EAL

CD: Bone Density (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To monitor changes in bone metabolism rates in children with celiac disease during consumption of a gluten-free diet.

Inclusion Criteria:

Patients diagnosed with celiac disease according to the recommendations of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition.
All patients were identified by clinical symptoms or screening programs.
All showed positive results on antiendomysium antibody tests and mucosal alterations were consistent with Marsh type II or III lesions in small bowel biopsy samples.
Clinical improvement after initiation of dietary treatment.

Exclusion Criteria:

History of chronic illness
One or more fractures
Regular use of any medication, hormones, vitamin preparations or calcium supplements.

Description of Study Protocol:

Recruitment

Patients and controls recruited from the same geographic area.

Design

Non-randomized clinical trial.

Blinding Used

No blinding used.

Intervention

12 months of gluten-free diet.
Supplemental iron and folate provided when indicated.
Calcium and vitamin D supplements were not given or recommended.

Statistical Analysis

Descriptive statistics calculated for all variables, data expressed as means ±SEM.
Distribution of the variables were checked by using Shapiro-Wilk W test.
Variables not normally distributed were log-transformed for statistical analyses.
ANOVA for repeated measures used to analyze changes in biochemical variables occurring during the follow-up period.
Tukey-Kramer post hoc tests performed to compare each time point.
Multiple regression analyses performed to evaluate differences between patients and controls after control for confounding variables.
Simple correlation analyses performed to assess relationship between variables.
A one-group T-test was also used to compare the changes that occurred during treatment in bone mineral measurements with those expected.

Data Collection Summary:

Timing of Measurements

Bone-specific alkaline phosphatase and N-terminal telopeptide of type I collagen measured at diagnosis and after two, six and 12 months of gluten-free diet.
Bone mineral content measured at diagnosis and after 12 months.
Physical exam at the beginning of study.
Control subjects measured once.

Dependent Variables

Body weight measured on balance-beam scale
Height measured with wall-mounted stadiometer
Intact parathyroid hormone concentrations measured by immunoradiometric assay
Bone-specific alkaline phosphatase measured in serum as a bone formation marker with a commercial immunoassay
Urinary concentrations of N-terminal telopeptide of type I collagen as a bone resorption index measured through enzyme-immunosorbent assay
Urinary creatinine measured by colorimetric method
Serum concentrations of calcium, phosphorus, magnesium and albumin determined with standard methods
Bone mineral content measured at the L2-L4 vertebrae level and in the whole skeleton with a dual-energy X-ray absorptiometer.

Independent Variables

Gluten-free diet not defined or monitored.

Description of Actual Data Sample:

Initial N: 26 children agreed to participate; 428 healthy white controls.
Attrition (final N): 22 children completed the one-year follow up, 11 males, 11 females.
Age: Aged 10.5±1.0 years at time of diagnosis; controls aged 11.3±0.2 years.
Ethnicity: White
Location: Italy.

Summary of Results:

	Diagnosis	Two months	Six months	One year	Controls or Reference Range
Spine BMC	18.9±2.3			23.2±2.6	29.6±1.3
Total-body BMC	1179.5±107.2			1421.6±114.9	1727.0±64.1
Serum Calcium	2.54±0.14			2.46±0.02	2.20-2.70
Serum Total Protein	62.7±1.6			63.9±0.9	60-80
Serum Phosphorus	1.97±0.24			1.68±0.05	0.95-1.75
Serum Magnesium	0.84±0.04			0.80±0.02	0.7-1.0
Urinary Creatinine	108.1±13.8			72.4±9.0	60-180
Urinary Calcium	1.51±0.23			2.70±0.5	2.1-2.8
Serum iPTH	30.8±4.3	34.0±3.7	27.5±2.7	25.9±2.4	16.0-59.0

Other Findings

At diagnosis, the bone mineral content of patients was significantly lower than that of control subjects (P=0.032 for spine, P=0.03 for total body) but not after one year of the gluten-free diet.
Concentrations of serum calcium, phosphorus, magnesium, albumin and intact parathyroid hormone showed no significant differences compared with baseline.
Serum bone-specific alkaline phosphatase concentrations of patients were significantly lower than those of control subjects at the time of diagnosis (P=0.0064) and increased gradually and significantly during the gluten-free diet (ANOVA F=4.71, P=0.024).
Patients with untreated disease had significantly higher urinary concentrations of N-terminal telopeptide of type I collagen than did healthy control subjects at all time points (P<0.0001). Urinary concentrations of N-terminal telopeptide of type I collagen were not significantly affected by treatment (P=0.37).

Author Conclusion:

In summary, the bone metabolism rate, as measured by specific biochemical markers, is altered in untreated children with celiac disease. The alterations (low bone formation and enhanced bone resorption) may be the cause of the osteopathy observed in children with celiac disease. Remarkable changes occur after the initiation of a gluten-free diet, which result in a more balanced equilibrium, despite a partial normalization of biochemical bone metabolism markers.

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Gluten-free diet not defined and compliance not monitored.
Data values of certain variables of interest not reported.

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)	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.)	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?		???
	4.1.	Were follow-up methods described and the same for all groups?	???
	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%.)	No
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	???
	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?		???
	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?	No
	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?	N/A
	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?	???
	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