EAL

CD: Bone Density (2006)

Citation:

Mora S, Barera G, Beccio S, Proverbio MC, Weber G, Bianchi C, Chiumello G. Bone density and bone metabolism are normal after long-term gluten-free diet in young celiac patients. Am J Gastroenterol 1999; 94: 398-403.

PubMed ID: 10022636

Study Design:

Non-Randomized Crossover Trial

Class:

C - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

To evaluate the impact of long-term gluten-free diet initiated during childhood and adolescence on bone mineralization and bone metabolism, through the measurement of bone density at the lumbar spine and of the whole skeleton, as well as specific markers of bone turnover.

Inclusion Criteria:

All celiac patients on a long-term gluten-free diet were eligible for the study. Inclusion criteria were a duration of gluten-free diet over 5 years and complete pubertal development. Diagnosis of celiac disease made according to the European Society of Pediatric Gastroenterology and Nutrition recommendations.

Exclusion Criteria:

Candidates were excluded if they had a chronic illness or if they had taken any medication that interferes with bone metabolism.

Description of Study Protocol:

Recruitment

39 celiac patients followed in the department were identified for study inclusion.

Design

Nonrandomized Clinical Trial, Cross-Sectional

Blinding used (if applicable)

No blinding used.

Intervention (if applicable)

Gluten-free diet for over 5 years.

Statistical Analysis

Multivariate analyses performed to evaluate the differences between celiac patients and control subjects after controlling for confounding variables. Celiac patients were divided into 2 groups according to their age at the beginning of gluten-free diet to assess the influence of an early beginning of dietary treatment on bone density and bone metabolism. Differences of age, anthropometric measurements, bone density values, and bone metabolism indices were evaluated by unpaired t tests.

Data Collection Summary:

Timing of Measurements

Bone mineral density, serum and urinary samples taken and compared to controls. Symptoms assessed through interview.

Dependent Variables

Bone mineral density measured in the lumbar spine and in whole skeleton by dual energy x-ray absorptiometry
Serum levels of bone-specific alkaline phosphatase measured by immunoassay and N-terminal propeptide of type I procollagen measured by radioimmunoassay as bone formation indices
Urine levels of N-telopeptide of type I collagen measured by ELISA as bone resorption index
Weight measured with an electric scale, and height measured with stadiometer
Presence or recurrence of gastrointestinal symptoms verified by interview
Hemoglobin and mean corpuscular volume evaluated with automated methods
Ferritin measured by fluorimetry
Folic acid measured by chemiluminescence
25-hydroxy-vitamin D measured in serum through radioimmunoassay
Serum levels of intact parathyroid hormones measured by a 2-site immunoradiometric assay

Independent Variables

Gluten free diet compliance measured through assessment of IgA antigliadin antibodies, IgA antiendomysium antibodies, and IgG antireticulin antibodies serum titers

Description of Actual Data Sample:

Initial N: 39 celiac patients identified for inclusion in study. 4 refused to participate and 5 excluded since they were not postpubertal.

Attrition (final N): 30 celiac patients (17 women, 13 men) and 240 healthy postpubertal controls (131 women, 109 men).

Age: Mean age at study: 21.9 +/- 4.4 years. Mean age of controls: 20.5 +/- 4.6 years.

Ethnicity: Not mentioned.

Other relevant demographics: Mean age at diagnosis was 11.4 +/- 5.0 years.

Anthropometrics: Height of celiac patients was 159.7 +/- 10.7 cm, controls was 167.2 +/- 10.5 cm.

Location: Italy

Summary of Results:

	Celiac Patients (n=30)	Controls (n=240)	Normal Range
Age (years)	21.9 +/- 4.4	20.5 +/- 4.6
Age at Diagnosis (years)	11.4 +/- 5.0
Height (cm)	159.7 +/- 10.7	167.2 +/- 10.5
Weight (kg)	55.0 +/- 10.3	58.8 +/- 12.5
BMI (kg/m2)	21.5 +/- 2.9	20.8 +/- 2.6
Spine BMD (g/cm2)	1.131+/- 0.121	1.131 +/- 0.184
Total Body BMD (g/cm2)	1.145 +/- 0.105	1.159 +/- 0.118
BALP (U/L)	25.8 +/- 12.6	19.8 +/- 6.4
PINP (micrograms/L)	93.6 +/- 75.6	54.1 +/- 21.6
NTx (nmol BCE/mmol Creat)	67.4 +/- 63.0	93.5 +/- 82.4
Hemoglobin (g/L)	139 +/- 14		120 - 180
MCV (fl)	86.9 +/- 6.7		80 - 99
Ferritin (micrograms/L)	64.3 +/- 84.7		15 - 200
Folate (mmol/L)	10.8 +/- 3.2		6.8 - 38.5
25OHvitD (nmol/L)	83.4 +/- 39.4		22.2 - 116.6
iPTH (pg/ml)	19.7 +/- 9.5		10 - 65

Other Findings

Mean duration of gluten-free diet was 10.7 +/- 4.3 years (range 5 - 21 years). Positive EmA were found in 3 patients, 2 of them also had AGA positivity. No one had ARA positivity.

Bone mineral density measurements of celiac patients (lumbar spine: 1.131 +/- 0.121 g/cm2, total body: 1.145 +/- 0.184 g/cm2) did not differ from those of control subjects (lumbar spine: 1.131 +/- 0.184 g/cm2; total body: 1.159 +/- 0.118 g/cm2).

The levels of bone-specific alkaline phosphatase, N-terminal propeptide of type I procollagen, and N-telopeptide of type I collagen of celiac patients did not differ from those of controls.

Patients who started gluten-free diets before puberty (age of 10) had bone mineral density and bone metabolism measurements comparable to those of patients who started gluten-free diets during puberty, after controlling for confounding variables of age, gender and weight. No differences were present between the 2 groups in bone density values, even when the results were corrected for differences in age, gender and anthropometric measurements.

Author Conclusion:

In conclusion, our data indicate that dietary treatment initiated during childhood or adolescence is able to maintain normal bone density and bone metabolism ater several years of gluten-free diet. Because of the difficulties reported in achieving optimal bone mineral density levels in celiac patients diagnosed in adulthood, early diagnosis should be enforced even in asymptomatic patients and first-degree relatives of celiac patients. Finally, because celiac patients are on average shorter than healthy subjects, attention should be paid to the evaluation of bone density values obtained with absorptiometric techniques for the influence of size on bone mineral density.

Funding Source:

University/Hospital:

University of Milan (Italy)

Reviewer Comments:

Gluten free diet for over 5 years. Compliance monitored through autoantibody measurement.

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
	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
	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
	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
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
	1.	Was the research question clearly stated?	Yes
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.1.	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
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
	1.3.	Were the target population and setting specified?	Yes
	2.	Was the selection of study subjects/patients free from bias?	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
	2.1.	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?	N/A
	2.2.	Were criteria applied equally to all study groups?	N/A
	2.3.	Were health, demographics, and other characteristics of subjects described?	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
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	3.	Were study groups comparable?	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
	3.1.	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?	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	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
	3.4.	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
	3.5.	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
	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.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	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
	4.2.	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
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	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
	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.	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
	5.1.	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
	5.2.	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
	5.3.	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
	5.4.	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
	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.	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
	6.1.	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
	6.2.	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
	6.3.	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
	6.4.	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?	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
	6.6.	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
	6.7.	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
	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.	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
	7.1.	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
	7.2.	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
	7.3.	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
	7.4.	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
	7.5.	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
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	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.	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
	8.1.	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
	8.2.	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
	8.3.	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
	8.4.	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
	8.5.	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
	8.6.	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
	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.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	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.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes