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Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Micronutrients and Human Health".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 29679

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Prof. Dr. Hermann Brenner

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Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Interests: aging research; cancer; epidemiology; prevention; screening; vitamin D
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Dear Colleagues,

Numerous observational and intervention studies have suggested adverse health effects of poor vitamin D status and health benefits of vitamin D intake. However, results have often been inconsistent. Plausible major explanations for such inconsistency include heterogeneity in consideration of dose–response relationships in observational studies and of the target populations and dosing schemes in intervention studies.

The goal of this Special Issue, “Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition”, is to contribute to a better understanding of the health effects of vitamin D status and vitamin D intake by paying significant attention to specific dose–response relationships of vitamin D status and vitamin D intake with a variety of health outcomes, including incidence and mortality of major acute and chronic diseases.

Prof. Dr. Hermann Brenner
Guest Editor

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Keywords

vitamin D
epidemiological studies
insufficiency
deficiency
randomized trials
supplementation
dose–response
incidence
mortality

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Published Papers (9 papers)

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Research

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14 pages, 1133 KiB

Open AccessArticle

Vitamin D and Cognitive Impairment

by Nalinee Imerbsin, Prapimporn Chattranukulchai Shantavasinkul, Pirada Witoonpanich, Jintana Sirivarasai, Naphat Taonam, Pariya Phanachet, Daruneewan Warodomwichit, Kulapong Jayanama, Kochawan Boonyawat, Nicha Somlaw, Boonsong Ongphiphadhanakul, Daochompu Nakawiro and Sookjaroen Tangwongchai

Nutrients 2025, 17(8), 1301; https://doi.org/10.3390/nu17081301 - 9 Apr 2025

Viewed by 1609

Abstract

Background: Vitamin D deficiency is recognized as a significant public health concern, and it has been identified as one of the potentially modifiable risk factors for mild cognitive impairment (MCI). However, evidence regarding the relationship between vitamin D status and cognitive function remains conflicting. Objective: Therefore, this study aimed to examine the prevalence of vitamin D deficiency in the Thai elderly population and an association between vitamin D status and cognitive function, adiposity, and insulin sensitivity. Methods: This study enrolled participants aged 55–80 years with normal cognitive function (normal group) or MCI from the prospective cohort in the “Holistic approach of Alzheimer’s disease in Thai people (HADThai study)”. We used the baseline clinical data to determine the prevalence of vitamin D deficiency and its association between vitamin D status and cognitive function, adiposity, and insulin sensitivity. Results: A total of 718 subjects (71.9% women) with a mean age of 65.7 ± 5.8 years and a mean BMI of 23.9 ± 3.7 kg/m² were enrolled. There were 470 (65.5%) participants with normal cognitive function and 248 (34.5%) with MCI. Vitamin D status did not differ significantly between individuals with normal cognitive function and those with MCI. The prevalence of vitamin D deficiency (<20 ng/mL) and vitamin D inadequacy (<30 ng/mL) in both normal cognitive function and MCI was around 6.5% and 40.0%, respectively. While serum 25(OH)D concentrations were inversely associated with body mass index (BMI), body fat, %body fat, and the homeostasis model assessment of insulin resistance (HOMA-IR), no relationship was found between vitamin D status and cognitive function. Conclusions: Our study emphasized the high prevalence of vitamin D inadequacy among elderly individuals and an inverse association of vitamin D status and adiposity and insulin resistance. These findings emphasize the importance of addressing vitamin D deficiency in the elderly population to improve overall health outcomes. Nevertheless, our results do not support a direct role of vitamin D status in cognitive decline in this population. Further research, particularly studies with longer follow-up periods and the inclusion of patients with dementia with details of vitamin D supplementation, is needed to clarify the potential role of vitamin D in cognitive decline and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition)

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24 pages, 361 KiB

Open AccessArticle

Vitamin D, B9, and B12 Deficiencies as Key Drivers of Clinical Severity and Metabolic Comorbidities in Major Psychiatric Disorders

by Mélanie Faugere, Éloïse Maakaron, Vincent Achour, Pierre Verney, Christelle Andrieu-Haller, Jade Obadia, Guillaume Fond, Christophe Lançon and Théo Korchia

