- Review Article
- Published: 06 May 2023
The Role of Vitamin D in Health and Disease: A Narrative Review on the Mechanisms Linking Vitamin D with Disease and the Effects of Supplementation
- Eleni Rebelos 1 , 2 ,
- Nikolaos Tentolouris 3 &
- Edward Jude ORCID: orcid.org/0000-0002-3186-4122 4 , 5 , 6
Drugs volume 83 , pages 665–685 ( 2023 ) Cite this article
Vitamin D insufficiency or deficiency (VDD) is a very prevalent condition in the general population. Vitamin D is necessary for optimal bone mineralization, but apart from the bone effects, preclinical and observational studies have suggested that vitamin D may have pleiotropic actions, whereas VDD has been linked to several diseases and higher all-cause mortality. Thus, supplementing vitamin D has been considered a safe and inexpensive approach to generate better health outcomes—and especially so in frail populations. Whereas it is generally accepted that prescribing of vitamin D in VDD subjects has demonstrable health benefits, most randomized clinical trials, although with design constraints, assessing the effects of vitamin D supplementation on a variety of diseases have failed to demonstrate any positive effects of vitamin D supplementation. In this narrative review, we first describe mechanisms through which vitamin D may exert an important role in the pathophysiology of the discussed disorder, and then provide studies that have addressed the impact of VDD and of vitamin D supplementation on each disorder, focusing especially on randomized clinical trials and meta-analyses. Despite there already being vast literature on the pleiotropic actions of vitamin D, future research approaches that consider and circumvent the inherent difficulties in studying the effects of vitamin D supplementation on health outcomes are needed to assess the potential beneficial effects of vitamin D. The evaluation of the whole vitamin D endocrine system, rather than only of 25-hydroxyvitamin D levels before and after treatment, use of adequate and physiologic vitamin D dosing, grouping based on the achieved vitamin D levels rather than the amount of vitamin D supplementation subjects may receive, and sufficiently long follow-up are some of the aspects that need to be carefully considered in future studies.
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Vitamin D insufficiency or deficiency (VDD) have been identified as very prevalent conditions in the general population, with some authors coining the use of the terms of “vitamin D deficiency epidemic, or pandemic” [ 1 , 2 ]. Other than the well-known effects of vitamin D on bone metabolism, vitamin D exerts pleiotropic actions. On one hand, VDD is associated with a series of adverse health conditions; on the other, supplementation with vitamin D is a low‐cost and safe intervention, making it an attractive therapeutic option in the clinician’s and researcher’s armature. These facts have contributed to the “explosion” in the interest of the scientific community on the understanding of the pleiotropic actions of vitamin D, among which is its immunomodulating effects.
Currently, there is vast research on the effects of vitamin D on human homeostasis, mechanisms of action, and supplementation outcomes. Up to June 2022, a PUBMED (MeSH) search on vitamin D yielded 65,758 results, with abrupt increases in the scientific publications in the last two decades. However, many of the published studies that have linked decreased vitamin D levels with poorer health outcomes are of associative nature, making the evidence whether vitamin D per se contributes or not to poor health relatively weak. In this narrative review, we present the links between VDD and a variety of diseases such as infections, COVID-19, type 2 diabetes (T2D), hypertension, cardiovascular, gastrointestinal, neurodegenerative and autoimmune diseases, and also the impact of vitamin D supplementation. First, we describe briefly, the mechanisms through which vitamin D could have an impact on the discussed pathology (Fig. 1 ). Then, we provide the available evidence from purely an association point of view. Since association does not prove causation, and there are often undetected confounders in reported associations, we then focused on meta-analyses and systematic reviews where vitamin D administration has been tested in the treatment or prognosis of the disease in question. Original articles and/or meta-analyses on the supplementation of vitamin D outcomes are also provided if available.
Mechanisms through which vitamin D may impact on bone health, immunity, cancer, cardiovascular disease, and neuroprotection
1.1 Regulation of Vitamin D
Vitamin D exists in two major forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol); the former is obtained with diet mainly from fungi and also plants, whereas the latter can be either obtained with diet (animal products) or synthesized in the skin from the conversion of the cholesterol precursor 7-dehydrocholesterol after exposure to adequate ultraviolet B radiation. Sun exposure for vitamin D synthesis may be efficient only when the angle of sun rays is more than 45°. As a result of this, inhabitants of the northern hemisphere do not receive sufficient amounts of vitamin D through skin synthesis during winter months, and in some northern areas, defective sun exposure may last up to 6 months of the year [ 3 ]. Moreover, a typical Western diet is poor in vitamin D [ 4 ]. To increase vitamin D ingestion, some countries have applied a policy of enriching milk products [ 5 , 6 ] and margarine [ 7 ] with vitamin D, while also the use of light bulbs for artificial UVB exposure is another tool to increase vitamin D synthesis.
Vitamin D needs to undergo activation, which consists of two consecutive hydroxylations; the first in the liver and the second predominantly in the kidneys, but also in extrarenal tissues. In the liver, cholecalciferol is quickly hydroxylated by the enzyme 25-hydroxylase (a CYP450-dependent enzyme also known as CYP2R1) yielding 25-hydroxyvitamin D (25(OH)D) in an uncontrolled process [ 8 ]. Low plasma calcium or phosphate levels regulate parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) levels, leading to the 1α-hydroxylation of 25(OH)D in the kidney and particularly in the mitochondria of the proximal convoluted tubule cells by the 1-hydroxylase enzyme (CYP27B1), resulting in the active vitamin D (1,25(OH) 2 D) [ 9 ] (Fig. 2 ). The 1α-hydroxylation may also occur in extrarenal tissues (epithelial tissues, placenta, bone, endocrine glands, brain, liver, and endothelium [ 10 , 11 ]), and especially in immune cells [ 12 ]. The 1,25(OH) 2 D can then de-activate 1α-hydroxylase and stimulate the 24-hydroxylase enzyme, which destroys 25(OH)D, providing a negative feedback loop that controls active vitamin D levels. The 24-hydroxylation of 25(OH)D yields 24,25(OH) 2 D, the inactive metabolite, the formation of which, along with saturation of the synthesis of vitamin D in the skin, guards against vitamin D intoxication. Even though the active form of vitamin D is 1,25(OH) 2 D, conventional blood tests measure 25(OH)D because of its long half-life (~15 days) [ 13 ], making it a suitable marker of vitamin D storage. In contrast, circulating 1,25(OH) 2 D does not reflect vitamin D status because of its short half-life of a few hours and its tight regulation by PTH, calcium, and phosphate levels [ 14 ]. The direct measurement of free (non-protein bound) 25(OH)D is also possible, with some authors proposing that the contemporaneous assessment of total and free 25(OH)D levels, as well as vitamin D binding protein (VDBP) and PTH should be measured in assessing vitamin D status and the effect of vitamin D supplementation on clinical outcomes [ 15 , 16 , 17 , 18 ].
Schematic representation of 1α-hydroxylation of 25 (OH)D in the active form in renal and extrarenal tissues. Several tissues have been described to have the CYP27B1 enzyme responsible for the 1α-hydroxylation of 25 (OH) D, but here emphasis is given in the immune and epithelial cells. Of note is that the control of the CYP27B1 activity differs between renal and extrarenal tissues. FGF23 fibroblast growth factor, IFN-γ interferon gamma, PTH parathyroid hormone, TLR toll-like receptor, TNF-α tumor necrosis factor alpha
The 1,25(OH) 2 D binds to the vitamin D receptor (VDR), a member of the nuclear receptor family of ligand-regulated transcription factors, which then forms a heterodimer with the retinoid X receptor. The heterodimer enters the cell nucleus and binds to vitamin D responsive elements (VDRE) in DNA, resulting in regulation of the expression of key genes in target organs to yield its actions. This is the basis for the genomic actions of vitamin D. Genomic actions of vitamin D require hours before any effects can be noticed. However, vitamin D also exerts actions that are rapid (within seconds to minutes); these are the nongenomic actions of vitamin D that are yielded without gene activation. The nongenomic actions of vitamin D may occur when vitamin D activates the VDR found outside the nucleus [ 19 ]. Furthermore, it has been suggested that vitamin D may also have a membrane receptor, which could explain the rapid nongenomic actions of vitamin D. However, the membrane target of vitamin D is currently not fully elucidated [ 20 ].
1.2 The Difficulty in Assessing the Effects of Vitamin D Supplementation in Health Outcomes
Vitamin D is a nutrient, but the major determinant of vitamin D levels is dependent on skin synthesis following sunlight exposure. Thus, placebo-controlled randomized controlled trials (RCTs) assessing the effects of vitamin D on health outcomes differ greatly from standard RCTs using drugs, since it is impossible to exclude vitamin D intake or sunlight exposure in the placebo arms of the vitamin D trials. [ 21 ]. Moreover, since VDD is a very prevalent condition, some RCTs (for instance, the large VITAL study [ 22 , 23 ]) also allow supplementation with low doses of vitamin D in the placebo group. While most RCTs are done in the general population to increase generalizability of the study results, it is well known that anthropometric characteristics of the study participants such as age, body mass index (BMI), and even skin pigmentation may affect the intake or metabolism of vitamin D, and therefore constitute confounders [ 24 , 25 ]. However, RCTs on vitamin D typically use standard doses of supplementation rather than personalized doses based on the characteristics of the participants. Moreover, in several RCTs, baseline and on-treatment 25(OH)D are not monitored; this is again a great confounder of the study results since subjects on the placebo arm may actually achieve higher 25(OH)D levels compared with subjects on treatment. Even when plasma 25(OH)D levels are monitored, there is large variance in the results, especially if the widely used immunoassay methodology is used [ 26 ]. Thus, data from different studies are not always comparable and could not be used in meta-analyses. Finally, the dose-response between vitamin D and its health effects is “S shaped” [ 21 , 27 ]. This implies that, on one hand, in subjects with VDD, large doses of vitamin D supplementation would be needed to elicit any meaningful effect, while on the other, supplementation in vitamin D replete subjects would not yield any effect. These are important confounders that make the interpretation and the execution of an RCT on vitamin D much more demanding compared with a drug RCT, and are expected to have affected the results of the RCTs that are presented in the following chapters.
2 Classical Vitamin D Actions
2.1 vitamin d and bone.
Mechanisms Vitamin D exerts both direct and indirect actions on bone [ 28 ]. Vitamin D is a major determinant of mineral homeostasis, promoting intestinal calcium and phosphorus absorption, which are required for optimal mineralization of bone. Vitamin D also exerts direct actions on bone. The direct actions of vitamin D on bone are more complex to demonstrate, and studies on VDR or CYP27B1 knockout animal models treated with a rescue high-calcium, high-phosphorus, and high-lactose diet have shown that even though severe bone abnormalities such as rickets (i.e., defective mineralization of the growth plate and adjacent metaphysis in the growing skeleton) and osteomalacia (i.e., the accumulation of unmineralized osteoid at sites other than the growing metaphysis) are prevented [ 29 , 30 ], changes in osteoblast number, mineral apposition rate, and bone volume remain [ 31 ]. Indeed, as reviewed in [ 28 ], direct effects of vitamin D on osteoblasts proliferation and survival and in the mineralization process have been shown.
Even though it is well established that acquired or genetic alterations in the vitamin D endocrine system can lead to rickets and osteomalacia and that, vice versa, treatment with an adequate quantity of vitamin D prevents rickets, osteomalacia [ 32 ], and renal osteodystrophy, the role of vitamin D in the skeleton of adults and older adults is often disputed.
In the large Vitamin D Assessment (VIDA) study—a trial in which participants were randomized to receive either 100,000 IU vitamin D3 or placebo monthly—correction of severe vitamin D deficiency led to improvement in bone mass density (BMD) [ 33 ], whereas vitamin D supplementation in already vitamin D replete adults was not associated with improved bone mass density (BMD) or bone quality [ 33 ]. Moreover, no effect was found in the VIDA trial in risk of fractures or falls after vitamin D supplementation in either the whole dataset or the vitamin D deplete group compared with placebo [ 33 ]. In the other large RCT Vitamin D and OmegA-3 TriaL (VITAL), supplemental vitamin D3 (2000 IU/d) was compared with placebo. Also in this study, vitamin D supplementation did not affect BMD of the spine, hip, or whole body, and this lack of effect was independent of baseline 25(OH)D levels [ 23 ]. However, among subjects with baseline free vitamin D levels below the median (< 14.2 pmol/L), those receiving vitamin D supplementation showed a slight increase in spine aBMD (0.75% versus 0%; p = 0.043) and attenuation in loss of total hip aBMD (−0.42% versus −0.98%; p = 0.044) compared with placebo [ 23 ]. In the Calgary study, the long-term outcomes of vitamin D supplementation at 400, 4000, and 10,000 IU per day were compared. It was found that subjects receiving the very high dose of vitamin D supplementation had decreased BMD at the radius and tibia compared with subjects receiving 400 IU daily [ 34 ], while no differences in BMD were noted between the 4000 and 400 IU groups. Moreover, very high-dose vitamin D supplementation (4000 and 10,000 IU/day) may result in hypercalciuria and/or hypercalcaemia [ 34 ]. The decrease in BMD with very high doses of vitamin D may be due to excessive bone resorption by increasing the number and activity of osteoclasts directly [ 35 ], or indirectly through activation of osteoblasts, which in turn activate osteoclastogenesis [ 36 ]. Another important aspect related to bone health often evaluated in clinical studies is the risk of fractures. In a large meta-analyses conducted by Bolland et al., administration of vitamin D had no effect on total fracture [36 trials; n = 44.790, relative risk (RR) 1.00, 95% confidence intervals (CI) 0.93–1.07], hip fracture (20 trials; n = 36.655, RR 1.11; 95% CI 0.97–1.26), or falls (37 trials; n = 34.144, RR 0.97; 95% CI 0.93–1.02), and similar results were found when comparing randomized controlled trials (RCTs) of high-dose versus low-dose vitamin D [ 37 ]. Moreover, regarding hip fractures, this meta-analysis showed that, whereas there is reliable evidence that vitamin D supplementation does not reduce hip fractures, it is uncertain whether it might increase the risk of hip fractures [ 37 ]. On the contrary, a meta-analysis of eight studies including 30,970 participants showed that the combined administration of vitamin D and calcium can reduce the risk of total fractures by 15% [odds ratio (OR) 0.85; 95% CI 0.73–0.98] and the risk of hip fractures by 30% (OR 0.70; 95% CI 0.56–0.87) [ 38 ].
2.2 Vitamin D, Muscle Strength, Muscle Mass, Muscle Power, and Risk of Falls
Mechanisms VDD has been associated with musculoskeletal dysfunction, a reduction in muscle strength and size, and increased intramuscular noncontractile tissue [ 39 , 40 ].
One of the largest meta-analyses evaluated the effect of vitamin D supplementation on muscle strength, including data of 29 RCTs involving 5533 subjects. It demonstrated that vitamin D supplementation had a small but significant effect on improving global muscle strength (SMD 0.17, 95% CI 0.03–0.31, p = 0.02), and in particular there was a significant positive effect of vitamin D supplementation on lower limb muscle strength (SMD 0.19; 95% CI 0.05–0.34; p = 0.01), but not on grip strength (SMD 0.01; 95% CI 0.06–0.07; p = 0.87) [ 41 ]. In a subgroup analyses, it was further demonstrated that the improvement in muscle strength was greater in patients who at baseline had 25(OH)D values < 30 nmol/L, compared with those who had 25(OH) D ≥ 30 nmol/L. Moreover, a meta-regression showed a significant association between changes in 25(OH)D concentration and changes in muscle strength [slope 95% CI 0.01 (0.00, 0.01); p = 0.01]. With regards to age, vitamin D supplementation in subjects older than 65 years resulted in a significant improvement of muscle strength (SMD 0.25; 95% CI 0.01–0.48), whereas supplementation in younger people did not (SMD 0.03; 95% CI 0.08–0.14) [ 41 ]. This meta-analysis also assessed the effects of vitamin D supplementation on muscle mass and muscle power, even though a limited number of studies had assessed these outcomes (six and five studies, with a total of only 538 and 245 subjects, respectively). It was shown that vitamin D supplementation does not improve muscle mass or muscle power [ 41 ].
