Top vitamin D publications in 2024

by William B. Grant, PhD

Vitamin D is arguably the most important nutrient for health. It acts mostly as a hormone, affecting expression of more than ten percent of the human genome (ref). According to Pubmed.gov, there were more than 114,000 publications with vitamin D or D3 in the title or abstract as of December 22, 2024. Over 101,000 have been published since January 1, 2002. Vitamin D status has been linked to over 200 health outcomes according to Henry Lahore’s tabulation
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The effects of vitamin D on human health are determined in several ways. They include observational studies such as ecological studies and prospective cohort studies, randomized controlled trials (RCTs), studies of mechanisms, and Mendelian Randomization studies. Ecological studies use a measure of solar UVB dose as a proxy for vitamin D production for populations defined geographically. Prospective cohort studies enroll participants, measure variables including serum 25-hydroxyvitamin D [25(OH)D] and follow the participants for some time, noting incidences of adverse health outcomes. RCTs enroll participants and randomly assign some to vitamin D supplementation and others to a placebo. The trial proceeds for some time and adverse health outcomes are compared between those in treatment and placebo arms. Most RCTs have failed to find beneficial effects of vitamin D supplementation due to enrolling participants with 25(OH)D concentrations high enough that increasing concentrations would not result in reduced risk. They also give low vitamin D doses, and do not consider achieved serum 25(OH)D concentration nor the vitamin D entering the body’s cells. Thus, it is not surprising that most vitamin D RCTs have failed. These problems have been discussed [1]. As pointed out in 2014 by Robert Heaney, RCTs involving nutrients such as vitamin D should be conducted differently from those for pharmaceutical drugs [2]. The crucial difference is that the RCTs should be based on serum w25(OH)D concentrations, not vitamin D dose.

Given the widespread failure of vitamin D RCTs, it is logical to use findings from observational studies as the best evidence for the effects of vitamin D [3]. That is the approach taken here in selecting papers to discuss for 2024. One caveat is that correlations with the serum 25(OH)D concentration might not be accurate if it is highly correlated with another independent variable that consistently affects health. However, this possibility is not a problem, because 25(OH)D concentrations are primarily determined by solar UVB. Liberation of nitric oxide from subcutaneous nitrate stores has also been proposed as an alternative mechanism to explain the effect of solar UV exposure [4]. While this effect has been linked to reduced risk of COVID-19, cardiovascular disease, and hypertension, nitric oxide has not been linked to risk of the many other diseases found inversely correlated with 25(OH)D concentrations.

The search for publications to highlight was based primarily on searching Google Scholar with the search term “vitamin D” for papers published in 2024. This database shows which papers cited each entry and where an open-access version of the paper could be found if available. Several criterions were selected for inclusion. First, the number of citations was one criterion. Second was whether the paper reported information useful for disease prevention and/or treatment. Third favored open-access papers. Fourth was that papers that concluded vitamin D had little health benefit should also be included with a discussion of why that conclusion was incorrect.

Papers with general vitamin D recommendations

One published on 27 April 2024 was a consensus review statement on vitamin D status assessment and supplementation [5]. There were 27 authors including many prominent vitamin D researchers. It discussed advances in vitamin D knowledge, effects of vitamin D on calcium, and findings from mega RCTs supporting effects on the immune system, development of type 2 diabetes mellitus, and, perhaps, cardiovascular events and mortality. The review states that vitamin D deficiency [25(OH)D <20 ng/mL (50 nmol/L)] increases risk of autoimmune and infectious diseases, cardio-respiratory diseases, impaired muscle function and strength, diabetes, cancer incidence and mortality, and acute COVID-19 severity and long COVID risk. It also supports vitamin D supplementation of up to 2000 IU/day to achieve 25(OH)D concentrations between 30‒50 ng/mL.

