How Much Vitamin D To Take For Ulcerative Colitis

How Much Vitamin D To Take For Ulcerative Colitis

Abstract

Background: The north–south geographical gradient of inflammatory bowel disease (IBD) prevalence, its epidemiology, the genetic association of vitamin D receptor polymorphisms, and results in animal models suggest that vitamin D plays an important role in the pathogenesis of IBD.

Aims: The purpose of this review was to critically appraise the effectiveness and safety of vitamin D therapy in patients with IBD.

Methods: MEDLINE, Scopus and Google Scholar were searched from inception to May 20, 2014 using the terms 'Crohn's disease', 'ulcerative colitis' and 'vitamin D'.

Results: Vitamin D deficiency is common in patients with IBD. Limited clinical data suggest an association between low vitamin D concentration and increased disease activity in both ulcerative colitis (UC) and Crohn's disease (CD). To date, only two small open label trials and one randomized controlled trial have shown a positive effect of vitamin D supplementation on disease activity in patients with CD; no effect has been shown for UC. An optimal vitamin D supplementation protocol for patients with IBD remains undetermined, but targeting serum 25-hydroxy vitamin D [25(OH)D] levels between 30 and 50ng/mL appears safe and may have benefits for IBD disease activity. Depending on baseline vitamin D serum concentration, ileal involvement in CD, body mass index, and perhaps smoking status, daily vitamin D doses between 1800–10000 international units/day are probably necessary.

Conclusion: Increasing preclinical and clinical evidence suggests a role for vitamin D deficiency in the development and severity of IBD. The possible therapeutic role of vitamin D in patients with IBD merits continued investigation.

1. Introduction

Inflammatory bowel diseases (IBDs), which include ulcerative colitis (UC) and Crohn's disease (CD), are idiopathic chronic relapsing inflammatory conditions of the gastrointestinal tract. Although the precise etiologies of IBD are not known, both diseases are thought to result from dysregulation of the host immune response to commensal intestinal flora in genetically predisposed persons. The north–south gradient of IBD prevalence, its epidemiology, the genetic association of vitamin D receptor (VDR) polymorphisms, and the many physiological studies of the effects of vitamin D on the immune system and mucosal barrier function suggest that vitamin D plays an important role in the pathogenesis of IBD. ^1–3 Moreover, recent clinical evidence shows that vitamin D has promising clinical effects on disease activity, bone health, cancer prevention and depression. Therefore, we conducted a non-systematic review of published and in press articles, including reviews, meta-analyses, original studies, clinical trials, and abstracts from scientific meetings (to the extent that they were identified in the PubMed, Scopus, MEDLINE or Google Scholar). The search terms included 'vitamin D' and 'Crohn's disease' or 'ulcerative colitis'. This review aims to explore the therapeutic potential of Vitamin D in IBD with CD and/or UC. Furthermore, based on current available evidence, we discuss the optimal target serum concentration, dosing, pharmacologic form and route of vitamin D supplementation.

2. Vitamin D

2.1 Vitamin D physiology

Vitamin D is a group of fat-soluble secosteroids with several hormonal functions in the human body. The physiology of vitamin D has been thoroughly reviewed. ⁴ The roles of vitamin D in calcium metabolism and healthy bone development have been recognized for more than a century. However, the discovery of the VDR in most tissues and cells of the body has provided new insights into the non-calcemic functions of vitamin D, including cell proliferation, immunomodulation and cell differentiation. ^5–7

The effects of vitamin D on the immune system are complex. The VDR is abundantly expressed on immune cells, especially on activated T lymphocytes and dendritic cells, and is also expressed on antigen-presenting cells, monocytes, macrophages, cytotoxic NK cells, and B lymphocytes. ^7,8 Vitamin D has been shown to stimulate the production of T-regulatory lymphocytes and the expression of interleukin (IL)-4, IL-10 and transforming growth factor-β, to inhibit the differentiation of CD4+ T lymphocytes into Th1 cells, and to suppress the effector functions of the latter. ^6,9 These immunomodulatory properties of vitamin D may explain the epidemiological associations between vitamin D status and a large number of immune-mediated diseases, including IBD, multiple sclerosis, rheumatoid arthritis, type I diabetes, systemic lupus erythematosus and psoriasis. ¹⁰ Vitamin D has also been associated with increased risks of infectious diseases, malignancies, transplant rejection, and cardiovascular disease. ¹¹ An overview of vitamin D sources, metabolism and effects on the immune system is outlined in Figure 1.

Figure 1.

Vitamin D sources, metabolism and effects on immune system

Figure 1.

Vitamin D sources, metabolism and effects on immune system

2.2 Vitamin D deficiency

Modern lifestyles appear to result in widespread vitamin D deficiency (~60%), especially at the end of winter.^12,13 The production of vitamin D3 depends on exposure to sunshine, the season of the year, latitude, clothing, skin pigmentation, and the use of sunscreen. The intake of vitamin D in a typical Western diet is limited (~40–100 international units (IU)/day). ^13–15 Therefore, a sun-deprived lifestyle is a major factor associated with vitamin D insufficiency.

3. Preclinical data linking vitamin D to IBD

Accumulating evidence from epidemiological, genetic, animal and in vitro studies has linked vitamin D to IBD (Table 1). ⁴

Table 1.

Summary of epidemiological, genetic and in vitro evidence for the role of vitamin D in the pathogenesis of IBD.

Epidemiology	North–south gradient of IBD prevalence in North America and Europe. 41,42 Low prevalence in countries near equator. 43 Low predicted vitamin D level increases risk of CD and UC. 44 Seasonality: UC and CD flares peak at the end of low-sunshine season. 45–49 Seasonality: Risk of UC higher in children born to mothers with lower predicted sunshine exposure in second trimester. 49
Genetic studies	Asians: ff genotype of FokI associated with UC, ApaI 'a' allele protective factor for CD. 2 Caucasians: ApaI tt genotype associated with CD. 55
Animal models	VDR KO mice develop severe colitis in several models of IBD colitis (IL-10 KO, DSS and TNBS). 58–60,63–65 Supplementation with vitamin D ameliorates experimental colitis in several IBD models. 59 Mice deficient in dietary vitamin D have decreased colonic antimicrobial activity and elevated levels of bacteria in colonic tissue. 61,62,85
In vitro studies	Vitamin D promotes maintenance of epithelial barriers (tight junctions and packaging of mucin in goblet cells). 63,83,84 Vitamin D enhances protective innate immune responses (NOD2 expression, cathelicid and defensin production). 66–73 Vitamin D regulates adaptive immune responses (increased Th2/Treg; decreased Th1/Th17 CD4+; inhibition of maturation of DCs; downregulation of TNF-α, IL12, IL-17, IL-21 and IFN-γ; upregulation of IL6, IL10 and FoxP3. 7,71,76,77,79–81

