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Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice

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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: 25 August 2025 | Viewed by 24185

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Dr. Spyridon N. Karras

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Laboratory of Biological Chemistry, Medical School of Aristotle University, 55535 Thessaloniki, Greece
Interests: intermittent fasting; periodic fasting; religious fasting: fasting glucose; obesity; impaired fasting glucose; non-fasting triglycerides; fasting blood glucose; caloric restriction; meal frequency; calorie restriction
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Dear Colleagues,

Vitamin D has been the focus of ongoing scientific research over the past two decades. Its undisputed primogenetic role in bone mineralization has been expanded to a strikingly disparate amalgamation of transparent scientific cases and observational studies, randomized controlled trials of dubious design, and sporadically personal aphorisms and dogma. This phenomenon configures a burgeoning scientific field in which substantial controversy is inevitably reflected in daily clinical practice, resulting in a precarious interpretation of not necessarily available results, lifestyle-affected vitamin D supplementation in vitamin D sufficient populations, and ineffective dosing and time regimens.

In this context, somewhere in between the dipole of inordinate enthusiasm and critical opposition, the vast majority of healthcare providers worldwide, who are involved in some part of the developed vitamin D agenda, postulate a sound individualized scientific approach unbiased from quandaries and oriented to improve long-term health outcomes and patient quality of life—beyond the Platonic caves of available knowledge in the field.

This Special Issue will draw attention to all the intriguing and conflicting aspects of vitamin D research, including the following: Vitamin D deficiency and its widespread epidemiology; musculoskeletal and extra-skeletal effects; and critical updates on published vitamin D supplementation prevention RCTs (cancer/CVD). It will also include discourse on the future agenda with the main questions: What has changed so far in the field? What are future research milestones? In collecting the results reported here, the editors have not endeavored to achieve any sort of completeness, but rather to shed light on the ongoing controversy of the vitamin D “friendly” perspective versus vitamin D skepticism, with a discourse on clinical implications and physicians’ daily decision making into the beginning of the new decade.

You may choose our Joint Special Issue in Dietetics.

Dr. Spyridon N. Karras
Guest Editor

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Keywords

vitamin D
nutrition
infections
epidemiology
cardiovascular disease

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Published Papers (8 papers)

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19 pages, 2188 KiB

Open AccessArticle

Assessment of Vitamin D Metabolism Disorders in Hemodialysis Patients

by Maksymilian Hryciuk, Zbigniew Heleniak, Sylwia Małgorzewicz, Konrad Kowalski, Jędrzej Antosiewicz, Anna Koelmer, Michał Żmijewski and Alicja Dębska-Ślizień

Nutrients 2025, 17(5), 774; https://doi.org/10.3390/nu17050774 - 22 Feb 2025

Viewed by 729

Abstract

Background: Patients with end-stage chronic diseases, especially those undergoing hemodialysis (HD), often experience mineral bone disease (MBD), leading to hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH). Vitamin D deficiency and metabolism disorders are also common, resulting from impaired conversion of 25(OH)D3 to its active form, 1,25(OH)2D3, and reduced inactivation to 24,25(OH)2D3. This study aimed to assess the levels of 25(OH)D2, 25(OH)D3, 24,25(OH)2D3, 3-epi-25(OH)D3, and the vitamin D metabolism ratio (VMR) in patients with maintenance HD. Methods: A cross-sectional study was conducted on 66 HD patients (22–90 years, average 61.3 ± 16.4), with a control group of 206 adults without chronic kidney disease (CKD), both without cholecalciferol supplementation. Results: the HD patients had significantly lower 25(OH)D3 levels (15 ng/mL vs. 22 ng/mL) and higher deficiency rates (69% vs. 39%) compared to the controls. However, both groups showed similarly low levels of optimal vitamin D3. The HD patients had lower 24,25(OH)D3 levels (0.1 vs. 2.1 ng/mL) and a lower VMR (0.9% vs. 9%). 3-epi-25(OH)D3 levels and its ratio to 25(OH)D3 were significantly lower in the HD group. Alphacalcidol supplementation raised 1,25(OH)2D3 levels (30.4 vs. 16.2 pg/mL) without affecting other vitamin D metabolites. The HD patients had higher levels of 25(OH)D2 compared to the controls (0.61 vs. 0.31 ng/mL). Conclusions: Vitamin D3 reserves are lower, and both functional deficiency and impaired catabolism of vitamin D3 are present in HD patients compared to the general population. The VMR index is the most sensitive parameter for vitamin D3 deficiency assessment, highlighting the importance of measuring 24,25(OH)D3. Alphacalcidol supplementation increases 1,25(OH)2D3 levels without affecting other vitamin D metabolites. 25(OH)D2 is the only metabolite that was higher in HD patients than the controls. Full article