The new Endocrine Society Clinical Practice Guideline for vitamin D for prevention of disease was published on 3 June 2024 [6] There were 16 authors, all vitamin D researchers. There was also a supporting systematic review [7]. Both papers were based solely on RCTs. The main recommendation was that only people aged 1 to 18 years and those over 75 years of age, those who are pregnant, and those with high-risk prediabetes need to be tested and supplemented. This guideline was a dramatic departure from the 2011 Endocrine Practice Guideline organized by Michael Holick [8]. Of course, Dr. Holick responded to the new Guideline: “Association studies have suggested that to obtain maximum extraskeletal benefits from vitamin D including reducing risk of upper respiratory tract infection for children and adults, autoimmune disorders, pre-eclampsia, low birth weight, neonatal dental caries, and deadly cancers, circulating concentrations of 25-hydroxyvitamin D should be at least 30 ng/mL (75 nmol/L) with a preferred range of 40-60 ng/mL as recommended by the 2011 Guidelines.” [9].

Another review in response proposed a framework for developing more effective country and region-specific recommendations for extraskeletal benefits to prevent multiple diseases and enhance public health [10]. It outlined the evidence for high vitamin D does and serum 25(OH)D concentrations. It also tabulated and discussed guidelines from nine countries.

A review by vitamin D researchers from five countries outlined the evidence supporting 2000 IU/d (50 µg/d) vitamin D supplementation in the general population [11]. This is expected to be sufficient to raise the mean population 25(OH)D concentration above 30 ng/mL. The prevalence of serum 25(OH)D <10 or 12 and <20 ng/mL ranges from ~5% to 18% and 24% to 49%, respectively, depending on the Food and Agriculture Organization of the United Nations world region [12]. Thus, considerable improvement in global health could be achieved by 2000 IU/d vitamin D supplementation.

Risk prevention

A synthesis of prospective cohort and Mendelian randomization analyses of dose-response relationships for vitamin D for coronary heart disease, stroke, and all-cause mortality rates shows why vitamin D RCTs have failed [13]. As shown in Figure 1 in this review, the hazard ratios are between 1.3 and 2.4 for 25(OH)D concentrations of 6 ng/mL (15 nmol/L), declining rapidly to 1.0 by 12‒20 ng/mL. Most vitamin D RCTs in Western developed countries enroll very few participants with such low 25(OH)D concentrations. In addition, they normally supplement those in the placebo arm with 400 IU/d vitamin D or more out of ethical concerns.

Two reviews evaluated the effect of follow-up period on the effect of high vs. low 25(OH)D concentration on incidence of adverse health outcomes: stroke and major cardiovascular disease effect [14] and Alzheimer’s disease and dementia [15]. Long follow-up studies underestimate the effect of variables on health outcomes due to “regression dilution” (reduction in spread of mean variable values due to changes in values of the variables for each participant) [16]. Figures 1 and 2 show representative results from those two papers.

Figure 1. A plot of relative risk for stroke versus years of follow-up concerning high vs. low 25(OH)D concentration, with regression, fits for studies of less than 10 years and those carried out over more than 10 years [14]. From an open access article.

Figure 2. Scatter plot of relative risk (RR) versus low to high 25(OH)D concentration for dementia concerning mean follow-up period less than 15 years [15]. From an open access article.

Prevention and Treatment

Here are representative papers published in 2024 regarding the effect of serum 25(OH)D concentrations on health outcomes.

