In the current narrative review, the bioavailability of the main vitamin D forms is evaluated. The mean intakes and main contributing forms of vitamin D in the European diet are estimated, as well as the major contributing dietary sources. The literature is reviewed for studies reporting on the proportion of users and non-users of fortified food with vitamin D intakes below reference intakes. In addition, the availability of vitamin D-fortified prepackaged retail products and fortification levels in the European market is assessed. Previously, vitamins D2 and D3 forms were considered the primary forms in the diet. Recent analytical methods suggest that dietary 25(OH)D3, when adjusted for higher bioequivalence, significantly contributes to total vitamin D intakes. When also considering 25(OH)D3 from foods, the estimated vitamin D intake from an average European diet was 3.8 µg/d of total Vitamin D Equivalents: vitamin D3, vitamin D2 and 25(OH)D3, contributing about 71 %, 2 %, and 27 %, respectively. Animal foods, fortified fats and spreads contributed most to total intakes. Literature suggests that 94-100 % of Europeans aged ≥ 13 y fail to meet the vitamin D reference intake of 10 µg/d. About 98-100 % of vitamin D-fortified food users and 99-100 % of non-users in the UK and Netherlands consumed less than 10 µg/d of vitamin D. About 1.2 % of prepackaged foods and drinks were voluntary fortified with vitamin D, margarine and plant-based drinks providing most of the daily vitamin D. Encouraging fortification and other strategies may support closing the gap between current and recommended vitamin D intakes.

There is growing evidence linking neonatal vitamin D deficiency to an increased risk of schizophrenia, ADHD, and autism spectrum disorder (ASD). The aim of this study was to examine the association between two vitamin D biomarkers (25 hydroxyvitamin D [25(OH)D] and vitamin D-binding protein [DBP], and their related genetic correlates) and the risk of six mental disorders.

We used a population-based, case-cohort sample of all individuals born in Denmark between 1981 and 2005. Using Danish health registers with follow-up to Dec 31, 2012, we identified individuals diagnosed with major depressive disorder, bipolar disorder, schizophrenia, ADHD, ASD, and anorexia nervosa based on ICD-10 criteria. Additionally, a random subcohort from the general population was selected. Based on neonatal dried blood spots, we measured concentrations of 25(OH)D and DBP. Our primary analyses were based on hazard ratios (HR) with 95% CI and absolute risks for the six mental disorders according to measured concentrations of 25(OH)D and DBP. As secondary analyses, we examined the association between genetic predictors of 25(OH)D and DBP, and the six mental disorders, and Mendelian randomisation analyses based on published summary statistics for 25(OH)D, DBP, and the six mental disorders. People with lived experience contributed to the development of the guiding hypothesis.

We used the total population from the iPSYCH2012 design (n=88 764), which included individuals who developed the six mental disorders, major depressive disorder (n=24 240), bipolar disorder (n=1928), schizophrenia (n=3540), ADHD (n=18 726), ASD (n=16 146), anorexia nervosa (n=3643), and the randomly sampled subcohort (n=30 000). Among those who met a range of inclusion criteria (eg, measured 25[OH]D, DBP or genotype, and predominantly European ancestry), we measured 25(OH)D or DBP in 71 793 individuals (38 118 [53·1%] male and 33 675 [46·9%] female); 65 952 had 25(OH)D and 66 797 the DBP measurements. Significant inverse relationships were found between 25(OH)D and schizophrenia (HR 0·82, 95% CI 0·78-0·86), ASD (HR 0·93, 95% CI 0·90-0·96), and ADHD (HR 0·89, 95% CI 0·86-0·92). A significant inverse relationship was found between DBP and schizophrenia (HR 0·84, 95% CI 0·80-0·88). Based on polygenic risk scores, higher concentrations of 25(OH)D (adjusted for DBP) were significantly associated with a reduced risk of both ASD and schizophrenia. Analyses based on Mendelian randomisation provided support for a causal association between both lower 25(OH)D and DBP concentrations and an increased risk of ADHD.

Convergent evidence finds that neonatal vitamin D status is associated with an altered risk of mental disorders. Our study supports the hypothesis that optimising neonatal vitamin D status might reduce the incidence of a range of neurodevelopmental disorders.

The Danish National Research Foundation.

Obesity is known to influence the circulating 25(OH)D level but less is known about whether it influences the time required to reach a stable 25(OH)D level after initiating vitamin D supplementation. This observational study was done to investigate whether BMI modified the time required to reach a steady-state 25(OH)D level in response to vitamin D supplementation. Participants in the Boston STOP IT study who were treated for 12 mo with 700 IU of vitamin D3 and 500 mg of calcium daily and had 25(OH)D measures at 0, 6, and 12 mo, were included. We assessed the trajectory of 25(OH)D levels by baseline BMI category (normal weight, BMI 18.5-24.9 kg/m2, n = 62; overweight and obese, BMI ≥ 25 kg/m2, n = 105). Baseline 25(OH)D levels were 78 ± 31.3 nmol/L (normal weight) and 74.7 ± 36.5 nmol/L (overweight and obese). In a linear mixed model examining the influence of time and baseline BMI category on change in the mean 25(OH)D level, there was a significant time x BMI group interaction (p = .024. The normal weight participants had reached steady-state 25(OH)D levels by 6 mo whereas 25(OH)D levels continued to rise between 6 and 12 mo in the overweight and obese participants. This analysis suggests that the time required to reach a steady-state 25(OH)D level after initiating vitamin D supplementation in overweight and obese adults is greater than the usual 3-mo time point commonly used in clinical practice. A more refined definition of the time course of circulating 25(OH)D response to supplementation is needed in overweight and obese individuals in order to optimize clinical monitoring of vitamin D status.

Vitamin D is crucial for immune regulation, and its deficiency is linked to multiple sclerosis (MS). The GC gene encodes Vitamin D Binding Protein (VDBP), which regulates vitamin D transport and bioavailability. This study examines the association of GC polymorphisms (rs7041, rs4588) with MS susceptibility and their impact on 25-hydroxyvitamin D [25(OH)D] levels in a Latvian cohort. This case-control study included 296 MS patients and 253 healthy controls. Genotyping of rs7041 and rs4588 was conducted using restriction fragment length polymorphism analysis and validated by Sanger sequencing. Plasma 25(OH)D levels were measured in 131 MS patients using an enzyme-linked immunosorbent assay. Statistical analysis included Hardy-Weinberg equilibrium testing, Fisher's exact test, allelic and genotypic frequency comparisons to assess MS risk, and the Kruskal-Wallis test for 25(OH)D level differences among genotypes. Our findings indicate that the rare rs7041-T and rs4588-A alleles, along with their corresponding haplotypes, exhibit a protective effect against MS (p < 0.001; OR = 0.65 for rs4588-A; p < 0.01; OR = 0.70 for rs7041-T). Conversely, the common rs7041-G and rs4588-C alleles were associated with an increased MS risk (p < 0.05). Individuals with the Gc1F/1F isotype had the highest average 25(OH)D levels (29.31 ng/mL), while Gc1S/2 carriers had the lowest (21.53 ng/mL). Our results indicate that GC polymorphisms may influence the susceptibility of Latvians to MS and vitamin D status.