Nutrients 2025, 17(7), 1167; https://doi.org/10.3390/nu17071167 - 27 Mar 2025

Viewed by 2035

Abstract

Background/Objectives: Severe mental illnesses such as schizophrenia, major depressive disorder, and bipolar disorder are often accompanied by metabolic comorbidities. While the role of vitamins in physical health is well-established, their involvement in psychiatric disorders has garnered increasing attention in recent years. Methods: We conducted a cross-sectional analysis of 1003 patients diagnosed with severe mental illnesses. Vitamin D, B9, and B12 serum levels were measured, and deficiencies were defined using established clinical cutoffs. Multivariate regression analyses were performed to identify associations between vitamin deficiencies and clinical outcomes. Results: Our findings revealed that vitamin deficiencies were prevalent across all diagnostic groups, with particularly high rates in patients with schizophrenia and major depressive disorder. Vitamin D deficiency was significantly associated with worse psychiatric outcomes, including increased depressive symptoms (adjusted OR = 1.89, p = 0.018), lower Global Assessment of Functioning scores (adjusted OR = −0.18, p < 0.001), and higher rates of metabolic syndrome (adjusted OR = 1.97, p = 0.007). Folate and B12 deficiencies were also linked to greater psychiatric symptom severity and metabolic disturbances, including increased risks of obesity and dyslipidemia. Conclusions: Our study highlights the critical role of vitamins deficiencies in both psychiatric and metabolic health of patients with severe mental illnesses. These findings underscore the importance of routine screening and correction of these deficiencies as part of comprehensive care in psychiatric populations. The integration of nutritional interventions may offer a novel and holistic approach to improving both mental and physical health outcomes. Full article

(This article belongs to the Special Issue Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition)

14 pages, 12332 KiB

Open AccessArticle

A Randomized Phase II/III Trial Evaluating the Efficacy and Safety of 100 and 125 µg of Calcifediol Weekly Treatment of Severe Vitamin D Deficiency

by Jose Luis Pérez-Castrillón, Esteban Jódar-Gimeno, Ján Nociar, Michal Lojka, Dimitar Nikolov, Fernando Cereto-Castro, Snežana Novković, Umberto Tarantino, Nadia Mehsen-Cetre, Paula Arranz, Cristina Martínez Ostalé, Aintzane García-Bea and Inmaculada Gilaberte

Nutrients 2025, 17(4), 672; https://doi.org/10.3390/nu17040672 - 13 Feb 2025

Cited by 1 | Viewed by 1146

Abstract

Background/Objectives: Given the crucial health benefits of vitamin D, addressing severe deficiencies is a pressing medical concern. This study aimed to evaluate the effectiveness and safety of two new weekly doses of calcifediol (100 µg and 125 µg) for long-term management in patients with severe vitamin D deficiency, defined as plasma 25(OH)D levels ≤10 ng/mL. Methods: This study was a randomized, two-cohort, controlled, double-blind, multicentre phase II–III trial. Subjects were randomized 2:2:1 to weekly calcifediol 100 µg, 125 µg or a placebo. The primary endpoint was the proportion of patients achieving plasma 25(OH)D levels of ≥20 ng/mL and/or ≥30 ng/mL by week 16. Results: A total of 276 patients (mean age: 55.2 years, SD 15.42) were randomized. By week 16, 92.3% and 91.8% of patients in the calcifediol 100 µg and 125 µg groups, respectively, reached ≥20 ng/mL, compared to 7.3% in the placebo group. Levels of ≥30 ng/mL were achieved by 49% (100 µg) and 76.4% (125 µg) of participants, with none in the placebo group. Calcifediol demonstrated superior efficacy at all response levels and time points (p < 0.0001). Plasma 25(OH)D concentrations increased by week 24 and remained stable. The incidence of adverse events was comparable across groups. Conclusions: A weekly calcifediol dose of 100 µg demonstrates the best profile of efficacy and tolerability, providing a reliable solution for achieving and maintaining adequate vitamin D levels in patients with severe deficiency. Full article

(This article belongs to the Special Issue Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition)