Epidemiology	North–south gradient of IBD prevalence in North America and Europe. 41,42 Low prevalence in countries near equator. 43 Low predicted vitamin D level increases risk of CD and UC. 44 Seasonality: UC and CD flares peak at the end of low-sunshine season. 45–49 Seasonality: Risk of UC higher in children born to mothers with lower predicted sunshine exposure in second trimester. 49
Genetic studies	Asians: ff genotype of FokI associated with UC, ApaI 'a' allele protective factor for CD. 2 Caucasians: ApaI tt genotype associated with CD. 55
Animal models	VDR KO mice develop severe colitis in several models of IBD colitis (IL-10 KO, DSS and TNBS). 58–60,63–65 Supplementation with vitamin D ameliorates experimental colitis in several IBD models. 59 Mice deficient in dietary vitamin D have decreased colonic antimicrobial activity and elevated levels of bacteria in colonic tissue. 61,62,85
In vitro studies	Vitamin D promotes maintenance of epithelial barriers (tight junctions and packaging of mucin in goblet cells). 63,83,84 Vitamin D enhances protective innate immune responses (NOD2 expression, cathelicid and defensin production). 66–73 Vitamin D regulates adaptive immune responses (increased Th2/Treg; decreased Th1/Th17 CD4+; inhibition of maturation of DCs; downregulation of TNF-α, IL12, IL-17, IL-21 and IFN-γ; upregulation of IL6, IL10 and FoxP3. 7,71,76,77,79–81

Table 1.

Summary of epidemiological, genetic and in vitro evidence for the role of vitamin D in the pathogenesis of IBD.

Epidemiology	North–south gradient of IBD prevalence in North America and Europe. 41,42 Low prevalence in countries near equator. 43 Low predicted vitamin D level increases risk of CD and UC. 44 Seasonality: UC and CD flares peak at the end of low-sunshine season. 45–49 Seasonality: Risk of UC higher in children born to mothers with lower predicted sunshine exposure in second trimester. 49
Genetic studies	Asians: ff genotype of FokI associated with UC, ApaI 'a' allele protective factor for CD. 2 Caucasians: ApaI tt genotype associated with CD. 55
Animal models	VDR KO mice develop severe colitis in several models of IBD colitis (IL-10 KO, DSS and TNBS). 58–60,63–65 Supplementation with vitamin D ameliorates experimental colitis in several IBD models. 59 Mice deficient in dietary vitamin D have decreased colonic antimicrobial activity and elevated levels of bacteria in colonic tissue. 61,62,85
In vitro studies	Vitamin D promotes maintenance of epithelial barriers (tight junctions and packaging of mucin in goblet cells). 63,83,84 Vitamin D enhances protective innate immune responses (NOD2 expression, cathelicid and defensin production). 66–73 Vitamin D regulates adaptive immune responses (increased Th2/Treg; decreased Th1/Th17 CD4+; inhibition of maturation of DCs; downregulation of TNF-α, IL12, IL-17, IL-21 and IFN-γ; upregulation of IL6, IL10 and FoxP3. 7,71,76,77,79–81

Epidemiology	North–south gradient of IBD prevalence in North America and Europe. 41,42 Low prevalence in countries near equator. 43 Low predicted vitamin D level increases risk of CD and UC. 44 Seasonality: UC and CD flares peak at the end of low-sunshine season. 45–49 Seasonality: Risk of UC higher in children born to mothers with lower predicted sunshine exposure in second trimester. 49
Genetic studies	Asians: ff genotype of FokI associated with UC, ApaI 'a' allele protective factor for CD. 2 Caucasians: ApaI tt genotype associated with CD. 55
Animal models	VDR KO mice develop severe colitis in several models of IBD colitis (IL-10 KO, DSS and TNBS). 58–60,63–65 Supplementation with vitamin D ameliorates experimental colitis in several IBD models. 59 Mice deficient in dietary vitamin D have decreased colonic antimicrobial activity and elevated levels of bacteria in colonic tissue. 61,62,85
In vitro studies	Vitamin D promotes maintenance of epithelial barriers (tight junctions and packaging of mucin in goblet cells). 63,83,84 Vitamin D enhances protective innate immune responses (NOD2 expression, cathelicid and defensin production). 66–73 Vitamin D regulates adaptive immune responses (increased Th2/Treg; decreased Th1/Th17 CD4+; inhibition of maturation of DCs; downregulation of TNF-α, IL12, IL-17, IL-21 and IFN-γ; upregulation of IL6, IL10 and FoxP3. 7,71,76,77,79–81

3.1 Epidemiology

Epidemiologic studies have shown that vitamin D deficiency is highly prevalent among patients with IBD. ^16–19 For example, vitamin D deficiency (<20ng/mL) has been reported in 18–50% of patients with IBD at the end of summer and in 50–68% at the end of winter, with an additional ~35% of patients being vitamin D insufficient (20–29.9ng/mL). ^{16–18,20–25}

Studies comparing vitamin D concentrations in IBD patients and healthy populations have yielded conflicting evidence. Although some of these studies have suggested that vitamin D concentrations are lower in IBD patients than in healthy controls, ^26,27 other studies have reported no difference. ^28–31 Vitamin D deficiency in IBD can be aggravated by several factors, including decreased exposure to sunlight, decreased intestinal absorption of vitamin D in patients with CD, and decreased oral intake. ^{20,22,32–37}

Epidemiological evidence suggests that living at higher latitudes and/or being less exposed to sunlight is associated with a number of autoimmune diseases, including CD, UC, multiple sclerosis and diabetes mellitus type I. ^38–40 This phenomenon, often called the north–south gradient, has been observed in Europe as well as in North America with respect to IBD prevalence. ^41,42 For example, data from large observational population-based studies with over 3428376 person-years of follow-up (the Nurses Health Studies I and II) showed that the incidence of CD and UC increased significantly with increasing latitude. ⁴³ Compared with 30-year-old women residing in northern latitudes, the multivariate-adjusted hazard ratios (HRs) for 30-year-old women residing in southern latitudes were 0.48 (95% confidence interval (CI), 0.30–0.77) for CD and 0.62 (95% CI, 0.42–0.90) for UC. This north–south gradient is probably associated with higher levels of residential sun exposure in southern latitudes. ⁴² A large prospective population-based observational study of 91870 healthy women aged 40–65 years from 1990 onward identified 123 incident cases of IBD, including 45 with CD, 71 with UC and 7 with indeterminate colitis. Higher levels of residential sun exposure were associated with a significant decrease in the risk of CD (HR 0.49; 95% CI, 0.23–1.01; p = 0.04), but not of UC (HR, 1.21; 95% CI, 0.61–2.11) for the third versus the first tertile of mean daily ultraviolet radiation dose. ⁴⁴

A third epidemiological investigation found that serum concentrations of vitamin D were lowest after winter. ^22,25 This correlates with seasonal patterns in the incidence and flares of IBD, which peak during the spring season. ^45–49

Lastly, smoking is a well-recognized risk factor for CD, and several studies have observed that smokers have lower vitamin D levels than non-smokers. ^18,50–52

3.2 Genetic studies

Four VDR polymorphisms have been associated with the risk of IBD: TaqI, BsmI, FokI and ApaI. ^53,54 A recent meta-analysis of nine studies revealed that, in Asians, the ff genotype of FokI was associated with an increased risk of UC (odds ratio [OR] = 1.65; 95% CI, 1.11–2.45), the "a" allele of ApaI appeared to protect against CD (OR = 0.81; 95% CI, 0.67–0.97) and the tt genotype of Taq1 increased the risk of CD in Europeans (OR = 1.23; 95% CI, 1.02–1.49). ² Another recent meta-analysis of 24 studies indicated that the AA genotype of ApaI significantly enhanced CD risk (AA versus aa: OR = 1.40; 95% CI, 1.05–1.88), the B allele of BsmI enhanced CD risk in East Asians (BB plus Bb versus bb: OR = 1.77; 95% CI, 1.14–2.74), and the T allele of TaqI was protective in Caucasians against CD (TT plus Tt versus tt: OR = 0.79; 95% CI, 0.63–1.00) and UC (T versus t: OR = 0.89, 95% CI, 0.80–0.99). ⁵⁵

3.3 Animal models

VDR agonists have shown beneficial effects in animal models of many immune-mediated diseases, including IBD, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and diabetes mellitus type I. ^56–58 Studies in murine models of colitis showed the importance of vitamin D in the pathogenesis of IBD. ¹⁷ Vitamin D was shown to ameliorate the severity of experimental colitis in IL-10–deficient knockout (KO) mice, in that vitamin D–deficient IL-10 KO mice rapidly developed severe colitis, whereas vitamin D-sufficient IL-10 KO mice did not. ⁵⁹ Moreover, supplementation with vitamin D ameliorated the severity of experimental colitis. In addition, mice deficient in both IL-10 and VDRs (double VDR/IL-10 KO) developed the most severe fulminant enterocolitis. ^58,60 Mechanistically, these mice had reduced numbers of CD8alphaalpha intraepithelial lymphocytes, low levels of IL-10, and showed increased inflammatory responses to normally harmless commensal flora. ⁶¹ Furthermore, vitamin D was shown to inhibit several TNF-alpha–related genes in these animal models. ⁶²

The findings in IL-10 KO mice were confirmed in dextrane sulphate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis models. ^63–65 The effects of vitamin D on immune system functions in these animal models were apparently influenced by dietary calcium. ³⁸ Vitamin D–deficient mice on low-calcium diets developed severe IBD, whereas treatment of these mice with alfacalcidiol (1,25(OH)2D3) improved IBD symptoms; this was even more evident in mice on high-calcium diets.

3.4 In vitro studies of vitamin D and innate immunity

Vitamin D signaling through its nuclear VDR has emerged as a key regulator of innate immunity in humans. Vitamin D has been shown to upregulate antimicrobial peptides (such as cathelicidins and beta-defensins) as well as autophagy processes. ^66–70 Physiologic concentrations of 1,25(OH)2D inhibited the maturation of dendritic cells (DCs) by inhibiting activation markers such as MHC class II, CD40, CD80 and CD86, and upregulating inhibitory molecules (ILT3), resulting in the maintenance of an immature and tolerogenic phenotype. ⁷¹ Following stimulation with cholecalciferol (25(OH)D3), dendritic cells from CD patients displayed a reduced response to lipopolysaccharide and a diminished ability to activate T cells. ⁷² Interestingly, vitamin D was found to robustly stimulate the expression of the NOD2 gene and protein in primary human monocytic and epithelial cells through distal enhancers in that gene. ⁷³ Transcription of the NOD2 gene was stimulated directly by 1,25D-bound VDR. ⁷⁴ In addition, the vitamin D analogue TX 527 blocked the TNF-alpha-induced activation of NF-kappaB and the nuclear translocation of the latter, together with the degradation of IKB-alpha. ⁷⁵

3.5 In vitro studies of vitamin D and adaptive immunity

The effects of 1,25(OH)2D on the adaptive immune system include decreasing the numbers of Th1/Th17 CD4+ T cells and cytokines, increasing regulatory T cells, and downregulating T cell-driven IgG production. ^7,76,77 Furthermore, 1,25(OH)2D was shown to downregulate IL-12 and augment IL-10 production by DCs, promoting a shift from a Th1 to a Th2 phenotype. ⁷¹ Supplementation with 140000 IU/month vitamin D for 2 months in healthy subjects was associated with significantly increased regulatory T cells (Tregs) in the peripheral circulation. ⁷⁸

Vitamin D is also involved in the regulation of many cytokines, including tumor necrosis factor alpha (TNF-α). Incubation of 1,25(OH)2D with DCs and T lymphocytes in vitro decreased the production of the pro-inflammatory cytokines TNF-α and interferon gamma (INF-γ). ^79,80 Incubation of peripheral blood mononuclear cells (PBMCs) isolated from UC patients with the vitamin D agonist calcitriol reduced IFN-γ and increased IL-10 production, whereas incubation of PBMCs from CD patients with calcitrol reduced TNF-α production. ⁸¹ Microarray analysis showed that 1,25(OH)2D3 downregulated the expression of several TNF-α-related genes in colonic biopsy tissue. ⁶² Moreover, the vitamin D analogue KH 1060 synergized with anti-TNF-α treatment in decreasing TNF-α levels and inhibiting PBMC proliferation in samples from patients with IBD. ⁸²

3.6 In vitro studies of vitamin D and mucosal barrier function

Vitamin D may also ameliorate IBD by playing a protective role in mucosal barrier homeostasis, maintaining the integrity of junction complexes and healing the colonic epithelium. ⁶³ In cell cultures, 1,25(OH)2D3 markedly increased the expression of tight junction proteins and mRNA, and reduced mucosal permeability. ⁸³ Vitamin D may also be involved in the physiological packaging of mucins in goblet cells. ⁸⁴ Restoration of ionized calcium levels in VDR-ablated mice prevented altered mucin packaging, supporting the hypothesis that calcium is required for the physiological packaging of mucins in goblet cells. Interestingly, mice fed a vitamin D–deficient diet showed dysregulated colonic antimicrobial activity and had ~50-fold elevated levels of bacteria in colonic tissue. ⁸⁵

4. Clinical evidence suggesting a role of vitamin D in the pathogenesis of IBD

Although considerable in vitro and animal experiments suggest that vitamin D has beneficial effects on the course of IBD, clinical data are scarce and are primarily observational. Low vitamin D concentration has been associated with increased disease activity in patients with both UC and CD, although the evidence is conflicting. ^86,87 To date, only two small open label trials (with 37 and 18 patients, respectively) and one randomized controlled trial (RCT) (with 104 patients) have analyzed the effects of vitamin D supplementation on disease activity in patients with CD, ^88–90 but there have been no clinical trials in patients with UC.

4.1 Crohn's disease

Data supporting a clinical association between vitamin D deficiency and disease activity in CD are conflicting. A large study of 504 IBD patients, 403 with CD and 101 with UC, reported a correlation between vitamin D concentrations and disease activity (Harvey–Bradshaw index, short inflammatory bowel disease questionnaire) in CD (regression coefficient, −2.21; 95% CI, −4.10 to −0.33) but not in UC patients. ¹⁷ A retrospective study of 3217 patients with IBD (55% with CD) found that plasma 25(OH)D concentrations < 30ng/mL in CD patients were associated with increased risks of surgery (OR 1.76; 95% CI, 1.24–2.51) and IBD-related hospitalization (OR 2.07; 95% CI, 1.59–2.68) when compared with patients with 25(OH)D ≥ 30ng/mL. ²⁴ Furthermore, CD patients with initial 25(OH)D < 30ng/mL followed by subsequent normalization had a reduced likelihood of surgery (OR 0.56; 95% CI, 0.32–0.98) compared with those who remained deficient. In a cross-sectional study of 182 CD patients and 62 healthy controls, serum 25(OH)D was inversely associated with disease activity. ⁵² Median vitamin D concentrations differed significantly among CD patients in remission [Crohn's disease activity index (CDAI) < 150, vitamin D 25ng/mL] and those with mild (CDAI 150–220, vitamin D 20ng/mL) and moderately active (CDAI 220–400, vitamin D 8ng/mL; p < 0.01) disease. A recent Chinese study on a cohort of 107 patients with CD found that 25(OH)D3 concentrations correlated negatively with disease severity (r=−0.285, p=0.030). ⁹¹

Several other small studies also confirmed the association of lower 25(OH)D concentrations and disease activity in CD patients, with correlation coefficients of ~−0.4. ^{28,30,87,92,93} A study examining whether pretreatment vitamin D status influences the durability of anti-TNF-α therapy in 74 patients with CD and 27 with UC found that patients with insufficient vitamin D ceased anti-TNF-α therapy earlier (HR, 2.13), due mainly to a loss of response (HR, 3.49), and that this effect was stronger for patients with CD (HR, 2.38) than UC. ⁹⁴ By contrast, another study showed no correlation between CD activity and vitamin D status. ²⁶ Thus, the link between vitamin D concentration and disease activity in patients with CD remains unclear. ⁹⁵

Only a few clinical trials have assessed the effects of vitamin D in patients with CD. In a small open label trial of 35 CD patients in remission, treatment with 0.25 µg 1,25(OH)2D3, but not 1000 IU 25(OH)D3, significantly reduced clinical activity, as measured by the CDAI, from 69 to 57, as well as the mean C-reactive protein concentration. ⁸⁹ In a small open label trial of 18 CD patients with low to moderate disease activity, supplementation for 24 weeks with up to 5000 IU/day vitamin D3 significantly increased serum 25(OH)D3 concentrations and reduced mean CDAI scores from 230±74 to 118±66 (p < 0.0001). ⁹⁰ No significant adverse effects or signs of vitamin D toxicity were observed. A multicentre, randomized, double-blind placebo-controlled trial evaluating vitamin D maintenance therapy in 108 CD patients in clinical remission (CDAI score < 150) found that treatment with 1200 IU/day vitamin D3 for 3 months improved vitamin D status significantly compared with placebo. ⁸⁸ After a follow-up of 12 months, disease relapse rates were lower in the vitamin D than in the placebo group (29% versus 13%, p = 0.06).

4.2 Ulcerative colitis

Little is known about the correlation between UC activity and vitamin D status. High disease activity was reported to be more frequent in UC patients who were vitamin D deficient than those who were not vitamin D deficient (<30ng/mL) (68%, n = 19 versus 33%, n = 14; p = 0.04). ⁸⁶ A large retrospective study found that low plasma 25(OH)D was associated with increased risks of surgery and hospitalization. ²⁴ A recent Chinese study of 124 patients with UC found that 25(OH)D3 levels were negatively correlated with disease severity (r=−0.371, p<0.001). ⁹¹

By contrast, a large study of 504 IBD patients (including 101 with UC) reported no correlation between 25(OH)D concentrations and disease activity in UC patients. ¹⁷ Similarly, small Romanian (n = 33) and Iranian (n = 34) studies found that vitamin D levels did not correlate with disease activity, CRP concentration, or erythrocyte sedimentation rate, ^92,93 and a study in 21 children newly diagnosed with UC found no correlation between UC activity and vitamin D concentration. ²⁶

To date, no clinical trials have evaluated the effect of vitamin D supplementation on disease activity in patients with UC.

4.3 Other benefits of vitamin D supplementation

Vitamin D therapy may offer additional benefits to IBD patients, including improving bone health, reducing the risk of colorectal cancer, and treating depressive symptoms. ⁹⁶

4.4 Osteoporosis

The prevalence of low bone mineral density (BMD) is greater in patients with IBD than in healthy controls. ⁹⁷ It has been estimated that 22–77% of patients with IBD have osteopenia and that 12–41% have osteoporosis. ^4,98 A review of 20 RCTs of 44605 postmenopausal non-IBD women (evaluating the ability of vitamin D with or without calcium supplementation to prevent non-vertebral fractures and falls) found that the higher dose (>380 IU/day), but not the lower dose, of vitamin D decreased hip fractures by 26% (RR, 0.74; CI, 0.61–0.88) and non-vertebral fractures by 23% (RR 0.77, CI 0.68–0.87). ⁹⁹ Optimal benefits were observed at the highest dose tested to date, 700–1000 IU per day, or a mean 25(OH)D between 30–44ng/mL. A meta-analysis of 19 RCTs of medical therapies for the treatment of low BMD in IBD patients concluded that data supporting the efficacy of calcium and current doses of vitamin D (400–800 IU/day) were insufficient. ⁹⁸ This is in agreement with a recently published study by van Bodegraven et al., where treatment with bisphosphonates concomitantly with vitamin D (800 IU) and calcium (1000g) supplementation in osteopenic CD patients had a more beneficial effect on BMD than supplementation with vitamin D and calcium alone. ¹⁰⁰

4.5 Prevention of colorectal carcinoma

The first study suggesting an inverse relationship between exposure to sunshine and colorectal cancer (CRC) risk was published 35 years ago. A meta-analysis of five studies revealed that patients with serum 25(OH)D levels ≥ 33 ngl/L had a 50% lower risk of CRC than patients with 25(OH)D levels ≤12 nmol/L. ¹⁰¹ Furthermore, vitamin D intake of 1000 IU/day was associated with a 50% lower CRC risk than intake of <100 IU/day. ¹⁰² A review of prospective cohort data on CRC prevention suggested that achieving a 25(OH)D serum concentration of 30–44ng/mL had the greatest benefits. ⁹⁹ Analysis of the incidence of malignancies in 2809 IBD patients with a median follow-up of 11 years found that patients with vitamin D deficiency (~33%) were at increased risk of cancer (adjusted OR, 1.82; 95% CI, 1.25–2.65) compared with patients with sufficient vitamin D. ¹⁰³ Each 1ng/mL increase in 25(OH)D plasma concentration was associated with an 8% reduction in the risk of CRC.

4.6 Depression

Depression and anxiety are common among IBD patients. ¹⁰⁴ Depression can add to disability in these patients, is a risk factor for disease flare-ups, and can even impair the effectiveness of medication. ^105,106 Several studies reported that vitamin D deficiency was significantly associated with mood disorders. ^107–109 Supplementation with high (3000–6000 IU/d) but not low (400–600 IU/d) doses of vitamin D seemed to ameliorate the symptoms of depression. ^110–112

5. Optimal supplementation protocol for IBD patients

5.1 Target vitamin D serum concentration

Vitamin D status is best evaluated by measuring the serum concentration of 25(OH)D. No consensus yet exists on the optimal serum levels of 25(OH)D, and health benefits may differ by target levels. 25(OH)D deficiencies are based largely on measurements of parathormone (PTH) concentrations and bone health. In most recent studies, 25(OH)D concentrations of >30ng/mL (>75 nmol/L) are considered normal, concentrations of <20ng/mL are considered vitamin D deficient, and levels of 20–30ng/mL are considered vitamin D insufficient. ^69,113

Physiological studies have shown maximal calcium and phosphate absorption at a 25(OH)D serum concentration of 34ng/mL (85 nmol/l), PTH increases at 25(OH)D levels below 31ng/mL, and maximal genomic stability at levels of at least 36ng/mL. ¹¹⁴ Two large patient cohorts showed minimal all-cause mortality rates at serum 25(OH)D concentrations of 40–48ng/mL. ^115,116 A meta-analysis of 18 RCTs assessing vitamin D supplementation for the prevention of falls and fractures found that serum 25(OH)D levels of ~30–44ng/l provided optimal benefits for all investigated endpoints, without increasing health risks. ⁹⁹ In an interesting study from Hawaii, the highest 25(OH)D3 concentration recorded following natural exposure to ultraviolet B was 60ng/mL. ¹¹⁷

The optimal vitamin D serum concentration in IBD remains undetermined. A recent study, however, found that disease activity was the lowest at vitamin D concentrations of 50–59ng/mL in all analyzed scenarios, including in patients with UC and CD, and in analyses performed during the summer and winter seasons. ²⁵

5.2 Vitamin D supplementation dose

Despite considerable research, the daily intake of vitamin D needed by healthy subjects, as well as by special populations, remains undetermined. ¹¹⁸

Currently, the Institute of Medicine of the National Academies has recommended an intake of 600 IU/day (800 IU/day for those aged >70 years) vitamin D for the general population, with a tolerable upper limit of 4000 IU/day for adults and for children aged >8 years. ¹¹⁹ By contrast, the Endocrine Society recommended a daily intake for adults of 1500–2000 IU/day, with an upper limit of 10000 IU/day. ¹¹³ The daily allowance and upper limits for patients with an increased vitamin D requirement due to malabsorption and vitamin D deficiencies have not been set.

It is generally believed that intake by healthy individuals of 100 IU/day vitamin D for 3 months increases serum 25(OH)D by ~1ng/mL. However, this increase depends on several factors, including pretreatment serum 25(OH)D concentration, body fat mass (since vitamin D is a fat-soluble hormone), the formulation of vitamin D administered (D3 > D2), the daily dose, and the absorption capacity of the gastrointestinal tract. ¹²⁰ Although a vitamin D3 dosage of 800 IU/day increased serum 25(OH)D levels to >20ng/L in 97.5% of healthy postmenopausal women, ¹²¹ vitamin D3 dosages required to attain serum concentrations of at least 30ng/mL are less well-defined and may be as high as 1800–4000 IU per day. ⁹⁹ Thus, dosages effective in raising serum 25(OH)D concentrations to the upper end of the normal range (30–60ng/mL) are probably disproportionate compared with the dosages necessary to increase serum 25(OH)D concentrations to just above 30ng/mL.

Table 2 shows an overview of the relationship between vitamin D dose for at least 4 weeks and serum vitamin D concentrations in an RCT for the prevention of osteoporosis. ⁹⁹ A more detailed review of the largest trials is shown in Table 3.

Table 2.

Effect of vitamin D supplementation during randomized clinical trials for fracture prevention on serum 25(OH)D concentrations.

Vitamin D dose (IU/day)	Number of RCTs	Mean serum vitamin D concentration achieved (ng/mL) [range]
400	3	23 [18–26]
700*	1	40*
800	9	30 [24–42]
2000	7	35 [28–41]
4000	3	48 [34–64]
5720–7600	4	51 [48–59]

Vitamin D dose (IU/day)	Number of RCTs	Mean serum vitamin D concentration achieved (ng/mL) [range]
400	3	23 [18–26]
700*	1	40*
800	9	30 [24–42]
2000	7	35 [28–41]
4000	3	48 [34–64]
5720–7600	4	51 [48–59]

Data based on. ⁹⁹

* The vitamin D concentration before supplementation was high in this trial (31ng/mL).

Table 2.

Effect of vitamin D supplementation during randomized clinical trials for fracture prevention on serum 25(OH)D concentrations.

Vitamin D dose (IU/day)	Number of RCTs	Mean serum vitamin D concentration achieved (ng/mL) [range]
400	3	23 [18–26]
700*	1	40*
800	9	30 [24–42]
2000	7	35 [28–41]
4000	3	48 [34–64]
5720–7600	4	51 [48–59]

Vitamin D dose (IU/day)	Number of RCTs	Mean serum vitamin D concentration achieved (ng/mL) [range]
400	3	23 [18–26]
700*	1	40*
800	9	30 [24–42]
2000	7	35 [28–41]
4000	3	48 [34–64]
5720–7600	4	51 [48–59]

Data based on. ⁹⁹

* The vitamin D concentration before supplementation was high in this trial (31ng/mL).

Table 3.

Effects of vitamin D supplementation on serum vitamin concentration in selected trials.

Study	Population	Vitamin D3 dose (IU/day unless stated otherwise)	Duration of supplementation	Baseline vitamin D (ng/mL)	Follow-up vitamin D (ng/mL)
Lyons 2007 145	3440 elderly people (2724 women)	A: 100000 IU every 4 months B: placebo	36 months	–	A: 32.17 (20 months) B: 21.69 *
Pfeifer (2009) 146	242 healthy seniors	A: 800 IU + 1g Ca B: placebo + 1g Ca	12+8 months free follow-up	A: 22.1±7.2 B: 21.7±7.6	A: 33.7±7.2 B: 22.9±8.0
Trivedi (2003) 147	2686 (2037 men)	A: 100000 IU every 4 months B: placebo	48 months	–	A: 29.83±8.3 B: 21.45±8.5
Chapuy (2002) 148	583 elderly women	A: 800 IU + 1.2g Ca B: placebo	24 months	A: 8.55±5.3 B: 9.16±6.9	A: 31.12 B: 6.02
Meyer (2002) 149	1144 elderly	A: 400 IU B: placebo	12 months	A: 18.88±10.4 B: 20.48±13.25	A: 25.7±8.4 B: 18.47±8.03
Grant (2004) 150	5292 elderly (measured on 60 patients)	A: 800 IU B: 1g Ca C: 800 IU + 1g Ca D: placebo	12 months	15.2±6.5	A: 24.9±8.7 B: 16.6±5.7 C: 24.8±6.9 D: 18.3±7.2
Lips (1996) 151	2578 adults	A: 400 IU B: placebo	12 months	A: 10.84 B: 10.44	A: 24.9 B: 9.23
Vieth (2001) 152	61 healthy	A: 1000 IU B: 4000 IU	3 months	A: 17.4±6.7 B: 15.2±5.4	A: 27.6±6.8 B: 38.7±5.9
Broe (2007) 153	124 elderly	A: 200 IU B: 400 IU C: 600 IU D: 800 IU E: 0	5 months	A:17.8±9.2 B: 20.7±11.6 C:16.5±7.4 D:21.4±9.2 E:21.2±11.4	A: 24.5±8.29 B: 21.89±9.22 C: 24.47±8.78 D: 29.82±6.26 E: 24.12±13.04
Yang (2013) 90	18 adult CD	5000 IU**	24 weeks	16±10	45±19
Pappa (2012) 122	61 children IBD	A: D2 2000 IU/day B: D3 2000 IU/day C: 50000 IU /week	6 weeks	A: 16.1±1.0 B: 14.7±0.8 C: 15.3±1.0 **	A: 25.7±2.2 B: 31.5±1.9 C: 40.8±2.6

Study	Population	Vitamin D3 dose (IU/day unless stated otherwise)	Duration of supplementation	Baseline vitamin D (ng/mL)	Follow-up vitamin D (ng/mL)
Lyons 2007 145	3440 elderly people (2724 women)	A: 100000 IU every 4 months B: placebo	36 months	–	A: 32.17 (20 months) B: 21.69 *
Pfeifer (2009) 146	242 healthy seniors	A: 800 IU + 1g Ca B: placebo + 1g Ca	12+8 months free follow-up	A: 22.1±7.2 B: 21.7±7.6	A: 33.7±7.2 B: 22.9±8.0
Trivedi (2003) 147	2686 (2037 men)	A: 100000 IU every 4 months B: placebo	48 months	–	A: 29.83±8.3 B: 21.45±8.5
Chapuy (2002) 148	583 elderly women	A: 800 IU + 1.2g Ca B: placebo	24 months	A: 8.55±5.3 B: 9.16±6.9	A: 31.12 B: 6.02
Meyer (2002) 149	1144 elderly	A: 400 IU B: placebo	12 months	A: 18.88±10.4 B: 20.48±13.25	A: 25.7±8.4 B: 18.47±8.03
Grant (2004) 150	5292 elderly (measured on 60 patients)	A: 800 IU B: 1g Ca C: 800 IU + 1g Ca D: placebo	12 months	15.2±6.5	A: 24.9±8.7 B: 16.6±5.7 C: 24.8±6.9 D: 18.3±7.2
Lips (1996) 151	2578 adults	A: 400 IU B: placebo	12 months	A: 10.84 B: 10.44	A: 24.9 B: 9.23
Vieth (2001) 152	61 healthy	A: 1000 IU B: 4000 IU	3 months	A: 17.4±6.7 B: 15.2±5.4	A: 27.6±6.8 B: 38.7±5.9
Broe (2007) 153	124 elderly	A: 200 IU B: 400 IU C: 600 IU D: 800 IU E: 0	5 months	A:17.8±9.2 B: 20.7±11.6 C:16.5±7.4 D:21.4±9.2 E:21.2±11.4	A: 24.5±8.29 B: 21.89±9.22 C: 24.47±8.78 D: 29.82±6.26 E: 24.12±13.04
Yang (2013) 90	18 adult CD	5000 IU**	24 weeks	16±10	45±19
Pappa (2012) 122	61 children IBD	A: D2 2000 IU/day B: D3 2000 IU/day C: 50000 IU /week	6 weeks	A: 16.1±1.0 B: 14.7±0.8 C: 15.3±1.0 **	A: 25.7±2.2 B: 31.5±1.9 C: 40.8±2.6

* Calculated from original data, reported as nmol/L using the formula 1ng/mL = 2.49 nmol/L.

** Mean ± SE.

*** Therapy initiated at 1000 IU/day and increased every 2 weeks to a maximum of 5000 IU/day or until serum vitamin D >40ng/mL; 14/18 patients required 5000 IU/day.

Table 3.

Effects of vitamin D supplementation on serum vitamin concentration in selected trials.

Study	Population	Vitamin D3 dose (IU/day unless stated otherwise)	Duration of supplementation	Baseline vitamin D (ng/mL)	Follow-up vitamin D (ng/mL)
Lyons 2007 145	3440 elderly people (2724 women)	A: 100000 IU every 4 months B: placebo	36 months	–	A: 32.17 (20 months) B: 21.69 *
Pfeifer (2009) 146	242 healthy seniors	A: 800 IU + 1g Ca B: placebo + 1g Ca	12+8 months free follow-up	A: 22.1±7.2 B: 21.7±7.6	A: 33.7±7.2 B: 22.9±8.0
Trivedi (2003) 147	2686 (2037 men)	A: 100000 IU every 4 months B: placebo	48 months	–	A: 29.83±8.3 B: 21.45±8.5
Chapuy (2002) 148	583 elderly women	A: 800 IU + 1.2g Ca B: placebo	24 months	A: 8.55±5.3 B: 9.16±6.9	A: 31.12 B: 6.02
Meyer (2002) 149	1144 elderly	A: 400 IU B: placebo	12 months	A: 18.88±10.4 B: 20.48±13.25	A: 25.7±8.4 B: 18.47±8.03
Grant (2004) 150	5292 elderly (measured on 60 patients)	A: 800 IU B: 1g Ca C: 800 IU + 1g Ca D: placebo	12 months	15.2±6.5	A: 24.9±8.7 B: 16.6±5.7 C: 24.8±6.9 D: 18.3±7.2
Lips (1996) 151	2578 adults	A: 400 IU B: placebo	12 months	A: 10.84 B: 10.44	A: 24.9 B: 9.23
Vieth (2001) 152	61 healthy	A: 1000 IU B: 4000 IU	3 months	A: 17.4±6.7 B: 15.2±5.4	A: 27.6±6.8 B: 38.7±5.9
Broe (2007) 153	124 elderly	A: 200 IU B: 400 IU C: 600 IU D: 800 IU E: 0	5 months	A:17.8±9.2 B: 20.7±11.6 C:16.5±7.4 D:21.4±9.2 E:21.2±11.4	A: 24.5±8.29 B: 21.89±9.22 C: 24.47±8.78 D: 29.82±6.26 E: 24.12±13.04
Yang (2013) 90	18 adult CD	5000 IU**	24 weeks	16±10	45±19
Pappa (2012) 122	61 children IBD	A: D2 2000 IU/day B: D3 2000 IU/day C: 50000 IU /week	6 weeks	A: 16.1±1.0 B: 14.7±0.8 C: 15.3±1.0 **	A: 25.7±2.2 B: 31.5±1.9 C: 40.8±2.6

Study	Population	Vitamin D3 dose (IU/day unless stated otherwise)	Duration of supplementation	Baseline vitamin D (ng/mL)	Follow-up vitamin D (ng/mL)
Lyons 2007 145	3440 elderly people (2724 women)	A: 100000 IU every 4 months B: placebo	36 months	–	A: 32.17 (20 months) B: 21.69 *
Pfeifer (2009) 146	242 healthy seniors	A: 800 IU + 1g Ca B: placebo + 1g Ca	12+8 months free follow-up	A: 22.1±7.2 B: 21.7±7.6	A: 33.7±7.2 B: 22.9±8.0
Trivedi (2003) 147	2686 (2037 men)	A: 100000 IU every 4 months B: placebo	48 months	–	A: 29.83±8.3 B: 21.45±8.5
Chapuy (2002) 148	583 elderly women	A: 800 IU + 1.2g Ca B: placebo	24 months	A: 8.55±5.3 B: 9.16±6.9	A: 31.12 B: 6.02
Meyer (2002) 149	1144 elderly	A: 400 IU B: placebo	12 months	A: 18.88±10.4 B: 20.48±13.25	A: 25.7±8.4 B: 18.47±8.03
Grant (2004) 150	5292 elderly (measured on 60 patients)	A: 800 IU B: 1g Ca C: 800 IU + 1g Ca D: placebo	12 months	15.2±6.5	A: 24.9±8.7 B: 16.6±5.7 C: 24.8±6.9 D: 18.3±7.2
Lips (1996) 151	2578 adults	A: 400 IU B: placebo	12 months	A: 10.84 B: 10.44	A: 24.9 B: 9.23
Vieth (2001) 152	61 healthy	A: 1000 IU B: 4000 IU	3 months	A: 17.4±6.7 B: 15.2±5.4	A: 27.6±6.8 B: 38.7±5.9
Broe (2007) 153	124 elderly	A: 200 IU B: 400 IU C: 600 IU D: 800 IU E: 0	5 months	A:17.8±9.2 B: 20.7±11.6 C:16.5±7.4 D:21.4±9.2 E:21.2±11.4	A: 24.5±8.29 B: 21.89±9.22 C: 24.47±8.78 D: 29.82±6.26 E: 24.12±13.04
Yang (2013) 90	18 adult CD	5000 IU**	24 weeks	16±10	45±19
Pappa (2012) 122	61 children IBD	A: D2 2000 IU/day B: D3 2000 IU/day C: 50000 IU /week	6 weeks	A: 16.1±1.0 B: 14.7±0.8 C: 15.3±1.0 **	A: 25.7±2.2 B: 31.5±1.9 C: 40.8±2.6

* Calculated from original data, reported as nmol/L using the formula 1ng/mL = 2.49 nmol/L.

** Mean ± SE.

*** Therapy initiated at 1000 IU/day and increased every 2 weeks to a maximum of 5000 IU/day or until serum vitamin D >40ng/mL; 14/18 patients required 5000 IU/day.

There have been few consensus recommendations regarding vitamin D supplementation for patients with IBD. Studies have suggested that the ability to absorb vitamin D is about 30% lower in CD patients than in healthy individuals, suggesting that the daily doses recommended for the general population should be increased by a factor of 1.5. ³² The European Crohn's and Colitis Organisation has recommended that patients on steroid therapy and those with reduced BMD receive vitamin D supplements but has provided no detail regarding dose. ¹²² The suggested vitamin D3 dose for IBD patients can also be based on baseline 25(OH)D and the presence of small bowel involvement, such that patients with serum 25(OH)D concentrations <4, 4–10, 10–16, 16–24 and 24ng/mL should receive 5000, 4000, 3000, 2000 and 1000 IU/day, respectively. ⁴ These doses should be multiplied by 1.5–2 for small bowel involvement in CD patients and for obesity.

The oral dose of 25(OH)D3 needed to raise the serum concentration to 40ng/mL in CD patients was investigated by starting 18 patients on 1000 IU/day once daily. ⁹⁰ Serum 25(OH)D3 levels were measured every 2 weeks, and vitamin D doses were increased biweekly by 1000 IU/day increments until serum 25(OH)D3 concentrations were above 40ng/mL or until patients were taking 5000 IU/day vitamin D3. Of the 18 patients, 14 required the maximum dose of 5000 IU. Moreover, following administration of this dose for 24 weeks, half the patients did not reach the target vitamin D serum concentration of 40ng/mL, although this protocol effectively and significantly increased mean serum 25(OH)D3 levels from 16±10ng/mL at baseline to 45±19ng/mL after 24 weeks. Another study, in pediatric IBD patients (mean age: 16 years), found that serum 25(OH)D3 levels increased from 0.8 to 1.1ng/mL for every 10000 IU of vitamin D2 and to 2ng/mL for every 10000 IU of vitamin D3. ¹²³ A recent prospective RCT involving 83 children aged 8–18 years with CD found that treatment with 2000 IU/day vitamin D3 for 6 months was more effective in raising vitamin D3 concentrations than 400 IU/day vitamin D3 (12 versus 2ng/mL, respectively, p < 0.001). ¹²⁴

Several other retrospective trials investigated the effect of current supplementation doses on 25(OH)D serum concentrations. For example, 25(OH)D concentrations were significantly higher in CD patients who took 400–800 IU/day vitamin D than in those who did not (31 versus 22ng/mL, respectively, p < 0.01). ⁵² In addition, a recent study of 83 pediatric CD patients found that supplementation with 400 IU and 2000 IU vitamin D daily for 3 months increased mean serum 25(OH)D concentrations by 2.8ng/mL and 16ng/mL, respectively, over baseline. ¹²⁴ In an Irish study, a supplement containing 200–400 IU/day vitamin D was insufficient in preventing vitamin D deficiency in patients with IBD. ²³ In a Slovak study of 220 IBD patients, a vitamin D3 supplement (400–800 IU/day) significantly reduced the decline in serum vitamin D3 concentrations from summer to winter in patients with CD (−0.7 vs. −7.5ng/mL, p < 0.05). ²⁵

Another factor that must be considered is the speed at which the target serum 25(OH)D concentration can be achieved. Little is known about the turnover of the vitamin D pool, although 25(OH)D is generally thought to have a half-life of 10–19 days, ¹²⁵ with four half-lives usually considered adequate to reach a steady state. Thus, vitamin D supplementation for 6–12 weeks should result in a steady state serum concentration. Most of this increase in serum 25(OH)D occurs early during the course of treatment with supplemental vitamin D3. ¹²⁶

The dosing schedule must also be considered. Data from clinical trials in non-IBD populations are inconsistent when comparing lower daily doses with higher weekly/monthly dosing of equipotent cumulative doses. A comparison of 40 elderly women taking 400 IU twice daily (800 IU/day) with 97333 IU of 25(OH)D3 every 4 months, yielding total doses of 292000 IU in both groups, found that, after 12 months of treatment, 47% and 28%, respectively, achieved serum 25(OH)D levels of 30ng/mL (p < 0.0001). ¹²⁷ However, compliance in these two groups was not compared.

5.3 Form of administration

Vitamin D can be administered in several oral or parenteral forms, including as cholecalciferol (vitamin D3), ergocalciferol (vitamin D2), 1- or 1,25-(di)hydroxyvitamin D3, or a vitamin D agonist (e.g. calcipotriol). These vitamin D supplements are available by prescription or without for a price of less than 10€ per month. Serum vitamin D concentration can also be increased by exposure to ultraviolet B radiation from sunshine or in a tanning bed.

The approach most often used to deliver vitamin D is oral supplementation with chole- or ergocalciferol. Several trials have compared the effectiveness of these two forms of vitamin D. In 69 rheumatology patients, a bolus of 300000 IU of vitamin D3 had greater potency than equimolar vitamin D2, with a higher, sustained serum 25(OH)D response and greater suppression of PTH. ¹²⁸ None of the patients who took vitamin D2 showed restoration of serum 25(OH)D to >20ng/mL, whereas 100% and 80% of the patients who took vitamin D3 achieved 25(OH)D concentrations of >20ng/L and >40ng/mL, respectively. Several other studies demonstrated that the potency of vitamin D2 is less than one-third that of vitamin D3, that vitamin D2 had a shorter duration of action than vitamin D3, and that vitamin D3 results in a 2- to 3-fold greater increase in vitamin D storage than vitamin D2. ^129,130 In an RCT of three vitamin D repletion regimens in 61 children with IBD, 6 weeks of oral supplementation with 2000 IU/day D2 (arm A), 2000 IU/day D3 (arm B) and 50000 IU/week D2 (arm C) increased serum 25(OH)D serum concentrations by 9.3±1.8ng/mL (arm A), 16.4±2.0ng/mL (arm B) and 25.4±2.5ng/mL (arm C), respectively (A versus C, p = 0.0004; A versus B, p = 0.03). ¹²³ However, 62% and 25% of participants in arms B and C, respectively, did not achieve a serum 25(OH)D concentration above 30ng/mL. A cumulative dose of 400000 IU vitamin D2 or 220000 IU vitamin D3 may be sufficient to achieve a serum concentration of 30ng/mL. Interestingly, a small retrospective study of 108 veterans with IBD who received D3 were less likely than those who received D2 to use laboratory, pharmacy, radiology and fee-based services. ¹³¹

Alternatively, vitamin D can be administered in its hydroxylated forms, as 1,25-(OH)2 D3 and 1-(OH)D3, both of which are used to treat osteoporosis, or as vitamin D analogues, such as paricalcitol, maxacalcitol, alfacalciferol, doxecalciferol and calcipotrol. Although these compounds have not been assayed in the treatment of IBD, they were shown to be effective in small open label trials in psoriasis and rheumatoid arthritis. ^132–135

Heliotherapy also increases serum vitamin D concentrations. Exposure of a human body in a bathing suit to one minimal erythema dose of sunlight has been reported to be equivalent to ingesting about 10000–25000 IU of vitamin D. ¹³⁶ In a single case report, a CD patient exposed to a tanning bed (UVB radiation 290–315nm) while wearing a one-piece bathing suit for 10 minutes per day, 3 times per week for 4 weeks experienced an increase in serum 25(OH)D concentration from 7 to 32ng/mL. ¹³⁷

5.4 Route of application

The ability to absorb vitamin D is reduced in patients with CD, due either to inflammatory involvement of the proximal part of the small intestine or to a reduced circulating bile acid pool after resection of the terminal ileum. Even patients with quiescent CD showed a mean 30% decrease in their ability to absorb vitamin D2. ³² Vitamin D absorption is especially impaired in patients with previous ileal resections. ^35,36,138 Treatment with oral cholecalciferol has been shown to be sufficient in patients with small or moderate resections (<300cm), although other options, such as parenteral or oral 25-hydroxycholecalciferol supplementation, may be preferred in patients with severe short-bowel syndrome. ³⁵

Topical applications of vitamin D have not yet been tested in patients with IBD. In animal models of IBD, the intrarectal application of the VDR agonists (BXL-62) and 1,25(OH)VD has been shown to be effective in ameliorating experimental DSS colitis. ¹³⁹

5.5 Safety of vitamin D supplementation

Excess vitamin D can be toxic, as manifested by hypercalcemia. Excessive sunlight, however, does not lead to toxicity. A review of 25 RCTs of vitamin D supplementation for the prevention of osteoporotic fractures, falls, cardiovascular and oncologic diseases found that vitamin D supplementation was exceptionally safe. ⁹⁹ Mean serum calcium levels did not correlate with oral vitamin D of up to 100000 IU/day or serum 25(OH)D concentrations of up to 257ng/mL. In all of these trials, only 24 patients experienced hypercalcemia, with most of these being asymptomatic and resolving after fasting. Hypercalcemia was reported in patients later diagnosed with primary hyperparathyroidism and in patients also taking calcium supplements of 1000–1500mg per day. Of the 24 patients with hypercalcemia, 22 had serum 25(OH)D concentrations above 96ng/mL. Even very large oral and parenteral loading doses of vitamin D3 (300000–500000 IU) were well tolerated and safe in small clinical trials. ^128,140

Risk analyses found that 10000 IU/day cholecalciferol is non-toxic in healthy adults, suggesting that it is safe as an upper limit of daily intake. ^141,142 However, calcium absorption improves at higher serum 25(OH)D concentrations, suggesting the need to re-evaluate calcium supplements in patients taking >2000 IU/day vitamin D. ⁹⁹

Of all controlled trials with vitamin D, an increased incidence of nephrolithiasis occurred only in the Women's Health Initiative trial, in which patients received 400 IU/day vitamin D plus 1000mg/day calcium, with an HR of 1.17 (95% CI, 1.02–1.34). ¹⁴³ However, the results of two large population-based cohorts suggest that nephrolithiasis was due to calcium, not vitamin D, intake. ^144,145

6. Conclusion

Vitamin D supplementation and saturation of 25(OH)D3 reserves may be a novel therapeutic approach in patients with IBD, an approach that is simple, effective, safe and inexpensive. Preliminary preclinical and clinical data suggest that vitamin D has therapeutic potential in IBD, particularly in CD.

Patients with CD (and perhaps those with UC) who are vitamin D insufficient may benefit from vitamin D supplementation. The optimal concentration for patients with IBD remains unknown, but targeting serum 25(OH)D concentrations between 30 and 50ng/mL appears safe and may have benefits for IBD disease activity, improving bone health, preventing CRC, and alleviating depression. The dose needed to achieve these levels is probably much higher than the currently recommended daily allowance for healthy populations or supplementation doses for the treatment of reduced BMD. Depending on the baseline vitamin D serum concentration, ileal involvement in CD, body mass index, and maybe also smoking status, daily doses of 1800–10000 IU vitamin D are probably necessary. Cholecalciferol is the preferred oral form for supplementation, and heliotherapy may also be effective.

Clinical trials are needed to determine the optimal therapeutic regime, including optimal target serum concentrations of vitamin D, and its forms, dosages and treatment protocols.

Funding

This work was supported by a grant from the Slovak APVV Agency (No. APVV-0672-11).

Abbreviations

Abbreviations

• IBD

  inflammatory bowel disease

• UC

• CD

• IU

• HR

• CI

• OR

• TNBS

  2,4,6-trinitrobenzenesulfonic

• DSS

• DC

• Treg

• TNF-α

  tumor necrosis factor alpha

• INF-γ

• RCT

  randomized controlled trial

• PBMC

  peripheral blood mononuclear cell

• CDAI

  Crohn's disease activity index

• 1,25(OH)2D3

• 25(OH)D3

• BMD

• CRC

• PTH

Acknowledgments

Contributors: All authors contributed to the critical revision of the manuscript and final approval of the version to be published. All authors agree to be accountable for all aspects of the work by ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Competing interest: In the last 5 years, Tibor Hlavaty has served as a speaker, consultant or advisory board member for MSD, Abbvie, Hospira, Egis, Alfa Wasserman, Pfizer and Vifor. He has received scientific grants from Ferring Pharmaceuticals and unrestricted educational grants from MSD and Abbvie.

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