FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, February 27, 2024

Annual Collection of Top Vitamin D Publications

William B. Grant, PhD

OMNS (Feb 27, 2024) The year 2023 marks 100 years after Elmer McCollum discovered vitamin D [1]. For the first 80 years after the discovery, vitamin D was mostly known for its role in regulating the absorption and metabolism of calcium. Beginning in the last decade of the twentieth century and accelerating in the early twenty-first century, it became apparent that vitamin D's health benefits extended far beyond bones. Many of the benefits occur through the hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D (calcitrol) entering the vitamin D receptor which nearly every cell in the body has, and affecting gene expression [2]. By 2013, it was apparent that "Adequate vitamin D status seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases, as well as infertility and adverse pregnancy and birth outcomes." [3]. Early evidence supporting vitamin D's health benefits came from ecological studies related to sun exposure and season. Later, observational studies based on serum 25-hydroxyvitamin D [25(OH)D] and vitamin D supplementation as well as studies of mechanisms provided additional information. Since the medical system bases approval of pharmaceutical drugs on results from randomized controlled trials (RCTs), they were conducted for vitamin D. Unfortunately, nearly all vitamin D RCTs followed the guidelines for drugs, not nutrients. In drug trials, the only source of the drug is in the trial, the control arm participants receive a placebo, and it is assumed that there is a linear dose-response relationship. Results are evaluated on the basis of intention to treat, comparing results for those in the treatment arm with those in the control arm. Robert Heaney outlined the guidelines for nutrient trials in 2014 [4]. The key guidelines as applied to vitamin D include measuring serum 25(OH)D concentration of prospective participants and enroll those with low concentrations, supplement with enough vitamin D to raise serum 25(OH)D concentrations to the optimal value for the outcome of interest, measure achieved 25(OH)D concentration and analyze the results based on 25(OH)D concentrations. Very few vitamin D RCTs have followed these guidelines. As a result, few have reported results that convince physicians to recommend vitamin D [5].

Big Pharma became concerned that vitamin D supplementation could impact the income and profit of the drug industry around 2009, and, in response, convened a select committee of physicians and researchers to set guidelines for vitamin D supplementation (5057 Google Scholar citations) [6]. The recommendation was that people aged 1 to 70 years should take 600 IU/d (15 mcg/d) vitamin D while those 71 and older should take 800 IU/d (20 mcg/d) to achieve > 20 ng/mL (50 nmol/L). This recommendation was based on an incorrect analysis of the vitamin D requirement for bone health [7]. About the same time, the Endocrine Society recommended higher vitamin D doses for people with vitamin D deficiency in order to achieve > 30 ng/mL, which has over 12,000 Google Scholar citations [8]. Big Pharma used the Disinformation Playbook to discredit vitamin D (Grant, 2018), and again in 2024 (Aschwanden, 2024).

Grant WB. Vitamin D acceptance delayed by Big Pharma following the Disinformation Playbook. 2018. http://orthomolecular.org/resources/omns/v14n22.shtml

Aschwanden C. How Much Vitamin D Do You Need to Stay Healthy. Sci Am. 2024. https://www.scientificamerican.com/article/how-much-vitamin-d-do-you-need-to-stay-healthy/

For this year's top vitamin D publications, I searched the databases Google Scholar and SCOPUS, both of which show how many citations each publication has. Google Scholar is open access and generally indicates the URL for an open-access version of the publication. SCOPUS is not open access. I tried to find good representative publications in a variety of topics likely of interest to physicians, especially those interested in health maintenance and disease prevention rather than treatment. For each publication, I extracted about 100 words from the abstract.

