EAL

CD: Bone Density (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate the occurrence and possible significance of secondary hyperparathyroidism with regard to bone mineral density in patients with untreated celiac disease.

Inclusion Criteria:

Newly diagnosed celiac disease. All had villous atrophy in the proximal small bowel of grade III or IV on the basis of Alexander's classification.

Exclusion Criteria:

None mentioned.

Description of Study Protocol:

Recruitment

Subjects examined from November 1989 to October 1997.

Design

Prospective nonrandomized clinical trial.

Blinding used (if applicable)

Not applicable.

Intervention (if applicable)

Gluten-free diet for up to 3 years. Patients with hypocalcemia were given supplementation with 10 micrograms vitamin D and 500 mg calcium daily for 3 to 18 months.

Statistical Analysis

Bone mineral density was expressed in g/cm2 and as a Z score, defined as the deviation of the individual value from the mean value of the sex- and age-matched reference group expressed in the number of standard deviations. Annual increase in bone mineral density was expressed in percentage. As the material was not normally distributed, all analyses involved non-parametric tests. The Wilcoxon signed-rank test was used when comparing paired data, and the Mann-Whitney U test and chi-square test when comparing non-paired data. Correlation was evaluated with the Spearman rank test. Significance was set at p < 0.05 (two-tailed).

Data Collection Summary:

Timing of Measurements

Bone mineral density measured within 3 months of starting dietary treatment with gluten-free diet and after 1, 2 and 3 years. Blood tests taken before start of dietary treatment and 1 year later.

Dependent Variables

Bone mineral density in lumbar spine and hip measured through DEXA
Bone mineral density in forearm measured by single-photon absorptiometry
Serum intact parathyroid hormone concentrations were determined using 2-site immunoradiometric assay
Serum concentration of 25-hydroxyvitamin D (25-OH-D3) measured with immunoradiometric assay
Serum ionized calcium and alkaline phosphatase analyzed with standard methods
Questionnaire about previous fractures and factors affecting bone mineral density

Independent Variables

Gluten free diet not defined or monitored
Dietary calcium intake assessed with questionnaire

Control Variables

Description of Actual Data Sample:

Initial N: 105 adults, 55 women and 50 men, 942 healthy controls (10 - 25 controls per subject)

Attrition (final N): Same as above.

Age: Median age 53.5 years (range 20.5 - 86.7 years)

Ethnicity: Not mentioned.

Other relevant demographics: None mentioned.

Anthropometrics For calculation of Z score, 10 - 25 controls for each patient were selected, matched for age, sex and menopausal state

Location: Sweden

Summary of Results:

	PTH < 65 ng/l (n=77)	PTH > 65 ng/l (n=28)	P value
Spine BMD - median	-0.534	-1.41	< 0.001
Forearm BMD - median	-0.560	-1.48	< 0.01
Hip total BMD - median	-0.507	-1.74	< 0.001
Residual Villous Atrophy (Grades I - II)	59 (76%)	17 (61%)	NS
Residual Villous Atrophy (Grades III - IV)	12 (16%)	10 (36%)	< 0.05
Compliant with Diet	67 (87%)	28 (100%)	NS
Not Compliant	10 (13%)	0 (0%)	< 0.05
Ca Supplementation	6 (8%)	9 (32%)	< 0.01
Vit D Supplementation	1 (1%)	5 (18%)	< 0.01
PTH - median at diagnosis	39	101	< 0.0001
PTH - median at 1 year	39	51.5	< 0.0001
25-OH-vit D - median at diagnosis	65	43	< 0.0001
25-OH-vit D - median at 1 year	66	59	NS
ALP - median at diagnosis	2.9	4.1	< 0.001
ALP - median at 1 year	2.6	3.2	< 0.05
Free Ca - median at diagnosis	1.24	1.22	NS
Free Ca - median at 1 year	1.24	1.23	NS

Other Findings

Secondary hyperparathyroidism was found in 27% (28 of 105) of the patients. In patients with SHPT, serum levels of 25-hydroxy-vitamin D were lower and those of alkaline phosphatase higher in patients with normal parathyroid hormone levels, but ionized serum calcium did not differ between the groups.

Age-adjusted bone mineral density was reduced at all sites in patients with untreated celiac disease, and more severely reduced in patients with SHPT. The median BMD expressed as Z-scores in the total group of patients was -0.79, -0.72 and -0.88 in the total hip, spine and distal forearm, respectively (P < 0.001).

Although the bone mineral density increment was more rapid in patients with than in those without SHPT, only in the latter group did mean bone mineral density become normal after 1 - 3 years on a gluten-free diet.

After 3 years of gluten-free diet, more than half of the patients with initial SHPT still had low bone mineral density in both the hip and forearm.

Furthermore, in patients with SHPT the intestinal mucosa more often remained atrophic at the 1-year follow-up, despite good compliance with the diet.

Author Conclusion:

In conclusion, we found adult patients with untreated celiac disease to have a low bone mineral density often associated with secondary hyperparathyroidism. In patients without secondary hyperparathyroidism, the low bone mineral density normalizes on a gluten-free diet alone, whereas after 3 years on a gluten-free diet, the bone mineral density remains low only in patients with initial secondary hyperparathyroidism. We therefore suggest that parathyroid hormone should be measured when the diagnosis of celiac disease is made, as an indicator of more serious intestinal disorder and complicating bone disease. The value of calcium and vitamin D supplementation in these patients needs further evaluation.

Funding Source:

Government:

Medical Research Council of Southwest Sweden

Reviewer Comments:

Compliance to gluten-free diet not monitored. High number of controls per subject.

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?		???
	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?	???
	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?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	???
	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?	Yes
	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?	No
	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?	Yes
	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?	No
	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?	???
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