CD: Bone Density (2006)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To compare bone mineral density in children and adolescents with asymptomatic celiac disease, who were on a gluten-free diet, with healthy control subjects and to evaluate diet adequacy for calcium, magnesium, phosphorus, and laboratory analysis of calcium metabolism of patients with celiac disease.
Inclusion Criteria:
Celiac disease diagnosed according to ESPGHAN criteria.  Dietary intake interview assured at least 1 year of compliance with diet.  Intestinal mucosa with normal villous architecture with no increase in intraepithelial lymphocytes at the time of the study.
Exclusion Criteria:
None of the healthy subjects had history of chronic illness, intestinal disease, congenital or acquired bone disease, bone fractures, involvement in excessive physical activities (more than 10 hours per week), regular medication with hormones, vitamin preparations, or calcium supplements.
Description of Study Protocol:

Recruitment

Patients selected consecutively as they came to their follow-up visits to assure compliance with gluten free diet.

Design

Cross-Sectional Study.

Blinding used (if applicable)

Not applicable.

Intervention (if applicable)

Gluten free diet.

Statistical Analysis

Sample size was calculated - adoption of the power of the test as 0.80 and alpha as 0.05 resulted in 10 patients per group.  Differences between paired data were calculated using Student's t distribution, and significance was determined by the paired t test.  ANOVA was used to compare bone mineral density in celiac patients and controls.  The statistical significance of differences between the age of starting a gluten-free diet between children and adolescents was calculated using the Mann-Whitney rank sum test.  A multiple regression model was used to analyze the association between height and bone mineral density controlled by age groups and celiac disease.  The proportion of adolescents and children with celiac disease who had started a gluten-free diet after the age of 2 years was calculated using the Fisher test.  The age at time of diagnosis of adolescents and children was compared by using the Mann-Whitney rank sum test.  A significant difference between groups was accepted at P < 0.05.  

Data Collection Summary:

Timing of Measurements

Selected consecutively as they came for follow-up visits.

Dependent Variables

  • Bone mineral density of the lumbar spine through DEXA
  • Serum levels of ionized calcium, total calcium, phosphorus, magnesium, alkaline phosphatase, and parathormone through standard laboratory methods
  • Body weight with standard clinical beam
  • Height measured with fixed stadiometer

Independent Variables

  • Gluten-free diet - food diaries for 9 nonconsecutive days, analyzed for intake of calcium, magnesium, and phosphorus.  Patients trained by dietitian to record consumption.  Long term compliance was monitored by IgA antigliadin antibodies during at least 3 years of follow-up.

Control Variables

 

Description of Actual Data Sample:

Initial N: 30 patients (17 children, 13 adolescents, 17 female, 13 male), 23 healthy subjects (12 children, 11 adolescents)

Attrition (final N):  Same as above

Age:  17 children:  6 - 9 years, 13 adolescents: 13 - 16 years 

Ethnicity:  Not mentioned 

Other relevant demographics:  All had continuously negative antibodies.  None of the patients was receiving vitamin D, calcium supplements, estrogens, steroids, or anticonvulsive drugs, and none reported the occurrence of any bone fracture. 

Anthropometrics  Healthy children controls matched for gender and age, healthy adolescent controls matched for gender, puberty stage, and time since menarche. 

Location:  Sao Paulo, Brazil 

 

Summary of Results:

 

Patients Controls P value
Age - children 7.6 +/- 1.4 7.6 +/- 1.4 0.958
Age - adolescents 14.3 +/- 1.4 14.8 +/- 1.4 0.525
Weight - children 23.1 +/- 6.5 23.9 +/- 5.6 0.750
Weight - adolescents 45.8 +/- 10.5 55.3 +/- 10.5 0.037
Height - children 115.0 +/- 12.0 121.0 +/- 13.0 0.217
Height - adolescents 153.0 +/- 11.0 167.0 +/- 12.0 0.007
Mean BMI Z score - children

0.58 +/- 1.37

0.16 +/- 0.53

0.320

Mean BMI Z score - adolescents

0.07 +/- 0.73

0.23 +/- 0.45

0.546

Other Findings

Mean height and weight of the adolescents with celiac disease were lower than those of control subjects (weight:  45.8 +/- 10.5 kg vs 55.3 +/- 10.5 kg, P = 0.037; height: 153.0 +/- 11.0 cm vs 167 +/- 12.0 cm, P = 0.007).

The mean bone mineral density in adolescents with celiac disease was significantly lower than that of the control subjects (0.917 +/- 0.116 g/cm2 vs 1.060 +/- 0.158 g/cm2, P = 0.015), whereas no significant difference was found between children with celiac disease and control subjects (P = 0.595).

The bone mineral density of adolescent patients and control subjects was higher than that of children with celiac disease and their controls (P < 0.05).

A multiple regression model shows that increases in bone mineral density relative to height were lower in adolescents with celiac disease than in control subjects.

There was a significant difference in the age of starting gluten-free diets between adolescents and children, 3.7 years (2.9 - 6.0 years) vs 1.9 years (1.5 - 2.3 years)(P< 0.001).  The proportion of adolescents who had started a gluten-free diet after 2 years of age was higher than that of children with celiac disease (13/13, 100% vs 5/17, 29%, P < 0.001).  The median duration of gluten-free diet was higher in the adolescents than the children, 10.2 years (7.1 - 11.4 years) vs 4.8 years (4.2 - 6.0 years)(P = 0.014).

The percentages of adolescents and children with dietary inadequacy compared with RDAs were 100.0% and 88.2% for magnesium, 84.6% and 88.2% for calcium, and 76.9% and 82.4% for phosphorus. 

The serum levels of ionized calcium, total calcium and parathormone and mean alkaline phosphatase were normal in all adolescents and children with celiac disease.  Phosphorus serum levels were below normal range in 7 (23.3%) patients and 1 of these 7 had a low serum magnesium level.

Author Conclusion:
In conclusion, the bone mineral density of adolescents with celiac disease was lower than that of control subjects, whereas no difference was found between the bone mineral density of children with celiac disease and that of control subjects.  Our findings emphasize the importance of increasing the dietary intake of calcium, phosphorus and magnesium to prevent deterioriation of bone structure, as well as the necessity for early diagnosis and treatment of celiac disease.  Thus, the screening for osteoporosis by measuring bone mineral density seems to be worthwhile in patients with celiac disease, particularly in malnourished adolescent patients who started treatment after 2 years of age.
Funding Source:
University/Hospital: Unversidade Federal de Sao Paulo (Brazil)
Reviewer Comments:

Dietary compliance monitored.

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? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
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) 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.) 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? 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? 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? Yes
  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? 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? 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