An improvement in lower limb muscle strength could be a promising mechanism through which vitamin D supplementation could reduce the risk of falls, since, on one hand, quadriceps strength is a significant predictor of falls [ 42 ] and, on the other hand, VDD has also been linked to an increased risk of falls [ 43 , 44 ]. Thus, whether vitamin D supplementation confers protection from falls has received a lot of interest, but meta-analyses on this topic have yielded conflicting results. Early meta-analyses reported beneficial effects of vitamin D supplementation on reducing falls, and two analyses reported that vitamin D supplementation combined with calcium, but not vitamin D supplementation alone, reduces the risk of falls [ 43 , 45 ]. However, subsequent meta-analyses reported neutral effects of vitamin D supplementation on falls [ 46 ], and when very high doses of vitamin D supplementation were used, there was an increased risk of falls [ 47 , 48 ].
In a 2014 trial, a sequential meta-analysis approach to reduce the risk of false positive effects, Bolland et al. analyzed data from 20 RCTs ( n = 29,535). They reported that vitamin D supplementation did not reduce the relative risk for falls by 15% or more, and similar null effects were reported when they performed a sensitivity analysis, reducing the risk reduction threshold at 10% [ 49 ]. There were no differences in the effects of vitamin D supplementation alone or vitamin D and calcium supplementation on the risk of falls. Based on their approach, the authors concluded that it is unlikely that similar future trials may alter these negative conclusions of vitamin D supplementation on the rick of falls [ 50 ]. The null effects of vitamin D supplementation on reducing the risk of falls were replicated in a subsequent meta-analysis of the same group in 2018, including data of 37 trials and a total of 34,144 subjects (RR 0.97; 95% CI 0.93–1.02). Of note is that in this meta-analysis, vitamin D supplementation did not decrease the RR of falls by 7.5%—i.e., the efficacy of vitamin D supplementation at a lower RR threshold was tested but still no clinically meaningful effect of vitamin D supplementation on reducing the risk of falls was found [ 37 ].
3 Non-Classical Vitamin D Actions
3.1 vitamin d and hypertension.
Mechanisms Preclinical studies have shown that VDD may predispose to hypertension through upregulation of the renin–angiotensin–aldosterone system (RAAS) and increased vascular resistance and vasoconstriction [ 51 , 52 , 53 ]. On the other hand, VDR activation has been shown to inhibit intrarenal mRNA levels and protein expression of key components of the RAAS [ 51 ].
Evidence shows that vitamin D supplementation is effective in reducing blood pressure in patients with hypertension and VDD [ 54 ]. Once again, the modality of vitamin D supplementation impacts the outcome, with daily [ 55 , 56 , 57 ] or weekly [ 58 ] administrations of vitamin D improving hypertension outcomes, whereas large bolus vitamin D dosing (e.g., 100,000 IU VD every 2 months) failed to reduce blood pressure in vitamin D deficient subjects [ 59 ]. Large doses of vitamin D might also have detrimental vascular effects, since they can result in vascular calcification [ 60 ]. On the contrary, vitamin D supplementation in vitamin D replete subjects has null effects on lowering blood pressure [ 61 ]. Antihypertensive medications may also affect whether vitamin D supplementation will affect blood pressure. For instance, Bernini et al. did not find any effect of acute or chronic vitamin D supplementation on RAAS in patients with essential hypertension on RAAS inhibitor treatment [ 55 ]; however, they also showed that chronic vitamin D receptor activation in drug-free essential hypertensives suppresses RAAS components [ 62 ]. This evidence further underlines that the blood pressure effects of vitamin D in humans are dependent on the activity of RAAS.
Low serum 25(OH)D levels have also been associated with an increased risk of developing hypertension [ 53 ], which raises the question of whether vitamin D supplementation can impact the incidence of hypertension, and this is of great clinical interest. It is important to note that to evaluate the effects of vitamin D supplementation on the incidence of chronic diseases, such as hypertension, the intervention period should be long enough (> 5 years) to record a sufficient number of events [ 54 ].
However, in the VITAL study (intervention for 5 years), vitamin D supplementation did not reduce the incidence of cardiovascular events [ 63 ], and there was no specific mention of whether the incidence of hypertension was affected. DO-HEALTH was a RCT on adults aged 70 years or older without major comorbidities. Treatment with 2000 IU/day of vitamin D did not improve systolic (SBP) or diastolic blood pressure (DBP) compared with placebo [ 64 ]. However, as the authors pointed out, in this trial only 40.7% of individuals had 25(OH)D levels less than 20 ng/ml at baseline, and all participants were allowed to take up to 800 IU/day of vitamin D outside the study medication [ 64 ].
3.2 Cardiovascular Events
Mechanisms VDR is expressed in endothelial cells, vascular smooth muscle cells, and cardiac myocytes [ 65 ]. Vitamin D preserves endothelial function through inhibition of the proliferation of vascular smooth muscle cells [ 66 ], and also reduces oxidative stress, inflammation, and thrombogenesis [ 67 ]. It has also been suggested that it can modify lipid metabolism by increasing the activity of lipoprotein lipase in adipose tissue [ 68 ] and by reducing fatty acid absorption [ 69 ]. As discussed earlier, it can also reduce RAAS activity, thereby decreasing blood pressure.
In a meta-analysis of nearly 850,000 individuals, patients were divided into tertiles for 25(OH)D supplementation. Patients on the lower tertile of 25(OH)D concentrations had an increased risk of death from cardiovascular disease compared with patients on the top thirds of 25(OH) D concentrations (RR 1.35; 95% CI 1.13–1.61) [ 70 ]. Moreover, another meta-analysis showed that subjects in the lowest quintile of 25(OH)D concentration had an increased risk of cardiovascular mortality compared with subjects in the highest quintile (RR 1.41, 95% CI 1.18–1.68 in subjects without a history of cardiovascular disease and RR 1.65, 95% CI 1.22–2.22 in subjects with a history of cardiovascular disease) [ 71 ]. In a recent large cohort study in 24,311 patients with T2D and 67.789 subjects with prediabetes (i.e., a study population with high CVD risk) it was shown that 25(OH)D levels were inversely and independently associated with the risk of incident cardiovascular outcomes and all-cause mortality. Moreover, in a recent large cohort study in 24,311 patients with T2D and 67,789 subjects with prediabetes (i.e.. a study population at increased risk for CVD [ 72 ]), 25(OH)D was associated with lower risk of incident CVD events and mortality [ 73 ]. In a dose-response analysis, it was shown that increasing 25(OH)D up to 50–60 nmol/L decreased mortality and cardiovascular events [ 73 ].
However, in the two large RCTs (VITAL and VIDA) with long follow-up, supplementation with vitamin D did not impact on major cardiovascular events or cardiovascular death compared with placebo [ 63 , 74 ]. The same conclusion was reached by Barbarawi and colleagues analyzing data of 21 RCTs with a total of 83,000 individuals [ 75 ].
Whether vitamin D supplementation affects the risk factors for CVD has also been investigated. Earlier systematic reviews and meta-analyses have reported a null effect of vitamin D supplementation on the modification of CVD risk factors [ 49 , 76 , 77 , 78 ]. Mirhosseini et al. recently performed a systematic review and meta-analysis with stringent inclusion criteria, including only studies in which the duration of vitamin D supplementation was at least 3 months; studies using a daily, weekly, or monthly frequency of vitamin D dosage; and studies where baseline and post-intervention serum 25 (OH)D levels were included. Eighty-one studies met the selection criteria. The authors showed that supplementation of vitamin D led to a reduction of SBP and DBP, a reduction of total cholesterol and triglycerides, an increase in HDL, and a reduction in high-sensitivity C-reactive protein (hs-CRP) [ 79 ]. In subgroup analyses, they also reported dose-effect responses comparing studies in which subjects received ≥ 4000 IU/day with studies in which patients received < 4000 IU/day. They showed that trials with vitamin D supplementation ≥ 4000 IU/day had greater reductions in SBP, DBP, and hs-CRP. Similar effects were reported when serum 25(OH)D levels higher or lower than 86 nmoL/L were considered, with subjects with higher 25(OH)D levels showing greater reductions in SBP, DBP, and hs-CRP. On the contrary, lipid changes were not associated with the dose or the achieved serum 25(OH)D concentrations [ 79 ]. As the authors state, the discrepancy with earlier systematic reviews and meta-analyses could be attributed to the quality of the studies included (small sample sizes, too low doses of vitamin D supplementation, and too narrow intervention length). The effect of vitamin D supplementation on markers of arterial stiffness [i.e., pulse wave velocity (PWV) and augmentation index (AI)] was also assessed, but the numbers of studies that evaluated these markers was small (11 and 10 studies, respectively). While there were no overall effects of vitamin D supplementation on these markers, subgroup analyses found that AI was lower in patients with serum 25(OH)D concentrations ≥ 86 nmol/L and in patients receiving vitamin D doses ≥ 4000 IU/day, with the authors concluding that vitamin D supplementation may improve the markers of arterial stiffness [ 79 ]. These results seem in line with the results of a prespecified analysis of a subsample of participants in the Vitamin D Assessment (VIDA) study who underwent suprasystolic oscillometry [ 74 ]. The VIDA study showed that monthly high-dose (i.e., 100,000 IU/month) supplementation with vitamin D led to improvements in AI, PWV, peak reservoir pressure, and backward pressure amplitude [ 74 ]. Aortic systolic blood pressure also improved, whereas SBP and DBP showed only small, nonsignificant reductions [ 74 ].
3.3 Acute Respiratory Tract Infection and Influenza
Mechanisms Vitamin D is involved in the control of both the innate and adaptive immune response. Virtually all immune cells express VDR and CYP27B1, and it has been shown that macrophages, activated T and B cells, dendritic cells, and endothelial cells lining the upper and lower respiratory tracts can hydroxylate 25(OH)D into the active form[ 80 , 81 , 82 ]. Neutrophils express VDR, but it seems that they do not possess CYP27B1 [ 83 ]. Evidence suggests that 1,25(OH) 2 D controls the innate immune response through a negative feedback loop on macrophages and other immune cells. More specifically, IFNγ-activated macrophages induce 1,25(OH) 2 D release, which in turn activates VDR on macrophages, suppressing the expression of key genes producing proinflammatory proteins [ 84 ]. Regarding regulation of adaptive immune responses, 1,25(OH) 2 D has been shown both to inhibit proliferation and differentiation of activated human B cells [ 85 ], to inhibit T helper cells, and also to promote Treg cells [ 86 ]; the net outcome of these effects would be to limit inflammatory processes. In the specific case of influenza virus, it has been shown that incubation of human lung A549 epithelial cells with 1,25(OH) 2 D before or after exposure to influenza A virus led to decreased production of TNF-α, IFN-β, and IFN-stimulated gene-15, and downregulated interleukin (IL-8 and IL-6 RNA levels [ 87 ]. An extensive review of the mechanisms through which vitamin D modulates and controls the immune responses has been performed recently [ 81 ].
A negative linear association among vitamin D levels and lung infections and function has been established in a large cross-sectional study of 6789 subjects, where for each 10 nM/L increase in vitamin D levels, the risk of infection was reduced by 7% [ 88 ]. Negative associations between vitamin D levels and the risk [ 89 ] or severity of pneumonia have also been described [ 90 ].
Urashima et al. performed an RCT in children ( N = 167 on vitamin D and N = 167 on placebo) receiving either a daily supplement of vitamin D (1200 IU/day) or placebo. They found that patients treated with vitamin D had a lower incidence of influenza A compared with placebo (incidence of influenza A, 10.8% in the vitamin D group versus 18.6% in the placebo group; RR 0.58; 95% CI 0.34–0.99; p = 0.04) [ 91 ]. Apart from these positive outcomes of higher vitamin D levels and of vitamin D supplementation on influenza and other lung infections, other studies have reported neutral [ 92 ] or even negative results [ 93 ] of vitamin D supplementation on the outcomes of lung infections. It is not clear if this discrepancy is due to methodological issues [low vitamin D supplementation [ 92 ] or weak endpoints used (questionnaires on self-reported symptoms) [ 93 ]], characteristics of the study population, or are dependent on the baseline vitamin D status. For instance, in another RCT conducted by Urashima et al. investigating the effects of vitamin D supplementation during the 2009 H1N1 pandemic, they showed that subjects in the vitamin D group (2000 IU/day) had a lower incidence of influenza A or B compared with the placebo group during the first month of intervention, whereas there was a higher incidence of infection during the second month [ 94 ]. It would be tempting to hypothesize that at the beginning of the intervention, vitamin D levels were low, allowing the treatment to show a positive protective effect, whereas once vitamin D levels were restored, the vitamin D had no impact in the prevention of infection. Unfortunately, in this study, serum levels of 25(OH)D were not measured, which could have explained the reasons for this difference at the two time periods, and thus this suggestion is speculative. A meta-analysis of 25 RCTs (including a total of 10,933 participants) supports the protective effects of vitamin D on acute lung infections. More specifically, vitamin D supplementation reduced the risk of acute respiratory infections among all participants [adjusted OR (aOR) 0.88; 95% CI 0.81–0.96; heterogeneity p < 0.001]. Importantly, the protective effects were seen in individuals receiving daily or weekly vitamin D (aOR 0.81;95% CI 0.72–0.91), but not in those receiving bolus doses (aOR 0.97; 95% CI 0.86–1.10; p = 0.05). Moreover, among subjects receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in those who baseline 25(OH)D concentrations < 25 nmol/l (aOR 0.30; 95% CI 0.17–0.53) compared with those with baseline 25(OH)D ≥ 25 nmol/L (aOR 0.75; 95% CI 0.60–0.95; p for interaction = 0.006) [ 95 ]. In a more recent meta-analysis by the same group, including data from 43 RCTs and a total of 48,488 participants, the protective effect of vitamin D supplementation when given using a daily dosing regimen, at daily dose equivalents of 400–1000 IU on acute respiratory infections was confirmed [ 96 ].
Vitamin D was used in the pre-antibiotic era for the treatment of patients with tuberculosis (TB), when the ancient Greeks had first introduced “heliotherapy” (i.e., sunlight exposure) to treat TB [ 97 ]. Moreover, in preclinical studies, it has been shown that 1,25(OH) 2 D induces antimycobacterial activity in vitro in monocytes and macrophages [ 98 , 99 ]. However, recent controlled trials and meta-analyses have produced either minimal or null effects in a variety of TB-associated outcomes. A systematic review showed that serum vitamin D levels are not associated with the incidence of latent tuberculosis infection [ 100 ]. As the authors pointed out, different 25(OH)D assays were used in the studies included, which have differences in their sensitivity and precision, and that may have affected the results of the meta-analysis. In a RCT on TB contacts, it was shown that a single dose of 2.5 mg vitamin D (i.e., 100,000 IU) suppressed recombinant Mycobacterium growth through Bacillus Calmette–Guérin (BCG)-lux analysis at 24 h but not at 96 h, suggesting improved innate but unmodified acquired immunity against mycobacteria compared with placebo [ 101 ]. In a large RCT on children with a negative Quantiferon test at randomization, supplementation with a weekly dose of 14,000 IU vitamin D for 3 years did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection compared with placebo [ 102 ]. Finally, in the, thus far, largest meta-analysis investigating the effects of vitamin D supplementation on patients with pulmonary TB, vitamin D supplementation resulted in an increase in lymphocyte count, an improvement in chest radiography (mean number of zones involved), and an increased proportion of sputum smear and culture conversion. On the contrary, compared with placebo, vitamin D yielded null effects on time to sputum smear and culture conversion, and on mortality [ 103 ].
