EAL

CD: Bone Density (2006)

Citation:

Sategna-Guidetti C, Grosso SB, Grosso S, Mengozzi G, Aimo G, Zaccaria T, Di Stefano M, Isaia GC. The effects of 1-year gluten withdrawal on bone mass, bone metabolism and nutritional status in newly diagnosed adult celiac disease patients. Aliment Pharmacol Ther 2000; 14: 35-43.

PubMed ID: 10632643

Study Design:

Non-Randomized Controlled Trial

Class:

C - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

To determine the prevalence and possible mechanisms of low bone mineral density, aiming to acquire insights into the diagnostic accuracy and predictivity of biochemical markers of bone turnover in comparison to bone mineral density values, the characterization of bone derangement by non-invasive tests, and the evaluation of the effect of a 1-year gluten-free diet on bone mineral density, bone metabolism and nutritional status, as well as evaluate the relationship between an eventual bone metabolism improvement and the degree of diet compliance.

Inclusion Criteria:

Newly diagnosed celiac disease, not following a gluten-free diet. Diagnosis performed according to the accepted criteria, i.e. clinical history and typical histological appearance of the small intestinal mucosa.

Exclusion Criteria:

Age < 19 years, presence of other diseases or the use of medications known to affect bone mineral metabolism.

Description of Study Protocol:

Recruitment

86 consecutive newly diagnosed celiac disease patients, recruited between January 1996 - January 1999.

Design

Nonrandomized Clinical Trial.

Blinding used (if applicable)

No blinding used.

Intervention (if applicable)

Gluten free diet for 1 year.

Statistical Analysis

For comparison of means, the unpaired Student's t test was used. Mean values of patients followed longitudinally before and after a gluten-free diet were compared by Student's paired t test. When data were regarded to be not normally distributed, the non-parametric Mann-Whitney U test and Wilcoxon signed rank test were used. Multiple comparisons for differences among normal, osteopenic and osteoporotic subjects were tested by the one way ANOVA or by the non-parametric Kruskal-Wallis method, followed by Student-Newman-Keuls or Dunn correction, respectively, when the formers were significant. Receiver operating characteristic analysis was used to compare the predictive ability of bone turnover markers as prognostic tests of bone mineral density values by stratifying patients at 2 levels of lumbar T score.

Data Collection Summary:

Timing of Measurements

Bone mineral density, serum indices of bone remodelling, intestinal biopsy, clinical and biochemical nutritional assessment evaluated at diagnosis and within 12 +/- 1 months of gluten-free diet.

Dependent Variables

Nutritional status was evaluated by calculating BMI
Biochemical assessment, performed by standard methods, included hemoglobin and serum albumin, prealbumin, transferrin, iron, ferritin, and folic acid
Bone mineral density of the lumbar spine and femoral neck measured by dual energy x-ray absorptiometry
Serum calcium and phosphate measured by standard methods
Serum intact parathyroid hormone determined by immunoradiometric assay
Serum 25-hydroxycholecalciferol measured by radioimmunoassay
Serum total alkaline phosphatase measured by standard enzymatic method
Bone specific alkaline phosphatase measured by immunoradiometric assay
Serum bone Gla-protein measured by radioimmunoassay
Serum carboxy-terminal propeptide of type I procollagen determined by radioimmunoassay
Urinary hydroxyproline determined with HPLC
Urinary calcium corrected for creatinine excretion was measured by standard colorimetric method
Urinary pyridinoline and deoxypyridinoline measured by immunoenzymatic assay
Serum carboxy-terminal telopeptide of type I collagen measured by radioimmunoassay
Intestinal biopsies from the second part of the duodenum during upper endoscopy

Independent Variables

Gluten free diet not defined but compliance to diet monitored through biopsy at end of study

Description of Actual Data Sample:

Initial N: 86 consecutive newly diagnosed patients (22 males, 64 females)

Attrition (final N): 72 out of 86 patients underwent complete reassessment.

Age: Males: median age 29 years (19 - 67 years). 54 premenopausal females: median age 29 years (19 - 51 years). 10 postmenopausal females: median age 55 years (45 - 67 years).

Ethnicity: Not mentioned.