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22 pages, 4332 KiB

Open AccessArticle

Vitamin D Binding Protein Gene Polymorphisms (rs4588 and rs7041) and VDBP Levels in Total Hip Replacement Outcomes

by Dominika Rozmus, Ewa Fiedorowicz, Janusz Płomiński and Anna Cieślińska

Nutrients 2025, 17(3), 378; https://doi.org/10.3390/nu17030378 - 21 Jan 2025

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Abstract

Background: Total hip replacement (THR) significantly improves patients’ quality of life; however, prosthesis loosening remains a significant complication. Vitamin D, essential for calcium homeostasis and bone mineralization, is transported and stabilized by vitamin D binding protein (VDBP). Common single nucleotide polymorphisms (SNPs) in the VDBP gene, rs4588 and rs7041, may influence serum vitamin D levels and potentially impact THR outcomes. This study aimed to analyze the association between these SNPs, serum levels of VDBP and 25(OH)D, and their potential roles in THR outcomes. Methods: The study included three patient groups: (1) patients undergoing arthroscopy after a THR without prosthesis loosening (CA—Control Arthroplasty), (2) patients with hip prosthesis loosening (L—Loosening), and (3) a control group (C—Control). Genotyping of rs4588 and rs7041 in the VDBP gene was conducted using PCR-RFLP and TaqMan Genotyping real-time PCR. Serum levels of VDBP and 25(OH)D were measured using ELISA. Comparisons between groups were performed using statistical analyses, including odds ratios (OR) and significance testing (p-values). Results: There are significant differences in VDBP concentrations between the groups: L vs. CA (p < 0.0001), L vs. C (p = 0.0118), L vs. L + CA (p = 0.0013), CA vs. C (p < 0.0001), and CA vs. L + CA (p < 0.0001), and in 25(OH)D concentrations between groups: L vs. C (p < 0.0001), CA vs. C (p = 0.0008), and C vs. L + CA (p < 0.0001). Conclusions: The study findings suggest a protective role of 25(OH)D against prosthesis loosening in THR. The rs4588 SNP in the VDBP gene may increase the risk of loosening, while differences in VDBP and 25(OH)D concentrations between patient groups highlight their potential importance in THR outcomes. Full article

(This article belongs to the Special Issue Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition)

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16 pages, 5045 KiB

Open AccessArticle

Curcumin and Vitamin D Supplement Attenuates Knee Osteoarthritis Progression in ACLT + MMx Rat Model: Effect on Cartilage Protection and Pain Reduction

by Lokesh Kumar Mende, Yaswanth Kuthati and Chih-Shung Wong

Nutrients 2025, 17(2), 349; https://doi.org/10.3390/nu17020349 - 19 Jan 2025

Viewed by 1762

Abstract

Background: Knee osteoarthritis (OA) is a common and debilitating disorder marked by joint degradation, inflammation, and persistent pain. This study examined the possible therapeutic effects of curcumin and vitamin D on OA progression and pain in a rat knee OA model by anterior cruciate ligament transection and meniscectomy (ACLT + MMx). Methods: Male Wistar rats were categorized into five groups: control, curcumin-treated (100 mg/kg/day), vitamin D-treated (25 µg/kg/day), a combination of vitamin D and curcumin, and sham-operated. All supplements were administered orally on a daily basis for 12 weeks. Pain behaviors were assessed, serum biomarkers were measured, and knee histology was examined. Results: Both curcumin and vitamin D independently reduced pain, while the combined group exhibited better analgesic effects. Serum inflammatory cytokines demonstrated a decrease in pro-inflammatory cytokines and an elevation in anti-inflammatory cytokine interleukin-10 (IL-10) in the supplement groups. The antioxidative markers were partially recovered by curcumin and vitamin D supplement. However, the oxidative stress marker Cartilage Oligomeric Matrix Protein (COMP) was significantly reduced. Histology analysis revealed a preservation of joint architecture and cartilage integrity and decreased synovium inflammation in the groups treated with curcumin and vitamin D. Conclusions: Our findings indicate a dual mechanism that encompasses the role of anti-inflammation and antioxidation on knee OA progression and pain reduction, underscoring the potential of these natural chemicals as therapeutic agents for knee OA; curcumin and vitamin D supplement may be added in delaying knee OA progression and associated pain management in clinical patient care. Full article

(This article belongs to the Special Issue Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition)

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14 pages, 1634 KiB

Open AccessArticle

Vitamins K2 and D3 Improve Long COVID, Fungal Translocation, and Inflammation: Randomized Controlled Trial

by Ornina Atieh, Joviane Daher, Jared C. Durieux, Marc Abboud, Danielle Labbato, Jhony Baissary, Ziad Koberssy, Kate Ailstock, Morgan Cummings, Nicholas T. Funderburg and Grace A. McComsey

Nutrients 2025, 17(2), 304; https://doi.org/10.3390/nu17020304 - 16 Jan 2025

Cited by 1 | Viewed by 10235

Abstract

Background: Long COVID (LC) is characterized by persistent symptoms at least 3 months after a SARS-COV-2 infection. LC has been associated with fungal translocation, gut dysfunction, and enhanced systemic inflammation. Currently, there is no approved treatment for this condition. The anti-inflammatory effect of vitamins K2 and D3 was shown to help attenuate the course of acute COVID-19 infection. Objective and hypothesis: This trial aims to investigate the effects of vitamins K2/D3 on LC symptoms, as well as gut and inflammatory markers, in people with established long COVID. Our hypothesis is that by attenuating systemic inflammation, vitamins K2/D3 will improve long COVID symptoms. Methods: This single-site randomized controlled study enrolled adults experiencing ≥2 moderate LC symptoms at least 3 months after a COVID-19 infection. The RECOVER Long COVID Research Index and number and type of LC symptoms were considered. Participants were randomized 2:1 to daily 240 µg K2 (pure MK-7 form) and 2000 UI vitamin D3 or standard of care (SOC) for 24 weeks. The endpoints were changes in symptomatology and in select inflammatory, metabolic, and gut biomarkers at 24 weeks. Results: We enrolled 151 participants (n = 98 received vit K2/D3 and 53 received SOC). The median age was 46 years; 71% were female and 29% were non-white. Baseline demographics were balanced between groups. At 24 weeks, the active treatment group only had a sharp increase in 25(OH) D, indicating good treatment adherence. In the vitamin K2/D3 arm, there was a 7.1% decrease in the proportion who had an LC Index ≥12 (vs. a 7.2% increase in the SOC group; p = 0.01). The average number of LC symptoms remained stable in the vitamin K2/D3 arm but increased in the SOC arm (p = 0.03). Additionally, reductions in oxidized LDL, inflammatory markers sTNF-RI and sCD163, and fungal translocation marker (1,3)-β-d-glucan were observed in the vitamin K2/D3 arm compared to the SOC arm (p < 0.01) over 24 weeks. Conclusions: Vitamins K2/D3 improved the RECOVER Long COVID Index, the number of LC symptoms, and several gut and inflammatory markers. Vitamins K2/D3 provide a promising safe intervention for people suffering from long COVID. Full article

(This article belongs to the Special Issue Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition)

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13 pages, 1435 KiB

Open AccessArticle

Serum 25-Hydroxyvitamin D Status and Vitamin D Supplements Use Are Not Associated with Low Back Pain in the Large UK Biobank Cohort

by Sha Sha, Li-Ju Chen, Hermann Brenner and Ben Schöttker

Nutrients 2024, 16(6), 806; https://doi.org/10.3390/nu16060806 - 12 Mar 2024

Cited by 1 | Viewed by 3226

Abstract

Longitudinal studies assessing the association of vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels < 30 nmol/L, and vitamin D supplement (VDS) use with low back pain (LBP) are sparse. This investigation assessed the cross-sectional and longitudinal association of vitamin D status and VDS use with LBP among 135,934 participants from the UK Biobank cohort. Approximately 21.6% of the participants had vitamin D deficiency, while only 4% regularly took VDS. In the month before study enrollment, 3.8% of the population reported experiencing LBP. An additional 3.3% of the population were diagnosed with LBP by their general practitioners for the first time during a median follow-up of 8.5 years. Vitamin D deficiency and VDS use were cross-sectionally associated with LBP in age- and sex-adjusted models, but these associations were not evident in comprehensively adjusted models. In longitudinal analyses, both vitamin D deficiency and VDS use were not associated with LBP in any model after correction for multiple testing. In conclusion, not unexpectedly due to the fact that LBP is multifactorial, our findings provide no evidence for the role of the vitamin D status in the etiology of LBP. Full article