Considering the previous implications of vitamin D in acute respiratory tract infections, soon after the outbreak of the COVID-19 pandemic the research community started investigating whether vitamin D supplementation may have an impact in preventing infection with Severe acute respiratory syndrome coronavirus (SARS-COV2), or on the severity of COVID-19. This was especially important at the beginning of the pandemic when the medical community had almost no treatments in the fight against COVID-19.
Mechanisms Several mechanisms have been proposed through which vitamin D could offer protection against COVID-19. First, by regulating the innate immune response, vitamin D induces the production of the antimicrobial peptides cathelicidin (or LL-37) and β defensin, blocking the viral entry into cells [ 104 ]. Because of the actions of vitamin D on the adaptive immune system, and specifically the shift away from a proinflammatory state, it reduces the risk of cytokine storm, which is particularly detrimental in severe cases of COVID-19 [ 105 ]. Finally, through regulation of the renin–angiotensin–aldosterone system (RAAS), it suppresses the angiotensin converting enzyme (ACE) while it induces ACE2, leading to a reduction of angiotensin 2 and an increase in angiotensin 1–7. These enzymatic changes restore the ACE: ACE2 imbalance induced by SARS-CoV-2 infection and reduce the risk of vasoconstriction and acute respiratory distress syndrome (ARDS) [ 105 ].
Observational studies have shown that patients with VDD have an increased risk for COVID-19 [ 106 ], and in the, thus far, largest observational study, we have shown that vitamin D insufficiency or deficiency is associated with a 2.3–3.6 times higher risk of severe COVID-19, necessitating hospital admission [ 107 ].
A small, nonrandomized study showed that administration of high doses of vitamin D before SARS-CoV-2 infection was associated with less severe COVID-19 and better survival in older frail patients [ 108 ]. Castillo and colleagues performed a pilot study on 76 consecutive patients hospitalized for COVID-19 [ 109 ]. Patients at admission and on top of optimal medical treatment were randomized in a 2:1 ratio to receive or not high doses of calcifediol. It was shown that calcifediol supplementation significantly reduced the need for intensive care unit (ICU) treatment [ 109 ]. On the contrary, Murai and colleagues randomized 240 subjects to receive either a 200,000 IU vitamin D bolus or placebo. Mean time lag from symptom onset to randomization was relatively long (i.e., mean of 10.3 days). They found that there was no difference in in-hospital stay length, mortality, admission to ICU, or need for mechanical ventilation between the vitamin D and placebo groups [ 110 ]. These (negative) results were also confirmed in a post hoc analysis involving only patients with VDD at baseline ( N = 115) [ 110 ]. In a systematic meta-analysis of our group, including data from nine studies and a total of 2078 patients, we found that vitamin D supplementation was associated with a significant reduction in the need for ICU admission, whereas vitamin D supplementation did not confer protection from COVID-19 mortality [ 111 ]. These results are essentially in line with a previous meta-analysis conducted by Shah et al., which was performed earlier and thus had a smaller sample size ( N = 532) of COVID-19 patients [ 112 ]. Moreover, in our study we performed a meta-regression analysis to identify the effect of dose supplementation; although no significant relationship was found between the dose of supplementation and either severity of disease or mortality, it was shown that low versus high vitamin D supplementation protected from severe disease requiring admission to ICU [ 111 ].
In the systematic review and meta-analysis by Pal et al. [ 113 ] including data from 13 studies, it was shown that supplementation with vitamin D was associated with improved clinical outcomes in COVID-19 (including mortality) patients, especially when vitamin D is administered in patients after the diagnosis of COVID-19. Based on this finding, the authors suggested that vitamin D can be used as a potential treatment addition in patients with COVID-19. However, it should be noted that in their analysis, only three studies were included where vitamin D supplementation was given before COVID-19 diagnosis [ 113 ]. Overall, the discrepancies in the results of vitamin D supplementation on COVID-19 outcomes may have been affected by relatively small sample sizes, and patient’ heterogeneity.
In a recently published phase 3 RCT (CORONAVIT) the investigators assessed the effect of vitamin D supplementation for 6 months on the incidence of all-cause acute respiratory tract infection and COVID-19 [ 114 ]. In this study, a test-and-treat approach was selected in which only subjects with 25(OH)D levels < 75 mmol/L were enrolled to receive low (800 IU/day) or high (3200 IU/day) vitamin D supplementation, and were compared with subjects who were not offered vitamin D supplementation (in the intention to treat, N = 1515, 1515, and 2949 for the low dose, high dose, and no supplementation, respectively). It was found that correction of suboptimal vitamin D levels with either supplementation dose was not associated with a reduction in risk of all-cause acute respiratory tract infection or infection from COVID-19 [ 114 ].
3.6 Type 2 Diabetes (T2D)
Mechanisms Preclinical studies have shown that vitamin D may modulate β-cell growth and differentiation, enhance insulin secretion [ 115 , 116 ], increase the expression of the insulin receptor [ 117 ], and enhance insulin-mediated glucose transport [ 118 ].
However, studies in humans assessing the effect of vitamin D supplementation on insulin secretion and insulin action with gold standard methods have not confirmed these findings. More specifically, in the Tromsö study, a case-control and RCT study, 104 nondiabetic subjects with low serum 25(OH)D levels at baseline were randomized to receive either 20,000 IU twice weekly or placebo. A hyperglycemic clamp was performed at baseline and 6 months after treatment, showing that vitamin D supplementation did not increase first- or second-phase insulin secretion, or insulin sensitivity (assessed as the insulin sensitivity index, ISI) compared with placebo [ 119 ]. Similar null effects of vitamin D on insulin secretion (assessed with the intravenous glucose tolerance test, IVGTT) were reported after 3 months of vitamin D supplementation on nondiabetic subjects with low baseline 25(OH)D receiving 50,000 IU/week compared with placebo [ 120 ]. These results were confirmed in a meta-analysis that included 12 RCTs and a total of 1181 participants with BMI > 23 kg/m 2 . It was shown that vitamin D supplementation did not modify whole-body insulin sensitivity (assessed by the HOMA-IR)[ 121 ]. Of note, tissue-specific insulin sensitivity may also be assessed using fluorodeoxyglucose positron emission tomography studies in conjunction with a euglycemic hyperinsulinemic clamp [ 122 , 123 , 124 , 125 ], but to the best of our knowledge, thus far, it has not been assessed whether there is any correlation between the vitamin D status and tissue-specific insulin sensitivity, or whether vitamin D supplementation may affect tissue-specific insulin sensitivity.
Several association studies have shown an inverse association among serum 25(OH)D levels and fasting glucose [ 126 , 127 ], glycated hemoglobin (HbA 1c ) 1c [ 128 ], insulin resistance, and prevalence of T2D [ 129 ].
In a large RCT in patients with prediabetes at a high risk of progression to T2D, supplementation with 4000 IU/day of vitamin D led to a nonsignificant tendency to slower progression to T2D compared with placebo. However, in a post hoc analysis on patients without obesity, severe vitamin D deficiency at baseline and excellent adherence to treatment during the intervention period, a significant effect in decreasing the progression to T2D was seen [ 130 ]. This finding was confirmed in two recent systematic reviews and meta-analyses. In a meta-analysis by Barbarawi et al., data from nine RCTs and a total of 43,559 patients were assessed. While in the whole population vitamin D supplementation did not affect the incidence of T2D, post hoc analyses according to the vitamin D dosage showed that subjects receiving ≥ 1000 IU/day had significantly lower incidence of T2D (RR 0.88; 95% CI, 0.79–0.99; p = 0.03). Moreover, patients without obesity who received high-dose treatment had a lower relative risk of T2D (RR 0.68; 95% CI 0.53–0.89; p = 0.005), while no benefit was seen in patients with obesity [ 131 ]. In the study by Zhang et al. analyzing data of eight RCTS and 4896 participants, vitamin D supplementation reduced the incidence of T2D (RR 0.89; 95% CI 0.80–1.00; p = 0.04). Similarly to the results of Barbarawi et al., subgroup analyses showed that vitamin D supplementation lowered the risk of new-onset T2D only among non-obese patients, whereas a difference with respect to dose received was not reported [ 132 ]. The authors also reported that from five trials in 1080 participants, reversion from prediabetes to normoglycemia was significantly increased by vitamin D supplementation (RR 1.48; 95% CI 1.14–1.92) [ 132 ].
The effect of vitamin D supplementation on glycemic control in patients with T2D has also been assessed. Wu et al. assessed 24 studies; supplementation of vitamin D improved HbA 1c levels [standardized mean difference (SMD) −0.25 (−0.45 to −0.05)] and this effect was larger among patients with vitamin D deficiency at baseline [SMD −0.39 (−0.67 to −0.10)] and in patients with BMI < 30 kg/m 2 [SMD −0.30 (−0.54 to −0.07)] [ 133 ]. On the contrary, a subsequent systematic review and meta-analysis by Li and colleagues showed that vitamin D supplementation did not influence fasting blood glucose, HbA 1c , or fasting insulin levels, whereas HOMA-IR (i.e., an index of insulin resistance) was improved [ 134 ].
There is also evidence that VDD is associated with gestational diabetes mellitus (GDM). In a meta-analysis including seven observational studies and a total of 2146 subjects, of whom 433 developed GDM, it was shown that 25(OH)D levels < 50 nmol/L were associated with development of GDM (OR 1.61; 95% CI 1.19–2.17; p = 0.002) [ 135 ]. In a recent systematic review and meta-analysis in a small number of women, supplementation with 2000 IU of vitamin D per day did not affect the incidence of GDM compared with placebo ( N = 95 on vitamin D and N = 88 placebo). However, in seven studies including a total of 1722 women comparing the effect of vitamin D supplementation > 2000 IU/day and ≤ 2000 IU/day, it was shown that the incidence of GDM was reduced in the group receiving > 2000 IU of vitamin D per day (RR = 0.70; 95% CI 0.51–0.95; p = 0.02) [ 136 ].
3.7 Diabetic Neuropathy and Diabetic Foot Ulcers (DFU)
Mechanisms The role of vitamin D in the function of peripheral nervous system has not been extensively studied [ 137 ]. Studies have suggested that vitamin D may be involved in pain perception [ 138 ] and that it can induce nerve-growth factor synthesis in human cell lines [ 139 ]. Low vitamin D levels have been also reported to impair the differentiation and proliferation of keratinocytes and skin fibroblasts, and to delay DFU healing [ 140 , 141 , 142 ]. Vitamin D has been shown to induce production of antimicrobial peptides in keratinocyte cells from DFU [ 143 ]. Preclinical studies have shown that topical application of vitamin D promotes wound healing in a dose-dependent manner [ 144 ], and activates the expression of angiogenic molecules in keratinocytes and the migration of endothelial and keratinocyte cells in a diabetic foot ulceration model [ 145 ].
Studies have shown that VDD is associated with painful diabetic neuropathy, diabetic foot ulceration, and diabetic foot infections [ 146 , 147 , 148 ]. Two recent meta-analyses including a total of 1115 and 1644 patients with T2D showed that severe VDD [i.e., 25(OH) D < 10 ng/ml] is associated with increased risk of diabetic foot ulceration (OR 3.2; 95% CI 2.4–4.3 [ 149 ] and OR 3.6; 95% CI 2.9–4.4; p < 0.0001) [ 150 ], respectively. In a small RCT on 60 patients with grade 3 DFU according to the “Wagner–Meggit” criteria, patients were randomized to receive either 50,000 IU of vitamin D every 2 weeks or placebo for 12 weeks. Vitamin D supplementation was shown to reduce the ulcer length, width, depth, and erythema rate [ 151 ]. A later RCT compared high-dose vitamin D supplementation with 170 μg/day (i.e., 6800 IU) compared with low dose (20 μg/day, i.e., 800 IU) for 48 weeks of treatment. The intention-to-treat analysis showed that patients receiving high-dose supplementation had a higher rate of ulcer healing (70% versus 35%, p = 0.01, in the high versus low supplementation group) [ 152 ].
Mechanisms VDR and 1α-hydroxylase are expressed throughout the brain, and they are particularly highly expressed in the substantia nigra and in the hippocampus [ 153 , 154 ], two important regions for Parkinson’s disease and cognition, respectively. It has been suggested that vitamin D may confer neuroprotection through several mechanisms, including regulation of neurotrophic factors and of nerve growth, protection against cytotoxicity, and reduced oxidative stress [ 155 , 156 , 157 ]. Vitamin D has also been implicated in the regulation of acetylcholine and clearing of amyloid beta [ 158 ].
Considering the high expression of VDR and 1α-hydroxylase in substantia nigra, the impact of VDD on Parkinson’s disease has been studied, yielding conflicting results. In a large prospective study from Finland ( N = 3173), patients in the highest quartile for baseline serum vitamin D levels had a 65% lower risk of developing Parkinson’s disease than those in the lowest quartile, suggesting that lower levels of vitamin D in mid-life may increase the risk of Parkinson’s disease [ 159 ]. However, later studies in an even larger study sample in the USA failed to confirm this association [ 160 ].
The literature regarding vitamin D levels and Parkinson’s disease severity appears more consistent. Cross-sectional studies have consistently reported an association between vitamin D levels and the motor disability in Parkinson’s disease: the lower the serum vitamin D levels, the worse the motor function [ 161 , 162 ]. However, it is not clear whether vitamin D may modify the severity of the disease, or whether these associations are due to “inverse causality,” since patients suffering worse motor symptoms are also expected to move less and get lower sun exposure.
A small RCT assessed whether high-dose vitamin D supplementation (10,000 IU/day) for 4 months improved balance in patients with Parkinson’s disease compared with placebo. Even though, in the whole dataset, vitamin D supplementation seemed not to have any impact on balance, as measured by the sensory organization test, a post hoc analysis showed that supplementation with vitamin D in younger patients (52–66 years of age) improved balance compared with older participants [ 163 ].
With regard to cognitive function in the general population, whereas numerous studies have shown an association between low vitamin D levels and worse cognition [ 164 , 165 ], intervention studies have failed to show benefits from vitamin D supplementation [ 165 ].
The effects of VDD and vitamin D deficiency on multiple sclerosis (MS) have also been studied and they are presented in the chapter regarding autoimmunity.
Mechanisms Early studies have shown that 1,25(OH) 2 D analogs have potent antiproliferative and pro-differentiating effects on cancer cells in vitro [ 166 ]. Also, vitamin D decreases tumor invasiveness, angiogenesis, and metastatic propensity [ 167 , 168 ].
Systematic reviews and meta-analyses on the levels of vitamin D and mortality outcomes in cancer patients have shown that higher vitamin D levels are protective in a series of cancers such as breast cancer [ 169 ], colorectal cancer [ 170 ], prostate cancer [ 171 ], and hematological malignancies [ 172 ]. However, these promising data, based on observational studies, may be biased by a generally better health status and/or a healthier lifestyle (e.g., exercising with greater sunlight exposure) in the subjects who had higher levels of 25(OH)D.
In the large VITAL RCT ( N = 25,871), participants were randomized to receive 2000 IU of vitamin D or placebo daily, and omega-3 fatty acids or placebo in a two-by-two factorial design (for a median follow-up time of 5.3 years). Participants had no history of cancer (except nonmelanoma skin cancer) [ 63 ]. Supplementation with vitamin D did not significantly reduce the primary endpoint of total invasive cancer incidence (HR 0.96; 95% CI 0.88–1.06), but there was a trend for reducing total cancer mortality (HR 0.83; 95% CI 0.67–1.02) [ 63 ]. The authors then accounted for latency, and after excluding events within the first or second year of supplementation, the vitamin D intervention significantly decreased the risk of mortality (HR 0.79; 95% CI 0.63–0.99 after excluding the first and second year cases, respectively). The effect of vitamin D supplementation on cancer mortality was evident in the cumulative incidence curves at 4 years of supplementation. Interestingly, the authors also assessed whether baseline participants’ characteristics could affect the results of the supplementation, and found a significant interaction with BMI, with lean participants having a significant reduction in cancer risk (HR 0.76; 95% CI 0.63–0.90), whereas overweight and obese individuals did not [ 63 ].
Earlier RCTs have generally produced null effects of vitamin D supplementation on cancer-related risk reduction, but these studies were either smaller or had methodological problems (low vitamin D supplementation [ 173 , 174 ] or intermittent bolus dosing [ 175 , 176 ]). In a meta-analysis, also including the VITAL trial, the protective effect of vitamin D supplementation on cancer mortality was confirmed (HR 0.87; 95% CI 0.79–0.96), whereas there was no effect on cancer incidence (HR 0.98; 95% CI 0.93–1.03) [ 177 ].
3.10 Inflammatory Bowel Disease (IBD)
Mechanisms IL-10 knockout mice is an animal model used for the study of IBD; these animals spontaneously develop enterocolitis within 5–8 weeks of birth due to an uncontrolled immune response to resident intestinal flora [ 178 , 179 ]. People who have an IL-10 gene polymorphism also have an increased risk of developing colitis [ 180 ]. In the animal model, it has been shown that VDD exacerbates the symptoms of IBD and increases morbidity and mortality in the affected mice, whereas supplementation with vitamin D improves symptoms and reduces inflammation and mortality [ 181 ]. Patients suffering from IBD are at risk for VDD, since they often undergo small-bowel resection, and are treated with cholestyramine to control postresectional diarrhea caused by malabsorprion of bile acids. Both these factors contribute to bile acids loss, which are essential for vitamin D absorption [ 182 ]. It has been hypothesized that vitamin D supplementation may reduce inflammation in patients with IBD through decreasing intestinal permeability and increasing the levels of cathelicidin, a peptide that reduces inflammation and promotes healing [ 183 , 184 ].
A systematic review and meta-analysis on data from 900 IBD patients showed that VDD is a very prevalent condition in these patients, affecting 38.1% of patients with Crohn’s disease (CD) and 31.6% of patients with ulcerative colitis (UC) [ 185 ]. Moreover, in a recent systematic review and meta-analysis by Gubatan and colleagues, it was shown that low vitamin D levels were associated with increased odds of clinically active disease and increased odds of clinical relapse among all IBD patients and separately for both CD and UC [ 186 ]. Mucosal inflammation and quality of life were also assessed, and it was shown that among all patients, low 25(OH)D levels were associated with increased odds of mucosal inflammation and lower quality of life among all patients and in patients with CD, but not in patients with UC. As the authors argued for the quality of life in UC patients, results may have been underpowered due to the smaller sample size of patients with UC compared with CD in the included studies. On the contrary, the sample sizes were similar for UC and CD regarding the mucosal inflammation outcome, with the authors suggesting that vitamin D may play a specific role in the pathogenesis of CD, and also that VDD may be more suggestive of mucosal inflammation in CD since small bowel inflammation (thus affecting vitamin D absorption) is characteristic of CD but not of UC [ 186 ].
Some small studies have assessed the effect of vitamin D supplementation on clinical relapse based on validated scores, serum CRP levels, and quality of life, yielding conflicting results [ 183 , 187 ]. In a recent, relatively large RCT assessing the effect of vitamin D supplementation on the outcomes of CD using a more robust endpoint (i.e., endoscopic recurrence), 143 patients with CD who had recently undergone ileocecal or ileocolonic resection with ileocolonic anastomosis were randomized to receive 25,000 IU of vitamin D weekly compared with placebo. Even though serum vitamin D levels were doubled in the vitamin D group, the intervention did not affect endoscopic or clinical recurrence compared with placebo [ 188 ].
3.11 Autoimmune Disorders
Mechanisms Activation of the VDR by 1,25(OH) 2 D has been shown to inhibit the differentiation and proliferation of B and T helper lymphocytes, promoting a shift from an inflammatory to a more tolerant immune status [ 189 ]. Also, 1,25(OH) 2 D inhibits the production of proinflammatory Th1 cytokines while stimulating Th2 and regulatory T-cell activity [ 190 ]. Independent of VDR activation, 1,25(OH) 2 D and other vitamin D hydroxyl-metabolites can bind to RORa and RORg, and result in IL17 inhibition [ 191 , 192 ]. Both these pathways have been implicated in the protective role of vitamin D from autoimmune disorders. An acquired form of vitamin D resistance has also been hypothesized to play a role in the development of autoimmune disorders [ 193 ].
VDD has been described in a series of autoimmune disorders, comprising IBD (discussed in the paragraph above), rheumatoid arthritis, Sjogren’s disease, autoimmune thyroiditis, multiple sclerosis (MS), type 1 diabetes, and psoriasis [ 194 , 195 , 196 , 197 ]. In this paragraph, we will focus mainly on MS, since the effects of vitamin D on MS have been thoroughly investigated, and to the recent positive findings of the VITAL trial. Of particular interest is also the fact that the CYP27B1 gene, which codes for 25(OH)D 1α-hydroxylase, lies within a genomic region associated with MS, as shown in genome-wide association studies [ 198 ]. Indeed, evidence suggests a casual association between genetically induced VDD and increased risk of MS [ 199 , 200 ].
Several studies have thus shown that patients with MS have lower levels of 25(OH)D compared with healthy subjects [ 201 ], and this finding was confirmed in a 2014 systematic review and meta-analysis, including 11 studies and a total of 1007 patients and 829 healthy subjects [ 202 ].
Vitamin D has also been used in the treatment of MS, with investigators applying varying doses of vitamin D supplementation from low to extremely high doses. In particular, the “Coimbra protocol” is a protocol of very high doses of vitamin D supplementation, which was originally applied in patients with autoimmune skin disorders (psoriasis and vitiligo) [ 203 ]. This protocol has also been applied in MS, with supplementation of vitamin D as high as 1000 IU/kg of body weight per day [ 193 ]. A relatively recent systematic review and meta-analysis on the effects of vitamin D supplementation for the treatment of MS has yielded substantially negative results [ 204 ]. More specifically, McLaughlin and colleagues evaluated three outcome measures [annualized relapse rate, expanded disability status scale (EDSS) and new gadolinium-enhancing lesions]. Vitamin D supplementation did not improve any of the tested outcomes [ 204 ]. However, as the authors discussed in their article, there could be a potential clinically meaningful treatment effect in favor of vitamin D supplementation in the placebo-controlled studies, suggesting that more well-planned and placebo-controlled studies are needed. Of note, in this meta-analysis, high-dose vitamin D supplementation had a significantly worse outcome in terms of relapse rate compared with low dose [ 204 ].
In the VITAL trial (i.e., a randomized, double blind, placebo-controlled study with a two-by-two factorial design), the potential benefits of vitamin D supplementation with 2000 IU of cholecalciferol per day with or without of omega 3 fatty acids (1 g/day) on autoimmunity were assessed in 25,871 participants [ 22 ]. The mean age of the participants was 67 years. The impact on autoimmunity was assessed by the total confirmed incidence of autoimmune diseases during the 5 years of observation. In particular, annual questionnaires were filled in, inquiring for new onset of rheumatoid arthritis, polymyalgia reumatica, psoriasis, autoimmune thyroiditis, and IBD. They found that subjects on the vitamin D arm had decreased risk for new onset of autoimmune diseases by 22% compared with the placebo group (adjusted HR 0.78; 95% CI 0.61–0.99; p = 0.05). Moreover, after excluding the first 2 years of follow-up to evaluate the latency of the intervention effect, it was confirmed that vitamin D supplementation reduces the incidence of autoimmune diseases and the effect was even stronger (adjusted HR 0.61; 95% CI 0.43–0.86; p = 0.005). Of interest, in a prespecified subgroup analyses, a significant interaction between BMI and the effect of vitamin D supplementation was found with participants with lower BMI being more protected compared with subjects with obesity in whom vitamin D supplementation did not seem to reduce the incidence of autoimmune diseases (adjusted HR 0.47, 95% CI 0.29–0.77 for BMI 18 kg/m 2 ; adjusted HR 0.69, 95% CI 0.52–0.90 for BMI 25 kg/m 2 ; adjusted HR 0.90, 95% CI 0.69–1.19 for BMI 30 kg/m 2 ). Considering the important positive results of this trial, the follow-up period of this study has been extended and more results on the effects of vitamin D supplementation on the incidence of autoimmune diseases are expected.
4 Mendelian Randomization Studies
Bouillon and colleagues reviewed Mendelian randomization studies on the effects of genetically determined low 25(OH)D levels on a variety of conditions such as T2D, cancer, cardiovascular disease, COVID-19, and asthma, showing null effects [ 205 ]. Genetic VDD was shown to associate with increased risk for multiple sclerosis [ 205 ]. In a very recent study, the approach of Mendelian randomization was also used to assess the association of genetically determined 25(OH)D with mortality [ 206 ]. In this study, genetic data of 307,601 participants from the UK Biobank were analyzed, showing evidence of a causal relationship between genetically predicted 25(OH)D and all-mortality outcomes (all-cause, cancer, CVD, and respiratory). More specifically, an L-shaped relationship was described among all-cause mortality, cancer mortality, and CVD mortality with 25(OH)D levels, with the strongest association at concentrations below 25 nmol/L, while the association plateaued at 50 nmol/L. The association of respiratory mortality and 25(OH)D levels was linear [ 206 ].
5 Targets for Vitamin D Supplementation
Even though daily vitamin D requirements may be met through synthesis of vitamin D from 7-dehydrocholesterol in the skin after sunlight exposure, deficiency in vitamin D levels is a very common condition. Serum concentrations of 25(OH)D < 10 ng/ml (i.e., 25 nmol/L) are generally indicative of VDD, but the proposed target cut-offs of ideal vitamin D levels vary across organizations. According to the Endocrine Society Practice Guidelines on vitamin D, VDD is defined as a serum 25(OH)D < 20 ng/ml (i.e., 50 nmol/L), insufficiency as 21–29 ng/ml (i.e., 52.5–72.5 nmol/L), and sufficiency as at least 30 ng/ml (i.e., 75 nmol/L) for maximum musculoskeletal health [ 207 ]. These cut-offs have also been endorsed by other organizations such as the American Association for Clinical Endocrinologists, the American Geriatric Society, the National Osteoporosis Foundation, and the International Osteoporosis Foundation [ 208 ]. Whereas, according to the World Health Organization (WHO) and the current National Institute for Health and Clinical Care Excellence (NICE), UK guidelines, VDD is defined as a serum 25(OH)D < 10 ng/ml (i.e., 25 nmol/L) and insufficiency as 10–20 ng/ml (i.e., 25–50 nmol/L) [ 209 ].
More aggressive supplementation should be followed in the elderly and subjects with low exposure to sunshine (dark skinned people, people with poor exposure to sunlight due to cultural reasons, institutionalized patients) and poor nutrition. Despite general recommendations, clinicians should tailor vitamin D prescriptions accounting for several parameters, (obesity, nutritional status, diet, sunlight exposure) since one-size-fits-all recommendations of vitamin D supplementation are doomed to fail. For instance, it has been shown that patients with obesity require two to three times higher vitamin D supplementation to treat VDD [ 210 , 211 ]. Even though toxicity from vitamin D is extremely rare, as with all treatments, moderation is safer than exaggeration. Interestingly the clinical utility of these cut-offs has been confirmed in large studies on mortality. Apart from the recent Mendelian randomization study showing higher mortality at 25(OH)D levels below 25 nmol/L, with the association plateauing at the deficiency cut-off level (50 nmol/L) [ 206 ], similar results were also yielded from the institute of medicine. In this report, a J-curve was shown in the relationship between mortality and blood levels of 25(OH)D, with a significant decline in mortality when 25(OH)D approached 30 ng/mL and then a slight increase that was apparent at 50 ng/mL [ 212 ]. However, some authors have argued that the increased mortality seen for 25(OH)D > 50 ng/ml, may be attributed to previous long-standing VDD for which subjects were treated [ 213 ].
Still, despite apparent optimal per os supplementation, many subjects do not achieve normal vitamin D levels. Predictive equations to guide vitamin D replacement doses have been formulated, such as the one by Singh et al., proposing a formula that accounts for initial vitamin D levels, age, BMI, serum albumin concentration, and desired change in vitamin D levels to estimate the optimal and personalized dose of vitamin D replacement needed [ 214 ]. Whether the application of this formula corrects vitamin D levels has not been confirmed in large-scale clinical studies.
Despite the pleiotropic actions of vitamin D, most RCTs on the effect of vitamin D supplementation on improving a disease outcome have been negative. There are several inherent difficulties in studying the effects of vitamin D supplementation using standard RCT designs, as discussed in chapter 1.2. Still, several other considerations can be made. First, to be able to modify the course of a chronic disease, long follow-up is needed. This was the purpose of the recent large VIDA and VITAL RCTs [ 23 , 176 ]. The mode of supplementation often varies, with some authors preferring intermittent bolus dosing and others daily dosing. Evidence suggests that intermittent bolus dosing (and generally extremely high dosing) should be avoided since it can even generate harmful events. Intermittent bolus dosing would also go against the ideal scenario in which there would be no fluctuations in the circulating levels of vitamin D, considering its multisystem homeostatic role. On the other hand larger doses (i.e., ~1000–2000 IU/day) should be preferred over too-small doses (i.e., ~400–800 IU/day) to expect any meaningful effect. Finally, it may be more appropriate in future investigations to compare subjects with high 25(OH)D vitamin levels with those not achieving normalization of vitamin D levels, rather than continue comparing groups based on the amount of vitamin D supplementation received.
Even though experts still debate the optimal cut-offs of 25(OH)D levels, it could be that these vary according to the disease of interest [ 215 ]. For instance, even though levels higher than 30 ng/ml are considered the target for maximum musculoskeletal health, it could be that this cut-off should be placed higher when vitamin D is given for its immunomodulation effects. Indeed, in the practice guidelines published in 2018 by Pludowski et al., 25(OH)D values in the range 30–50 ng/ml were recommended to achieve the pleiotropic actions of vitamin D and for optimal overall health [ 216 ]. Future studies should probably contemporaneously assess total and free 25(OH)D levels, as well as DBP and PTH values. This would be an important advancement in the planning of RCTs if we consider the studies by Carlberg and colleagues [ 217 ]. These investigators gave 0, 1600, or 3200 IU of vitamin D daily for 5 months to elderly prediabetic subjects. After assessing PTH response and other vitamin D biomarkers, they showed that 24% of their studied subjects were low responders, 51% mid responders, and 25% high responders [ 217 ], and similar rates were found also in healthy young individuals [ 218 ]. These studies set the groundwork, demonstrating that in humans in vivo, there is a spectrum of responsiveness to vitamin D supplementation, or a varying degree of vitamin D resistance.
The present narrative review provides an overview of the current evidence regarding the applications of vitamin D in a series of diseases. Despite the inherent difficulties in assessing the effects of vitamin D supplementation in RCTs, vitamin D supplementation has been shown to decrease acute respiratory infections, cancer mortality, and the incidence of T2D and autoimmune diseases. Moreover, subjects without obesity seem to benefit more from vitamin D supplementation, a finding that warrants further investigation. It also clearly emerges that VDD should be treated as it is associated with poor health outcomes and increased morbidity and mortality. However, vitamin D supplementation in vitamin D replete subjects does not seem to induce any clinically meaningful benefits. Considering that universal testing for vitamin D is not possible and is expensive, in everyday clinical practice it should be advisable to give vitamin D supplementation, which is cheap, well-tolerated, and easily available. In research settings, a holistic approach when studying the effects of vitamin D supplementation, such as evaluation of the whole vitamin D endocrine system, rather than only of 25(OH)D levels before and after treatment, the use of adequate and physiologic vitamin D dosing, controlling for the amount of vitamin D supplementation subjects on the placebo arms may receive, and sufficiently long follow-up are some aspects that need to be carefully considered in future studies.
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Department of Medicine, Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne , England
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Rebelos, E., Tentolouris, N. & Jude, E. The Role of Vitamin D in Health and Disease: A Narrative Review on the Mechanisms Linking Vitamin D with Disease and the Effects of Supplementation. Drugs 83 , 665–685 (2023). https://doi.org/10.1007/s40265-023-01875-8
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DOI : https://doi.org/10.1007/s40265-023-01875-8
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Vitamin D: The “sunshine” vitamin
Medical Services Department, Torrent Pharmaceuticals Ltd., Ahmedabad, Gujarat, India
Vitamin D insufficiency affects almost 50% of the population worldwide. An estimated 1 billion people worldwide, across all ethnicities and age groups, have a vitamin D deficiency (VDD). This pandemic of hypovitaminosis D can mainly be attributed to lifestyle (for example, reduced outdoor activities) and environmental (for example, air pollution) factors that reduce exposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin. High prevalence of vitamin D insufficiency is a particularly important public health issue because hypovitaminosis D is an independent risk factor for total mortality in the general population. Current studies suggest that we may need more vitamin D than presently recommended to prevent chronic disease. As the number of people with VDD continues to increase, the importance of this hormone in overall health and the prevention of chronic diseases are at the forefront of research. VDD is very common in all age groups. As few foods contain vitamin D, guidelines recommended supplementation at suggested daily intake and tolerable upper limit levels. It is also suggested to measure the serum 25-hydroxyvitamin D level as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D2 or vitamin D3 is recommended for deficient patients. A meta-analysis published in 2007 showed that vitamin D supplementation was associated with significantly reduced mortality. In this review, we will summarize the mechanisms that are presumed to underlie the relationship between vitamin D and understand its biology and clinical implications.
Vitamin D insufficiency affects almost 50% of the population worldwide.[ 1 ] An estimated 1 billion people worldwide, across all ethnicities and age groups, have a vitamin D deficiency (VDD).[ 1 – 3 ] This pandemic of hypovitaminosis D can mainly be attributed to lifestyle and environmental factors that reduce exposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin. Black people absorb more UVB in the melanin of their skin than do white people and, therefore, require more sun exposure to produce the same amount of vitamin D.[ 4 ]
The high prevalence of vitamin D insufficiency is a particularly important public health issue because hypovitaminosis D is an independent risk factor for total mortality in the general population.[ 5 ] Emerging research supports the possible role of vitamin D against cancer, heart disease, fractures and falls, autoimmune diseases, influenza, type-2 diabetes, and depression. Many health care providers have increased their recommendations for vitamin D supplementation to at least 1000 IU.[ 6 ] A meta-analysis published in 2007 showed that vitamin D supplementation was associated with significantly reduced mortality.[ 7 ] In this review, we will focus on the biology of vitamin D and summarize the mechanisms that are presumed to underlie the relationship between vitamin D and its clinical implications.
Biology of the sunshine vitamin
Vitamin D is unique because it can be made in the skin from exposure to sunlight.[ 3 , 8 – 10 ] Vitamin D exists in two forms. Vitamin D 2 is obtained from the UV irradiation of the yeast sterol ergosterol and is found naturally in sun-exposed mushrooms. UVB light from the sun strikes the skin, and humans synthesize vitamin D 3 , so it is the most “natural” form. Human beings do not make vitamin D 2 , and most oil-rich fish such as salmon, mackerel, and herring contain vitamin D 3 . Vitamin D (D represents D 2 , or D 3 , or both) that is ingested is incorporated into chylomicrons, which are absorbed into the lymphatic system and enter the venous blood. Vitamin D that comes from the skin or diet is biologically inert and requires its first hydroxylation in the liver by the vitamin D-25-hydroxylase (25-OHase) to 25(OH)D.[ 3 , 11 ] However, 25(OH)D requires a further hydroxylation in the kidneys by the 25(OH)D-1-OHase (CYP27B1) to form the biologically active form of vitamin D 1,25(OH)2D.[ 3 , 11 ] 1,25(OH)2D stimulates intestinal calcium absorption.[ 12 ] Without vitamin D, only 10–15% of dietary calcium and about 60% of phosphorus are absorbed. Vitamin D sufficiency enhances calcium and phosphorus absorption by 30–40% and 80%, respectively.[ 3 , 13 ]
Vitamin D receptor (VDR) is present in most tissues and cells in the body.[ 6 , 14 ] 1,25(OH)2D has a wide range of biological actions, such as inhibition of cellular proliferation and inducing terminal differentiation, inhibiting angiogenesis, stimulating insulin production, inhibiting renin production, and stimulating macrophage cathelicidin production.[ 6 , 14 – 16 ] The local production of 1,25(OH)2D may be responsible for regulating up to 200 genes[ 17 ] that may facilitate many of the pleiotropic health benefits that have been reported for vitamin D.[ 3 , 8 , 9 , 14 ]
Vitamin D deficiency: Prevalence
VDD has been historically defined and recently recommended by the Institute of Medicine (IOM) as a 25(OH)D of less than 0.8 IU. Vitamin D insufficiency has been defined as a 25(OH)D of 21–29 ng/mL.[ 1 , 18 – 23 ] Children and young- and middle-aged adults are at equally high risk for VDD and insufficiency worldwide. VDD is common in Australia, the Middle East, India, Africa, and South America.[ 1 , 24 , 25 ] Pregnant and lactating women who take a prenatal vitamin and a calcium supplement with vitamin D remain at high risk for VDD.[ 26 – 28 ]
Vitamin D deficiency, why it happens?
The major source of vitamin D for children and adults is exposure to natural sunlight.[ 1 , 29 – 32 ] Thus, the major cause of VDD is inadequate exposure to sunlight.[ 29 , 33 – 35 ] Wearing a sunscreen with a sun protection factor of 30 reduces vitamin D synthesis in the skin by more than 95%.[ 36 ] People with a naturally dark skin tone have natural sun protection and require at least three to five times longer exposure to make the same amount of vitamin D as a person with a white skin tone.[ 37 , 38 ] There is an inverse association of serum 25(OH)D and body mass index (BMI) greater than 30 kg/m 2 , and thus, obesity is associated with VDD.[ 39 ]
Patients with one of the fat malabsorption syndromes and bariatric patients are often unable to absorb the fat-soluble vitamin D, and patients with nephritic syndrome lose 25(OH)D bound to the vitamin D-binding protein in the urine.[ 1 ] Patients on a wide variety of medications, including anticonvulsants and medications to treat AIDS/HIV, are at risk because these drugs enhance the catabolism of 25(OH)D and 1,25(OH)2D.[ 40 ] Patients with chronic granuloma-forming disorders (sarcoidosis, tuberculosis, and chronic fungal infections), some lymphomas, and primary hyperparathyroidism who have increased metabolism of 25(OH)D to 1,25(OH)2D are also at high risk for VDD.[ 41 , 42 ]
Vitamin D deficiency: Consequences
VDD results in abnormalities in calcium, phosphorus, and bone metabolism. VDD causes a decrease in the absorption of dietary calcium and phosphorus, resulting in an increase in PTH levels.[ 1 , 3 , 18 , 43 ] The PTH-mediated increase in osteoclastic activity creates local foci of bone weakness and causes a generalized decrease in bone mineral density (BMD), resulting in osteopenia and osteoporosis. An inadequate calcium–phosphorus product causes a mineralization defect in the skeleton.[ 1 , 44 ] In young children who have little mineral in their skeleton, this defect results in a variety of skeletal deformities classically known as rickets.[ 45 , 46 ] VDD also causes muscle weakness; affected children have difficulty in standing and walking,[ 46 , 47 ] whereas the elderly have increasing sway and more frequent falls,[ 48 , 49 ] thereby increasing their risk of fracture.
Groups at risk of vitamin-D inadequacy
Obtaining sufficient vitamin D from natural food sources alone is difficult. Consumption of vitamin D-fortified foods and exposure to some sunlight are essential for maintaining a healthy vitamin D status. Dietary supplements might be required to meet the daily need for vitamin D in some group of people.[ 50 ]
Vitamin D requirements cannot ordinarily be met by human milk alone,[ 23 , 51 ] which provides <25 IU/L to 78 IU/L.[ 52 ] Vitamin D content of human milk is related to the mother's vitamin D status; therefore mothers who supplement with high doses of vitamin D may have high levels of vitamin D in their milk.[ 52 ] American Association of Paediatricians (AAP) recommends that exclusively and partially breastfed infants must be supplemented with 400 IU of vitamin D per day,[ 52 , 53 ] the recommended daily allowance for this nutrient during infancy.
Older adults are at high risk of developing vitamin D insufficiency because of aging. Their skin cannot synthesize vitamin D as efficiently, they are likely to spend more time indoors, and they may have inadequate intakes of the vitamin.[ 23 ]
People with limited sun exposure
Homebound individuals, women who wear long robes and head coverings for religious reasons, and people with occupations that limit sun exposure are unlikely to obtain adequate vitamin D from sunlight.[ 54 , 55 ] The significance of the role that sunscreen may play in reducing vitamin D synthesis is still unclear.[ 23 ] Intake of RDA levels of vitamin D from foods and/or supplements will provide adequate amounts of this nutrient to these individuals.
People with dark skin
Larger amounts of the pigment melanin in the epidermal layer result in darker skin and reduce the skin's ability to produce vitamin D from sunlight.[ 23 ] It is not sure that lower levels of 25(OH)D for persons with dark skin have significant health consequences. Intake of RDA levels of vitamin D from foods and/or supplements will provide adequate amounts of this nutrient to these individuals.
People with fat malabsorption
Vitamin D is fat soluble, therefore it requires some dietary fat in the gut for absorption. Individuals with reduced ability to absorb dietary fat might require vitamin D supplements.[ 56 ] Fat malabsorption is associated with a variety of medical conditions including some forms of liver disease, cystic fibrosis, and Crohn's disease.[ 57 ]
People who are obese or who have undergone gastric bypass surgery
A BMI value of ≥30 is associated with lower serum 25(OH)D levels compared with nonobese individuals. Obese people may need larger than usual intakes of vitamin D to achieve 25(OH)D levels comparable to those of normal weight.[ 23 ] Greater amounts of subcutaneous fat sequester (captivate) more of the vitamin and alter its release into the circulation. Individuals who have undergone gastric bypass surgery may become vitamin D deficient over time without a sufficient intake of vitamin D from food or supplements; moreover part of the upper small intestine where vitamin D is absorbed is bypassed.[ 58 , 59 ]
Sources of vitamin D
A major source of vitamin D for most humans is synthesized from the exposure of the skin to sunlight typically between 1000 h and 1500 h in the spring, summer, and fall.[ 1 , 29 , 33 , 60 ] Vitamin D produced in the skin may last at least twice as long in the blood compared with ingested vitamin D.[ 61 ] When an adult wearing a bathing suit is exposed to one minimal erythemal dose of UV radiation (a slight pinkness to the skin 24 h after exposure), the amount of vitamin D produced is equivalent to ingesting between 10,000 and 25,000 IU.[ 33 ] A variety of factors reduce the skin's production of vitamin D 3 , including increased skin pigmentation, aging, and the topical application of a sunscreen.[ 1 , 36 , 37 ] An alteration in the zenith angle of the sun caused by a change in latitude, season of the year, or time of day dramatically influences the skin's production of vitamin D 3 .[ 1 , 33 ]
Physiological actions of vitamin D
Vitamin D is a fat-soluble vitamin that acts as a steroid hormone. In humans, the primary source of vitamin D is UVB-induced conversion of 7-dehydrocholesterol to vitamin D in the skin [ Figure 1 ].[ 1 , 62 ] Vitamin D influences the bones, intestines, immune and cardiovascular systems, pancreas, muscles, brain, and the control of cell cycles.[ 63 ]
Vitamin D synthesis
Vitamin D undergoes two hydroxylations in the body for activation. Calcitriol (1,25-dihydroxyvitamin D 3 ), the active form of vitamin D, has a half-life of about 15 h, while calcidiol (25-hydroxyvitamin D 3 ) has a half-life of about 15 days.[ 63 ] Vitamin D binds to receptors located throughout the body. 25(OH)D is transformed by renal or extrarenal 1α-hydroxylase into 1,25-dihydroxyvitamin D (1,25[OH]2D), which circulates at much lower serum concentrations than 25(OH)D, but has a much higher affinity to the VDR.[ 64 ] Studies have, however, shown that many other cell types, including those of the vascular wall, express 1α-hydroxylase with subsequent intracellular conversion of 25(OH)D to 1,25(OH)2D, which exerts its effects at the level of the individual cell or tissue before being catabolized to biologically inactive calcitroic acid.[ 1 , 65 , 66 ] Factors such as fibroblast growth factor 23 and Klotho, which suppress 1α-hydroxylase expression, have also been shown to regulate the renal conversion of 25(OH)D to 1,25(OH)2D.[ 67 ] Importantly, extrarenal 1α-hydroxylase expression also underlies various regulatory mechanisms. In this context, extrarenal 1,25(OH)2D productions in macrophages are stimulated by Toll-like receptor as part of the innate immune response against intracellular bacteria.[ 68 ] Another example of extrarenal regulation of 1α-hydroxylase is that the increased production of 1,25(OH)2D by keratinocytes in wounds[ 69 ] therefore provides a good estimate of vitamin D status, but regulation of 1α-hydroxylase activity should also be considered. Vitamin D crosses the blood–brain barrier and the receptors for vitamin D are found across the brain, but its precise role is still not known.
Vitamin D supplements may interact with several types of medications. Corticosteroids can reduce calcium absorption, which results in impaired vitamin D metabolism.[ 9 ] Since vitamin D is fat soluble, Orlistat and Cholestyramine can reduce its absorption and should be taken several hours apart from it.[ 9 ] Phenobarbital and phenytoin increase the hepatic metabolism of vitamin D to inactive compounds and decrease calcium absorption, which also impairs vitamin D metabolism.[ 9 ]
Only a few foods are a good source of vitamin D. The best way to get additional vitamin D is through supplementation. Traditional multivitamins contain about 400 IU of vitamin D, but many multivitamins now contain 800 to 1000 IU. A variety of options are available for individual vitamin D supplements, including capsules, chewable tablets, liquids, and drops. Cod liver oil is a good source of vitamin D, but in large doses there is a risk of vitamin A toxicity.[ 70 ]
Clinical benefits of vitamin D
Vitamin D decreases cell proliferation and increases cell differentiation, stops the growth of new blood vessels, and has significant anti-inflammatory effects.[ 71 , 72 ] Many studies have suggested a link between low vitamin D levels and an increased risk of cancer, with the strongest evidence for colorectal cancer. In the Health Professionals Follow-up Study (HPFS), subjects with high vitamin D concentrations were half as likely to be diagnosed with colon cancer as those with low concentrations.[ 71 ] A definitive conclusion cannot yet be made about the association between vitamin D concentration and cancer risk, but results from many studies are promising. There is some evidence linking higher vitamin D intake to a lower risk for breast cancer.[ 72 ] The effect of menopausal status on this association is still unclear.