(This article belongs to the Special Issue Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice)

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24 pages, 21050 KiB

Open AccessArticle

Single-Cell Analysis Dissects the Effects of Vitamin D on Genetic Senescence Signatures Across Murine Tissues

by Emilio Sosa-Díaz, Helena Reyes-Gopar, Guillermo de Anda-Jáuregui and Enrique Hernández-Lemus

Nutrients 2025, 17(3), 429; https://doi.org/10.3390/nu17030429 - 24 Jan 2025

Viewed by 1187

Abstract

Background/Objectives: Vitamin D (VD) plays a crucial role in age-related diseases, and its influence on cellular senescence (CS) could help clarify its function in aging. Considering VD’s pleiotropic effects and the heterogeneity of CS. Methods: we utilized single-cell RNA sequencing (scRNA-seq) to explore these dynamics across multiple tissues. We analyzed three murine tissue datasets (bone, prostate, and skin) obtained from public repositories, enriching for senescence gene signatures. We then inferred gene regulatory networks (GRNs) at the tissue and cell-type levels and performed two cell communication analyses: one for senescent cells and another for interactions between senescent and non-senescent cells. Results: VD supplementation significantly decreased senescence scores in the skin (p =

3.96 \times 10^{- 134}

) and prostate (

p = 1.56 \times 10^{- 34}

). GRN analysis of the prostate revealed an altered macrophage–fibroblast regulatory relationship. In bone, distinct aging-related modules emerged for different bone lineages. In skin, contrary differentiation patterns between suprabasal and basal cells were observed. The main VD-modulated pathways were involved in inflammation, extracellular matrix remodeling, protein metabolism, and translation. VD reduced fibroblast–macrophage interactions in the prostate and skin but increased overall cellular crosstalk in bone. Conclusions: Our findings demonstrate that VD alleviates CS burden across tissues by modulating inflammation and metabolic processes and promoting differentiation. Key aging-related genes modulated by VD were linked to anabolism and cellular differentiation, suggesting VD’s potential for therapeutic interventions targeting age-related diseases. Full article

(This article belongs to the Special Issue Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice)

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9 pages, 930 KiB

Open AccessArticle

The Role of Vitamin D in the Treatment of Carpal Tunnel Syndrome: Clinical and Electroneuromyographic Responses

by Antônio Vicente D. Andrade, Dallianny G. S. Martins, Gabriel S. Rocha, Gustavo S. Damasceno, Francisca T. S. Gomes, Yasmin P. F. Albuquerque, Paloma K. M. Melo, Marco A. M. Freire, Dayane P. Araújo, Lucidio C. Oliveira, Fausto P. Guzen, Paulo L. A. G. Morais and José R. L. P. Cavalcanti

Nutrients 2024, 16(12), 1947; https://doi.org/10.3390/nu16121947 - 19 Jun 2024

Cited by 1 | Viewed by 2948

Abstract

Carpal tunnel syndrome (CTS) is the most common cause of peripheral compressive neuropathy and consists of compression of the median nerve in the wrist. Although there are several etiologies, idiopathic is the most prevalent origin, and among the forms of treatment for CTS, conservative is the most indicated. However, despite the high prevalence in and impact of this syndrome on the healthcare system, there are still controversies regarding the best therapeutic approach for patients. Therefore, noting that some studies point to vitamin D deficiency as an independent risk factor, which increases the symptoms of the syndrome, this study evaluated the role of vitamin D supplementation and its influence on pain control, physical examination and response electroneuromyography to conservative treatment of carpal tunnel syndrome. For this, the sample consisted of 14 patients diagnosed with CTS and hypovitaminosis D, who were allocated into two groups. The control group received corticosteroid treatment, while the experimental group received corticosteroid treatment associated with vitamin D. Thus, from this study, it can be concluded that patients who received vitamin D, when compared to those who did not receive it, showed improvement in the degree of pain intensity, a reduction in symptom severity and an improvement in some electroneuromyographic parameters. Full article

(This article belongs to the Special Issue Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice)

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14 pages, 259 KiB

Open AccessArticle

Residential Greenness, Lifestyle, and Vitamin D: A Longitudinal Cohort of South Asian Origin and Caucasian Ethnicity Women Living in the South of the UK

by Keila Valente de Souza de Santana, Helena Ribeiro, Andrea Darling, Israel Henrique Ribeiro Rios and Susan Lanham-New