Vitamin D was discovered as the cure for nutritional rickets, a disease of bone growth arising from inadequate intestinal calcium absorption, and for much of the 20th century, it was studied for its critical role in calcium homeostasis. However, we now recognize that the vitamin D receptor and vitamin D metabolic enzymes are expressed in numerous tissues unrelated to calcium homeostasis. Notably, vitamin D signaling can induce cellular differentiation and cell cycle arrest. Moreover, the vitamin D receptor and the enzyme CYP27B1, which produces the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), are expressed throughout the immune system. In addition, CYP27B1 expression in immune cells is regulated by physiological inputs independent of those controlling its expression in calcium homeostatic tissues. These observations have driven the development of 1,25D-like secosteroidal analogs and nonsecosteroidal analogs to separate the effects of vitamin D on cell differentiation and function from its calcemic activities. Notably, some of these analogs have had considerable success in the clinic in the treatment of inflammatory and immune-related disorders. In this review, we described in detail the mechanisms of vitamin D signaling and the physiological signals controlling 1,25D synthesis and catabolism, with a focus on the immune system. We also surveyed the effects of 1,25D and its analogs on the regulation of immune system function and their implications for human immune-related disorders. Finally, we described the potential of vitamin D analogs as anticancer therapeutics, in particular, their use as adjuncts to cancer immunotherapy. SIGNIFICANCE STATEMENT: Vitamin D signaling is active in both the innate and adaptive arms of the immune system. Numerous vitamin D analogs, developed primarily to minimize the dose-limiting hypercalcemia of the active form of vitamin D, have been used widely in preclinical and clinical studies of immune system regulation. This review presents a description of the mechanisms of action of vitamin D signaling, an overview of analog development, and an in-depth discussion of the immunoregulatory roles of vitamin D analogs.

This systematic review (SR) highlights principles for nutrient clinical trials and explore the diverse physiological functions of vitamin D beyond its traditional role in the musculoskeletal system related to clinical study designs.

Thousands of published research articles have investigated the benefits of vitamin D (a nutrient example taken in this SR) beyond the musculoskeletal system, including the immune, pulmonary, and cardiovascular systems; pregnancy; autoimmune disorders; and cancer. They illustrated vitamin D's molecular mechanisms, interactions, and genomic and nongenomic actions.

This SR was designed to identify shortcomings in clinical study designs, statistical methods, and data interpretation that led to inconsistent findings in vitamin D-related publications. SR also highlights examples and insights into avoiding study design errors in future clinical studies, including randomized controlled clinical trials (RCTs). The SR adheres to the latest PRISMA statement, guidelines, and the PICOS process.

Inappropriate or flawed study designs were frequent in clinical trials. Major failures discussed here include too short clinical study duration, inadequate or infrequent doses, insufficient statistical power, failure to measure baseline and achieved levels, and recruiting vitamin D-sufficient participants. These design errors have led to misleading interpretations. Thus, conclusions from such studies should not be generalized or used in guidelines, recommendations, or policymaking.

Adequately powered epidemiological studies and RCTs with sufficient vitamin D and duration in individuals with vitamin D deficiency reported favorable clinical outcomes, enriching the literature, enabling to understand its physiology and mechanisms. Proper study designs with rigorous methodologies and cautious interpretation of outcomes are crucial in advancing the nutrient field. The principles discussed apply not only to vitamin D, but also other micro-nutrients and nutraceutical research. Adhering to them enhances the credibility and reliability of clinical trials, SRs, and meta-analysis outcomes. The study emphasizes the importance of focused, hypothesis-driven, well-designed, statistically powered RCTs to explore the diverse benefits of nutrients, conducted in index nutrient deficient participants, and avoidance of study design errors. Findings from such studies should be incorporated into clinical practice, policymaking, and public health guidelines, improving the health of the nation and reducing healthcare costs.

Findings from the Maternal Vitamin D Osteoporosis Study (MAVIDOS) trial demonstrated a positive effect of gestational cholecalciferol supplementation on offspring bone mineral density (BMD) at age 4 y. Demonstrating the persistence of this effect is important to understanding whether maternal vitamin D supplementation could be a useful public health strategy to improving bone health.

We investigated whether gestational vitamin D supplementation increases offspring BMD at ages 6-7 y in an exploratory post-hoc analysis of an existing trial.

In the MAVIDOS randomized controlled trial, pregnant females <14 wk' gestation with a singleton pregnancy and serum 25-hydroxyvitamin D 25-100nmol/l at 3 United Kingdom hospitals (Southampton, Sheffield, and Oxford) were randomly assigned to either 1000 IU/d cholecalciferol or placebo from 14 to 17-wk gestation until delivery. Offspring born at term to participants recruited in Southampton were invited to the childhood follow-up at ages 4 and 6-7 y. The children had a dual-energy X-ray absorptiometry (DXA, Hologic discovery) scan of whole-body-less-head (WBLH) and lumbar spine, from which bone area, bone mineral content (BMC), BMD, and bone mineral apparent density (BMAD) were derived. Linear regression was used to compare the 2 groups adjusting for age, sex, height, weight, duration of consumption of human milk, and vitamin D use at 6-7 y.

A total of 454 children were followed up at ages 6-7 y, of whom 447 had a usable DXA scan. Gestational cholecalciferol supplementation resulted in higher WBLH BMC [0.15 SD, 95% confidence interval (CI): 0.04, 0.26], BMD (0.18 SD, 95% CI: 0.06, 0.31), BMAD (0.18 SD, 95% CI: 0.04, 0.32), and lean mass (0.09 SD, 95% CI: 0.00, 0.17) compared with placebo. The effect of pregnancy cholecalciferol on bone outcomes was similar at ages 4 and 6-7 y.

Supplementation with cholecalciferol 1000 IU/d during pregnancy resulted in greater offspring BMD and lean mass in mid-childhood compared with placebo in this exploratory post-hoc analysis. These findings suggest that pregnancy vitamin D supplementation may be an important population health strategy to improve bone health.

This trial was registered at the ISRCTN (https://doi.org/10.1186/ISRCTN82927713) as 82927713 and EUDRACT (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001716-23/results) as 2007-001716-23.

Vitamin D binding protein (VDBP) serves as a key transporter protein responsible for binding and delivering vitamin D and its metabolites to target organs. VDBP plays a crucial part in the inflammatory reaction following tissue damage and is engaged in actin degradation. Recent research has shed light on its potential role in various diseases, leading to a growing interest in understanding the implications of VDBP in psychiatric and neurological disorders. The purpose of this review was to provide a summary of the existing understanding regarding the involvement of VDBP in neurological and psychiatric disorders. By examining the intricate interplay between VDBP and these disorders, this review contributes to a deeper understanding of underlying mechanisms and potential therapeutic avenues. Insights gained from the study of VDBP could pave the way for novel strategies in the diagnosis, prognosis, and treatment of psychiatric and neurological disorders.

Ablation of Cyp27b1 eliminates calcitriol but does not disturb fetal mineral homeostasis or skeletal development. However, independent of fetal genotypes, maternal loss of Cyp27b1 altered fetal mineral and hormonal levels compared to offspring of WT dams. We hypothesized that these maternal influences would alter postnatal skeletal development. Cyp27b1 null and WT females were mated to bear only Cyp27b1+/- offspring. Forty-eight hours after birth, pups were cross-fostered to dams of the same or opposite genotype that bore them. Maternal and offspring samples were collected on days 21 (weaning) and 42. Offspring measurements included minerals and hormones, BMC by DXA, ash weight and mineral content, gene expression, 3-point bending tests, and microCT. Maternal lactational behavior was evaluated. Milk was analyzed for nutritional content. At day 21, offspring fostered by nulls, independent of birth dam, had ~20% lower weight, BMC, ash weight, and ash calcium than pups fostered by WT dams. Adjustment for body weight accounted for the lower BMC but not the lower ash weight and ash calcium. Hormones and serum/urine minerals did not differ across offspring groups. Offspring fostered by nulls had shorter femurs and lower cortical thickness, mean polar moment of inertia, cortical area, trabecular bone volume, and trabecular number. Dam lactational behaviors and milk nutritional content did not differ between groups. At day 42, body weight, ash weight, lengths, BMC, and tibial bone strength were no longer different between pups fostered by null vs WT dams. In summary, pups fostered by Cyp27b1 nulls, regardless of birth dam, have proportionately smaller skeletons at 21 d, impaired microstructure, but normal mineral homeostasis. The skeletal effects are largely recovered by day 42 (3 wk after weaning). In conclusion, maternal loss of calcitriol impairs early postnatal cortical bone growth and trabecular bone mass, but affected offspring catch up after weaning.