Several studies are providing evidence that the protective effect of vitamin D on the heart could be via the renin–angiotensin hormone system, through the suppression of inflammation, or directly on the cells of the heart and blood-vessel walls.[ 17 ] In the Framingham Heart Study, patients with low vitamin D concentrations (<15 ng/mL) had a 60% higher risk of heart disease than those with higher concentrations.[ 17 ] In another study, which followed men and women for 4 years, patients with low vitamin D concentrations (<15 ng/mL) were three times more likely to be diagnosed with hypertension than those with high concentrations (>30 ng/mL).[ 73 ]
The third National Health and Nutrition Examination Survey (NHANES-III),[ 74 ] which is representative of the noninstitutionalized US civilian population, showed that systolic blood pressure and pulse pressure were inversely and significantly correlated with 25(OH)D levels among 12,644 participants. Age-associated increase in systolic blood pressure was significantly lower in individuals with vitamin D sufficiency.[ 75 , 76 ] The prevalence of arterial hypertension was also associated with reduced serum 25(OH)D levels in 4030 participants of the German National Interview and Examination Survey,[ 77 ] in 6810 participants of the 1958 British Birth Cohort,[ 78 ] and in other study populations.[ 79 – 87 ] The antihypertensive effects of vitamin D are mediated by renoprotective effects, suppression of the RAAS, by beneficial effects on calcium homeostasis, including the prevention of secondary hyperparathyroidism, and by vasculoprotection.[ 85 ]
Low concentrations of circulating vitamin D are common with obesity and may represent a potential mechanism explaining the elevated risk of certain cancers and cardiovascular outcomes. Levels of 25(OH)D are inversely associated with BMI, waist circumference, and body fat but are positively associated with age, lean body mass, and vitamin D intake.
The prevalence of VDD is higher in black versus white children regardless of season predictors of VDD in children include black race, female sex, pre-pubertal status, and winter/spring season.[ 88 ] Weight loss is associated with an increase in 25(OH)D levels among postmenopausal overweight or obese women.[ 89 ]
Type 2 diabetes
A trial of nondiabetic patients aged 65 years and older found that those who received 700 IU of vitamin D (plus calcium) had a smaller rise in fasting plasma glucose over 3 years versus those who received placebo.[ 90 ] A correlation between vitamin D and the risk diabetes can be ruled in from the results.
A Norwegian trial of overweight subjects showed that those receiving a high dose of vitamin D (20,000 or 40,000 IU weekly) had a significant improvement in depressive symptom scale scores after 1 year versus those receiving placebo.[ 91 ] The result determines a correlation between vitamin D and the risk of depression.
In the Invecchiare in Chianti (InCHIANTI) Italian population-based study, low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied during a 6-year period.[ 92 ] Low levels of 25(OH)D may be especially harmful to executive functions, whereas memory and other cognitive domains may be relatively preserved.
Parkinson's disease is a major cause of disability in the elderly population. Unfortunately, risk factors for this disease are relatively unknown. Recently, it has been suggested that chronically inadequate vitamin D intake may play a significant role in the pathogenesis of Parkinson's disease. A cohort study based on the Mini-Finland Health Survey demonstrated that low vitamin D levels may predict the development of Parkinson's disease.[ 93 ]
Fractures and falls
Vitamin D is known to help the body absorb calcium, and it plays a role in bone health. In addition, VDRs are located on the fast-twitch muscle fibers, which are the first to respond in a fall.[ 94 ] It is theorized that vitamin D may increase muscle strength, thereby preventing falls.[ 6 ] Many studies have shown an association between low vitamin D concentrations and an increased risk of fractures and falls in older adults.
A combined analysis of 12 fracture-prevention trials found that supplementation with about 800 IU of vitamin D per day reduced hip and nonspinal fractures by about 20%, and that supplementation with about 400 IU per day showed no benefit.[ 95 ] Researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University have examined the best trials of vitamin D versus placebo for falls. Their conclusion is that “fall risk reduction begins at 700 IU and increases progressively with higher doses.”[ 94 ]
VDD can contribute to autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes, rheumatoid arthritis, and autoimmune thyroid disease.[ 96 ]
A prospective study of white subjects found that those with the highest vitamin D concentrations had a 62% lower risk of developing MS versus those with the lowest concentrations.[ 97 ] A Finnish study that followed children from birth noted that those given vitamin D supplements during infancy had a nearly 90% lower risk of developing type 1 diabetes compared with children who did not receive supplements.[ 98 ]
VDD in the winter months may be the seasonal stimulus that triggers influenza outbreaks in the winter.[ 96 ] In a Japanese randomized, controlled trial, children given a daily vitamin D supplement of 1200 IU had a 40% lower rate of influenza type A compared with those given placebo; there was no significant difference in rates of influenza type B.[ 99 ]
An analysis of data from the National Health and Nutrition Examination Survey showed that in pregnant women, VDD was associated with nearly a 3-fold increased risk for Bacterial Vaginosis (BV).[ 100 ] In non-pregnant women, VDD modulated the association between smoking and BV.
Pelvic floor disorders
The frequency of Pelvic floor disorders, including urinary and fecal incontinence, is increasing with age. Pelvic floor disorders have been linked to osteoporosis and low BMD and remain one of the most common reasons for gynaecologic surgery, with a failure rate of 30%. Subnormal levels of 25(OH)D are common among women, and lower levels are associated with a higher likelihood of pelvic floor disorders.[ 101 ] Results from the National Health and Nutrition Examination Survey confirmed that lower 25(OH) D levels are associated with a greater risk for urinary incontinence in women older than 50 years.
Age-related macular regeneration
High vitamin D blood levels appear to be associated with a decreased risk for the development of early age-related macular degeneration (AMD) among women younger than 75 years.[ 102 ] Among women younger than 75 years, there is a lower risk for early AMD with higher vitamin D levels, with a threshold effect at 15.22 ng/L serum 25 (OH)D.
RECOMMENDATION GUIDELINES: ENDOCRINE SOCIETY OF CLINICAL PRACTICE
ESCP recommend screening for VDD in individuals at risk for deficiency and not for patients who are not at risk. Serum circulating 25-hydroxyvitamin D [25(OH) D] level should be measured to evaluate vitamin D status in patients who are at risk for VDD. VDD is defined as a 25(OH) D below 20 ng/mL (50 nmol/L).[ 103 ]
Recommended dietary intakes of vitamin D
ESCP suggests that obese children and adults on anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for AIDS should be given at least two to three times more vitamin D for their age group to satisfy their body's vitamin D requirement[ Table 1 ].
Recommended dietary intakes of vitamin D for patients at risk for vitamin D deficiency[ 103 ]
ESCP suggests that the maintenance tolerable upper limits (UL) of vitamin D, which is not to be exceeded without medical supervision, should be 1000 IU/d for infants up to 6 months, 1500 IU/d for infants from 6 months to 1 year, at least 2500 IU/d for children aged 1–3 years, 3000 IU/d for children aged 4–8 years, and 4000 IU/d for everyone over 8 years. Higher levels of 2000 IU/d for children 0–1 year, 4000 IU/d for children 1–18 years, and 10000 IU/d for children and adults 19 years and older may be needed to correct VDD.[ 103 ]
Treatment and prevention strategies
Vitamin D 2 or vitamin D 3 can be used for the treatment and prevention of VDD [ Table 2 ]. In patients with extrarenal production of 1,25(OH)2D, serial monitoring of 25(OH)D levels and serum calcium levels during treatment with vitamin D to prevent hypercalcemia is suggested [ Table 2 ]. Primary hyperparathyroidism and VDD need treatment with vitamin D.[ 103 ]
Treatment and prevention strategies[ 103 ]
Noncalcemic benefits of vitamin D
ESCP recommends prescribing vitamin D supplementation for fall prevention and do not recommend supplementation beyond recommended daily needs for the purpose of preventing cardiovascular disease or death or improving quality of life.[ 103 ]
Vitamin D analogs
Vitamin D has five natural analogs, called vitamers, and four synthetic analogs which are made synthetically. Vitamin D analogs are chemically classified as secosteroids, which are steroids with one broken bond.
Natural analogs of vitamin D
- Vitamin D 1 is a molecular compound of ergocalciferol (D 2 ) with lumisterol in a 1:1 ratio.
- Vitamin D 2 (ergocalciferol) is produced by invertebrates, some plants, and fungi. Biological production of D 2 is stimulated by ultraviolet light.
- Vitamin D 3 (cholecalciferol) is synthesized in the skin by the reaction of 7-dehydrocholesterol with UVB radiation, present in sunlight with an UV index of three or more.
- Vitamin D 4 is an analog scientifically known as 22-dihydroergocalciferol.
- Vitamin D 5 (sitocalciferol) is an analog created from 7-dehydrositosterol.
Synthetic analogs of vitamin D
- Maxacalcitol (22-oxacalcitriol or OCT) is the first analog found to have a wider therapeutic window than 1,25(OH)2D 3 .[ 104 ]
- Calcipotriol is derived from calcitriol was first discovered during trials involving the use of vitamin D for treating osteoporosis.
- Dihydrotachysterol (DHT) is a synthetic form of vitamin D that many consider superior to natural D 2 and D 3 . It becomes active by the liver without needing to go through hydroxylation in the kidneys.
- Paricalcitol (19-norD 2 ) is also derived from calcitriol. It is the first of the new vitamin D analogs to be approved for secondary hyperparathyroidism and differs from calcitriol in that it lacks the exocyclic carbon 19 and has a vitamin D 2 side chain instead of a vitamin D 3 side chain.[ 105 ]
- Tacalcitol is a derivative of vitamin D 3 . It is known to hinder keratinocytes in the skin.
- Doxercalciferol (1α(OH) D2 ) is a prodrug and must be activated in vivo . It is less toxic than 1α (OH) D3 [ 106 ] when administered chronically.
- Falecalcitriol (1,25(OH) 2-26, 27-F6-D3) is approved for secondary hyperparathyroidism in Japan.[ 105 ] It is more active than calcitriol because of its slower metabolism.[ 107 ]
Numbers of people with VDD are continuously increasing; the importance of this hormone in overall health and the prevention of chronic diseases are at the forefront of research. VDD is very common in all age groups. Very few foods contain vitamin D therefore guidelines recommended supplementation of vitamin D at tolerable UL levels. It is also suggested to measure the serum 25-hydroxyvitamin D level as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D 2 or vitamin D 3 is recommended for the deficient patients. More research is required to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection.
We would like to acknowledge Mr. Anand Iyer, VP, Marketing and Sales, Torrent Pharmaceuticals Ltd., for providing us moral and infrastructural support for drafting this scientific review and Mr. Ramesh Jayswal, Executive—Information Science, Torrent Pharmaceuticals Ltd., who has enabled us with the required reference articles and scientific inputs to draft this review article.
Source of Support: Nil
Conflict of Interest: None declared.
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- Review Article
- Published: 01 December 2010
Vitamin D, disease and therapeutic opportunities
- Lori A. Plum 1 &
- Hector F. DeLuca 1
Nature Reviews Drug Discovery volume 9 , pages 941–955 ( 2010 ) Cite this article
- Calcium and vitamin D
- Drug discovery
The discovery of the vitamin D endocrine system in 1970 sparked a new interest in the relationship between vitamin D and metabolic bone disease. In particular, the identification of the vitamin D receptor in tissues not related to calcium and bone has led to the investigation of vitamin D and its action in a number of other medical areas.
Many studies evaluating the effects of high-dose vitamin D in supplemental form in suppressing a wide range of diseases have been conducted, and many clinical investigators have interpreted that vitamin D does have a beneficial effect.
In metabolic bone disease, vitamin D cures rickets in children and osteomalacia in adults. However, in vitamin D-dependency type I and type II rickets, treatment with the vitamin D hormone, 1α,25-dihydroxyvitamin D 3 , offers more benefits. For osteoporosis, vitamin D does have a role; however, the development of oral vitamin D analogues that have anabolic properties would fulfil an unmet need.
Several vitamin D analogues have been marketed for the treatment of secondary hyperthyroidism associated with chronic renal failure, and are successful as they provide a wider therapeutic window compared with 1α,25-dihydroxyvitamin D 3 and its synthetic precursor 1α-hydroxyvitamin D 3 . They have also proved successful in treating psoriasis.
Vitamin D and sunlight exposure has also been associated with various immune disorders (for example, multiple sclerosis and type 1 diabetes) and numerous cancers; however, the role of vitamin D-based therapies for these indications remains to be evaluated in large-scale studies.
Toxic effects of vitamin D and hypercalcaemia can occur when vitamin D is taken in doses above 25,000 IU per day (625 μg per day) or when the vitamin D endocrine system is dysregulated, such as in granuloma-forming disease or in various malignancies, such as Hodgkin's lymphoma.
Future development of vitamin D-based therapeutics will probably target specific aspects of vitamin D function, which will be aided by the identification of key specific genes responsible for the various functions of vitamin D.
It is likely that more efficacious vitamin D analogues selective for bone formation or resorption will be developed, and analogues selective for intestinal calcium absorption will also be developed. However, with the current status of knowledge, it seems that development of vitamin D analogues specific for components of the immune system is less promising.
The discovery of the vitamin D endocrine system and a receptor for the hormonal form, 1α,25-dihydroxyvitamin D 3 , has brought a new understanding of the relationship between vitamin D and metabolic bone diseases, and has also established the functions of vitamin D beyond the skeleton. This has ushered in many investigations into the possible roles of vitamin D in autoimmune diseases, cardiovascular disorders, infectious diseases, cancers and granuloma-forming diseases. This article presents an evaluation of the possible roles of vitamin D in these diseases. The potential of vitamin D-based therapies in treating diseases for which the evidence is most compelling is also discussed.
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This work was supported by a fund from the Wisconsin Alumni Research Foundation.
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Correspondence to Hector F. DeLuca .
Hector F. DeLuca is a founder of Deltanoid Pharmaceuticals, and Lori A. Plum is the Director of Research and Development at Deltanoid Pharmaceuticals, a company involved in the development of vitamin D analogues.
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Plum, L., DeLuca, H. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov 9 , 941–955 (2010). https://doi.org/10.1038/nrd3318
Published : 01 December 2010
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DOI : https://doi.org/10.1038/nrd3318
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Vitamin D is a nutrient your body needs for building and maintaining healthy bones. That's because your body can only absorb calcium, the primary component of bone, when vitamin D is present. Vitamin D also regulates many other cellular functions in your body. Its anti-inflammatory, antioxidant and neuroprotective properties support immune health, muscle function and brain cell activity.
Vitamin D isn't naturally found in many foods, but you can get it from fortified milk, fortified cereal, and fatty fish such as salmon, mackerel and sardines. Your body also makes vitamin D when direct sunlight converts a chemical in your skin into an active form of the vitamin (calciferol).
The amount of vitamin D your skin makes depends on many factors, including the time of day, season, latitude and your skin pigmentation. Depending on where you live and your lifestyle, vitamin D production might decrease or be completely absent during the winter months. Sunscreen, while important to prevent skin cancer, also can decrease vitamin D production.
Many older adults don't get regular exposure to sunlight and have trouble absorbing vitamin D. If your doctor suspects you're not getting enough vitamin D, a simple blood test can check the levels of this vitamin in your blood.
Taking a multivitamin with vitamin D may help improve bone health. The recommended daily amount of vitamin D is 400 international units (IU) for children up to age 12 months, 600 IU for people ages 1 to 70 years, and 800 IU for people over 70 years.
What the research says
Research on vitamin D use for specific conditions shows:
- Cancer. Findings on the benefits of vitamin D for cancer prevention are mixed. More studies are needed to determine whether vitamin D supplementation may reduce the risk of certain cancers.
- Cognitive health. Research shows that low levels of vitamin D in the blood are associated with cognitive decline. However, more studies are needed to determine the benefits of vitamin D supplementation for cognitive health.
