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 determine whether the bone loss in untreated chronic obstructive pulmonary disease (COPD) was associated with hypercapnia and/or respiratory acidosis.
Inclusion Criteria:
  • Male patients with COPD (diagnosed according to the criteria defined by the World Health Organization)
  • No therapy for at least 3 months before enrollment
  • No therapy (drugs that could affect bone metabolism - calcitonins, bisphosphonates, fluorides, androgens, calcium, thiazides or thyroid hormones) for more than 3 months within the past 3 years.
  • No corticosteroids (oral, inhaled or injection) previously.

 

Exclusion Criteria:
  • Primary or tertiary hyperparathyroidism - patients with secondary hyperparathyroidism (i.e. elevated serum intact parathyroid hormone, normal serum total and ionized calcium, decreased serum phosphorus) were not excluded unless the cause was associated with other clinical conditions than COPD.
  • Patients with elevated serum or urine creatinine
  • Diabetes mellitus

 

Description of Study Protocol:

Recruitment

Patients and controls were recruited from a single pneumology unit during December 1994 to January 1996.

Design:   Case-Control Study 

Patients were evaluated on their pulmonary functions, physical activity index, bone mineral density, blood gas analysis. These results were compared to values from the healthy age- and weight-matched controls. The patients were then subgrouped into hypercapnic and eucapnic categories to evaluate the effect of hypercapnia on bone mineral density. The hypercapnic patients were also subgrouped  into compensated and uncompensated respiratory acidosis to assess if uncompensated respiratory acidosis had an effect on bone metabolism.

Blinding used (if applicable):  Not applicable.

Intervention (if applicable):  Not applicable. 

Statistical Analysis

  • Statistical significance of the difference between groups was determined with analysis of variance (ANOVA) followed by Tukey post hoc analysis.
  • Multiple correlation analysis was perfomed with the Pearson correlation matrix test.
  • Multiple linear regression analyses were performed to determine the partial correlation coefficient of multiple factors to assess relative contribution of each factor on a given parameter.
  • The difference was statistically significant when p <0.05.
Data Collection Summary:

Timing of Measurements:  one time measurements 

Dependent Variables

  • Pulmonary functions (pulmonary function testing)
  • Physical activity (Physical activity index)
  • Bone Mineral Density (BMD analysis at the distal forearm of the non-dominant arm using peripheral quantitative computerized tomography
  • Blood gas analysis (ph, blood gases, serum calcium and magnesium from arterial blood gas analysis)
  • Serum markers of bone metabolism and inflammation [osteocalcin, carboxy-terminal cross-linked telopeptide of type I collagen (ICTP), interleukin-1, etc]

Independent Variables

  • COPD or healthy controls 

Control Variables

  • Age and weight were matched between the patients and controls

 

Description of Actual Data Sample:

Initial N: 71 patients, 40 controls, all male

Attrition (final N): as above, with 36 in subgroup with eucapnia, 35 in hypercapnia (20 in hypercapnia with compensated acidosis, 15 in hypercapnia without compensated acidosis)

Age: patients mean is 64.5± 0.9 years , controls mean 64.9 ± 1.5 years

Ethnicity:  Not stated

Other relevant demographics:

Anthropometrics:

There were no significant differences between the patients and controls with regards to age, BMI, weight, and physical activity index.  Controls were taller (175.4 +  1.3 cm) than the patients (171.9 +. 0.8 cm), p <0.05.

Location:

University of Graz Medical School, Graz, Austria.

Summary of Results:

 Comparison between controls and patients with untreated COPD

Parameters

Control Group

Mean ± SEM

Patients with COPD

Mean ± SEM

P value

FEV1%VC

79.5 ± 0.7

55.6  ±1.9 <0.001

Total BMD (g/cm3)

 327.0 ± 7.5

 249.4 ± 7.8

<0.001

   T score

 - 0.058 ± 0.157

 - 1.628  ± 0.168

<0.001

Trabecular BMD (g/cm3) 210.4  ±7.5 141.4 ± 5.8 <0.001
   T score - 0.225 ±  0.238 - 2.297  ± 0.182 <0.001
Cortical BMD (g/cm3) 418.7 ±  11.9 335.5 ± 10.0 <0.001
 Calcitonin (ng/liter)  18.9 ± 1.3  34.1 ± 2.1 <0.001
 Osteocalcin (mcg/liter)  9.5 ± 0.5  7.4 ± 0.5 <0.001

 

Comparison between patients with eucapnia and hypercapnia
Parameter (mean  SEM) Patients with eucapnia Patients with hypercapnia P value
BMI 26.5 ± 0.6 25.0  ±0.6 NS
Blood p02 (mm Hg)

68.2 ± 2.0 

62.3 ± 1.9 <0.001
Calcium - ionized (mmol/l) 1.212 ± 0.008 1.177 ± 0.010 <0.05
Mg - total (mmol/l) 0.805 ± 0.018 0.804  ±0.020 <0.05
Calcitonin (ng/liter) 38.7 ± 3.1 29.3 ± 2.6 <0.05
Osteocalcin (mcg/l) 7.8 ± 0.7 7.0 ± 0.6 <0.01*
ICTP (mcg/l) 4.26 ±  0.25 6.10 ±  0.34 <0.001

* compared with age- and weight-matched controls

Other Findings

Patients with the lowest BMD T scores (both total BMD and trabecular BMD) were in the hypercapnic group (p <0.001).

Other than arterial pH none of the other test parameters was significantly different between the two hypercapnic subgroups.

 

 

Author Conclusion:

This study presents the first associative evidence that the bone loss in COPD is at least in part attributed to an increased bone resorption that is associated primarily with hypercapnia rather than an uncompensated respiratory acidosis.  In conclusion, this study shows for the first time that chronic hypercapnia could be a significant risk factor for osteoporosis.

Funding Source:
Reviewer Comments:

Results of the study may not be extrapolated to women.  Authors note that they did not assess certain confounding variables, such as calcium intake and sex steroids/gonadal function.  Authors also note that the lack of difference between subgroups could be caused by the lack of sufficient statistical power due to the relatively small number of patients in the 2 groups.

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) N/A
  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) N/A
 
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? ???
  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) N/A
  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.) N/A
  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.) Yes
  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? N/A
  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? 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? N/A
  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? ???
  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? ???
  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)? 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? ???
  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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes