EAL

CD: Bone Density (2006)

Citation:

Bai JC, Gonzalez D, Mautalen C, Mazure R, Pedreira S, Vazquez H, Smecuol E, Siccardi A, Cataldi M, Niveloni S, Boerr LA, Maurino E. Long-term effect of gluten restriction on bone mineral density of patients with celiac disease. Aliment Pharmacol Ther. 1997;11:157-164.

PubMed ID: 9042988

Study Design:

Non-Randomized Controlled Trial

Class:

C - Click here for explanation of classification scheme.

Quality Rating:

NEUTRAL: See Quality Criteria Checklist below.

Research Purpose:

To assess the long-term effect of a gluten-free diet on bone mineral density in adults with untreated celiac disease and to evaluate whether remineralization was related to the degree of compliance with the diet.

Inclusion Criteria:

Diagnosis of celiac disease based on the combination of clinical features (chronic diarrhea with or without malabsorption, iron deficiency anemia, malnutrition) and on the presence of severe mucosal atrophy on small bowel biopsy.

Exclusion Criteria:

None specifically mentioned. Controls had no chronic diseases or ingestion of medications that might affect the skeleton.

Description of Study Protocol:

Recruitment: 45 consecutive unselected adult patients with newly diagnosed celiac disease recruited between September 1991 and October 1993.
Design: Non-randomized Clinical Trial.
Blinding used: No blinding used.
Intervention: Gluten-free diet after a mean duration of 38 months (range: 25-48 months).
Statistical Analysis: Values of bone mineral density for patients were compared with results of healthy Argentine population. Results are reported as absolute values, Z-score or percentage of variation from the mean normal value. Comparison between baseline and final measurements in the overall population made by paired T-test. Statistical significance of differences between data of patients who strictly followed gluten avoidance and those with partial restriction were calculated using the Mann-Whitney rank sum test. Correlations between parameters were calculated by the Spearman's correlation test.

Data Collection Summary:

Timing of Measurements

Clinical assessment, laboratory studies, nutritional parameters and bone mineral density assessed at baseline and after gluten-free diet for a mean duration of 38 months (range 25-48 months).

Dependent Variables

Bone mineral density and body composition parameters measured with dual-energy X-ray absorptiometry at lumbar spine (L2-L4), total skeleton and at head, trunk, spine, pelvis, legs and arms
IgA and IgG antigliadin antibodies measured through micro-ELISA
Antiendomysial antibodies determined through indirect immunofluorescence
Fecal alpha-1 antitrypsin clearance performed by radial immunodiffusion method
Nutritional parameters: Body weight, BMI, triceps skinfold, mid-arm muscle circumference, muscular mass.

Independent Variables

Gluten-free diet: Patients received dietary instruction at diagnosis and during interviews. Dietary assessment based on consecutive seven-day weighed food record analyzing compliance. Calcium and caloric intake only performed at end of study. Based on degree of adherence to the diet, patients were allocated to two groups: "Strict adherence" and "partial adherence."

Description of Actual Data Sample:

Initial N: 45 unselected newly diagnosed celiac patients originally recruited. 31 healthy men (aged 20 to 40 years) and 120 women (aged 20 to 80 years) were controls.
Attrition (final N): All 45 patients were recalled at the end of 1995, but only 25 patients completed study (24 females, one male).
Age: Mean age 45 years (range 21-73 years).
Ethnicity: Not mentioned.
Other relevant demographics: Patients divided into two groups, based on dietary compliance.
Location: Argentina.

Summary of Results:

	Strict GFD (N=15)	Partial GFD (N=10)
Age at Study Entry	43 years (21-73)	45 years (23-66)
Premenopausal	Eight	Four
Postmenopausal	Seven	Five
Duration of Disease Before Diagnosis	Nine years	Eight years
BMI	18.9±0.8kg/m²	20.4±1.4kg/m²
Fractures Before Study	Two	N/A
Lumbar Spine BMD	0.91±0.23	0.93±0.15
Total Skeleton BMD	0.93±0.12	0.93±0.15
Median Duration of Follow-Up (months)	47 (23-75)	47 (26-70)
Change from Baseline Weight	+19%	+9%
Final BMI	22.0±0.8kg/m²	22.5±1.4kg/m²
Calcium Intake	824±104mg/day	827±117mg/day
Number with Hgb <12g/dL	1/13	1/9
Number with Serum Albumin <3.5g/dL	1/12	3/9
Alpha-1 Antitrypsin Clearance 16ml per day	0/12	3/9
Elevated AGA-A	0/13	1/9
Elevated AGA-G	0/13	3/9
Lumbar Spine BMD	1.01±0.18	1.00±0.25
Total Skeleton BMD	1.01±0.10	0.99±0.13

Other Findings

At baseline, osteopenia (more than one SD below normal) was evident in the lumbar spine and total skeleton in 18 (72%) and 21 (84%) patients, respectively. Furthermore, 14 (56%) patients had bone mineral density values lower than two SD below normal in both areas. Baseline Z-score for all patients was -1.8±0.4 in the lumbar spine and -2.2±0.3 in the total skeleton.
At the end of the study, bone density had increased (mean bone mass Z-score increase: Z-score +1.0 for the lumbar spine and +1.1 for total skeleton) in 22 and 23 patients, respectively.
For all patients, the institution of a gluten-free diet produced a highly significant bone remineralization in the lumbar spine, measured as absolute values (P<0.0001) and Z-score (P<0.0001).
Patients who adhered to strict gluten restriction (N=15) demonstrated a similar bone remineralization in the spine than those patients with partial compliance (N=10, mean Z-score increase: +1.0 in both areas).
A greater mean annual change in Z-score in the total skeleton was noted in patients who followed strict gluten restriction (0.4±0.1) in respect to those with partial compliance (0.3±0.1). However, this difference was not statistically significant.
At the end of the follow-up, the group which was partially compliant with the diet included more patients with hypoalbuminemia, abnormal alpha-1 antitrypsin clearance and elevated titres of AGA type IgA and endomysial antibodies.
Premenopausal women had significantly greater remineralization than postmenopausal women (P<0.05). Remineralization showed an inverse correlation with the degree of basal osteopenia (R=-0.525, P<0.002).

Author Conclusion:

In summary, long-term treatment with a gluten-free diet produces a significant improvement in bone mineral density in celiac disease patients. Although the increase in bone mass did not bear a linear correlation to the duration of treatment, the findings obtained in the small group of patients who were followed at different intervals of time suggest that the mineralization induced by treatment was greater during the first year on gluten-free diet. Univariate analyses showed that remineralization was greater in premenopausal women, both in patients with the lowest baseline bone mineral density values and in those who followed strict gluten restriction. However, patients with partial compliance as a whole had a similar degree of mineralization. Only a few patients had normalized bone mineral density completely by the end of the follow-up.

Funding Source:

Government:

National Council of Research

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Only 25 out of 45 returned for the follow-up.
Gluten-free diet defined and 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?		N/A
	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?	No
	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?		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
	3.3.	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?	No
	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%.)	???
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	???
	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?		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?	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?		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