• Cancer. Perhaps the most important vitamin D-cancer article in a couple of years: “Vitamin D regulates microbiome-dependent cancer immunity” published in Science [17]. It first described mouse model studies of vitamin D and cancer. In mice, higher vitamin D status resulted in greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. This resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Studies involving Danish cancer patients, those with the highest vitamin D-vitamin D receptor (VDR) signature levels had significantly survival rates than those with the lowest levels over 33 years for skin cancer, 12 years for sarcoma, and 10 years for liver hepatocellular cancer. This study strengthens the case for an important role of vitamin D in reducing risk of cancer.
• Cancer. A bibliometric analysis of global research on vitamins and cancer between 2003 and 2022 found vitamin D to be the most important vitamin for cancer prevention [18]. As shown in Table 5 in that review, nine of the ten most cited papers were for vitamin D.
• Colorectal cancer. A review of the benefits of vitamin D for colorectal cancer was published [19]. Figure 2 in it shows the mechanisms related to proliferation, epithelial differentiation, cell death, WNG/β-catenin signaling, immunomodulation, angiogenesis, microbiome, detoxification, fibroblasts, and stem cells.
• Colorectal cancer. A systematic review regarding metastatic colorectal cancer that low 25(OH)D concentrations were significantly correlated with increased risk of progression and death [20].
• COVID-19. A systematic review found vitamin D supplementation had a significant beneficial effect on prevention of incidence in both RCTs and observational studies as well as admission to the ICU in observational studies [21]. In a subsequent systematic review, reduced risk of intubation in RCTs and mortality rates in observational studies were also found [22].
• Diabetes mellitus type 1. An intervention study was conducted in Iran with 90 type 1 diabetes mellitus patients aged 5‒18 years [23]. At baseline, 59% had 25(OH)D concentrations below 20 ng/mL and 41% had concentrations between 20 and 30 ng/mL. Those with 25(OH)D concentration below 30 ng/mL were supplemented with vitamin D according to the 2011 Endocrine Society Guideline [8], then 1000 IU/day after achieving 30 ng/mL. After six months, 50% had concentrations between 30 and 50 ng/mL and 36% had >50 ng/mL. Levels of HbA1c declined to <8% for 10% of those with concentration between 30‒50 ng/mL, but to 69% for those with concentrations >50 ng/mL (p <0.01).
• Dyslipidemia. A narrative review found “on the one hand, numerous observational studies suggest a link between higher serum 25(OH)D concentrations and a beneficial lipid profile, while on the other hand, interventional studies do not demonstrate a significant effect.” [24].
• Fatigue. A narrative review outlined the role of vitamin D on fatigue mitigation [25]. The effects include some related to oxidative stress and inflammatory cytokines. Some control over the neurotransmitters dopamine and serotonin have also been found.
• Fibromyalgia. A cross-sectional study was conducted in Turkey involving 180 female fibromyalgia patients [26]. Sixty-five percent had baseline 25(OH)D concentrations below 20 ng/mL. They were given 50,000 IU/week for 12 weeks. As a result, Visual Analogue Scale scores decreased from 7.7±1.2 to 5.1±1.2 (p <0.01) and the Fibromyalgia Impact Questionnaire score decreased from 67±10 to 54±9 (p <0.05).
• Parkinson’s disease. A review pointed out that vitamin D plays a role in the management of Parkinson’s disease but the potential therapeutic effect of vitamin D on established Parkinson’s disease remains controversial [27].
• Uterine leiomyomas. A case-control study conducted in Nigeria found a significant inverse correlation between serum 25(OH)D concentration and incident uterine leiomyomas. The mean 25(OH)D concentration in cases was 15±5 ng/mL and 22±7 ng/mL in controls [28].

The above findings for various health outcomes illustrate that research continues to find benefits of vitamin D for many health outcomes.

The year 2024 also marked the availability of the fifth edition of Feldman and Pike’s “Vitamin D.” Each edition includes reviews by vitamin D researchers covering many topics. Volume One: Biochemistry, Physiology and Diagnostics [29] has 50 chapters spanning 1178 pages, while Volume Two: Diseases and Therapeutics [30] has 56 chapters spanning 1327 pages.

Some of the chapters in Volume One are:

• Chapter 3 – Photobiology of vitamin D, Michael F. Holick, Andrzej T. Slominski
• Chapter 41 – Vitamin D and the renin–angiotensin system, Yan Chun Li

Some of the chapters in Volume Two are:

• Chapter 51 – Defining thresholds for vitamin D I: scientific rationale for serum 25-hydroxyvitamin D cutoffs of 25 and 50 nmol/L, Andrea L. Darling and Susan A. Lanham-New
• Chapter 54 – Worldwide vitamin D status, Natasja van Schoor, Renate de Jongh, Paul Lips
• Chapter 58 – Vitamin D and food fortification, Kevin D. Cashman, Mairead Kiely
• Chapter 70 – Vitamin D and osteoporosis, Peter R. Ebeling
• Chapter 106 – Vitamin D and acute illness, Karin Amrein and Kenneth B. Christopher
• Individual chapters can be purchased for US $31.50

Summary: The above findings on the effect of vitamin D illustrate that research continues to find benefits of vitamin D for many health outcomes.