Conversions: 50 nmol/L = 20 ng/mL; 1 mcg vitamin D = 40 IU (125 mcg = 5,000 IU); 1 mmol calcium = 40 mg; 1 mmol phosphorus = 30 mg

Autoimmune diseases

Vitamin D deficiency has been observed in patients with rheumatoid arthritis (RA) and has been shown to be inversely related to disease activity, and vitamin D deficiency (VDD) may be implicated in the pathogenesis of the disease. VDD has also been observed in patients with systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, and idiopathic inflammatory myopathies. VDD has also been observed in systemic sclerosis. VDD may be implicated in the pathogenesis of autoimmunity, and it may be administered to prevent autoimmune disease and reduce pain in the context of autoimmune rheumatic disorders. [9]

Cancer

A post hoc subgroup of a vitamin D placebo-controlled trial found that 2000 IU/d vitamin D greatly reduced the risk of death for digestive cancer patients with p53 immunoreactive, defined by positivity for anti-p53 antibodies in serum and nuclear accumulation of p53 oncosuppressor protein in more than 99% of cancer cells, In the p53-immunoreactive subgroup (80 patients), 5-year relapse-free survival was significantly higher in the vitamin D group (13 patients [80.9%]) than the placebo group (1 patient [30.6%]; hazard ratio (HR), 0.27; 95% CI, 0.11-0.61; P = 0.002). [10]

See this accompanying editorial [11]

Cardiovascular disease

"Results: Of the 1,321 records identified using the search strategy, a total of 19 cohort studies were included in the final meta-analysis. The pooled estimate of HR (95% CI) for low vs. high circulating 25(OH)D level was 1.75 (1.49-2.06) with I² value of 30.4%. In subgroup analysis, strong effects of circulating vitamin D were observed in healthy general population (pooled HR, 1.84; 95% CI, 1.43-2.38) and the clinical endpoint of sudden cardiac death (pooled HRs, 2.68; 95% CI, 1.48-4.83). The dose-response analysis at the reference level of < 50 nmol/L showed a significant negative association between circulating 25(OH)D and risk of sudden cardiac death and cardiovascular disease mortality." [12]

Cerebrovascular disorder

"Vitamin D modulates the various molecular pathways, i.e., Nitric Oxide, PI3K-Akt Pathway, cAMP pathway, NF-kB Pathway, Sirtuin 1, Nrf2, FOXO, in cerebrovascular disorder. The current review shows evidence for vitamin D's mitigating or slowing the progression of these cerebrovascular disorders, which are significant causes of disability and death worldwide." [13]

Circulatory system

"This brief overview focuses on the cardiovascular and cerebrovascular effects of VitD and the cellular, molecular, and functional changes that occur in the circulatory system in VitD deficiency (VDD). It explores the links among VDD and adverse vascular remodeling, endothelial dysfunction, vascular inflammation, and increased risk for cardiovascular and cerebrovascular diseases. Improved understanding of the complex role of VDD in the pathogenesis of atherosclerotic cardiovascular diseases, stroke, and vascular cognitive impairment is crucial for all cardiologists, dietitians, and geriatricians, as VDD presents an easy target for intervention." [14]

Dementia

"We prospectively explored associations between vitamin D supplementation and incident dementia in 12,388 dementia-free persons from the National Alzheimer's Coordinating Center.

Highlights: In a prospective cohort study, we assessed effects of Vitamin D on dementia incidence in 12,388 participants from the National Alzheimer's Coordinating Center dataset. Vitamin D exposure was associated with 40% lower dementia incidence versus no exposure. Vitamin D effects were significantly greater in females versus males and in normal cognition versus mild cognitive impairment. Vitamin D effects were significantly greater in apolipoprotein E ε4 non-carriers versus carriers. Vitamin D has potential for dementia prevention, especially in the high-risk strata." [15]

Depression and anxiety

"Results: We identified 20 RCTs that matched all eligibility criteria, totaling 2,256 subjects, diagnosed with MDD, GAD, and depressive or anxiety symptoms. Supplementation with folic acid or L-methylfolate, B1, B12 or methylcobalamin, and vitamin D (in different doses and study duration) significantly decreased depression score scales by increasing response to standard pharmacological treatment or as monotherapy, including partial or complete remission. As for anxiety symptoms, the availability of results is limited to adjuvant vitamin D therapy." [16]

