EAL

CD: Bone Density (2006)

Citation:

McFarlane XA, Bhalla AK, Reeves DE, Morgan LM, Robertson DAF. Osteoporosis in treated adult celiac disease. Gut 1995; 36: 710-714.

PubMed ID: 7797121

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 study the prevalence of osteoporosis in asymptomatic adults with treated celiac disease, and utilize serial bone mineral density measurements to detect any change in bone mineral density over 12 months.

Inclusion Criteria:

Celiac disease diagnosed in adult life (over 18 years) and already following a gluten-free diet. Celiac disease was defined as small intestinal malabsorption associated with the characteristic small intestinal mucosal lesion together with clinical and histological improvement on a gluten-free diet.

Exclusion Criteria:

None specifically mentioned.

Description of Study Protocol:

Recruitment

Recruited from the gastroenterology outpatients department at the Royal United Hospital, Bath between September 1991 - October 1992.

Design

Nonrandomized Clinical Trial.

Blinding used (if applicable)

No blinding used.

Intervention (if applicable)

Patients already consuming a gluten-free diet.

Statistical Analysis

Bone mineral density was expressed as in absolute terms, and as a Z score and T score when compared with the mean bone mineral density of an age- and sex-matched normal population and with the peak bone mineral density (at age 30) of a sex-matched normal population. Statistical significance of differences between unpaired data was calculated using Wilcoxon rank sum test. Correlation coefficient was calculated using Spearman's rank correlation. 95% confidence intervals for the difference between paired data were calculated using Student's t distribution and significance was determined by paired t test.

Data Collection Summary:

Timing of Measurements

Patients had serial bone mineral density measurements at study entry, and again at 6 and 12 months. Blood tested at entry, as well as dietary intake and osteoporosis risk factors also assessed.

Dependent Variables

Bone mineral density measured at lumbar spine and femoral neck using dual energy x-ray bone densitometry
Osteoporosis risk factors (smoking, level of physical activity, immobilization, presence of diabetes mellitus or thyroid disease, drugs ingested) determined through standard questionnaire
Plasma calcium, phosphate, total alkaline phosphatase, 25 hydroxyvitamin D, and intact parathyroid hormone as well as red cell folate and 24 hr urinary calcium measured

Independent Variables

Gluten free diet - dietary assessment performed based on 10 day weighed food record of all food consumed and dietary intakes of calcium, protein and energy were calculated.

Description of Actual Data Sample:

Initial N: 55 adult patients, 45 women, 10 men

Attrition (final N): 55 adult patients

Age: Average age of men: 50.2 years (range 27.0 - 65.0 years), and average age of women: 51.3 years (range 33.6 - 69.1 years)

Ethnicity: Not mentioned.

Other relevant demographics: For women, average age at menarche was 14 years (range 10 - 20 years; 5 patients had menarche at age 16 or older). 5 women had a history of an episode of premenopausal amenorrhea of at least 6 months. 16 women were premenopausal, 11 were perimenopausal, and 18 were postmenopausal (average age at menopause was 46.3 years, range 34 - 57 years. 8 women had menopause at less than age 45.)

7 patients had previously received oral vitamin D preparations, 6 had been on glucocorticoids in past, 5 of women were on or had been on HRT for more than 12 months. 14 patients (2 men) had a history of a serious fracture.

Mean times spent on a gluten-free diet were 4.25 years in men (0.4 - 10 years) and 9.2 years in women (0.3 - 40 years).