See also:

2023 Annual Collection of Top Vitamin D Papers
https://orthomolecular.org/resources/omns/v20n02.shtml

2022 Top Vitamin D Papers
https://orthomolecular.org/resources/omns/v19n07.shtml

2021 Top Vitamin D Papers
https://orthomolecular.org/resources/omns/v18n02.shtml

2020 Top 25 Vitamin D Publications
https://orthomolecular.org/resources/omns/v17n01.shtml

2019 Top Advances in the Understanding of the Impact of Vitamin D on Human Health
https://orthomolecular.org/resources/omns/v16n01.shtml

Vitamin D Reduces Cancer Risk: Why Scientists Accept it, but Physicians Do Not
https://orthomolecular.org/resources/omns/v15n05.shtml

2017 Top 12 Vitamin D Papers
https://orthomolecular.org/resources/omns/v14n03.shtml

2015-2016 Top Vitamin D Papers
https://orthomolecular.org/resources/omns/v13n08.shtml

2014 Top Vitamin D Research
https://orthomolecular.org/resources/omns/v11n03.shtml

2013 Top 20 Vitamin D Papers
https://orthomolecular.org/resources/omns/v10n03.shtml

Disclosure. W.B.G. received grants for vitamin D research from Bio-Tech Pharmacal, Inc. (Fayetteville, AR, USA) for many years through the end of 2023.

References:

1. Pilz S, Trummer C, Theiler-Schwetz V, et al. (2022) Critical Appraisal of Large Vitamin D Randomized Controlled Trials. Nutrients, 14:303. https://doi.org/10.3390/nu14020303

2. Heaney RP (2014) Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 72:48-54. https://doi.org/10.1111/nure.12090

3. Grant WB, Boucher BJ, Al Anouti F, Pilz S (2022) Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D. Nutrients, 14:3811. https://doi.org/10.3390/nu14183811

4. Weller RB (2024) Sunlight: Time for a Rethink? J Invest Dermatol. 144:1724-1732. https://doi.org/10.1016/j.jid.2023.12.027

5. Giustina A, Bilezikian JP, Adler RA, et al. (2024) Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows. Endocr Rev. 45:625-654. https://doi.org/10.1210/endrev/bnae009

6. Demay MB, Pittas AG, Bikle DD, et al. (2024) Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 109:1907-1947. https://doi.org/10.1210/clinem/dgae290

7. Shah VP, Nayfeh T, Alsawaf Y, et al. (2024) A Systematic Review Supporting the Endocrine Society Clinical Practice Guidelines on Vitamin D. J Clin Endocrinol Metab. 109:1961-1974. https://doi.org/10.1210/clinem/dgae312

8. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 96:1911-1930. https://doi.org/10.1210/jc.2011-0385

9. Holick MF (2024) Revisiting Vitamin D Guidelines: A Critical Appraisal of the Literature. Endocr Pract. 30:1227-1241. https://doi.org/10.1016/j.eprac.2024.10.011

10. Wimalawansa SJ, Weiss ST, Hollis BW (2024) Integrating Endocrine, Genomic, and Extra-Skeletal Benefits of Vitamin D into National and Regional Clinical Guidelines. Nutrients, 16:3969. https://doi.org/10.3390/nu16223969

11. Pludowski P, Grant WB, Karras SN, et al. (2024) Vitamin D Supplementation: A Review of the Evidence Arguing for a Daily Dose of 2000 International Units (50 microg) of Vitamin D for Adults in the General Population. Nutrients, 16:391. https://doi.org/10.3390/nu16030391

12. Cashman KD (2022) Global differences in vitamin D status and dietary intake: a review of the data. Endocr Connect. 11:e210282. https://doi.org/10.1530/EC-21-0282

13. Emerging Risk Factors Collaboration/EPIC-CVD/Vitamin D Studies Collaboration (2024) Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses. Lancet Diabetes Endocrinol. 12:e2-e11. https://doi.org/10.1016/S2213-8587(23)00287-5

14. Grant WB, Boucher BJ (2024) How Follow-Up Period in Prospective Cohort Studies Affects Relationship Between Baseline Serum 25(OH)D Concentration and Risk of Stroke and Major Cardiovascular Events. Nutrients, 16:3759. https://doi.org/10.3390/nu16213759

