.01–2.03)  
  >1600 µg 101 20     6.11 (3.73–10.01) 1.85 (1.01–3.38) 269 79 4.15 (3.19–5.41) 1.62 (1.11–2.36)  

Author Conclusion:

In conclusion, patients using higher doses of inhaled corticosteroids have an increased risk of osteoporotic fracture. However, patients using bronchodilators and those with more severe obstructive airway disease also have an increased risk of fracture, and the dose-response relationship between inhaled corticosteroids and fracture risk almost disappears after adjustment for disease severity. Consequently, adequate adjustment for disease severity is essential when the association between use of inhaled corticosteroids and the risk of fracture is studied in observational research.

Funding Source:
Reviewer Comments:
Did not have BMI on 40% of both groups - researchers did not run statistical analyses on the cases and controls at the beginning of the study to see if there were signficant differnces which might have accounted for the fractures.  Authors note several limitations - data on physical activity, smoking and loss of fat free mass was not available.
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? ???
  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) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? ???
  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.) ???
  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? Yes
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? Yes
  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? N/A
  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? No
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? ???
  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? 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? ???
  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? Yes
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? No