EAL

CD: Bone Density (2006)

Citation:

Valdimarsson T, Lofman O, Toss G, Strom M. Reversal of osteopenia with diet in adult celiac disease. Gut 1996; 38: 322-327.

PubMed ID: 8675082

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 investigate the occurrence of low bone mineral density in patients with untreated celiac disease and in particular the effect of gluten-free diet in patients of different ages.

Inclusion Criteria:

Clinical suspicion of celiac disease, such as diarrhea, weight loss, dyspepsia, or biochemical abnormalities. All patients had villous atrophy in the proximal small bowel of grade III or IV based on Alexander's classification.

Exclusion Criteria:

The presence of other diseases known to affect bone mineral density.

Description of Study Protocol:

Recruitment

65 consecutive patients with newly diagnosed celiac disease examined from November 1989 to December 1993.

Design

Nonrandomized Clinical Trial.

Blinding used (if applicable)

No blinding used.

Intervention (if applicable)

Gluten-free diet for 1 year. 13 patients with low ionised serum calcium, low dietary calcium intake or both, received oral calcium supplementation (750 mg calcium carbonate daily for 3 - 12 months). 5 of the 13 also had low 25 hydroxy-vitamin D and were given 500 units/day of Vitamin D supplementation for 6 - 12 months.

Statistical Analysis

Bone mineral density expressed as Z score. The Wilcoxon signed rank test and the Mann-Whitney U test were used when comparing paired and non-paired data, respectively. Correlation was evaluated by the Spearman rank test.

Data Collection Summary:

Timing of Measurements

Bone mineral density measured at diagnosis and after 1 year of gluten-free diet. Blood tests taken before the start of dietary treatment.

Dependent Variables

Bone mineral density measured in forearm using single photon absorptiometry, and in the lumbar spine, femoral neck, and trochanter using dual energy x-ray absorptiometry
Intact serum parathyroid hormone determined using a two site immunoradiometric assay
Serum concentrations of 25-OH-D3 measured by immunoradiometric assay
Ionized serum calcium and alkaline phosphatase analyzed by standard methods.

Independent Variables

Compliance to gluten-free diet for 1 year confirmed through histological improvement in biopsies for 58 patients. 2 were unwilling to have second biopsy and 3 patients still had severe mucosal atrophy (grade III-IV). Of these 5, all but 1 claimed adherence to a strict gluten-free diet.

Description of Actual Data Sample:

Initial N: 65 consecutive patients originally included, 680 randomly selected healthy controls.

Attrition (final N): 63 adult patients, 28 men and 35 women. Each patient compared to 25 healthy age-, sex- and menopausal state-matched controls. 1 excluded due to history of hypercalcemic hyperparathyroidism and 1 was unwilling to have bone density measurement performed at completion of gluten-free diet for 1 year.

Age: Aged 17 - 79 years, median 53.5 years.

Ethnicity: Not mentioned

Other relevant demographics: 7 patients also had dermatitis herpetiformis.

Anthropometrics: Controls were age-, sex- and menopausal state-matched.

Location: Sweden

Summary of Results:

Change in bone mineral density during 1 year in percent of initial value (g/cm3), median (IQR)

	Forearm	p Value	Spine	p Value	Neck	p Value
All Patients (n=63)	1 (-1/+4)	<0.01	3 (+1/+7)	<0.001	2 (-1/+10)	<0.001
< 25 years (n=8)	2(+3/+3)	<0.05	2 (+1/+3)	<0.05	0 (-1/+3)	NS
> 25 years (n=55)	1 (-2/+4)	<0.05	3 (+1/+8)	<0.001	3 (-1/+11)	<0.001
> 65 years (n=14)	0 (-4/+5)	NS	5 (+2/+16)	<0.01	8 (-1/+11)	<0.05
All women (n=35)	1 (0/+5)	<0.05	2 (+1/+4)	<0.001	1 (-1/+4)	<0.05
All men (n=28)	1 (-2/+3)	NS	4 (0/+13)	<0.001	6 (+1/+12)	<0.001

Other Findings

Before being given a gluten-free diet, age-adjusted bone mineral density was reduced at all sites (p < 0.001). Patients over the age of 25 and particularly those over age 65 had low bone mineral density even when correlated with the expected decline in bone mineral density with increasing age. Age adjusted bone mineral density in the lumbar spine was inversely correlated with age (p < 0.05, r = 0.31). The magnitude of the reduction did not differ between men and women or between pre- and post-menopausal women.

Patients under age had normal age-adjusted bone mineral density and higher than those over age 25 (p < 0.05 all sites). Patients who had dermatitis herpetiformis also had normal age-adjusted bone mineral density.

Age adjusted bone mineral density in the spine was positively correlated to serum 25-OH-D3 (p < 0.05, r = 0.32) and negatively correlated to serum alkaline phosphatase (p < 0.01, r = 0.42) and parathyroid hormone (p < 0.01, r = 0.43). Similar correlation was found for the age adjusted bone mineral density in the forearm, femoral neck, and trochanter.

During the first year of gluten-free diet, bone mineral density increased at all sites (p < 0.01). This was seen in patients of all ages and in patients who were without symptoms of malabsorption (weight loss or diarrhea) before treatment.

The increase of bone mineral density in the group of patients over 65 years was as great as in young patients. After 1 year the bone mineral density was still reduced at all sites (p < 0.05).

The increase of lumbar and femoral bone mineral density was greater in the group of 13 patients receiving calcium or vitamin D supplementation but these patients also had lower bone mineral density before dietary treatment. When excluding these 13 from calculations, the bone mineral density was in the other 50 patients still was reduced before treatment and increased in the neck (p < 0.01) and spine (p < 0.001) during the first year of gluten-free diet.

Author Conclusion:

In this prospective study the bone mass increased rapidly during the first year of dietary treatment but was still reduced. Celiac disease is associated with pronounced osteopenia and a gluten free diet results in a rapid increase of bone mineral density. This is seen even in patients with minor or no gastrointestinal symptoms and in subjects over the age of 65. These findings emphasize the importance of early diagnosis and treatment in all patients with celiac disease.

Funding Source:

University/Hospital:

University Hospital of Linkoping (Sweden)

Reviewer Comments:

Some patients given calcium and vitamin D supplementation.

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)	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?		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?	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