Nutrients 2024, 16(8), 1214; https://doi.org/10.3390/nu16081214 - 19 Apr 2024

Viewed by 1412

Abstract

The global population is at risk of vitamin D deficiency due to low exposure to sunlight and low intake of the vitamin through diet. The aim of this study was to investigate in women the association between vitamin D status and parathyroid hormone (PTH), ultraviolet radiation, lifestyle, ethnicity, social conditions, and residential greenness. A 1-year longitudinal study assessed vitamin D status in 309 women living at latitude 51°14′ N. Blood samples were taken four times throughout the year for analysis of 25(OH)D and serum PTH concentration. After each seasonal visit, the individuals completed 4-day diet diaries and used two dosimeter badges for 1 week to estimate weekly UVR exposure. A questionnaire was applied to provide information about lifestyle and their ethnicity. Residential greenness was measured by Normalized Difference Vegetation Index (NDVI), within a 1000 m radius around each participant’s home address. Women living in greener spaces were more likely to have improved vitamin D status (RR: 1.51; 95%CI: 1.13–2.02), as well as those who were more exposed to UVR (RR: 2.05; 95%CI: 1.44–2.92). Our results provide an insight into the connection between residential greenness, lifestyle, and vitamin D status comparing two ethnicities in a country with a temperate climate and with a high degree of urbanization. Full article

(This article belongs to the Special Issue Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice)

16 pages, 1436 KiB

Open AccessArticle

Intense Testing and Use of Vitamin D Supplements Leads to Slow Improvement in Vitamin D Adequacy Rates: A Cross-Sectional Analysis of Real-World Data

by Rodis D. Paparodis, Dimitra Bantouna, Evangelos Karvounis, Ioannis Zoupas, Sarantis Livadas, Nicholas Angelopoulos, Shahnawaz Imam, Dimitrios T. Papadimitriou and Juan C. Jaume

Nutrients 2024, 16(1), 111; https://doi.org/10.3390/nu16010111 - 28 Dec 2023

Viewed by 1964

Abstract

Background: Vitamin D testing (VDT) and supplement use (VDS) are on the rise, but most patients remain deficient (<30 ng/mL-VDD). We designed the present real-world study to assess this paradox. Methods: We reviewed data from all patients visiting our clinics between 2014 and 2022. We estimated the rate of patients with vitamin D adequacy (≥30 ng/mL) (VDA) by year and month of testing, the dose of VDS (low (≤1200 IU/day), medium (1201–3000 I/day) and high dose (>3000 IU/day)), intake duration (short-term (<12 months) and long-term use (≥12 months)), and timing of use (current use, former use, no use). Results: We enrolled n = 6912 subjects with vitamin D measurements: n = 5195 females (75.2%), age 44.0 ± 16.8 years, BMI 27.9 ± 6.5 kg/m²; never users: n = 5553 (80.3%), former users: n = 533 (7.7%), current users: n = 826 (12.0%). Current use of VDS was higher in females. VDT rose from 42.1% in 2014 to 92.7% in 2022, and VDA rose from 14.8% to 25.5% for the same time. VDA was found overall in n = 1511 (21.9%); Never users: n = 864 (15.6%), Former users: n = 123 (23.2%); and Current users: n = 370 (44.8%). The maximal VDA (67.9%) was found in subjects using high-dose VDS in the long term. Conclusions: Despite the significant rise in VDT and VDS use, VDA was found in a minority of patients. Prolonged use of high-dose supplements produces modest improvements in VDA. Full article

(This article belongs to the Special Issue Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice)

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16 pages, 319 KiB

Open AccessFeature PaperArticle

Maternal and Neonatal Vitamin D Binding Protein Polymorphisms and 25-Hydroxyvitamin D Cutoffs as Determinants of Neonatal Birth Anthropometry

by Spyridon N. Karras, Erdinç Dursun, Merve Alaylıoğlu, Duygu Gezen-Ak, Stefan Pilz, Cedric Annweiler and Fatme Al Anouti