"Ten meta-analyses of randomised controlled trials (RCTs) revealed significant reduction in depression symptoms comparing participants on vitamin D supplements to those on placebo (Pooled standardised mean difference: - 0.40; 95 % CI: - 0.60, - 0.21, p < 0.01: I2 = 89.1 %, p < 0.01). Four meta-analyses of cohort studies (with one having two subgroups) revealed that participants with lower levels of serum 25(OH)D were at increased odds of depression than those with higher levels of serum 25(OH)D (Pooled odds ratio: 1.60; 95 % CI: 1.08, 2.36, p < 0.01; I2 = 91.3 %, p < 0.01)." [17]

Diabetes mellitus type 2

"Three randomized trials regarding vitamin D supplementation in prediabetic patients were included. Vitamin D reduced risk for diabetes by 15% (HR, 0.85 [95% CI, 0.75 to 0.96. Among participants assigned to the vitamin D group who maintained an intratrial mean serum 25(OH)D level of at least 125 nmol/L (≥50 ng/mL) compared with 50 to 74 nmol/L (20 to 29 ng/mL) during follow-up, cholecalciferol reduced risk for diabetes by 76% (HR, 0.24 [CI, 0.16 to 0.36]). Vitamin D increased the likelihood of regression to normal glucose regulation by 30% (rate ratio, 1.30 [CI, 1.16 to 1.46])." [18]

Foot ulcers

"Materials and methods. We included people with diabetes with one or more foot ulcers lasting for more than 6 weeks. Patients were randomly allocated to either a daily oral intake of high-dose (6800 IU/d or 170 μg/d) or low-dose (800 IU/ or 20 μg/d) vitamin D3. Findings/results. The intention-to-treat analysis showed a significantly higher rate of ulcer healing in the high-dose group with 21 of 30 (70%) healed ulcers compared to 12 of 34 (35%) in the low-dose group (P = 0.01). Median ulcer reduction at final follow-up was 100% in the high-dose group and 57% in the low-dose group." [19]

Microvascular complications

"Research design and methods: This analysis included 14,709 participants with T2D who were free of microvascular complications from the UK Biobank.

Results: Compared with participants with 25(OH)D < 25 nmol/L, individuals with 25(OH)D ≥75 nmol/L had a multivariable-adjusted HR of 0.65 (95% CI 0.51, 0.84) for composite diabetic microvascular complications, 0.62 (0.40, 0.95) for diabetic retinopathy, 0.56 (0.40, 0.79) for diabetic nephropathy, and 0.48 (0.26, 0.89) for diabetic neuropathy.

Conclusions: Our findings suggest a potential beneficial role of maintaining adequate vitamin D status in the prevention of diabetic microvascular complications." [20]

Respiratory tract infections

"Results: This study included 31,466 United States adults ≥20 y of age (47.1 y, 55.5% women) with a mean serum 25(OH)D concentration of 66.2 nmol/L. After adjustments, compared with participants with a serum 25(OH)D concentration ≥75.0 nmol/L, those with a serum 25(OH)D concentration <30 nmol/L had higher risk of head or chest cold (OR: 1.17; 95% CI: 1.01, 1.36) and other respiratory diseases, including influenza, pneumonia, and ear infections (OR: 1.84; 95% CI: 1.35, 2.51). In the stratification analyses, lower serum 25(OH)D concentrations were associated with a higher risk of head or chest cold in obese adults but not in nonobese adults." [21]

Wound healing

"Conclusion: Vitamin D and calcium signaling are critical for the ability of epidermal and hair follicle stem cells to respond to wounding. VDD with the accompanying decrease in calcium signaling can result in delayed and/or chronic wounds, a major cause of morbidity, loss of productivity, and medical expense." [22]

Vitamin D recommendations

"The consensus group, representing eight Polish/international medical societies and eight national specialist consultants, prepared the final Polish recommendations.