- Inherited bone disorders. Vitamin D supplements can be used to help treat inherited disorders resulting from an inability to absorb or process vitamin D, such as familial hypophosphatemia.
- Multiple sclerosis. Research suggests that long-term vitamin D supplementation reduces the risk of multiple sclerosis.
- Osteomalacia. Vitamin D supplements are used to treat adults with severe vitamin D deficiency, resulting in loss of bone mineral content, bone pain, muscle weakness and soft bones (osteomalacia).
- Osteoporosis. Studies suggest that people who get enough vitamin D and calcium in their diets can slow bone mineral loss, help prevent osteoporosis and reduce bone fractures. Ask your doctor if you need a calcium and vitamin D supplement to prevent or treat osteoporosis.
- Psoriasis. Applying vitamin D or a topical preparation that contains a vitamin D compound called calcipotriene to the skin can treat plaque-type psoriasis in some people.
- Rickets. This rare condition develops in children with vitamin D deficiency. Supplementing with vitamin D can prevent and treat the problem.
Without vitamin D your bones can become soft, thin and brittle. Insufficient vitamin D is also connected to osteoporosis. If you don't get enough vitamin D through sunlight or dietary sources, you might need vitamin D supplements.
Safety and side effects
Taken in appropriate doses, vitamin D is generally considered safe.
However, taking too much vitamin D in the form of supplements can be harmful. Children age 9 years and older, adults, and pregnant and breastfeeding women who take more than 4,000 IU a day of vitamin D might experience:
- Nausea and vomiting
- Poor appetite and weight loss
- Confusion and disorientation
- Heart rhythm problems
- Kidney stones and kidney damage
Possible interactions include:
- Aluminum. Taking vitamin D and aluminum-containing phosphate binders, which may be used to treat high serum phosphate levels in people with chronic kidney disease, might cause harmful levels of aluminum in people with kidney failure in the long term.
- Anticonvulsants. The anticonvulsants phenobarbital and phenytoin (Dilantin, Phenytek) increase the breakdown of vitamin D and reduce calcium absorption.
- Atorvastatin (Lipitor). Taking vitamin D might affect the way your body processes this cholesterol drug.
- Calcipotriene (Dovonex, Sorilux). Don't take vitamin D with this psoriasis drug. The combination might increase the risk of too much calcium in the blood (hypercalcemia).
- Cholestyramine (Prevalite). Taking vitamin D with this cholesterol-lowering drug can reduce your absorption of vitamin D.
- Cytochrome P-450 3A4 (CYP3A4) substrates. Use vitamin D cautiously if you're taking drugs processed by these enzymes.
- Digoxin (Lanoxin). Avoid taking high doses of vitamin D with this heart medication. High doses of vitamin D can cause hypercalcemia, which increases the risk of fatal heart problems with digoxin.
- Diltiazem (Cardizem, Tiazac, others). Avoid taking high doses of vitamin D with this blood pressure drug. High doses of vitamin D can cause hypercalcemia, which might reduce the drug's effectiveness.
- Orlistat (Xenical, Alli). Taking this weight-loss drug can reduce your absorption of vitamin D.
- Thiazide diuretics. Taking these blood pressure drugs with vitamin D increases your risk of hypercalcemia.
- Steroids. Taking steroid mediations such as prednisone can reduce calcium absorption and impair your body's processing of vitamin D.
- Stimulant laxatives. Long-term use of high doses of stimulant laxatives can reduce vitamin D and calcium absorption.
- Verapamil (Verelan, Calan SR). Taking high doses of vitamin D with this blood pressure drug can cause hypercalcemia, and might also reduce the effectiveness of verapamil.
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- Vitamin D: Fact sheet for health professionals. Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/. Accessed Dec. 6, 2020.
- Vitamin D: Fact sheet for consumers. Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/VitaminD-Consumer/. Accessed Dec. 6, 2020.
- Vitamin D. Natural Medicines. https://naturalmedicines.therapeuticresearch.com. Accessed Dec. 6, 2020.
- AskMayoExpert. Vitamin D deficiency. Mayo Clinic; 2017.
- Cholecalciferol. IBM Microdemex. https://www.microdemexsolutions.com. Accessed Dec. 11, 2020.
- Gold J, et al. The role of vitamin D in cognitive disorders in older adults. US Neurology. 2018; doi:10.17925/USN.2018.14.1.41.
- Sultan S, et al. Low vitamin D and its association with cognitive impairment and dementia. Journal of Aging Research. 2020; doi:10.1155/2020/6097820.
- Pazirandeh S, et al. Overview of vitamin D. https://www.uptodate.com/contents/search. Accessed Dec. 13, 2020.
- Hassan-Smith ZK, et al. 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exerct distinct effects on human skeletal muscle function and gene expression. PLOS One. 2017; doi:10.1371/journal.pone.0170665.
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Review article: vitamin D and inflammatory bowel diseases
- 1 Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.
- PMID: 24236989
- PMCID: PMC3872479
- DOI: 10.1111/apt.12553
Background: Vitamin D is traditionally associated with bone metabolism. The immunological effects of vitamin D have increasingly come into focus.
Aim: To review the evidence supporting a role of vitamin D in inflammatory bowel diseases.
Methods: A comprehensive search was performed on PubMed using the terms 'crohn's disease' 'ulcerative colitis' and 'vitamin D'.
Results: Vitamin D deficiency is common in patients with inflammatory bowel diseases (IBD) (16-95%) including those with recently diagnosed disease. Evidence supports immunological role of vitamin D in IBD. In animal models, deficiency of vitamin D increases susceptibility to dextran sodium sulphate colitis, while 1,25(OH)2 D3 ameliorates such colitis. One prospective cohort study found low predicted vitamin D levels to be associated with an increased risk of Crohn's disease (CD). Limited data also suggest an association between low vitamin D levels and increased disease activity, particularly in CD. In a large cohort, vitamin D deficiency (<20 ng/mL) was associated with increased risk of surgery (OR 1.8, 95% CI 1.2-2.5) in CD and hospitalisations in both CD (OR 2.1, 95% CI 1.6-2.7) and UC (OR 2.3, 95% CI 1.7-3.1). A single randomised controlled trial demonstrated that vitamin D supplementation may be associated with reduced frequency of relapses in patients with CD compared with placebo (13% vs. 29%, P = 0.06).
Conclusions: There is growing epidemiological evidence to suggest a role for vitamin D deficiency in the development of IBD and also its influence on disease severity. The possible therapeutic role of vitamin D in patients with IBD merits continued investigation.
© 2013 John Wiley & Sons Ltd.
- Research Support, N.I.H., Extramural
- Colitis, Ulcerative / epidemiology
- Colitis, Ulcerative / etiology*
- Colitis, Ulcerative / immunology
- Colitis, Ulcerative / metabolism
- Crohn Disease / epidemiology
- Crohn Disease / etiology*
- Crohn Disease / immunology
- Crohn Disease / metabolism
- Vitamin D / immunology
- Vitamin D / metabolism
- Vitamin D Deficiency / complications*
- Vitamin D Deficiency / epidemiology
- Vitamin D Deficiency / immunology
- Vitamin D Deficiency / metabolism
Grants and funding
- K23 DK097142/DK/NIDDK NIH HHS/United States
- P30 DK043351/DK/NIDDK NIH HHS/United States
- Open access
- Published: 16 November 2023
The impact of vitamin D, vitamin C, and zinc supplements on immune status among Jordanian adults during COVID-19: cross-sectional study findings
- Hala K. Nawaiseh 1 ,
- Dana N. Abdelrahim 2 ,
- Hayder Al-Domi 1 ,
- Mohammad S. AL-Assaf 3 &
- Furat K. AL-Nawaiseh 4
BMC Public Health volume 23 , Article number: 2251 ( 2023 ) Cite this article
Background and aims
Nutritional status is essential for the maintenance of the immune system, with malnutrition suppressing immunity. The aims of the current study were to assess the immune status of a group of Jordanian adults and to evaluate the association between vitamin C, vitamin D, and zinc consumption and the Immune Status during the COVID-19 pandemic.
A total of 615 adults Jordanian participants were enrolled in this study, an online- based cross sectional survey was used as a tool for this study. Data was collected by distributing the questionnaire form link through social media platforms. The association between ISQ score and the supplement intake pattern (daily, weekly, monthly and rarely) was assessed using multinomial logistic regression analysis, described as Odds ratio and 95% CI.
Data have indicated that the majority of the participants did not take Vitamin D supplements during the pandemic (46.3%). Also, there was a significant association between the frequency of Vitamin D supplement intake and ISQ (r = 12.777; P < 0.05). Data showed that the majority of participants used vitamin C supplementation (49.4%). Also, there was a significant association between the frequency of Vitamin C supplement intake and ISQ (r = 12.797; P < 0.05). Data also have indicated that the majority of the participants did not increase their consumption of Zinc during the COVID-19 pandemic (55.6%).
The findings of this study suggest a significant association between the frequency of Vitamin D, and vitamin C supplement intake and ISQ. Nutritional status is essential for the maintenance of the immune system, with malnutrition suppressing immunity.
Peer Review reports
COVID-19 remains a worldwide problem [ 1 ]. With nearly 170,000 reported fatalities to date, the coronavirus disease 2019 (COVID-19) pandemic has affected nearly 2.5 million people worldwide [ 2 ]. Malnutrition, particularly deficiencies in vitamins A, D, C, zinc, and selenium, has been linked to COVID-19 infection [ 1 ]. Numerous studies have shown that during the COVID-19 epidemic, people in the Middle East consumed more dietary supplements and herbal remedies to ward off the disease. [ 3 ]. To protect patients, it is also important to use evidence-based practices to manage nutritional supplements an herbal items [ 3 ]. Supplementation with vitamins C and D, as well as with zinc and selenium, for people who are at risk of respiratory viral infections or for those who are nutrient deficient, has been emphasized as potentially useful [ 4 ].
Elderly people, African Americans, obese people, and institutionalized people are disproportionately affected by coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 5 ]. These groups have also been identified as high-risk populations for vitamin D deficiency [ 5 ]. In addition to vitamin D playing a crucial role in the metabolism of calcium and phosphate, it is known for its biological effects on immunological regulation [ 6 ].
Vitamin C has been shown to improve immunity, wound healing, energy metabolism, and nervous system function [ 7 ]. A healthy and effective host defence mechanism requires vitamin C, and it is thought that administering vitamin C pharmacologically can improve immune performance [ 2 ]. Previous research has demonstrated that vitamin C inhibits the replication of some viruses, including influenza, poliovirus, and herpes simplex virus [ 2 ]. Vitamin C may be useful in treating viral infections and possibly COVID-19 [ 2 ].
Zinc, the second most prevalent trace metal in the body after iron, is crucial for many cellular processes, including the preservation of immune function [ 8 ]. Zinc is an anti-inflammatory and antioxidant micronutrient [ 8 ]. In some clinical trials on COVID-19, it was proven that zinc has a well-established role in immunity, and it is currently being used [ 8 ]. The scant research on the benefits of zinc supplementation do not support its effectiveness [ 9 ]. Therefore, COVID-19 prevention or treatment strategies based on selenium or zinc supplementation are currently unjustified [ 9 ].
Nutritional status is essential for the maintenance of the immune system, with malnutrition suppressing immunity [ 10 ]. Specific essential nutrients are correlated with viral infection and mortality from COVID-19 [ 11 ]. Vitamin D, vitamin C, and the trace element zinc are known to support immune function [ 11 ]. Data have indicated that deficiencies and suboptimal nutritional status of these micronutrients can potentially decrease resistance to infections and reinfections. [ 12 ]. Therefore, considering the effects of the COVID-19 pandemic and the controversial evidence, this research aimed to assess the immune status of a group of Jordanian adults and to evaluate the association between vitamin C, vitamin D, and zinc consumption and the Immune Status during the COVID-19 pandemic.
To assess the nutritional status, immune status, and dietary intake of specific types of nutrients during the COVID-19 pandemic, a total of 615 adult Jordanian participants were enrolled in this study, and an online-based cross-sectional survey was conducted. All healthy Jordanian adults aged 18–65 years old were eligible to participate in this study, except cancer patients, who were excluded. Data were collected from June 2021 to November 2021 by distributing the questionnaire form link through social media platforms.
Data collection tools
The online questionnaire instrument contained the following domains: (1) sociodemographic data, (2) dietary intake of specific nutrients, (3) diagnosis of COVID-19, and (4) immune status. The participants’ sociodemographic data included age, sex, education, type of job, height and weight and history of any disease.
Dietary intake questionnaire
The dietary intake section asked semiqualitative dietary intake questions for 15 food items (the sources of vitamin D, C and zinc in a normal healthy diet), the frequency of vitamin C, D and zinc supplementation during the COVID-19 pandemic and the dose of consumption. The diagnosis of COVID-19 section asked whether the participants or their families had previously or currently had COVID-19 and whether they were vaccinated or planned to be vaccinated.
The choices for the vitamin D supplementation questions were recategorized as follows: from no intake to less than 1 per month was considered “rarely”, 1–3 times per month was considered “monthly”, 1 time per month, 2–4 times per week and 5–6 times per week were considered “weekly”, and once daily up to 6 times or more daily were considered “daily”. The choices for the zinc supplementation questions were recategorized as follows: no intake was considered “rarely”, 1–2 times per month was considered “monthly”, 1 time per month and 2–3 times per week were considered “weekly”, and once daily up to 2–3 times daily was considered “daily”. The choices for the vitamin C supplementation questions were recategorized as follows: rarely was defined as “monthly”, sometimes was defined as “weekly”, and approximately every day was defined as “daily”.
The actual content of one serving of each food item that included vitamin D, zinc and vitamin C was obtained from ESHA SQL food analyser software. Total consumption was calculated by multiplying the actual content of one serving of food by the frequency of consumption and recategorized. For the questions that contained more than one food item, the average content of all items was used as the actual content of each supplement.
The Immune Status Questionnaire (ISQ)
The Immune Status Questionnaire (ISQ) is a valid and reliable 7-item scale used to assess perceived immune status over the past 12 months. The ISQ asks about “sudden high fever”, “diarrhoea”, “headache”, “skin problems (e.g., acne and eczema)”, “muscle and joint pain”, “common cold” and “coughing”. The responses were collected through 5-point Likert scale descriptors (“never”, “sometimes”, “regularly”, “often” and “(almost) always)”. Then, a total score was obtained, and a cut-off value was applied (< 6) to determine the status of immune functioning and differentiate between those with poor and normal immune health [ 13 ].
Each item of the Immune Status Questionnaire (ISQ) was scored as follows: never = 0 points; sometimes = 1 point; regularly = 2 points; often = 3 points; and (almost) always = 4 points; then, the sum score of the 7 ISQ items was calculated. The raw score was recoded to obtain the final ISQ score (where 0 = very poor and 10 = excellent perceived immune status), and the ISQ final score was recoded by the cut-off score for reduced immune functioning, which was ISQ < 6, and a value greater than or equal to 6 was considered good immune functioning [ 13 ]. The Arabic version of the questionnaire was used in the data collection process [ 13 , 14 ].
Data identification and statistical analysis
Participants’ response data were encoded and analysed using IBM SPSS Statistics, version 26.0. Sociodemographic continuous data are presented as the means and standard deviations. The categorical variables are expressed as frequencies and percentages of observed values. The questions on vitamin D, zinc and vitamin C intake are described using frequencies and percentages. The correlation between supplement intake and the ISQ score was assessed using correlation analysis. Subsample analysis was performed for the questions on the diagnosis and history of COVID-19 using the independent sample t test and 95% confidence intervals (CIs). Additionally, an independent sample t test was performed to assess the relationship between the ISQ score and disease occurrence.