15. Grant WB (2024) Follow-Up Period Affects the Association between Serum 25-Hydroxyvitamin D Concentration and Incidence of Dementia, Alzheimer’s Disease, and Cognitive Impairment. Nutrients, 16:3211. https://doi.org/10.3390/nu16183211

16. Clarke R, Shipley M, Lewington S, et al. (1999) Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol. 150:341-353. https://doi.org/10.1093/oxfordjournals.aje.a010013

17. Giampazolias E, Pereira da Costa M, Lam KC, et al. (2024) Vitamin D regulates microbiome-dependent cancer immunity. Science, 384:428-437. https://doi.org/10.1126/science.adh7954

18. Wang W, Ye X, Wang S (2024) Bibliometric analysis of global research on vitamins and cancer between 2003 and 2022. Medicine (Baltimore) 103:e37108. https://doi.org/10.1097/MD.0000000000037108

19. Pereira F, Fernandez-Barral A, Larriba MJ, et al. (2024) From molecular basis to clinical insights: a challenging future for the vitamin D endocrine system in colorectal cancer. FEBS J. 291:2485-2518. https://doi.org/10.1111/febs.16955

20. Ottaiano A, Iacovino ML, Santorsola M, et al. (2024) Circulating vitamin D level before initiating chemotherapy impacts on the time-to-outcome in metastatic colorectal cancer patients: systematic review and meta-analysis. J Transl Med. 22:119. https://doi.org/10.1186/s12967-024-04889-2

21. Sartini M, Del Puente F, Oliva M, et al. (2024) Preventive Vitamin D Supplementation and Risk for COVID-19 Infection: A Systematic Review and Meta- Analysis. Nutrients, 16:679. https://doi.org/10.3390/nu16050679

22. Sartini M, Del Puente F, Carbone A, et al. (2024) The Effect of Vitamin D Supplementation Post COVID-19 Infection and Related Outcomes: A Systematic Review and Meta-Analysis. Nutrients, 16:3794. https://doi.org/10.3390/nu16223794

23. Al-Awady MS, Ali BM (2024) Effect of vitamin D supplementation on glycemic control in type 1 diabetes mellitus. Cell. Mol. Biomed. Rep. 4:189-198. https://doi.org/10.55705/cmbr.2024.436594.1218

24. Al Refaie A, Baldassini L, Mondillo C, et al. (2024) Vitamin D and Dyslipidemia: Is There Really a Link? A Narrative Review. Nutrients, 16:1144. https://doi.org/10.3390/nu16081144

25. Di Molfetta IV, Bordoni L, Gabbianelli R, et al. (2024) Vitamin D and Its Role on the Fatigue Mitigation: A Narrative Review. Nutrients, 16:221. https://doi.org/10.3390/nu16020221

26. Ersoy S, Kesiktas FN, Sirin B, et al. (2024) The effect of vitamin D treatment on quality of life in patients with fibromyalgia. Ir J Med Sci. 193:1111-1116. https://doi.org/10.1007/s11845-023-03521-4

27. Al-Kuraishy HM, Al-Gareeb AI, Selim HM, et al. (2024) Does vitamin D protect or treat Parkinson’s disease? A narrative review. Naunyn Schmiedebergs Arch Pharmacol. 397:33-40. https://doi.org/10.1007/s00210-023-02656-6

28. Okoro CC, Ikpeze OC, Eleje GU, et al. (2024) Association between serum vitamin D status and uterine leiomyomas: a case-control study. Obstet Gynecol Sci. 67:101-111. https://doi.org/10.5468/ogs.23143

29. Feldman and Pike’s Vitamin D, Volume One: Biochemistry, Physiology and Diagnostics, Fifth ed.; Hewison M, Bouillon R, Giovannucci E, et al., Eds., Elsevier: 2023; pp. 1178. ISBN-13: 978-0323913867 https://www.sciencedirect.com/book/9780323913867/feldman-and-pike-s-vitamin-d

30. Feldman and Pike’s Vitamin D: Volume Two: Disease and Therapeutics, Fifth ed.; Hewison, M., Giovannucci, E., Goltzman D, et al., Eds., Academic Press: 2023; pp. 1327. ISBN-13: 978-0323913386 https://doi.org/10.1016/C2021-0-00151-6

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