Nutrients 2022, 14(18), 3799; https://doi.org/10.3390/nu14183799 - 15 Sep 2022

Viewed by 1973

Abstract

Background: Vitamin D-binding protein (VDBP) is a vital regulator of optimal vitamin D homeostasis and bioavailability. Apart from its well-documented role as a key component in vitamin D dynamic transfer and circulation, it has a myriad of immunoregulatory functions related to innate immunity, which becomes particularly critical in states of increased immunological tolerance including pregnancy. In this regard, VDBP dyshomeostasis is considered to contribute to the development of several fetal, maternal, and neonatal adverse outcomes. However, precise physiological pathways, including the contribution of specific VDBP polymorphisms behind such phenomena, are yet to be fully deciphered. Our aim was to assess the combined effect of maternal and neonatal VDBP polymorphism heterogeneity in conjunction with different maternal and neonatal 25(OH)D cutoffs on the neonatal anthropometric profile at birth. Methods: The study included data and samples from a cohort of 66 mother–child pairs at birth. The inclusion criterion was full-term pregnancy (gestational weeks 37–42). Neonatal and maternal 25(OH)D cutoffs were included according to vitamin D status at birth and delivery. Concentrations of 25(OH)D2 and 25(OH)D3 were measured using liquid chromatography–tandem mass spectrometry. Results: The upper arm length of neonates with 25(OH)D ≤ 25 nmol/L was higher in neonate CC carriers for rs2298850. The upper thigh neonatal circumference was also higher in the ones with either 25(OH)D ≤ 50 or ≤75 nmol/L in rs2298850 CG + GG or rs4588 GT + TT carriers. We did not observe any significant effect for maternal VDBP polymorphisms nor for birth maternal 25(OH)D concentrations, on birth neonatal anthropometry. Conclusions: Our findings emphasize a potential role for neonatal VDBP genotypes rs2298850 and rs4588, in conjunction with specific neonatal 25(OH)D cutoffs, in the range of sufficiency on neonatal growth and development. Full article

(This article belongs to the Special Issue Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice)

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18 pages, 1523 KiB

Open AccessReview

Recent Updates and Advances in the Association Between Vitamin D Deficiency and Risk of Thrombotic Disease

by Amirhossein Faghih Ojaroodi, Fatemeh Jafarnezhad, Zahra Eskandari, Shayan Keramat and Agata Stanek

Nutrients 2025, 17(1), 90; https://doi.org/10.3390/nu17010090 - 29 Dec 2024

Cited by 2 | Viewed by 1417

Abstract

Vitamin D (VD) is a vital lipophilic secosteroid hormone known for its essential role in maintaining skeletal health and regulating calcium and phosphate metabolism. Recent evidence has begun to illuminate its significance beyond bone health, particularly in relation to thrombosis—a condition characterized by blood clot formation within the vascular system that can lead to serious cardiovascular events such as myocardial infarction and stroke. VD deficiency, defined as a plasma 25-hydroxyVD level below 25 nmol/L, affects a substantial portion of the global population, with prevalence rates ranging from 8% to 18%. This study systematically explores the relationships between VD levels and the risk of thrombosis, investigating the underlying mechanisms including VD’s anticoagulant properties, influence on inflammatory pathways, and interactions with endothelial cells. Epidemiological data suggest that low serum levels of VD correlate with an increased risk of venous thromboembolism (VTE), although the reported findings remain inconsistent. Mechanisms that potentially link VD to thrombotic risk include modulation of thrombomodulin and tissue factor expression, as well as enhancement of anti-inflammatory cytokines. Given the prevalence of VD insufficiency, particularly among populations with limited exposure to sunlight, this research highlights the urgent need for strategies to increase VD levels through dietary modifications and supplementation in order to prevent thrombotic events. Full article

(This article belongs to the Special Issue Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice)

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24 pages, 987 KiB

Open AccessEditor’s ChoiceReview

The Power of Vitamin D: Is the Future in Precision Nutrition through Personalized Supplementation Plans?

by Mladen Mavar, Tamara Sorić, Ena Bagarić, Ana Sarić and Marijana Matek Sarić

Nutrients 2024, 16(8), 1176; https://doi.org/10.3390/nu16081176 - 15 Apr 2024

Cited by 15 | Viewed by 10851

Abstract

In the last few decades, vitamin D has undeniably been one of the most studied nutrients. Despite our ability to produce vitamin D through sunlight exposure, its presence in several natural food sources and fortified foods, and its widespread availability as a dietary supplement, vitamin D deficiency is a serious public health problem, affecting nearly 50% of the global population. Low serum levels of vitamin D are being associated with increased susceptibility to numerous health conditions, including respiratory infections, mental health, autoimmune diseases, and different cancer types. Although the association between vitamin D status and health is well-established, the exact beneficial effects of vitamin D are still inconclusive and indefinite, especially when considering the prevention and treatment of different health conditions and the determination of an appropriate dosage to exert those beneficial effects in various population groups. Therefore, further research is needed. With constant improvements in our understanding of individual variations in vitamin D metabolism and requirements, in the future, precision nutrition and personalized supplementation plans could prove beneficial. Full article

(This article belongs to the Special Issue Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice)

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