The association between the ISQ score and the supplement intake pattern (daily, weekly, monthly and rarely) was assessed using multinomial logistic regression analysis, described as odds ratios and 95% CIs. Total supplement consumption was compared to the dietary recommendations by age and sex groups using a t test. The sex-specific effect was assessed in comparison with the ISQ score using crosstabs, chi-square tests and risk assessment analysis. Body mass index (BMI) was calculated by the weight and height of participants and categorized using the WHO definition. Then, the correlation between BMI categories and ISQ score was evaluated for both sexes. All the data significance levels were set at P < 0.05.
A total of 615 participants from different areas in Jordan were recruited in this study; 80.2% were females. A greater proportion were aged 18–29 (47.6%) and had a bachelor’s degree (67.0%). A greater proportion of participants had jobs in education (39.2%), followed by medical jobs (36.7%). The majority of the participants had a normal body weight (48.0%). The majority of participants with chronic disease were obese (34.3%), and the smallest proportion of the participants were diagnosed with cancer (0.5%) (Tables 1 and 2 ).
Table 3 shows the vitamin D supplementation status and its correlation with ISQ score. The majority of the participants did not take vitamin D supplements during the pandemic (46.3%). The highest proportion of the participants took vitamin D supplements once during the last month (39.7%), and the majority used a 50,000-mg dose (30.1%). The majority of the participants indicated that they did not increase their consumption of vitamin D during the COVID-19 pandemic (57.2%). The data indicated a significant association between the frequency of vitamin D supplement intake and ISQ score (r = 12.777; P < 0.05).
Table 4 shows the zinc and vitamin C supplement status of the participants. The data showed that the majority of participants used vitamin C supplementation (49.4%). Moreover, the participants’ consumption of vitamin C supplements increased during the COVID-19 pandemic (57.7%). Most of the participants took vitamin C supplements once during the last month (73.2%), and the greatest proportion of participants used a 50-mg dose (30.1%). The data indicated a significant association between the frequency of vitamin C supplement intake and ISQ score (r = 12.797; P < 0.05). However, there was no significant association between the dose of vitamin C and the ISQ score (P > 0.05). The data indicated that the majority of the participants did not increase their consumption of zinc during the COVID-19 pandemic (55.6%).
Table 5 shows the association between the frequency of food item consumption and the ISQ score in the study population. A significant effect was reported for only one food item, nuts, and consuming nuts on a daily basis may have significantly (P < 0.05) led to good immune functioning by 63%. The intake of no other food item had a significant effect on immune functioning (P > 0.05). Table 6 shows the average intake of each of the micronutrients for the whole population. Compared to the ISQ score, this table indicates that there was no significant association (P > 0.05) between vitamin D, zinc or vitamin C and the ISQ score.
Nutritional status is essential for the maintenance of the immune system, with malnutrition suppressing immunity [ 10 ]. It has been reported that malnutrition is associated with an increased risk of SARS-CoV-2 infection, severity, and mortality [ 10 ]. Nutritional status and specific essential nutrients are correlated with viral infection and mortality from COVID-19 [ 11 ]. Vitamin D, vitamin C, and the trace element zinc are known to support immune function [ 11 ]. In the current study, different patterns of dietary supplement use were identified in a group of individuals during the COVID-19 pandemic in Jordan.
The majority of the participants did not take vitamin D supplements during the pandemic (46.3%). Moreover, the greatest proportion of the participants took vitamin D supplements once during the last month (39.7%), and the majority used a dose of 50,000 mg (30.1%). However, the majority of the participants reported that they did not increase their consumption of vitamin D during the COVID-19 pandemic (57.2%). Our findings also indicated a significant association between the frequency of vitamin D supplement intake and ISQ score (r = 12.777; P < 0.05). In parallel to the current findings, data from an online cross-sectional questionnaire among Japanese adults indicated that most participants (91.7%) reported not currently using dietary supplements for the prevention of SARS-CoV-2 infection; however, only 8.3% reported that they used it as a therapeutic tool [ 1 ]. The current data are similar to the data from studies conducted through online surveys in Lebanon, the Kingdom of Saudi Arabia, Palestine, Jordan, and the United Arab Emirates, which indicated that only 21.3% of respondents agreed that nutritional supplements may minimize the risk of being infected with COVID-19; however, 45.4% believed that dietary supplements have therapeutic effects against COVID-19, and only 15.2% recognized that dietary supplements are useful only in cases of deficiencies [ 15 ]. The most common supplements used were vitamin C (77.8%), vitamin D (55.7%), and zinc (42.9%). [ 15 ]However, there were increases in the use of antioxidants (14% vs. 15.6%), vitamin C (35.3% vs. 42.1%), vitamin D (35.5% vs. 41%), vitamin E (15.2% vs. 17.5%), and zinc (18.8% vs. 29.3%) [ 16 ]. However, data from a cross-sectional web-based survey in the United Arab Emirates (UAE) population indicated that 56.6% of participants reported using dietary supplements to prevent or cure COVID-19, with vitamin C (84.5%), vitamin D (31.6%), and multivitamins (17%) being the most commonly reported supplements [ 17 ]. In a randomized control trial, the administration of two weeks of oral supplementation of vitamin D (1000 UI vs. 5000 UI) to patients with suboptimal vitamin D status was associated with fast recovery from cough and sensory loss among those who received a greater amount [ 19 ]. On the basis of these results, it seems appropriate to prescribe vitamin D as an adjuvant to COVID-19 treatment for individuals with mild to severe symptoms [ 19 ].
Vitamin D is efficient at alleviating SARS-CoV-2 infection, according to a retrospective observational analysis of SARS-CoV-2 positivity in relation to serum 25(OH) D concentration measurements in the United States [ 18 ]. Data indicated that SARS-CoV-2 positivity in those with a serum concentration of 55 ng/mL was roughly half that of those with a serum value of 20 ng/ml. Data from a meta-analysis of 43 observational studies with a total of 612,601 patients indicated that among subjects with vitamin D deficiency (a serum 25(OH)D concentration < 20 ng/ml), the risk for COVID-19 infection was higher compared to those with serum 25(OH)D concentrations > 30 ng/mL (OR, 1.26; P < 0.01) [ 6 ]. Additionally, data from a large cohort study conducted in the United Kingdom indicated that supplementation with omega-3 fatty acids, probiotics, multivitamins, or vitamin D was related to a reduced risk of infection with the COVID-19 virus; however, vitamin C, zinc, or garlic supplementation did not show therapeutic effects against COVID-19 [ 19 ].
The therapeutic effects of vitamin D in relation to COVID-19 are due to its potential immunomodulatory effects, such as maintenance of epithelial cell integrity, promotion of antimicrobial peptides, modulation of antigenic presentation by dendritic cells, promotion of anti-inflammatory cytokines, and regulation of renin production [ 20 ]. The other function of vitamin D is to reduce the possibility of a cytokine storm, which is linked to COVID-19-induced acute respiratory distress syndrome and may cause considerable multiorgan damage [ 21 ]. The nutritional status of people regarding vitamin D may have been exacerbated during the COVID-19 pandemic because of limitations in mobility, which may suppress normal immune functions [ 11 , 22 ]. Recent research has demonstrated that vitamin D regulates and suppresses the cytokine inflammatory response that causes acute respiratory distress syndrome observed in severe and frequently fatal COVID-19 infections [ 23 ]. It has been recommended to maintain serum 25(OH)D concentrations between 40 and 60 ng/ml [ 24 ]. However, to achieve these concentrations, an adult would require 4000 to 6000 IU/day of vitamin D [ 24 ]. Elderly people and those who already have chronic diseases stand to gain the greatest benefits [ 24 ].
To maximize the immunological response, it has even been suggested that micronutrient RDAs can be exceeded through supplementation as long as care is taken not to exceed the upper intake limits [ 4 ].
Our results indicated that the majority of participants used vitamin C supplementation (49.4%). Moreover, the participants’ consumption of vitamin C supplements increased during the COVID-19 pandemic (57.7%). The majority of participants took vitamin C supplements once during the last month (73.2%), and the greatest proportion of the participants used a dose of 50 mg (30.1%). The data indicated a significant association between the frequency of vitamin C supplement intake and ISQ score (r = 12.797; P < 0.05). However, there was no significant association between the dose of vitamin C and the ISQ score (P > 0.05). In parallel to the current findings, a cross-sectional study in Saudi Arabia reported that approximately 22% of the 5258 participants reported that they had used herbal and nutritional supplements to prevent the disease during the epidemic [ 25 ]. In addition, vitamin C was the most often utilized supplement to boost immunity and reduce the likelihood of developing COVID-19 [ 25 ]. Similarly, a cross-sectional study that included 1460 participants aged between 12 and 86 years in Riyadh, Saudi Arabia, demonstrated a considerable increase in the intake and frequency of nutritional supplements during the COVID-19 pandemic period compared to the period preceding the COVID-19 pandemic (P = 0.000). Moreover, the majority of participants reported utilizing vitamin C (56%) [ 3 ]. Due to its essential function in innate (nonspecific) and acquired (specific) immunity, vitamin C is one of the most widely utilized vitamins across different communities [ 26 , 27 ]. Additionally, a study among Lithuanian adults reported that the majority of respondents (73.7%) said that the pandemic had no impact on their usage of dietary supplements, and one-fourth of respondents’ consumption increased (24.6%) [ 28 ].
Data from a randomized controlled trial among patients with severe COVID-19 infection in Tehran, Iran, found that an intervention with 6 g/day of vitamin C for 5 days among 30 patients with severe COVID-19 did not affect COVID-19-related symptoms, including body temperature, peripheral capillary oxygen saturations (SpO2), length of ICU admission, or mortality, compared to a placebo control group. [ 7 ].
Previous research that included 17 patients with confirmed COVID-19 found that three days of vitamin C supplementation (1 g/8 h) was associated with decreased inflammatory markers in all hospitalized patients [ 2 ]. Moreover, in a study among 46 patients, a greater dose (6 g every 12 h on Day 1 and 6 g for the next four days) decreased the risk of mortality and improved oxygen support [ 29 ]. A cross-sectional, questionnaire-based study among adult patients (≥ 18 years) in Saudi Arabia found that some dietary supplements were consumed by participants even before their infection with COVID-19, which may indicate their belief in the protective and immune-boosting effects of these supplements, including vitamin C (48.8%) [ 30 ].
Although vitamin C deficiency was observed in COVID-19 patients (110) and could be utilized to reduce susceptibility to alleviate respiratory tract infections, there are inadequate data to support its efficacy in protecting people from SARS-CoV-2 infection [ 31 , 32 ]. Human infections, degenerative diseases, oral diseases, and behavioural disorders are all more common when zinc is deficient [ 33 ]. Current information indicates a link between lower zinc intake and COVID-19 disease severity [ 33 , 34 ].
This study found that more than half (55.6%) of the study sample did not increase their intake of zinc supplements during COVID-19. A study performed among elderly individuals, who are the most vulnerable age group to be infected with COVID-19 and documented in the NHANES III, agreed with our study results and indicated that approximately 35-45% of elderly people consumed much less zinc than recommended [ 33 ]. A study performed among 935 Polish residents reported that consumption of zinc and vitamin D was increased among participants with higher education levels (59%) compared with noneducated or participants with lower education levels and increased among participants with a medical background compared with participants with backgrounds in other fields (54.5%) [ 35 ]. Another study in Egypt demonstrated that only 5.6% of the participants consumed zinc supplements during the pandemic [ 36 ].
This study found that the average daily intake of zinc was 3.23 mg, which had a very weak correlation with the ISQ score (0.008) and was not significant (P > 0.05). This correlation is still largely debated in many studies. A study conducted in Japan among 62 patients with COVID-19 showed a strong association between low serum zinc levels and the severity of the disease, which can be justified by the fact that zinc may reduce viral replication and increase the immune response by providing an additional shield against the initiation and progression of COVID-19 [ 37 , 38 ]. Another study performed in the United States found a correlation between zinc supplementation and the mitigation of COVID-19 severity when they gave 10-, 25-, and 50-mg daily doses, which may explain why in our results, no correlation was shown since the intake was much less than one-third of the minimum given dose in the study [ 39 ]. Furthermore, a meta-analysis performed in Iran suggested that zinc supplementation is associated with a lower risk of mortality among COVID-19 patients [ 40 ]. In addition, a Bangladeshi study confirmed that the duration of vitamin D, C and zinc supplementation and medication was significantly associated with reduced patient hospitalization [ 41 ].
In this study, 46.3% of the participants did not take vitamin D supplements during the pandemic. Additionally, the current data indicated a significant association between the frequency of vitamin D supplement intake and ISQ scores. Regarding zinc consumption, 55.6% of the participants did not consume zinc supplements, and the average daily intake of zinc was 3.23 mg, which had a very weak correlation with the ISQ score. These nutrients might be beneficial for health by helping to avoid excess nutritional intake, even though there is no scientific evidence that they can help prevent SARS-CoV-2 infection. Data have indicated that deficiencies and suboptimal nutritional status of these micronutrients can potentially decrease resistance to infections and reinfections. This study has some strengths and limitations that should be acknowledged. To the best of our knowledge, this is the first study in Jordan to assess the use of vitamin D, vitamin C, and zinc supplements and its association with ISQ scores in a group of Jordanian individuals during the COVID-19 pandemic. In addition, one of the characteristics of online surveys is their efficacy in reaching people who live in different geographical areas and, moreover, the speed of data collection. However, there are a few limitations that need to be considered while interpreting the results of the present study. First, the major limitation of the current study is the self-report nature of the data obtained. Therefore, response biases associated with over-reporting and under-reporting could be included in the dataset. Secondly, we recruited our subjects via social networks using a non-probability snowball sampling technique. This created selection bias, which may have limited the generalizability of the current results. Thirdly, Due to the cross-sectional nature of the study design, exact causality between the studied variables cannot be determined. Finally, the small sample size affects the representativeness of the sample to the population of Jordan.
The data that support the findings of this study are available upon request from the corresponding author. The data cannot be publicly available due to privacy and ethical considerations.
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The authors would like to thank the participants for their contributions to the study by filling in the questionnaire.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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Department of nutrition and food technology, Faculty of Agriculture, The University of Jordan, 11942, Amman, Jordan
Hala K. Nawaiseh & Hayder Al-Domi
Research Institute for Medical and Health Sciences, Sharjah University, 27272, Sharjah, United Arab Emirates
Dana N. Abdelrahim
Department of Ears, Nose and Throat, King Hussein Medical Centre (KHMC), Amman, Jordan
Mohammad S. AL-Assaf
Jordan Center for Disease Control (JCDC), Amman, Jordan
Furat K. AL-Nawaiseh
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HN conceived this studyHN and DA contributed data collection, statistical analysis, interpreted the results and writing the manuscript.HN, DA, HD,MA,and FN contributed to writing the manuscript.All authors contributed to the final design of the study and provided relevant contributions to its intellectual content.
Correspondence to Hala K. Nawaiseh .
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was obtained from all the participants and/or legal guardians for the study’. All methods were carried out in accordance with declaration of Helsinki’’.
All procedures performed in this study were in accordance with the ethical standards followed by the principle investigator’s institution and approved by the Research Ethics Committee / institutional review board in the University of Jordan (REC/IRB/49/2022).
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Nawaiseh, H.K., Abdelrahim, D.N., Al-Domi, H. et al. The impact of vitamin D, vitamin C, and zinc supplements on immune status among Jordanian adults during COVID-19: cross-sectional study findings. BMC Public Health 23 , 2251 (2023). https://doi.org/10.1186/s12889-023-17172-8
Received : 29 July 2023
Accepted : 06 November 2023
Published : 16 November 2023
DOI : https://doi.org/10.1186/s12889-023-17172-8
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