CD: Bone Density (2006)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To evaluate the radial bone mineral content and density in children and adolescents who are asymptomatic on a gluten-free diet.
Inclusion Criteria:
Based on clinical symptoms, such as steatorrhea, malabsorption and weight loss, diagnosis of celiac disease based on ESPGAN criteria.  Biopsy of proximal small intestine confirmed subtotal atrophy of villi before treatment in all patients.  Anti-gliadin antibodies were detected in all.  2-3 years after introduction of gluten-free diet, a gluten tolerance test was performed, which led to histological relapse in all patients, clinical relapse in most patients, who became asymptomatic again on restoration of the diet.
Exclusion Criteria:
The patients had no other disease related to bone metabolism and did not take drugs that may have affected bone metabolism.
Description of Study Protocol:

Recruitment

Not specifically mentioned.

Design

Cross-sectional cohort.

Blinding used (if applicable)

Not applicable.

Intervention (if applicable)

Gluten-free diet.

Statistical Analysis

In the statistical analysis, the deviations from zero of bone mineral content and bone mineral density Z-score means were evaluated by one-sample t test.  The percentages of patients with low body weight and height were evaluated by binomial tests.  The correlation coefficients between body weight and height on one hand and bone mineral content on the other were determined in celiac children.  The age-dependency of the radius bone mineral content, bone mineral density and diameter values in both control and celiac groups was demonstrated by cubic polynomial regression curves.  The age-related curves of the healthy and the celiac groups were compared at selected ages, using the unpaired t test method.

Data Collection Summary:

Timing of Measurements

Upon diagnosis and in asymptomatic period, serum calcium, phosphorus, protein, albumin, iron, iron-binding capacity and alkaline phosphatase determinations were performed.  Serum intact parathormone conentrations were also measured in all patients before the diet and in 16 patients who were asymptomatic on the diet for at least 3 years.

Dependent Variables

  • Bone mineral content and density of non-dominant radius midshaft determined by single-photon absorptiometry
  • Serum calcium, phosphorus, albumin, iron, iron-binding capacity and alkaline phosphatase measured through spectrophotometric methods
  • Intact parathormone concentrations measured by immunoluminometric assay

Independent Variables

  • Gluten-free diet

Control Variables

 

Description of Actual Data Sample:

Initial N: 91 children (53 girls, 38 boys), age- and sex-matched healthy Hungarian children.

Attrition (final N):  Same as above

Age:  Mean age 11.7 years, range 2 - 19 years 

Ethnicity:  Not mentioned 

Other relevant demographics:  Mean duration of celiac disease was 8.7 years.  None of the subjects under 10 showed signs of maturation.  All girls over 11 and boys over 12 showed signs of puberty.  In adolescent girls (12 - 19 years), menarche occurred at mean age of 13.8 +/- 1.4 years.  All girls and boys over 18 had completed sexual development. 

Anthropometrics:  Boys and girls compared.  There was no significant difference between the 2 sexes regarding age and duration of disease, diet and the untreated period.

Location:  Budapest, Hungary 

 

Summary of Results:

 

Boys (n=38) Girls (n=53) All (n=91)
Mean age 10.9 (2-19) 12.1 (2-19) 11.7 (2-19)
Duration of disease 7.9 +/- 5.6 9.1 +/- 5.5 8.7 +/- 5.6
Age at diagnosis 3.6 +/- 2.9 3.5 +/- 3.2 3.6 +/- 3.0
Duration of diet 6.4 +/- 4.9 7.9 +/- 5.4 7.3 +/- 5.2
Duration without treatment 1.4 +/- 1.8 1.1 +/- 1.7 1.3 +/- 1.8
Body height percentile 35.4 (3-95) 37.0 (5-95) 36.3 (3-95)
Body weight percentile 39.5 (5-95) 35.6 (5-95) 36.2 (5-95)
BMC Z-score

-0.17 +/- 1.49

-0.36 +/- 1.66

-0.27 +/-  1.58

BMD Z-score

+0.53 +/- 1.39

+1.36 +/- 1.64

+1.01 +/- 1.58

Other Findings

The mean bone mineral content Z-score value in the female adolescent group only was significantly lower than normal (mean Z-score -1.04, P < 0.01).  In contrast, the mean bone mineral density Z-score was significantly higher compared to a healthy population in both girls (mean Z-score +1.36, P < 0.001) and boys (mean Z-score +1.01, P < 0.001). 

The median body weights and heights of celiac children and adolescents were less than the population median.  Incidence rates significantly higher than 50% were found concerning low body weight in girls (36/53, 67.9%, P < 0.02) and the whole groups of patients (60/91, 66.5%, P < 0.01) and concerning lower than average body height in the whole patient group (57/91, 63%, P < 0.05).

The radial diameter was significantly smaller than normal in both pre-pubertal and adolescent groups. 

Serum calcium, phosphorus, alkaline phosphatase, albumin and iron values in asymptomatic patients on a gluten-free diet were in the normal range.  The parathormone mean value was significantly lower after at least 3 years of gluten-free diet than at diagnosis (mean +/- SD 3.77 +/- 1.07 vs 7.89 +/- 2.54 pmol/l, P < 0.01), but significantly higher compared to controls (2.89 +/- 0.90 pmol/l, P < 0.05).

Author Conclusion:
Our data show that in children and adolescents with celiac disease rendered asymptomatic on a gluten-free diet, bone mineral content in the radius mid-shaft was abnormally low.  They may have normal or even higher radius mineral density values than controls, but the bone size remains reduced.  Our data suggest that, in celiac children treated with a gluten-free diet, bone development disorders are expressed more in girls than in boys.  In summary, it has been established that bone development is disturbed even in patients with celiac disease  recognized early in childhood and rendered free of symptoms by dietary management.  Although there is no direct evidence of calcium malabsorption in this cohort of celiac patients, the slightly higher parathormone levels, together with some other factors, particularly delayed puberty, may result in reduced bone size.
Funding Source:
Government: NSF
Reviewer Comments:

Long duration of diet.  Compliance monitored carefully.  Controls not well described - unclear if they were measured at same time with same methodology.

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? ???
  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) Yes
  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.) ???
  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? ???
  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? N/A
5. Was blinding used to prevent introduction of bias? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  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.) N/A
  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? Yes
  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? 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? ???
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? 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