Inconsistencies exist regarding the influence of vitamin D2 (ergocalciferol) supplementation on serum vitamin D levels. These inconsistencies could be attributed to numerous factors, such as dosage, baseline vitamin D levels, and duration of intervention. Hence, this dose-response meta-analysis of randomized controlled trials was conducted to assess the efficacy of vitamin D2 supplementation on vitamin D levels.

Relevant studies were searched in PubMed/Medline, Web of Science, Embase, and Scopus, from their inception to 3 January 2023. Variable alterations were considered to calculate the pooled weighted mean difference (WMD) with 95% confidence interval (CI) using the random effects model.

Pooled results from 33 study arms demonstrated that Vitamin D2 treatment significantly increases total vitamin D concentrations (WMD: 11.47 ng/mL, 95 %CI: 9.29 to 13.64, p < 0.001), 25(OH)D2 concentrations (WMD: 11.40 ng/mL, 95 %CI: 4.72 to 18.09, p = 0.001), and 1,25(OH)D concentrations (WMD: 5.61 ng/mL, 95 %CI: 0.74 to 10.48, p = 0.024), but decreases 25(OH)D3 concentrations (WMD: -4.63 ng/mL, 95 %CI: -6.46 to -2.81, p < 0.001). In subgroup analyses, increase in total vitamin D concentrations was more significant in vitamin D2 doses >2000 IU/day (WMD: 13.82 ng/mL), studies with duration ≤12 weeks (WMD: 12.53 ng/mL), participants aged ≥60 years (WMD: 14.40 ng/mL), and trials with basal 25(OH)D concentrations <20 ng/mL (WMD: 11.47 ng/mL).

This meta-analysis indicates that the supplementation of vitamin D2 significantly increases the serum concentrations of total vitamin D, 25(OH)D2, and 1,25(OH)D, but decreases 25(OH)D3 concentrations. Careful consideration of patient characteristics, dosage, and treatment duration is recommended for vitamin D2 supplementation.

Vitamin D deficiency and insufficiency is a public health issue, with low dietary vitamin D intakes a contributing factor. Rates of vitamin D deficiency are 31% in Australia, and up to 72% in some regions globally. While supplementation is often prescribed as an alternative to additional sun exposure, complementary approaches including food-based solutions are needed. Yet, food-centric dietary guidelines are not always adequate for meeting vitamin D needs. Edible mushrooms such as Agaricus bisporus can produce over 100% of vitamin D recommendations (10 μg/day, Institute of Medicine) per 75 g serve (18 μg) on exposure to UV-light, with the vitamin D2 produced showing good stability during cooking and processing. However, mushrooms are overlooked as a vitamin D source in dietary guidelines. Our dietary modelling shows that four serves/week of UV-exposed button mushrooms can support most Australian adults in meeting vitamin D recommendations, and UV-exposed mushrooms have been found to increase vitamin D status in deficient individuals. While recent evidence suggests some differences between vitamin D2 and vitamin D3 in physiological activities, vitamin D2 from mushrooms can be part of a larger solution to increasing dietary vitamin D intakes, as well as an important focus for public health policy. Mushrooms exposed to UV represent an important tool in the strategic toolkit for addressing vitamin D deficiency in Australia and globally. Health authorities lead the recognition and promotion of mushrooms as a natural, vegan, safe, and sustainable vitamin D food source.

Obesity is associated with low vitamin D status, and the optimal supplement and dosage of cholecalciferol (vitamin D3) or calcidiol (25OHD) for individuals with obesity have been debated. We aimed to determine the effect of high-dose vitamin D3 supplementation on achieving adequate vitamin D levels among infertile men with normal weight v. obesity. Here, we present secondary end points from a single-centre, double-blinded, randomised clinical trial, comprising 307 infertile men randomised to active or placebo treatment for 150 days. Men in the active group initially received an oral bolus of 300 000 mg of vitamin D3, followed by daily supplementation with 1400 mg of vitamin D3 and 500 mg of calcium. Baseline BMI was listed as a predefined subgroup. At baseline, serum 25OHD was significantly higher in men with normal weight (BMI < 25 kg/m2) compared with men with overweight (BMI 25-30 kg/m2) and obesity (BMI > 30 kg/m2) (48 nmol/l v. 45 nmol/l and 39 nmol/l, respectively; P = 0·024). After the intervention, men with normal weight, overweight and obesity treated with vitamin D3 had a significantly higher serum 25OHD compared with corresponding placebo-treated men (BMI < 25 kg/m2: 92 nmol/l v. 53 nmol/l, BMI = 25-30 kg/m2: 87 nmol/l v. 49 nmol/l and BMI > 30 kg/m2: 85 nmol/l v. 48 nmol/l; P < 0·001 for all, respectively). In conclusion, we show that high-dose vitamin D3 supplementation to infertile men with obesity and low vitamin D status is sufficient to achieve adequate serum 25OHD levels.

Two previous meta-analyses showed smaller differences between vitamin D3 and vitamin D2 in raising serum 25-hydroxyvitamin D [25(OH)D] and a consistently high heterogeneity when only including daily dosing studies.

This study aimed to compare more frequently dosed vitamin D2 and vitamin D3 in improving total 25(OH)D and determine the concomitant effect of response modifiers on heterogeneity, and secondly, to compare the vitamin D2-associated change in 25(OH)D2 with the vitamin D3-associated change in 25(OH)D3.

PubMed, EMBASE, Cochrane, and the Web of Science Core collection were searched for randomized controlled trials of vitamin D2 compared with vitamin D3, daily or once/twice weekly dosed. After screening for eligibility, relevant data were extracted for meta-analyses to determine the standardized mean difference when different methods of 25(OH)D analyses were used. Otherwise, the weighted mean difference (WMD) was determined.

Overall, the results based on 20 comparative studies showed vitamin D3 to be superior to vitamin D2 in raising total 25(OH)D concentrations, but vitamin D2 and vitamin D3 had a similar positive impact on their corresponding 25(OH)D hydroxylated forms. The WMD in change in total 25(OH)D based on 12 daily dosed vitamin D2-vitamin D3 comparisons, analyzed using liquid chromatography-tandem mass spectrometry, was 10.39 nmol/L (40%) lower for the vitamin D2 group compared with the vitamin D3 group (95% confidence interval: -14.62, -6.16; I2 = 64%; P < 00001). Body mass index (BMI) appeared to be the strongest response modifier, reducing heterogeneity to 0% in both subgroups. The vitamin D2- and vitamin D3-induced change in total 25(OH)D lost significance predominantly in subjects with a BMI >25 kg/m2 (P = 0.99). However, information on BMI was only available in 13/17 daily dosed comparisons.

Vitamin D3 leads to a greater increase of 25(OH)D than vitamin D2, even if limited to daily dose studies, but vitamin D2 and vitamin D3 had similar positive impacts on their corresponding 25(OH)D hydroxylated forms. Next to baseline 25(OH)D concentration, BMI should be considered when comparing the effect of daily vitamin D2 and vitamin D3 supplementation on total 25(OH)D concentration. This study was registered in PROSPERO as CRD42021272674.

Several studies have shown the importance of vitamin D3 supplementation in small animals. In dogs, a low vitamin D3 status is associated not only with bone metabolism but also with different kinds of disorders, such as congestive heart failure, gastrointestinal diseases, chronic kidney diseases, and some types of cancer. However, it is crucial to maintain balance and monitor the introduction of this essential nutrient through the diet because over-supplementation can result in toxicity. Due to the clinical importance of assessing the vitamin D3 status in small animal patients, a quick, simple, and highly performing analytical method for its measurement is needed. In this study, we describe the development of a novel liquid chromatography-tandem mass spectrometry method for 25-hydroxyvitamin D3 quantification in canine serum. The approach was successfully validated following current European guidelines, proving excellent linearity (R2 always ≥0.996), accuracy (always within ±13%) and precision (always <10%). The application of the validated approach to samples collected from 40 healthy dogs made possible the definition of a reliable reference interval for 25-hydroxyvitamin D3, the main biomarker of vitamin D3. In addition, variations below 5% in the results obtained quantifying the same samples using a water-based calibration curve demonstrated that a surrogate matrix may be used without affecting data accuracy. Thanks to its simplicity, the proposed technique represents a useful tool for supporting clinical routine and investigating correlations between serum concentrations of this metabolite and multiple diseases. Additionally, it could enable the monitoring of supplementation in small animal patients in veterinary clinical practice.

Vitamin D (VD) plays a crucial role in regulating calcium homeostasis, while the wealth of its pleiotropic actions is gaining increasing research interest. Sufficient VD concentrations are of clinical relevance, particularly in the context of physiological alterations, such as those occurring during pregnancy when maternal VD is the sole source for the developing fetus. As a result, inadequate VD concentrations in pregnancy have been associated with perinatal complications and adverse neonatal outcomes, including preeclampsia, gestational diabetes mellitus, increased rates of cesarean section, low birth weight, small-for-gestational-age infants, poor immune and skeletal growth, allergies, and respiratory infections. Over the past few decades, several observational studies have underlined the important role of maternal VD in the neural, musculoskeletal, and psychomotor growth and bone health of the offspring. However, the complexity of the factors involved in regulating and assessing VD homeostasis, including race, sun exposure, dietary habits, and laboratory measurement techniques, makes the interpretation of relevant research findings challenging. The aim of this narrative review is to summarize the evidence on the importance of VD in maintaining optimal health during pregnancy, infancy, childhood, and adolescence.

Vitamin D is essential for optimal bone health, and vitamin D deficiency has been associated with an increased risk of adverse pregnancy, growth and developmental outcomes. In early life, and in the absence of endogenous vitamin D production from UVB light, infants are reliant on vitamin D stores established in utero and the vitamin D supply from human milk (HM). However, comprehensive data on vitamin D in HM is lacking. Thus, in this review we explore the application of liquid-chromatography tandem mass spectrometry (LC-MS/MS) to the assessment of vitamin D in HM. We discuss the challenges of extracting and measuring multiple vitamin D metabolites from HM including the frequent requirement for a large sample volume, and inappropriate poor sensitivity. Shortcomings in the reporting of experimental procedures and data analysis further hinder advances in the field. Data collated from all studies that have applied LC-MS/MS reveal that, in general, cholecalciferol concentration is greater and more variable than 25-hydroxyvitamin D concentration, and that the vitamin D content of HM is low and less than the currently recommended dietary requirement of infants, although maternal supplementation can increase the vitamin D content of HM. Improvements in analytical methods and their validation and larger, more representative studies are required to better characterize HM milk vitamin D metabolite concentrations and their relationship with maternal status. These data are essential to understand relationships with infant health and to inform public health policies around vitamin D fortification and supplementation.

Vitamin D deficiency and insufficiency is common among populations globally, and in Asia and Malaysia. The purpose of this Position Paper is to propose recommendations for both clinicians and non-clinicians to promote vitamin D sufficiency in Malaysian adults. Formation of a national multisector, multidisciplinary alliance is also proposed to progress initiatives relating to safe sun exposure, adequate vitamin D intake through food fortification, and vitamin D supplementation for high-risk groups.

Literature reviews were undertaken to inform summaries of the following: vitamin D status globally and in Asian and Malaysian populations, vitamin D status among individuals with common medical conditions, and current recommendations to achieve vitamin D sufficiency through sun exposure, food intake and supplementation. Recommendations were based on the findings of the literature reviews, recent European guidance on vitamin D supplementation, the 2018 road map for action on vitamin D in low- and middle-income countries, and research recommendations proposed by the Malaysian Ministry of Health in 2017.

Recommendations on assessment of vitamin D in the adult Malaysian population include using serum or plasma 25-hydroxyvitamin D concentration as a biomarker, widespread participation by Malaysian laboratories in the Vitamin D Standardization Program, adoption of the US Endocrine Society definitions of vitamin D deficiency and insufficiency, and development of a comprehensive nationwide vitamin D status study. Specific high-risk groups are identified for vitamin D assessment and recommendations relating to loading doses and ongoing management are also made.

This Position Paper provides individual clinicians and national stakeholder organisations with clear recommendations to achieve vitamin D sufficiency in the adult population of Malaysia.

Vitamin D deficiency (VDD) is widespread in the Arab world despite ample sunshine throughout the year. In our previous study, lifestyle and socio-demographic factors could explain only 45% of variability in vitamin D levels in Kuwaiti adolescents, suggesting that genetics might contribute to VDD in this region. Single nucleotide polymorphisms (SNP) in the 25-hydroxylase (CYP2R1) and the GC globulin (GC) genes have been reported to affect vitamin D levels in various ethnic groups in adults. In this study, we investigated the association of two SNPs from GC (rs4588 and rs7041) and three SNPs from CYP2R1 (rs10741657, rs11023374 and rs12794714) with vitamin D levels and VDD in a nationally representative sample of adolescents of Arab ethnicity from Kuwait. Multivariable linear regression, corrected for age, sex, parental education, governorate, body mass index, and exposure to sun, demonstrated that each of the 5 study variants showed significant associations with plasma 25(OH)D levels in one or more of the additive, recessive, and dominant genetic models - the rs10741657 under all the three models, rs12794714 under both the additive and recessive models, rs7041 under the recessive model; and rs4588 and rs11023374 under the dominant model. Minor alleles at rs4588 (T), rs7041 (A), rs11023374 (C), and rs12794714 (A) led to a decrease in plasma 25(OH)D levels - rs4588:[β (95%CI) = -4.522 (-8.66,-0.38); p=0.033]; rs7041:[β (95%CI) = -6.139 (-11.12,-1.15); p=0.016]; rs11023374:[β (95%CI) = -4.296 (-8.18,-0.40); p=0.031]; and rs12794714:[β (95%CI) = -3.498 (-6.27,-0.72); p=0.014]. Minor allele A at rs10741657 was associated with higher levels of plasma 25(OH)D levels [β (95%CI) = 4.844 (1.62,8.06); p=0.003)] and lower odds of vitamin D deficiency (OR 0.40; p=0.002). These results suggest that the CYP2R1 and GC SNP variants are partly responsible for the high prevalence of VDD in Kuwait. Genotyping these variants may be considered for the prognosis of VDD in Kuwait.

This study aimed to investigate the long-term effect of vitamin D supplementation compared to placebo over 5 years in participants with knee osteoarthritis (OA). We also aimed to describe the effect of maintaining sufficient serum vitamin D levels over five years in knee OA.

Participants (n = 173) from the Hobart centre of the Vitamin D Effects on Osteoarthritis (VIDEO) trial were extensively followed up 3 years after the cessation of 2-year investigational treatment. Participants were classified as maintaining sufficient vitamin D (n = 79) and not maintaining sufficient vitamin D (n = 61) groups.

There was no significant difference in change in the knee symptoms, depression, and serum levels of IL6 and hs-CRP between both comparisons after 3 years of cessation of the clinical trial. However, among participants who reported no knee surgery (KS), there was a significant improvement in WOMAC function (β: - 83.7, 95% CI: - 167.3, 0) and depression scores (β: - 1.3, 95% CI: - 2.3, - 0.2) in vitamin D group compared to the placebo group. Similarly, those who maintained adequate vitamin D levels over 5 years had significantly less WOMAC knee pain (β: - 33.9, 95% CI: - 65.7, - 2) and physical dysfunction (β: - 105.5, 95% CI: - 198.2, - 12.8) than participants with vitamin D deficiency over 5 years.

Vitamin D supplementation over 2 years or maintaining vitamin D sufficiency for 5 years was not associated with statistically significant differences in change in knee symptom scores over 5 years. However, among participants who did not report KS, 2-year vitamin D supplementation and maintaining sufficient vitamin D was linked to modest improvements in knee symptoms and depression scores in knee OA.

The predictive role of vitamin D (VD) in breast cancer (BC) patients' survival is still being investigated. This paper aims to evaluate the changes in VD metabolites during chemotherapy (CTH) and the predictive role of VD status in Caucasian BC patients treated with CTH.

Vitamin D and its metabolites were assessed with reference LC-MS/MS methodology in 98 consecutive BC patients starting CHT, after 3 and 6 months, and compared to the control group.

The frequency of VD deficiency in BC patients was greater than in the control group (56.1% vs. 37.2%). After 6 months of CTH, the number of VD-deficient BC patients slightly increased to 60%. The concentrations of VD active forms [25(OH)D2, 25(OH)D3], and catabolites [24,25(OH)2D3 and 3-epi-25(OH)D3] decreased after 3 and 6 months of CTH compared to the baseline values. Strong positive correlations between concentrations of 3-epi-25(OH)D3 and 25(OH)D in both groups were found. Similar correlations were also observed between 24,25(OH)2D3 and 25(OH)D levels. Kaplan-Meier survival analysis showed significantly longer survival in BC patients without deficiency (>20 ng/mL) at baseline (HR = 2.44 (95% CI 1.07-5.59), p = 0.026).

(1) Our data provide further evidence that BC patients before CTH are more VD-deficient than the general population and this deficiency increases further during CTH treatment, as observed using the reference LC-MS methodology. (2) Presented results show that VD catabolism is not affected in BC patients. (3) The poorer survival in VD-deficient BP patients supports the importance of VD supplementation in BC patients with 25(OH)D levels below 20 ng/mL.

Preeclampsia is a multifactorial disease characterized by high blood pressure and protein in the urine. In this study, we investigated the association of vitamin D binding protein (GC) and vitamin D receptor (VDR) gene polymorphism with the risk of developing preeclampsia.

25-hydroxyvitamin D was measured using High-performance Liquid Chromatography. Vitamin D binding protein and vitamin D receptor gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism.

The control subjects have significant higher level of 25-hydroxyvitamin D (33.5 ± 1.194 ng/mL) relative to patients (23.97 ± 1.604 ng/mL) (p < 0.05). Vitamin D receptor rs1544410 and rs2228570 dominant model (GA + AA; TC + CC) showed significant higher risk of developing Preeclampsia (OR = 4.11, 95% CI = 0.62-27.09, p < 0.01; OR = 3.58, 95%CI = 0.78-16.38, p < 0.001 respectively). Similarly, vitamin D binding protein rs7041 and rs4588, dominant model (TG + GG; CA + AA) showed higher risk of preeclampsia development compared to control people (OR = 1.69, 95%CI = 0.35-8.19, p < 0.05; OR = 1.06, 95%CI = 0.25-4.44, p < 0.05 respectively). AA genotype of rs4588 of GC gene was significantly associated with 25-hydroxyvitamin D level in serum relative to CC and CA (p < 0.05).

From our study, we can conclude that a low level of 25-hydroxyvitamin D, GC (rs1544410 and rs2228570), and VDR (rs4588 and rs7041) gene polymorphism is linked with an increased risk of developing preeclampsia.

Antiretroviral therapy for people living with HIV-1 must be taken lifelong due to the persistence of latent virus in long-lived and proliferating CD4+ T cells. Vitamin D3 is a steroidal gene transcription regulator which exerts diverse effects on immune and epithelial cells including reductions in CD4+ T cell proliferation and improvement in gut barrier integrity. We hypothesised that a high dose of vitamin D3 would reduce the size of the HIV-1 reservoir by reducing CD4+ T cell proliferation.

We performed a randomised placebo-controlled trial evaluating the effect of 24 weeks of vitamin D3 (10,000 international units per day) on the HIV-1 reservoir and immunologic parameters in 30 adults on antiretroviral therapy; participants were followed for 12 weeks post-treatment. The primary endpoint was the effect on total HIV-1 DNA at week 24. Parameters were assessed using mixed-effects models.

We found no effect of vitamin D3 on the change in total HIV-1 DNA from week 0 to week 24 relative to placebo. There were also no changes in integrated HIV-1 DNA, 2-long-terminal repeat (2-LTR) circles or cell-associated HIV-1 RNA. Vitamin D3 induced a significant increase in the proportion of central memory CD4+ and CD8+ T cells, a reduction in the proportion of senescent CD8+ T cells and a reduction in the natural killer cell frequency at all time points including week 36, 12 weeks after the study drug cessation. At week 36, there was a significant reduction in total HIV-1 DNA relative to placebo and persistently elevated 25-hydroxyvitamin D levels. No significant safety issues were identified.

Vitamin D3 administration had a significant impact on the T cell differentiation but overall effects on the HIV-1 reservoir were limited and a reduction in HIV-1 DNA was only seen following cessation of the study drug. Additional studies are required to determine whether the dose and duration of vitamin D3 can be optimised to promote a continued depletion of the HIV-1 reservoir over time.

ClinicalTrials.gov NCT03426592.

Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH).

MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records.

A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode.

Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD.

Periodontitis is accompanied by attachment loss and alveolar bone resorption. Vitamin D (VD) deficiency was closely associated with bone loss or osteoporosis. The study aims to investigate the potential relationship between different VD levels and severe periodontal attachment loss in American adults.

A cross-sectional analysis was conducted including 5749 participants in the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2014. The association of periodontal attachment loss progression with total VD, vitamin D3 (VD3), and vitamin D2 (VD2) levels was assessed using multivariable linear regression models, hierarchical regression, fitted smoothing curves, and generalized additive models.

Based on the indicators of 5749 subjects, we found that severe attachment loss tended to occur in the elderly or males and was accompanied by less total VD levels, or VD3 levels, as well as a lower poverty-income ratio (PIR). Total VD (below the inflection point: 111 nmol/L) or VD3 were negatively associated with the progression of attachment loss in each multivariable regression model. In threshold analysis, VD3 is linearly correlated with the progression of attachment loss (β =  - 0.0183, 95% CI: - 0.0230 to - 0.0136). The relationship between VD2 and attachment loss progression was an S-shaped curve (inflection point: 5.07 nmol/L).

Increasing total VD (below 111 nmol/L) and VD3 levels may be beneficial to periodontal health. VD2 levels above 5.07 nmol/L were a risk factor for severe periodontitis.

The present study reports that different vitamin D levels may serve as different associations with periodontal attachment loss progression.