(This article belongs to the Special Issue Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition)

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13 pages, 1195 KiB

Open AccessArticle

Vitamin D Status, Cdx2 Genotype, and Colorectal Cancer Survival: Population-Based Patient Cohort

by Tafirenyika Gwenzi, Petra Schrotz-King, Ben Schöttker, Michael Hoffmeister and Hermann Brenner

Nutrients 2023, 15(12), 2717; https://doi.org/10.3390/nu15122717 - 12 Jun 2023

Cited by 5 | Viewed by 2224

Abstract

According to recent evidence, the prognostic value of Vitamin D (VitD) status for colorectal cancer (CRC) patients might be confined to patients with the GG genotype of Cdx2, a functional polymorphism of the VitD receptor gene. We aimed to validate these findings in a cohort of CRC patients. Post-operative serum 25-hydroxyvitamin D concentration was determined by mass spectrometry and Cdx2 genotyping was performed from blood or buccal swabs using standard methods. Joint associations of VitD status and Cdx2 with overall survival (OS), CRC-specific survival (CSS), recurrence-free survival (RFS), and disease-free survival (DFS) were assessed using Cox regression. For patients with GG genotype, adjusted hazard ratios (95% confidence interval) for the associations of sufficient compared with deficient VitD were 0.63 (0.50–0.78), 0.68 (0.50–0.90), 0.66 (0.51–0.86), and 0.62 (0.50–0.77) for OS, CSS, RFS, and DFS, respectively. These associations were weaker and not statistically significant for the AA/AG genotype. Interaction between VitD status and genotype did not reach statistical significance. VitD deficiency is an independent predictor of poorer survival, particularly for the GG Cdx2 carriers, suggesting a potential role of VitD supplementation according to VitD status and genotype, which should be evaluated in randomised trials. Full article

(This article belongs to the Special Issue Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition)

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Review

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31 pages, 793 KiB

Open AccessReview

Vitamin D and Colorectal Cancer Prevention: Immunological Mechanisms, Inflammatory Pathways, and Nutritional Implications

by Mónika Fekete, Andrea Lehoczki, Ágnes Szappanos, Virág Zábó, Csilla Kaposvári, Alpár Horváth, Árpád Farkas, Vince Fazekas-Pongor, Dávid Major, Ágnes Lipécz, Tamás Csípő and János Tamás Varga

Nutrients 2025, 17(8), 1351; https://doi.org/10.3390/nu17081351 - 15 Apr 2025

Cited by 1 | Viewed by 5132

Abstract

Vitamin D plays a crucial role in the regulation of the immune system, with immunomodulatory effects that are key in the prevention of colorectal cancer (CRC). Over the past decades, research has shown that this steroid hormone impacts much more than bone health, significantly influencing immune responses. Vitamin D enhances immune organ functions such as the spleen and lymph nodes, and boosts T-cell activity, which is essential in defending the body against tumors. Additionally, vitamin D mitigates inflammatory responses closely linked to cancer development, reducing the inflammation that contributes to CRC. It acts via vitamin D receptors (VDRs) expressed on immune cells, modulating immune responses. Adequate vitamin D levels influence gene expression related to inflammation and cell proliferation, inhibiting tumor development. Vitamin D also activates mechanisms that suppress cancer cell survival, proliferation, migration, and metastasis. Low levels of vitamin D have been associated with an increased risk of CRC, with deficiency correlating with higher disease incidence. Lifestyle factors, such as a diet high in red meat and calories but low in fiber, fruits, and vegetables, as well as physical inactivity, contribute significantly to CRC risk. Insufficient calcium and vitamin D intake are also linked to disease occurrence and poorer clinical outcomes. Maintaining optimal vitamin D levels and adequate dietary intake is crucial in preventing CRC and improving patient prognosis. This review explores the role of vitamin D in immune regulation and summarizes findings from randomized clinical trials assessing the effects of vitamin D supplementation on CRC outcomes. Full article

(This article belongs to the Special Issue Dose–Response Relationships of Vitamin D Status and Vitamin D Intake with Health Outcomes—2nd Edition)

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