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Systematic review and meta-analysis of observational studies on the prevalence of fractures in coeliac disease

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Abstract

Background/Aims

Evidence of an increased bone fracture risk in coeliac disease is on debate. Our aim was to review systematically the current published information on fractures in coeliac disease and to perform a meta-analysis.

Methods

Case–control and cohort designs were identified by searching MEDLINE (1966–April 2007) and LILACS (1982–April 2007). Participants were adult coeliac disease patients of any sex and the outcome measure was the presence of any fracture. Studies were screened for inclusion by two authors who independently extracted the data. Methodological quality was assessed using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology Statement) recommendations. Data were analysed using the RevMan Analyses statistical package in Review Manager (version 4.2.8) and reported as pooled odds ratio using a random effect model. Heterogeneity was investigated (standard χ2 test) and sensitivity analysis was performed based on the reported quality and design type.

Results

While 60 of 405 studies met the initial screening criteria, only 8 met inclusion criteria after detailed review. These studies evaluated a total of 20,955 coeliac disease patients having 1819 (8.7%) fractures and 96,777 controls with 5955 (6.1%) fractures (pooled odds ratio = 1.43; 95% confidence interval 1.15–1.78) with considerable heterogeneity among studies (p < 0.00001).

Conclusions

Our meta-analysis confirms a significant association between bone fractures and coeliac disease. However, qualitative and quantitative differences among studies were evident. Further research is necessary to investigate the relevance of this heterogeneity.

Introduction

Coeliac disease (CD) is common multisystemic, immune-mediated disorder induced by dietary proteins in wheat, rye and barley in genetically susceptible individuals. Although epidemiological studies have shown that the disease has an approximate prevalence of 0.3–1%, the majority of cases remain undiagnosed [1], [2]. Despite the disease primarily affecting the gastrointestinal tract, its clinical presentation is highly variable with most patients having an indolent clinical course. While classical CD is dominated by gastrointestinal symptoms and malnutrition, atypical CD is characterised by few or no gastrointestinal complaints but extraintestinal manifestation predominant. Finally, family studies have facilitated the knowledge that a substantial proportion of patients may have no symptoms at all (silent CD). Recent large screening programs have noted a high prevalence of CD in the general population and that, up to two thirds of new patients are clinically silent cases [2]. Recognition of atypical features of CD is considered one of the responsible factors for the increased prevalence of the disorder, and now may be the most common clinical presentation [1].

Osteoporosis is a systemic skeletal disease characterised by a low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture [3]. Coeliac disease as a cause of bone mass and mineral metabolism deterioration and metabolic osteopathy was recognised in the scientific literature only some years ago [1], [2], [3]. Marked deformities, rickets and fractures were described as the prominent bone clinical features in the early literature. More recently, the advent of non-invasive techniques such as bone densitometry has demonstrated that an important number of CD patients are affected by impaired bone mass and have a potential risk of fractures [3]. Interestingly, bone mineral deterioration has been shown in patients with classical malabsorption symptoms but also in asymptomatic patients. Despite the strong body of information about bone metabolism in CD patients, its clinical relevance is far from being completely understood. Thus, the knowledge about the risk of fractures in CD patients has just been considered in recent years. The first study suggesting a high prevalence of fractures in CD patients compared with controls was published in 2000 [4]. While further authors confirmed such high prevalence of bone fracture, others failed to demonstrate such association. Therefore, reasonable doubts have been expressed about an increased risk of bone fracture [3].

Our aim in this study was to perform a systematic review and a meta-analysis of the current epidemiological information on the occurrence of fractures in CD patients.

Section snippets

Criteria for considering studies for this review

The review was achieved following the Cochrane Collaboration steps [5] and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) Group [6]. The types of studies considered to be included were controlled studies with case–control and cohort designs. Series of cases, descriptive reports and uncontrolled studies were excluded from the analysis. Participants in the studies were biopsy-proven CD patients of any sex with classical clinical presentation, atypical symptoms or silent

Results

After the initial screening of 405 title and abstracts detected by the general search strategy, we identified 60 papers (κ between reviewers = 0.85) that were evaluated in more detail. Of these, eight studies [4], [9], [10], [11], [12], [13], [14], [15] (κ = 0.82) met the inclusion criteria for the meta-analysis (Fig. 1, flow chart). Main reasons for exclusion were a different outcome from bone fractures (n: 23) (in all of them the outcome measurement was the bone mineral density) and an inadequate

Discussion

There is a general consensus on that CD predisposes to metabolic osteopathy [1], [2], [3]. Thus, our systematic review identified a great number of papers (>400) recognising the association between CD and bone metabolic alterations. This body of evidence strongly suggests that CD should be considered as one of the leading conditions predisposing to bone damage. However, although bone derangement in CD was first reported several years ago, the true clinical magnitude of the problem was ignored

Conflict of interest statement

None declared.

Acknowledgements

The authors thank Dr. Graciela Berenstein for her technical support in the statistical analysis. The authors also thank to Christina Surawicz from the University of Washington for critical reviewing our manuscript.

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