Following two requests from the European Commission (EC), the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for vitamin D and to propose a conversion factor (CF) for calcidiol monohydrate into vitamin D3 for labelling purposes. Vitamin D refers to ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), and calcidiol monohydrate. Systematic reviews of the literature were conducted to assess the relative bioavailability of calcidiol monohydrate versus vitamin D3 on serum 25(OH)D concentrations, and for priority adverse health effects of excess vitamin D intake, namely persistent hypercalcaemia/hypercalciuria and endpoints related to musculoskeletal health (i.e. falls, bone fractures, bone mass/density and indices thereof). Based on the available evidence, the Panel proposes a CF for calcidiol monohydrates of 2.5 for labelling purposes. Persistent hypercalciuria, which may be an earlier sign of excess vitamin D than persistent hypercalcaemia, is selected as the critical endpoint on which to base the UL for vitamin D. A lowest-observed-adverse-effect-level (LOAEL) of 250 μg/day is identified from two randomised controlled trials in humans, to which an uncertainty factor of 2.5 is applied to account for the absence of a no-observed-adverse-effect-level (NOAEL). A UL of 100 μg vitamin D equivalents (VDE)/day is established for adults (including pregnant and lactating women) and for adolescents aged 11-17 years, as there is no reason to believe that adolescents in the phase of rapid bone formation and growth have a lower tolerance for vitamin D compared to adults. For children aged 1-10 years, a UL of 50 μg VDE/day is established by considering their smaller body size. Based on available intake data, European populations are unlikely to exceed the UL, except for regular users of food supplements containing high doses of vitamin D.

In this review, we explore the potential drivers of heterogeneity in response to Vitamin D (VitD) therapy, such as bioavailability, sex-specific response, and autoimmune pathology, in those at risk for and diagnosed with T2DM. In addition, we propose distinct populations for future interventions with VitD. The literature concerning VitD supplementation in the prevention, treatment, and remission of type 2 diabetes mellitus (T2DM) spans decades, is complex, and is often contradictory with mixed findings upon intervention. By association, VitD status is powerfully predictive with deficient subjects reporting greater risk for T2DM, conversion to T2DM from prediabetes, and enhanced response to VitD therapy. Preclinical models strongly favor intervention with VitD owing to the pleiotropic influence of VitD on multiple systems. Additional research is crucial as there remain many questions unanswered that are related to VitD status and conditions such as T2DM. Future research must be conducted to better understand the potentially spurious relationships between VitD status, supplementation, sun exposure, health behaviors, and the diagnosis and management of T2DM. Public health practice can greatly benefit from a better understanding of the mechanisms by which we can reliably increase VitD status and how this can be used to develop education and improve health behaviors.

The present study aimed to compare the effects of vitamin D₂ and vitamin D₃ supplementation on concentrations of total and free 25(OH)D in plasma and the expression of genes involved in the innate immune system in peripheral blood mononuclear cells (PBMC) in weaned pigs. Five groups of pigs (with an initial body weight of around 9 kg) received basal diets supplemented with either 500 (control group), 1000 or 2000 IU vitamin D₃/kg diet or 1000 or 2000 IU vitamin D₂/kg diet for a period of 4 weeks. Vitamin D supplementation did not influence feed intake, body weight gain, feed conversion ratio, apparent total tract digestibility of calcium and phosphorus, and serum concentrations of calcium, inorganic phosphate and parathyroid hormone. Supplementation of vitamin D₃ led to a dose-dependent increase of the concentrations of total and free 25(OH)D in serum. In contrast, pigs supplemented with 1000 or 2000 IU vitamin D₂/kg diet did not have higher concentrations of total and free 25(OH)D in serum than the control group. The ratio of free/total 25(OH)D in serum was not influenced by vitamin D₃ supplementation, whereas the group supplemented with 2000 IU vitamin D₂/kg diet had a higher free/total 25(OH)D ratio than the groups supplemented with 1000 or 2000 IU vitamin D₃/kg diet. Genes involved in vitamin D signalling (CYP27B1, VDR), as well as pro-inflammatory and immune regulatory genes (TLR4, TNF, IL1B and TGFB1) and genes encoding porcine protegrins (NPG1, NPG4), proteins belonging to the group of antimicrobial peptides, in PBMC were not different among groups supplemented with vitamin D₃ or vitamin D₂ and the control group. Therefore, the study indicates that supplementation of vitamin D₂ causes much lower levels of total 25(OH)D than supplementation of vitamin D₃ and that supplementation of vitamins D₂ or D₃ at moderate levels does not have an impact on the innate immune function in healthy pigs.

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.

Over the past 100 years, many major breakthroughs and discoveries have occurred in relation to vitamin D research. These developments include the cure of rickets in 1919, the discovery of vitamin D compounds, advances in vitamin D molecular biology, and improvements in our understanding of endocrine control of vitamin D metabolism. Furthermore, recommended daily allowances for vitamin D have been established and large clinical trials of vitamin D, aimed at clarifying the effect of Vitamin D in the prevention of multiple diseases, have been completed. However, disappointingly, these clinical trials have not fulfilled the expectations many had 10 years ago. In almost every trial, various doses and routes of administration did not show efficacy of vitamin D in preventing fractures, falls, cancer, cardiovascular diseases, type 2 diabetes, asthma, and respiratory infections. Although concerns about side-effects of long-term high-dose treatments, such as hypercalcaemia and nephrocalcinosis, have been around for four decades, some trials from the past 5 years have had new and unexpected adverse events. These adverse events include increased fractures, falls, and hospitalisations in older people (aged >65 years). Several of these clinical trials were powered appropriately for a primary outcome but did not include dose response studies and were underpowered for secondary analyses. Furthermore, more attention should be paid to the safety of high doses of vitamin D supplementation, particularly in older people. In addition, despite universal recommendations by osteoporosis societies for combining calcium supplements with vitamin D there remains insufficient data about their efficacy and effect on fracture risk in the highest risk groups. More trials are needed for people with severe vitamin D deficiency (ie, serum 25-hydroxyvitamin D <25nmol/L [10ng/mL]). In this Personal View, we summarise and discuss some of the major discoveries and controversies in the field of vitamin D.

In 1755 in Bergemoletto, Italy, an avalanche buried 4 people (2 women, a girl, and a boy) and several animals in a stable. After 37 d in a pitch-dark confined space, 3 of the 4 people were rescued alive. The 3 survivors had only goat milk, a few chestnuts, a few kg of raw kid meat, and meltwater for nutrition. We describe the longest-known survival in an avalanche burial and discuss the medical and psychological problems of the survivors. The boy died. When they were extricated, all 3 survivors were exhausted, cachectic, and unable to stand or walk. They were severely malnourished and were experiencing tingling, tremors, and weakness in the legs; constipation; changes in taste; and amenorrhea. One of the women had persistent eye problems and developed symptoms consistent with post-traumatic stress disorder. The survivors were given slow refeeding. It took from 1 to 6 wk before they could walk. We compare this case to other long-duration burials, especially mining accidents, and describe the rescue and patient care after long-duration burials. This case demonstrates that people can overcome extremely adverse conditions and survive.

The vitamin D binding protein (DBP), encoded by the group-specific component (GC) gene, is a component of the vitamin D system. In a genome-wide association study of DBP concentration in 65,589 neonates we identify 26 independent loci, 17 of which are in or close to the GC gene, with fine-mapping identifying 2 missense variants on chromosomes 12 and 17 (within SH2B3 and GSDMA, respectively). When adjusted for GC haplotypes, we find 15 independent loci distributed over 10 chromosomes. Mendelian randomization analyses identify a unidirectional effect of higher DBP concentration and (a) higher 25-hydroxyvitamin D concentration, and (b) a reduced risk of multiple sclerosis and rheumatoid arthritis. A phenome-wide association study confirms that higher DBP concentration is associated with a reduced risk of vitamin D deficiency. Our findings provide valuable insights into the influence of DBP on vitamin D status and a range of health outcomes.