Results: Based on networking discussions, the ranges of total serum 25(OH)D concentration indicating VDD [<20 ng/mL (<50 nmol/L)], suboptimal status [20-30 ng/mL (50-75 nmol/L)], and optimal concentration [30-50 ng/mL (75-125 nmol/L)] were confirmed. Practical guidelines for cholecalciferol (vitamin D3) as the first choice for prophylaxis and treatment of VDD were developed." [23]

"Maintaining the population's vitamin D sufficiency (above 40 ng/mL) with vitamin D3 supplements and/or daily sun exposure is the most cost-effective way to reduce chronic diseases and sepsis, overcome viral epidemics and pandemics, and reduce healthcare costs. Furthermore, vitamin D sufficiency improves overall health (hence reducing absenteeism), reduces the severity of chronic diseases such as metabolic and cardiovascular diseases and cancer, decreases all-cause mortality, and minimizes infection-related complications such as sepsis and COVID-19-related hospitalizations and deaths. Properly using vitamin D is the most cost-effective way to reduce chronic illnesses and healthcare costs: thus, it should be a part of routine clinical care." [24]

FELDMAN AND PIKE'S VITAMIN D

This two-volume tome has 50 chapters in Vol.1 and 56 chapters in Vol. 2. The chapters were written by leading authorities in the field of vitamin D research. The contents of the book are copyright protected. However, it should be possible to obtain the pre-publication content of various chapters by contacting the authors of the chapters. The URLs include the chapter titles. The authors of each chapter can be found by searching Google Scholar with "Hewison, vitamin D" and restricting the search to 2024.

FELDMAN AND PIKE'S VITAMIN D

Volume One: Biochemistry, Physiology and Diagnostics
https://shop.elsevier.com/books/feldman-and-pike-s-vitamin-d/hewison/978-0-323-91386-7

Volume Two: Health, Disease and Therapeutics
https://shop.elsevier.com/books/feldman-and-pike-s-vitamin-d/hewison/978-0-323-91338-6

FIFTH EDITION

Edited by Hewison M, Bouillon R, Giovannucci E, Goltzman D, Meyer M, Welsh J.
Academic Press, Elsevier, 2024

References

1. Holick, M.F., The One-Hundred-Year Anniversary of the Discovery of the Sunshine Vitamin D(3): Historical, Personal Experience and Evidence-Based Perspectives. Nutrients, 2023. 15(3). https://www.mdpi.com/2072-6643/15/3/593

2. Shirvani, A., et al., Disassociation of Vitamin D's Calcemic Activity and Non-calcemic Genomic Activity and Individual Responsiveness: A Randomized Controlled Double-Blind Clinical Trial. Sci Rep, 2019. 9(1): p. 17685. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881448/

3. Pludowski, P., et al., Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmun Rev, 2013. 12(10): p. 976-89.

4. Heaney, R.P., Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev, 2014. 72(1): p. 48-54. https://academic.oup.com/nutritionreviews/article/72/1/48/1933554

5. Gallagher, J.C. and C.J. Rosen, Vitamin D: 100 years of discoveries, yet controversy continues. Lancet Diabetes Endocrinol, 2023. 11(5): p. 362-374.

6. Ross, A.C., et al., The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab, 2011. 96(1): p. 53-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046611/

7. Holick, M.F., Evidence-based D-bate on health benefits of vitamin D revisited. Dermatoendocrinol, 2012. 4(2): p. 183-90. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427198/

8. Holick, M.F., et al., Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2011. 96(7): p. 1911-30. https://academic.oup.com/jcem/article-pdf/96/7/1911/20288177/jcem1911.pdf

9. Athanassiou, L., et al., Vitamin D and Autoimmune Rheumatic Diseases. Biomolecules, 2023. 13(4). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10135889/

10. Kanno, K., et al., Effect of Vitamin D Supplements on Relapse or Death in a p53-Immunoreactive Subgroup With Digestive Tract Cancer: Post Hoc Analysis of the AMATERASU Randomized Clinical Trial. JAMA Netw Open, 2023. 6(8): p. e2328886. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10445201/

