EAL

CD: Bone Density (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate total bone mineral density and indices of bone metabolism and remodeling in adults with untreated celiac disease, adults with celiac disease receiving a gluten-free diet, and healthy volunteers.

Inclusion Criteria:

Diagnosis of celiac disease based on finding of subtotal villous atrophy in jejunal biopsy specimens which subsequently improved after gluten-free diet.

Exclusion Criteria:

None of the patients or volunteers had other diseases or had taken drugs known to influence bone and calcium metabolism. None reported bone pain nor the occurrence of nontraumatic fractures.

Description of Study Protocol:

Recruitment

Untreated celiac disease patients were consecutive.

Design

Cross-sectional study.

Blinding used (if applicable)

Not applicable.

Intervention (if applicable)

Gluten-free diet.

Statistical Analysis

Bone mineral density values (Z scores) expressed as means +/- SD. Parametric one-way ANOVA and the Scheffe method used for the comparison of means between the groups and for the multiple comparisons of the means between other pairs of groups, respectively. All other variables were expressed as median, interquartile ranges and total ranges. The nonparametric ANOVA (Kruskal-Wallis test) was used for the comparison of the medians of all variables between the groups. The medians of each possible pair of the 3 groups were compared again using Kruskal-Wallis, but after correction of the critical values for multiple comparisons. The Spearman's correlation coefficients were computed for the nonparametric estimates of the level of association between 2 variables. When appropriate, Kendall's partial correlation coefficients were also computed with the aim of estimating the level of association between 2 variables after adjustment for the effect of other variables.

Data Collection Summary:

Timing of Measurements

All untreated patients, treated patients and volunteers measured.

Dependent Variables

Bone mineral density assessed by total body dual-photon absorptiometry
Serum calcium level measured by standard methods and corrected for albumin where appropriate
Serum intact parathyroid hormone level measured by 2-site immunoradiometric assay
Serum 25-OH-D3 level measured by radioimmunoassay
Serum 1,25-OH-D3 level measured by radioreceptor assay
Serum osteocalcin, serum carboxy-terminal propeptide of type I collagen and serum carboxy-terminal pyridinoline-cross-linked telopeptide of type I collagen measured by radioimmunoassay

Independent Variables

Gluten-free diet. Experienced dietitian judged the compliance to gluten-free diet as "good" in all treated patients. At post-treatment biopsy, 8 of 14 had normal jejunal mucosa and remaining 6 had mild partial villous atrophy.

Control Variables

Description of Actual Data Sample:

Initial N: 17 patients with untreated celiac disease (12 women, 5 men), 14 with celiac disease on gluten-free diet (11 women, 3 men), and 24 healthy volunteers (20 women, 4 men).

Attrition (final N): See above

Age: Untreated celiac disease patients: median age of 39 years (range 19 - 63 years), treated celiac disease patients: median age of 36 years (range 20 - 66 years), healthy volunteers: median age 38 years (range 24 - 65 years).

Ethnicity: Not mentioned.

Other relevant demographics: Mean duration of gluten-free diet for treated patients was a median of 28.5 months (range 8 - 208 months).

Anthropometrics: Healthy volunteers had similar ages to the celiac groups.

Location: Milan, Italy

Summary of Results:

	Untreated Pts	Treated Pts	Volunteers
Serum Ca - median	1.75	2.27	2.39
Serum Ca - range	1.30 - 2.20	2.00 - 2.37	2.24 - 2.49
Serum iPTH - median	51	21	26
Serum iPTH -range	5 - 255	7 - 53	10 - 55
Serum 25-OH-D3 - median	14	24	27
Serum 25-OH-D3 - range	5 - 29	8 - 50	14 - 33
Serum 1, 25-OH-D3 - median	57	42	25
Serum 1, 25-OH-D3 - range	31 - 72	33 - 71	17 - 39
Osteocalcin - median	3.6	2.2	2.1
Osteocalcin - range	0.5 - 13.8	0.5 - 5.3	0.5 - 3.5
PICP - median	193	99.5	135
PICP - range	73 - 500	59 - 238	82 - 145
ICTP - median	6.0	2.9	2.5
ICTP - range	2.0 - 30.0	2.0 - 8.4	1.3 - 5.9

Other Findings

Mean bone mineral density, expressed as a Z score, was significantly lower both in untreated and treated patients with celiac disease (-2.1 +/- 0.9 and -1.5 +/- 0.6, respectively) than in volunteers (0.2 +/- 0.6) and significantly higher in treated than untreated patients.

In the untreated patients, a significant positive correlation (r = 0.60) was found between bone mineral density and BMI, whereas there was no significant correlation (r = 0.39) between bone mineral density and age at diagnosis. In the treated patients, bone mineral density did not correlate significantly with the duration in months of gluten-free diet (r = 0.10).

Serum calcium level was significantly lower in untreated than in treated patients and volunteers, whereas no significant difference was found between the latter 2 groups. Serum intact parathyroid hormone level was significantly higher in untreated than in treated patients and volunteers, and no difference was found between the latter 2 groups.

25-OH vitamin D level was significantly lower and 1,25-vitamin D level significantly higher in untreated celiac disease than in treated celiac disease and volunteers.

Serum osteocalcin, PICP and ICTP levels were significantly higher in untreated than in treated patients and volunteers, with no significant difference between the latter 2 groups. All 3 indices were significantly and positively correlated with intact parathyroid hormone in untreated patients with celiac disease.

Author Conclusion:

Our results suggest that the major determinant to osteopenia in celiac disease is the chain of events resulting from hypocalcemia. Bone mineral density is almost invariably low in patients with untreated celiac disease. Results in treated patients suggest that gluten-free diet improves but does not normalize bone mineral density. Untreated celiac disease is characterized by high levels of 1,25-vitamin D and by increased bone turnover, caused by the increase in intact parathyroid hormone level. This study indicates the need for a combination of gluten-free diet and drugs active on bone metabolism to be subjected to clinical trials.

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Compliance to gluten-free diet judged by dietitian and confirmed with biopsy. Control subjects only age-matched. P-values not reported, only assumed significance at <0.05.

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?		???
	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?	???
	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?	???
	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?	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?		???
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	???
	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?	No
	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)?	???
	8.6.	Was clinical significance as well as statistical significance reported?	No
	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