Location: Italy

Summary of Results:

	Untreated: Abnormal Values	Untreated: Mean +/- SD	Treated: Mean +/- SD	P value
Ca	24%	4.54 +/- 0.28	4.73 +/- 0.23	<0.0001
uCa	9%	0.052 +/- 0.057	0.065 +/- 0.056	NS
P	0%	1.26 +/- 0.22	1.15 +/- 0.19	0.02
ALP	14%	100.2 +/- 57.3	64.5 +/- 23.8	<0.0001
BAP	51%	23.8 +/- 20.2	11.7 +/- 8.4	<0.0001
uOHP	72%	32.1 +/- 17.2	20.1 +/- 8.3	0.0002
BGP	6%	3.6 +/- 1.7	2.4 +/- 1.7	0.001
iPTH	30%	63.2 +/- 50.5	40.1 +/- 31.4	0.0003
25-OH D	59%	15.4 +/- 9	24.1 +/- 15.2	0.0004
D-PYR	75%	9.45 +/- 4.69	7.6 +/- 2.73	NS
ICTP	32%	5.68 +/- 2.57	5.58 +/- 5.41	NS
PICP	35%	168.21 +/- 75.73	130.64 +/- 52.82	0.002
BMI	33%	20.8 +/- 3.1	20.85 +/- 2.99	0.01
PA	21%	23.01 +/- 5.7	24.92 +/- 5.05	0.04
Alb	1%	4.5 +/- 0.5	4.8 +/- 0.3	0.003
Hb	40%	12.6 +/- 2	13.8 +/- 1.4	<0.0001
Fe	33%	65.4 +/- 40.8	82.6 +/- 37.4	<0.04
Ferr	59%	30.5 +/- 50.4	33.6 +/- 39.9	NS
Trans	33%	306.2 +/- 65.6	269.5 +/- 41.7	0.002
Fol	42%	4.35 +/- 3.68	6.54 +/- 3.92	0.002
T-Lumbar Score	66%	-1.72 +/- 1.3	-1.29 +/- 1.36	<0.0001
Z-Lumbar Score	66%	-1.47 +/- 1.12	-0.97 +/- 1.25	<0.0001
T-Femoral Score	67%	-1.33 +/- 1.34	-1.22 +/- 1.31	<0.0002
Z-Femoral Score	66%	-0.89 +/- 1.22	-0.67 +/- 1.19	0.004

Other Findings

According to WHO criteria, at diagnosis, 29 out of 86 (34%) of patients had a normal bone mineral density, 34 (40%) had osteopenia and 23 (26%) had osteoporosis.

Between males and females there were no statistical differences in bone metabolism or in most of the nutritional indices (except hemoglobin and ferritin).

Between fertile and postmenopausal women, bone mineral density and several bone metabolism markers were significantly different. Bone mineral density in the lumbar spine was 0.940 +/- 0.118 g/cm2 for premenopausal vs 0.670 +/- 0.104 g/cm2 for postmenopausal, P < 0.0001; bone mineral density in the femoral neck was 0.783 +/- 0.121 g/cm2 for premenopausal vs 0.621 +/- 0.118 for postmenopausal, P = 0.001.

Compared to subjects with a normal bone mineral density, osteopenics had higher bone specific alkaline phosphatase and Bone-GLA-protein values. In patients with a concomitant bone specific alkaline phosphatase increase and 25-OH vitamin D serum level reduction, bone mineral density (T-Lumbar values, P <0.001, Z-Lumbar values, P = 0.03) and several bone turnover markers were statistically different compared to patients without such a serological pattern.

Intestinal biopsies were repeated in 65 out of 72 (90.3%) patients, showing mucosal recovery in 37 (57%) and persisting partial or total villous atrophy in the others, indicating incomplete compliance with the diet.

1 year gluten-free diet led to significant improvement of lumbar spine and femoral neck mean bone mineral density values (from 0.886 +/- 0.15 to 0.933 +/- 0.14 g/cm2, P < 0.0001, and from 0.754 +/- 0.21 to 0.813 +/- 0.15 g/cm2, P = 0.0009, respectively).

Gluten-free diet led, even in postmenopausal women, to a significant improvement in bone mineral density, bone metabolism and nutrition, except for folic acid, albumin and prealbumin serum levels which persisted as abnormal in patients with mucosal impairment.

Author Conclusion:

In conclusion, our study confirms that celiac disease patients are at high risk for developing a low bone mineral density and bone turnover impairment. A gluten-free diet can improve this situation even in patients with a low vitamin D serum level, in postmenopausal women and in patients with incomplete mucosal recovery. In these patients further stdies are needed to evaluate both the efficacy of these new therapies and the clinical usefulness of bone turnover biochemical markers for the assessment of therapeutic response.

Funding Source:

Government:

Medical Research Council of Southeast Sweden

Reviewer Comments:

Gluten free diet monitored through final biopsy.

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?		N/A
	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?	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	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
	3.6.	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?	???
	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?	N/A
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