This cross-sectional study aimed to develop and validate a vitamin D food frequency questionnaire (VitD-FFQ) to assess vitamin D intake in Moroccan women of reproductive age. Using the method of triads, the VitD-FFQ was validated against seven-day dietary records (7d-FR) and 25-hydroxyvitamin D (25(OH)D) as a biomarker of vitamin D status in 152 women (aged 18-45 years). Participants' sun exposure scores (SES) were assessed using a specific questionnaire (SEQ). Predictors of vitamin D status were identified via linear regression models. Several statistical tests were applied to evaluate the criterion validity of the FFQ against two references methods (7d-FR and the biomarker-serum 25(OH)D). Median (Interquartile range) intakes were 7.10 ± 6.95 µg /day and 6.33 ± 5.02 µg/ day, respectively, for VitD-FFQ and 7d-FR. Vitamin D status was mainly determined by SES (R = 0.47) and vitamin D absolute food intakes derived by the VitD-FFQ (R = 0.56), which demonstrated a more significant prediction ability compared to 7d-FR (R = 0.36). An agreement was observed between the VitD-FFQ and 7d-FR (BA index of 3.29%) with no proportional bias (R² = 0.002, p = 0.54). <10% of participants were incorrectly classified, and weighted kappa statistics showed that VitD-FFQ had an acceptable ranking ability compared to the 7d-FR and the biomarker. The validity coefficient for the VitD-FFQ was high: ρQR = 0.90 (95%CI: 0.89-0.92), and a range from 0.46 to 0.90. Adjustment for the participants' SES and BMI (body mass index) improved the biomarker's validity coefficient (ρRB 0.63 (95% CI 0.39-0.82). Our results indicate that the VitD-FFQ is valid for estimating absolute vitamin D intake in Moroccan women of reproductive age.

Vitamin D is an important immune modulator that is linked to infection susceptibility. It has been suggested that vitamin D deficiency plays a role in sepsis and septic shock because vitamin-D-related pathways are associated with various immunological, endocrine, and endothelial functions. Previous research has yielded inconclusive results regarding the link between mortality and vitamin D deficiency in sepsis patients. In patients with sepsis and severe vitamin D deficiency, an adequate vitamin D concentration may reduce mortality. Randomized controlled trials to assess the influence of vitamin D supplementation on clinical outcomes in sepsis patients with vitamin D deficiency are uncommon. We will provide an overview of the current knowledge about the relationship between vitamin D and sepsis in this review, as well as consider the potential value of vitamin D supplementation in this situation.

Vitamin D and osteoporosis in Graves' disease (GD) have been examined in cross-sectional studies with divergent results. Here, we prospectively studied vitamin D metabolism and bone health in patients with newly diagnosed GD.

Thirty consecutive patients with de novo overt thyrotoxicosis diagnosed with GD were included. At diagnosis, none of the patients were treated with vitamin D or anti-osteoporotic drugs. All patients were initially treated with antithyroid drugs. Blood samplings were taken at baseline and at 6 weeks, 3, 6, 12 and 24 months after treatment start. Serum levels of 25OHD3, 1,25OH2D3, calcium, parathyroid hormone (PTH), and C-terminal telopeptides of Type I collagen (CTX-I) were analysed. Bone mineral density (BMD) was measured at baseline, and 1 and 2 years after treatment initiation.

At diagnosis, patients with GD did not have vitamin D deficiency. There were no significant correlations between levels of 25OHD3 and thyrotoxicosis. Upon treatment of the thyrotoxicosis, serum calcium fell transiently, and PTH and 1,25OH2D3 increased. 25OHD3 fell within the normal range and stabilised at 6 months. CTX-I fell over 12 months, BMD increased significantly up to 2 years, p = 0.002, < 0.001 and 0.005 in the spine, left total hip and left femoral neck, respectively.

The present data underline that thyrotoxicosis has a negative impact on bone health and demonstrate fine-tuned dynamics in bone and vitamin D metabolism. Upon treatment, bone health improved over a follow-up period of 24 months despite rising PTH. Increased conversion of 25OHD3 to 1,25OH2D3 occurs during treatment of GD.

Circulating 25-hydroxyvitamin D [25(OH)D] concentration is used to monitor vitamin D status. Plasma protein binding may influence the 25(OH)D dose-response to vitamin D treatment through a direct relationship between the plasma unbound ("free") fraction and clearance of 25(OH)D. We previously evaluated 25(OH)D3 clearance in relation to kidney function using intravenous administration of deuterium labeled 25(OH)D3. In this follow up study, we determined the free fraction of 25(OH)D3 in plasma (i.e., percent free 25(OH)D3) and the serum concentration and haplotype of vitamin D binding protein in these participants. We hypothesized that the percent free 25(OH)D3 would be positively associated with 25(OH)D3 clearance and would mediate associations between clearance and vitamin D binding protein (GC) haplotypes. Participants were mean (SD) age 64 (10) years and included 42 individuals with normal kidney function (controls), 24 individuals with chronic kidney disease, and 19 individuals with kidney failure on hemodialysis. Free plasma 25(OH)D2 and 25(OH)D3 concentrations were quantified with a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Because there is no reference measurement procedure for free 25(OH)D, we compared the new method with a widely-used predictive equation and a commercial immunoassay. The percent free 25(OH)D3 determined by predictive equation was weakly associated with 25(OH)D3 clearance (R = 0.27; P = 0.01). However, this association was absent when percent free 25(OH)D3 was determined using LC-MS/MS-measured free and total 25(OH)D3 concentrations. Method comparison uncovered a negative bias in immunoassay-measured free 25(OH)D concentrations among participants with kidney failure, so immunoassay results were not used to evaluate the association between percent free 25(OH)D3 and clearance. GC2 haplotype carriage was associated with 25(OH)D3 clearance. Among individuals with 2 relative to no GC2 alleles, clearance was 87 (95% CI: 15-158) mL/d greater. However, in contrast with the literature, GC2 carriage was not significantly related to DBP concentration or the percent free 25(OH)D3 (either predicted or measured). In conclusion, the free fraction of 25(OH)D3 is not strongly associated with 25(OH)D3 clearance but may explain small differences in clearance according to GC haplotype.

One hundred years ago, the role of vitamin D for bone mineralization and the prevention of rickets was discovered. Vitamin D comprises a group of over 50 metabolites with multiple functions that go far beyond calcium homeostasis and bone mineralization. Approximately 50 years ago, first methods for the measurement of 25-hydroxyvitamin D (25(OH)D) in human blood were developed. Over the years, different analytical principals were employed including competitive protein binding assays, high-performance liquid chromatography, various immunoassay and mass spectrometric formats. Until the recent standardization of serum 25(OH)D measurement, agreement between methods was unsatisfactory. Since then, comparability has improved, but substantial variability between methods remains. With the advent of liquid chromatography tandem mass spectrometry (LC-MS/MS), the accurate determination of 25(OH)D and other metabolites, such as 24,25(OH)2D, becomes increasingly accessible for clinical laboratories. Easy access to 25(OH)D testing has triggered extensive clinical research showing that large parts of the population are vitamin D deficient. The variable response of vitamin D deficient individuals to supplementation indicates that assessing patients' vitamin D stores by measuring 25(OH)D provides limited insight into the metabolic situation. Meanwhile, first evidence has emerged suggesting that the simultaneous measurement of 25(OH)D, 24,25(OH)2D and other metabolites allows a dynamic evaluation of patients' vitamin D status on metabolic principals. This may help to identify patients with functional vitamin D deficiency from those without. It can be expected that research into the assessment vitamin D status will continue for another 50 years and that this will help rationalizing our approach in clinical practice.

