Reply: Effectiveness of Vitamin D Supplementation on Disease Course in Inflammatory Bowel Disease Patients

To the Editor:

We greatly appreciate the interest of Dai and Huang in our systematic review with meta-analysis on vitamin D in inflammatory bowel disease (IBD)¹ and read their valuable comments with great interest. We are pleased that our article on vitamin D in IBD has generated interest and debate on this topic, given its potential implications in IBD clinical practice and research. The importance of vitamin D in the treatment and clinical course of IBD has been repeatedly highlighted.

In our study, we conducted a systematic review and meta-analysis on randomized clinical trials (RCT) involving IBD patients treated with vitamin D supplementation, compared with placebo, and reported data on clinical relapse and disease activity. This meta-analysis showed that vitamin D supplementation can reduce the risk of clinical relapse in IBD patients, especially in Crohn’s disease patients in clinical remission.

To find conflicting results in the literature is not a novelty, especially among observational or retrospective designs: evidence collected from RCTs should be more cogent in deriving a conclusion on the magnitude of effects.^2,3 For this reason, we have included only RCTs in our meta-analysis.

Moreover, concerning the correlation between vitamin D deficiency, disease activity, and clinical relapse, an elegant and well-designed meta-analysis of observational studies, published by Gubatan et al,⁴ helped to clarify this issue showing that low vitamin D status is a biomarker for disease activity and predictor of poor clinical outcomes in IBD patients.

We agree that optimal vitamin D dosage and duration should be subject to further research, especially considering that this field, unfortunately, lacks high-power and high-quality RCTs. However, given the difference in vitamin D dosage regimen among treatment groups in retrieved studies, its relationship with clinical relapse was investigated by a meta-regression analysis showing that the optimal effect was obtained with a vitamin D dosage in a range between 10 000 and 15 000 IU/d. The practical objective is to correct the vitamin D deficiency and the dosage of supplementation should be related to the degree of deficiency. Most of the retrieved literature shows a lack of bias adjustment for potential confounders. Besides the ones correctly identified, the lack of a clear definition of low vitamin D serum level, the different status in disease activity or disease pattern, and the usage of proxy outcomes (such as quality of life) rather than hard ones (such as surgery-free survival, or reintervention) can also be mentioned.

Concerning the last remark, we agree that the various methods to evaluate vitamin D are very different in terms of test accuracy. Nevertheless, in the included studies vitamin levels were often not reported, and unfortunately, no relevance was given to the test used to assess vitamin D levels. However, this issue does not put into the background the relevance of vitamin D supplementation as potential adjunctive therapy. Moreover, the different definition of sufficient or insufficient vitamin D levels refers to the risk of bone fractures and good bone health. Thus, this cutoff is hardly generalizable to the disease activity in IBD.

Primary research with controversial conduction is a major problem in medical research, and the importance of secondary research lies in its role of synthesis and critique, and in the notion that incorporating more studies can contribute to a more precise effect estimation. However, this last notion has been challenged in most recent times, on the basis that meta-analysis may average out the differences among studies and lead to a loss of information.⁵ Individual patient data secondary studies are certainly a more valid alternative; however, the possibility of carrying them out is not always a reality. High-quality RCTs still represent the optimum in current medical science, a potential alternative being quasi-experimental design studies, such as propensity score–matched retrospective ones.^6,7

In conclusion, we strongly support the notion that today’s research on IBD could and should raise its quality bar, given the resource and expertise current researchers have access to now, and we hope that future RCTs will be designed with a more cautious approach toward confounding sample selection and bias reduction. These elements, in our experience, represent the most lacking part of the medical literature on functional micronutrient supplementation in IBD.

Author Contribution

M.V.: conception of the work, writing of the original draft; A.V.: methodological assessment, writing of the original draft; G.L.: writing of the original draft, critical revision of the manuscript.

Funding

None received.

Conflict of Interest

The authors declare that they have no competing interests.

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