Location: Royal United Hospital, Bath, UK

Summary of Results:

	Reference Range	Z < -2 (n=11)	-2 < Z < -1 (n=13)	Z > -1 (n=31)
Women/Men		9/2	10/3	26/5
Age (years)		48.7	51.9	51.6
GFD length (years)		8.9	4.5	9.2
% change in lumbar spine BMD/year		+0.75	+2.40 (p < 0.05)	- 0.03
% change in femoral neck MD/year		+2.08 (p < 0.02)	+3.14 (p < 0.02)	-0.31
BMI		21.3 (p < 0.02)	23.1	25.2
Calcium intake (mg/day)		860 (p < 0.05)	1105	1054
Energy intake (kJ/day)		7879	9120	8115
Protein intake (g/day)		70	79	75
Serum calcium (mmol/l)	2.20 - 2.70	2.37	2.25	2.31
Serum phosphate (mmol/l)	0.8 - 1.5	1.02	1.04	1.01
Alkaline phosphatase (IU/l)	21 - 92	77.9	64.6	70.0
Red cell folate (umol/l)	0.28 - 1.36	0.83	0.83	0.96
PTH (pmol/l)	< 4.3	2.37	4.12	3.54
25-OH vit D (nmol/l)	10 - 100	55.5	58.3	59.0
24 hr urine calcium (mmol/24 hr)	2.5 - 7.5	4.4	3.2	3.9
Hemoglobin (g/l)		137	140	135
MCV (fl)	75 - 95	89.9	89.6	90.1

Other Findings

Osteoporosis, defined as bone mineral density <2 SD below normal peak bone mass, was found in 50% of male (5) and 47% of female celiac patients (21).

There was a close correlation between the bone mineral density at the lumbar spine and the femoral neck (men: r = 0.782, p < 0.02, and women: r = 0.704, p < 0.001).

Patients with a bone mineral density <2 SD below age- and sex-matched normal controls had significantly lower BMI (21.3 kg/m2 vs 25.2 kg/m2, p < 0.02) and lower average daily calcium intake (860 mg/day vs 1054 mg/day, p < 0.05) than patients with normal bone mineral density. There was no significant difference (p > 0.10) between these groups in the length of time on a gluten-free diet, age at diagnosis of celiac disease, any of the blood or urine biochemical indices, or osteoporosis risk factors.

The mean plasma concentrations of calcium, phosphate, total alkaline phosphatase, 25 hydroxyvitamin D, red cell folate and 24 hr urinary calcium were in the normal range, however, some patients had a minor reduction of calcium or phosphate, or a slight increase in total alkaline phosphatase or intact parathyroid hormone.

There was no significant difference between premenopausal, perimenopausal, or postmenopausal women at either the lumbar spine or femoral neck. In postmenopausal women with celiac disease there was a strong correlation between the age of menopause and bone mineral density at both the lumbar spine (r = 0.681, p < 0.01) and femoral neck (r = 0.632, p < 0.01).

No overall loss of bone was shown over the 12 months of follow up, and relative to the reference population there was significant improvement in bone mineral density at the lumbar spine in women (p < 0.025) and at the femoral neck in men (p < 0.05).

There was no significant correlation betwee duration ofr gluten-free diet and femoral or lumbar Z score, but there was a significant negative correlation between the annual percentage change in bone mineral density at the lumbar spine and the duration of gluten free diet (r = -0.429, p < 0.01; women: r = -0.405, p < 0.01, men: r= -0.709, p < 0.05), with the largest gain in bone mineral density in patients with most recently diagnosed celiac disease.

Author Conclusion:

Recognized risk factors for osteoporosis in the general population including low body mass index, dietary calcium intake, and early menopause are particularly important in celiac disease. Treatment of celiac disease with a gluten free diet probably protects against further bone loss, and in the early stages is associated with a gain in bone mineral density. Screening for osteoporosis by measuring bone mineral density in adult celiac disease seems to be worthwhile with a high yield, many patients having reduced bone mineral density. This has therapeutic potential, and having identified at risk individuals the need for adherence to gluten-free diet can be emphasized and advice regarding treatment can be offered, which may include increasing dietary calcium intake or considering HRT in postmenopausal women, in particular those with an early menopause.

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Some of the patients had been on gluten-free diets for less than 1 year.

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?	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?	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)?	N/A
	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