CD: Bone Density (2006)

Citation:

Ciacci C, Maurelli L, Klain M, Savino G, Salvatore M, Mazzacca G, Cirillo M.  Effect of dietary treatment on bone mineral density in adults with celiac disease:  factors predicting response.  Am J Gastroenterology 1997; 92(6): 992-996.

PubMed ID: 9177517
 
Study Design:
Non-Randomized Controlled Trial
Class:
C - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To analyze the effect on bone mineral density induced by treatment with a calcium-rich, gluten-free diet in adults with nonsilent celiac disease.
Inclusion Criteria:
Adults (over age 18) with newly diagnosed celiac disease.  Diagnostic workup was based on upper endoscopy, jejunal biopsy to prove the existence of subtotal villous atrophy, and a search for plasma antibodies to gliadin and endomysium.  Procedures were repeated after 1 year treatment with gluten-free diet to confirm the diagnosis of celiac disease. 
Exclusion Criteria:
Patients with severe malabsorption (severe diarrhea, tetany, cachexia, or need for acute parenteral therapy) were excluded from the study.  Patients with silent celiac disease were excluded since duration of clinically evidence celiac disease could not be measured.
Description of Study Protocol:

Recruitment

41 patients selected for study.

Design

Nonrandomized Clinical Trial.

Blinding used (if applicable)

No blinding used.

Intervention (if applicable)

Gluten-free diet containing ~2000 kcal and 1250 mg elemental calcium per day.

Statistical Analysis

Student's t test for paired observations, univariate and multivariate regression analyses, and analysis of 95% confidence intervals were used.  For any given variable, the treatment-induced change was calculated as the posttreatment value minus the pretreatment value.

Data Collection Summary:

Timing of Measurements

At baseline, detailed info was collected to assess age at which celiac disease became clinically evident.  Bone mineral density and biochemical determinations measured under untreated conditions and after 1 year of calcium-rich, gluten-free diet.

Dependent Variables

  • Bone mineral density measured at the right proximal femur (femoral neck and right Ward's triangle) and the lumbar spine by dual energy x-ray absorptiometry
  • Biochemical determinations included urinary and serum calcium, plasma vitamin D, fecal fat, plasma concentrations of albumin, alkaline phosphatase, cholesterol and blood hemoglobin

Independent Variables

  • Gluten-free diet with elemental calcium explained to each participant by a trained dietitian.  After 1 month of diet, patient's compliance was controlled.  At 1 month visit, calcium-enriched yogurt also added to diet.  Thereafter, the diet was maintained constant and compliance controlled every 2 months by same dietitian.

 

 

Description of Actual Data Sample:

Initial N: 41 subjects with newly diagnosed celiac disease, 30 women and 11 men

Attrition (final N):  41 subjects

Age:  Age at diagnosis:  34.3 +/- 13.7 years; age at which disease became clinically evident:  23.0 +/- 10.7 years   

Ethnicity:  Not mentioned. 

Other relevant demographics:  22 of the 30 women were premenopausal.  Of these 22, 6 were taking estrogen-progesterone oral contraception. 

Location:  Italy 

 

Summary of Results:

 

 

Pretreatment

Posttreatment

p Value

Lumbar spine BMD (g/cm2)

0.795 +/- 0.177

0.907 +/- 0.180

< 0.001

Femoral neck BMD (g/cm2)

0.741 +/- 0.189

0.818 +/- 0.145

0.002

Ward's triangle BMD (g/cm2)

0.654 +/- 0.160

0.703 +/- 0.158

< 0.001

Plasma alkaline phosphatase (U/L)

72 +/- 24

62 +/- 12

0.006

Plasma 25-OH D3 (ng/ml)

20.1 +/- 13.8

23.2 +/- 14.6

NS

Urinary Calcium (mmol/24 hr)

2.95 +/- 1.20

4.60 +/- 1.32

< 0.001

Serum Calcium (mmol/L)

1.19 +/- 0.02

1.20 +/- 0.02

NS

Other Findings

After diagnosis, patients were reexamined after 12.3 +/- 0.8 months (range 11 - 15) of treatment with a calcium-rich gluten-free diet.  Compared with pretreatment, treated celiac disease patients had a higher BMI (mean change:  +2.06 kg/m2, p < 0.001), blood hemoglobin, and plasma albumin and cholesterol (data not shown).

On average, post-treatment bone mineral density was greater than pretreatment bone mineral density at the lumbar spine (0.907 +/- 0.028 and 0.795 +/- 0.028 g/cm2, respectively, p < 0.001), the femoral neck (0.818 +/- 0.023 and 0.741 +/- 0.030 g/cm2, respectively, p = 0.002) and the Ward's triangle (0.703 +/- 0.025 and 0.654 +/- 0.025 g/cm2, respectively, p < 0.001).

The greatest bone mineral density change from baseline was observed at the lumbar spine (+14.1%), the smallest of the Ward's triangle (+7.5%).

Treatment with a calcium-rich gluten-free diet was followed by an increase in urinary calcium, a decrease in plasma alkaline phosphatase, and no significant change in serum ionized calcium and plasma vitamin D.

In the absence of appropriate controls, the bone mineral density change expected in the patients under untreated conditions was estimated by regressing pretreatment bone mineral density over duration of celiac disease with control for gender and age at which celiac disease became clinically evident.  The regression coefficient of this analysis indicated that 1 year of untreated celiac disease was associated with a bone mineral density decrease at the lumbar spine by 0.00570 g/cm2 (95% CI: -0.0103 to -0.0011 g/cm2).  The 95% CI of the treatment-induced change in bone mineral density at the lumbar spine (+0.060 to +0.160 g/cm2) did not overlap the 95% CI of the bone mineral density change expected under untreated conditions.

A large interindividual variability was observed in the bone mineral density response to treatment.  Compared with patients in whom bone mineral density increase or did not decrease (responders), nonresponders (patients in whom bone mineral density decreased after treatment) were older at diagnosis (p < 0.05), had lower pretreatment bone mineral density (p < 0.05), and among women, were less likely to be premenopausal (p < 0.05).

 

Author Conclusion:
he data show the bone mineral density is increased by dietary treatment of celiac disease in most but not all patients.  In conclusion, data from the present study show that the dietary treatment of celiac disease can increase bone mineral density also in adulthood.  Gender, pretreatment age, and pretreatment bone mineral density are factors that predict the bone mineral density response to the treatment.  Further studies are needed to investigate whether vitamin D supplementation or treatment with other drugs can improve bone mineral density in celiac disease patients who do not respond to a calcium-rich gluten-free diet. 
Funding Source:
University/Hospital: University Federico II (Naples Italy), Northwestern University, Second University of Naples (Italy)
Reviewer Comments:
Diet was calcium-rich and compliance checked regularly by a dietitian.
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? N/A
  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? 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? 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
  5.1. 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? 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