Nutritional prevention of osteoporosis management is an important issue for children with severe disabilities. Due to the coronavirus disease 2019 (COVID-19) pandemic that started in 2020, children admitted to institutions had fewer opportunities for ultraviolet (UV) exposure owing to restrictions on attending school and going out. Hence, the vitamin D (VD) status of these children has been a cause of concern. This study aimed to assess the correlation between VD intake and VD status among children with severe disabilities who had limited UV exposure.

This research included patients admitted to Iwate Prefectural Rehabilitation and Nursery Center for Disabled Children. Serum 25-hydroxyvitamin D [25(OH)D] levels were assessed during school/outing restriction periods and after restriction removal and the introduction of sunbathing periods. The trends in 25(OH)D levels and oral VD intake before the two measurements were analyzed.

Although 17 of 32 patients had VD intake above the recommended level of Dietary Reference Intakes for Japanese during the first measurement, 31 patients had VD deficiency. The 25(OH)D levels of 13 patients without UV exposure before the first evaluation and those with UV exposure before the second evaluation were 2.03 times higher, despite of constant VD intakes. In contrast, there were no remarkable changes in both VD intakes and 25(OH)D levels in five patients without UV exposure before both assessments.

Japanese children with severe disabilities who consume the recommended oral VD intake but who have limited UV exposure can still present VD deficiency.

Vitamin D (VD) deficiency (serum 25 hydroxy vitamin D (25(OH)D) concentration of < 20 ng/ml), in endemic proportions, demands a supplementation strategy with optimal dosing regimens. A randomised parallel-group, active-controlled trial was conducted among apparently healthy, VD-deficient subjects, aged 18-60 years who received 600 μg/d (Group A), 1000 μg/d (Group B), 2000 μg/d (Group C) and 60 000 μg/month (Group D) of oral cholecalciferol. The intervention was carried in two phases (I and II) of 12 weeks each, with same dose, separated by a washout phase of 12 weeks. Serum 25(OH)D, intact parathyroid hormones (iPTH), Ca, phosphorous (PO4), alkaline phosphatase (ALP) and spot urine Ca/Cr were measured at baseline, 12, 24 and 36 weeks following the intervention, and adverse events were recorded at each occurrence and at 12, 24 and 36 weeks. A statistically significant time-group interaction was found in serum 25(OH)D concentration (P < 0·05). Serum 25(OH)D concentration increased significantly from baseline to 12 weeks (P < 0·05) in all the groups with no change at 24 weeks but further increase at 36 weeks (P < 0·05). At the end of the study, Group C had maximum increment in serum 25(OH)D concentration, while as Groups C and D (95 %, and 90 %) had higher proportion of subjects VD sufficient than Groups A and B (65 % and 78 %) (P < 0·05). No significant time-dose interactions were observed in serum iPTH, Ca, PO4 and ALP or urine Ca/Cr ratio. Three subjects (two in Group C and one in Group D) developed transient hypercalciuria. Supplementation with daily 2000 μg or monthly 60 000 μg of oral cholecalciferol among adults seems optimal and safe.

Vitamin D delivered transdermally may suppress hyperactivity in nociceptor pain receptors and alter pain intensity, offering a useful addition to localised pain management in varying clinical settings. Currently, little is known about long-term usage of continuous-release vitamin D patches.

We conducted a randomised parallel pilot trial to evaluate safety and tolerability of daily application of patented (US8821921B2) transdermal vitamin D patches over 8 weeks and assess time-level profile of serum vitamin D. Compliance, tolerance and sun exposure were monitored daily, serum 25(OH)D measured 2-weekly and dietary intake and safety markers 4-weekly.

Thirty healthy adults were randomised to two treatment groups: big patch and small patch. mean age was 36 years (20-68 years) with a 63% female to 37% male split. Patches differed in size but contained identical ingredients including 30 000 IU cholecalciferol. Physical and blood safety markers remained stable, within normal clinical parameters, and with no clinically meaningful changes throughout. Five big patch participants experienced skin irritation, which was mild and occasional for three, but continuous for two leading to patch withdrawal. There were no skin reactions in small patch group. average, serum 25(OH)D levels increased by +14 nmol/L (SD 11.63, range, -4 to 40 nmol/L) between baseline and week 8, with no significant differences between patch sizes. There was a shift in overall vitamin D status between baseline and week 8 (23% deficient (<30 nmol/L) decreasing to 0%, and normal (>50 nmol/L) increasing from 37% to 70% at week 8).

Based on these results, long-term (8 weeks) application of patented transdermal vitamin D patches was found to be safe. There may be minor skin tolerance issues with big patches for some, which appears to relate to patch size. Larger trials are warranted to explore the increase in vitamin D levels beyond 8 weeks.

NCT04851990.

Background: Vitamin D3 complexed to deglycosylated vitamin D binding protein (VitD-dgVDBP) is a water-soluble vitamin D dimeric compound (VitD-dgVDBP). It is not clear how VitD-dgVDBP affects circulating monocytes, macrophages, other immune cell systems, including phagocytosis and apoptosis, and the generation of reactive oxygen species (ROS) compared to dgVDBP. Methods: Flow cytometry was used to measure superoxide anion radical (O2*−) levels and macrophage activity in the presence of VitD-dgVDBP or dgVDBP. VitD-dgVDBP was incubated with normal human lymphocytes (nPBMCs), and several clusters of determination (CDs) were estimated. dgVDBP and VitD-dgVDBP apoptosis was estimated on malignant prostatic cells. Results: The macrophage activity was 2.8-fold higher using VitD-dgVDBP (19.8·106 counts) compared to dgVDBP (7.0·106 counts), but O2*− production was 1.8-fold lower in favor of VitD-dgVDBP (355·103 counts) compared to dgVDBP (630·106 counts). The calculated ratio of the radical/macrophage activity was 5-fold lower compared to that of dgVDBP. Only VitD-dgVDBP activated caspase-3 (8%), caspase-9 (13%), and cytochrome-C (11%) on prostatic cancer cells. PE-Cy7-labeled VitD-dgVDBP was found to bind to cytotoxic suppressor cells, monocytes/macrophages, dendritic and natural killer cells (CD8+), and helper cells (CD4+). After 12 h of co-incubation of nPBMCs with VitD-dgVDBP, significant activation and expression were measured for CD16++/CD16 (0.6 ± 0.1% vs. 0.4 ± 0.1%, p < 0.05), CD45k+ (96.0 ± 6.0% vs. 84.7 ± 9.5%, p < 0.05), CD85k+ (24.3 ± 13.2% vs. 3.8 ± 3.2%, p < 0.05), and CD85k+/CD123+ (46.8 ± 8.1% vs. 3.5 ± 3.7%, p < 0.001) compared to the control experiment. No significant difference was found using CD3+, CD4+, CD8+, CD4/CD8, CD4/CD8, CD16+, CD16++, CD14+, or CD123+. A significant decline in CD14+/CD16+ was obtained in the presence of VitD-dgVDBP (0.7 ± 0.2% vs. 3.1 ± 1.7%; p < 0.01). Conclusion: The newly developed water-soluble VitD3 form VitD-dgVDBP affected cytotoxic suppressor cells by activating the low radical-dependent CD16 pathway and seemed to induce apoptosis in malignant prostatic cells.