11. Holick, M.F., The Death D-Fying Vitamin D3 for Digestive Tract Cancers-The p53 Antibody Connection. JAMA Netw Open, 2023. 6(8): p. e2328883. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808574

12. Kong, S.Y., et al., Circulating Vitamin D Level and Risk of Sudden Cardiac Death and Cardiovascular Mortality: A Dose-Response Meta-Analysis of Prospective Studies. J Korean Med Sci, 2023. 38(33): p. e260. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10442497/

13. Rihal, V., et al., Vitamin D as therapeutic modulator in cerebrovascular diseases: a mechanistic perspectives. Crit Rev Food Sci Nutr, 2023. 63(25): p. 7772-7794.

14. Pal, E., et al., Role of Vitamin D Deficiency in the Pathogenesis of Cardiovascular and Cerebrovascular Diseases. Nutrients, 2023. 15(2). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864832/

15. Ghahremani, M., et al., Vitamin D supplementation and incident dementia: Effects of sex, APOE, and baseline cognitive status. Alzheimers Dement (Amst), 2023. 15(1): p. e12404. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9976297/

16. Borges-Vieira, J.G. and C.K.S. Cardoso, Efficacy of B-vitamins and vitamin D therapy in improving depressive and anxiety disorders: a systematic review of randomized controlled trials. Nutr Neurosci, 2023. 26(3): p. 187-207. https://www.tandfonline.com/doi/full/10.1080/1028415X.2022.2031494

17. Musazadeh, V., et al., Vitamin D protects against depression: Evidence from an umbrella meta-analysis on interventional and observational meta-analyses. Pharmacol Res, 2023. 187: p. 106605.

18. Pittas, A.G., et al., Vitamin D and Risk for Type 2 Diabetes in People With Prediabetes : A Systematic Review and Meta-analysis of Individual Participant Data From 3 Randomized Clinical Trials. Ann Intern Med, 2023. 176(3): p. 355-363. https://www.acpjournals.org/doi/epdf/10.7326/M22-3018

19. Halschou-Jensen, P.M., et al., Improved Healing of Diabetic Foot Ulcers After High-dose Vitamin D: A Randomized Double-blinded Clinical Trial. Int J Low Extrem Wounds, 2023. 22(3): p. 466-474. https://journals.sagepub.com/doi/abs/10.1177/15347346211020268

20. Chen, X., et al., Vitamin D Status, Vitamin D Receptor Polymorphisms, and Risk of Microvascular Complications Among Individuals With Type 2 Diabetes: A Prospective Study. Diabetes Care, 2023. 46(2): p. 270-277. https://diabetesjournals.org/care/article/46/2/270/147520/Vitamin-D-Status-Vitamin-D-Receptor-Polymorphisms

21. Li, B., et al., Association between Serum 25-Hydroxyvitamin D Concentrations and Respiratory Infection among United States Adults. J Nutr, 2023. 153(1): p. 260-267. https://www.sciencedirect.com/science/article/pii/S0022316622131081?via%3Dihub

22. Bikle, D.D., Role of vitamin D and calcium signaling in epidermal wound healing. J Endocrinol Invest, 2023. 46(2): p. 205-212. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9859773/

23. Pludowski, P., et al., Guidelines for Preventing and Treating Vitamin D Deficiency: A 2023 Update in Poland. Nutrients, 2023. 15(3). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9920487/

24. Wimalawansa, S.J., Physiological Basis for Using Vitamin D to Improve Health. Biomedicines, 2023. 11(6). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295227/

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Ilyès Baghli, M.D. (Algeria)
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William B. Grant, Ph.D. (USA)
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Ron Hunninghake, M.D. (USA)
Bo H. Jonsson, M.D., Ph.D. (Sweden)
Dwight Kalita, Ph.D. (USA)
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