OMNS (Jan 27, 2023) Although the role of vitamin D in reducing risk of SARS-CoV-2 infection and COVID-19 severity and death was kept from the mass media due to Big Pharma using the Disinformation Playbook against vitamin D ^[1], research on this topic continued in the peer-reviewed journal literature. Early in 2022 an observational study from Barcelona was published reporting that inhabitants who received vitamin D supplements and raised serum 25-hydroxyvitamin D [25(OH)D] concentrations above 30 ng/mL compared to those who did not have vitamin D prescriptions and had had serum 25(OH)D < 20 ng/mL had lower rates of SARS-CoV-2 infection and severe COVID-19. For mortality, the hazard ratio = 0.66 [CI 95% 0.46-0.93] ^[2]. Similar results were found for calcifediol [25(OH)D] prescriptions.

The vitamin D article with the potential for the greatest impact on health related to COVID-19 was one based on COVID-19 outcomes by US veterans receiving care at the Department of Veterans Administration in the United States [3]. They used the VA database to identify patients treated with vitamin D2 or D3 in 2020 and from March 1-December 31, 2020. They then used propensity score matching for controls and compared COVID-19 incidence and mortality rates. Data for over 400,000 patients were included. Not included in the analysis were patients whose first vitamin D prescription was during the COVID-19 pandemic. Serum 25(OH)D concentrations and vitamin D dose were inversely correlated with COVID-19 incidence and mortality. For example, at an average daily dosage of 50,000 IU, there was a 49% associated reduction in COVID-19 infections (hazard ratio = 0.51, [95% CI 0.36, 0.70]) in patients with low serum (0-19 ng/mL) vitamin D levels. When we extrapolate our results for vitamin D3 supplementation to the entire US population in 2020, there would have been approximately 4 million fewer COVID-19 cases and 116,000 deaths avoided. We calculated these values by applying our estimated 20% average reduction in infection and 33% reduction in mortality after infection for vitamin D3 to a total of 19,860,000 cases and 351,999 deaths through 2020. It has been a tragedy that the public was not informed about the benefits of vitamin D and physicians in most hospitals were not permitted to treat COVID-19 patients with vitamin D during this epidemic.

There are several ways used to determine whether vitamin D affects health outcomes in a causal manner. The approach used in medicine is the randomized controlled trial (RCT). In this approach, participants are randomly assigned to treatment or control group, generally given a drug or a placebo, then followed for some time and health outcomes of interest are recorded. In the analysis, the risk of health outcome for those treated is compared with that for the controls. The general assumptions are that the only source of the drug is in the trial and that there is a linear dose-response relationship. This approach has been widely adopted for studies of vitamin D. Most vitamin D RCTs have enrolled participants with relatively high 25(OH)D concentrations relative to disease risk, given relatively low vitamin D doses to participants and permitted both treatment and control groups to take a few hundred IU/d vitamin D in addition to the treatment dose, and analyzed results according to intention to treat. As reviewed in 2022, most such trials failed to find a beneficial effect according to intention to treat; however, some did find beneficial effects in the secondary analyses, such as for participants with low BMI [4]. Health outcomes are generally related to serum 25-hydroxyvitamin D [25(OH)D] concentrations. Oral or UVB-generated vitamin D is converted in the liver to 25(OH)D within a few days. What is really important is what the baseline 25(OH)D concentration was and what the achieved concentration becomes. Robert Heaney figured this out for nutrients, including vitamin D, in 2014 ^[5].

Another way to determine causality is through what is called Mendelian randomization (MR). In this approach, genetically-predicted 25(OH)D concentrations are calculated for participants based on data from genome-wide association studies (GWAS). The GWAS findings are based on variations (alleles) of some of the genes involved in the vitamin D pathways from production through transport and conversion to 25(OH)D. With large enough datasets, often over 100,000 participants, the non-genomic variations in serum 25(OH)D concentration are averaged out. These genetically-predicted concentrations are then compared statistically with various health outcomes for the participants. The main advancement in the use of MR studies in 2022 was using a stratified analysis with, perhaps, 40 different genetically-predicted concentrations. It turns out that for many health outcomes, there is a non-linear 25(OH)D concentration-health outcome relationship, approaching a L-shape with a sharp rise for lower 25(OH)D concentrations then slow decreases as the concentrations increase. An important finding was that the MR analysis was used to find an L-shaped relationship for 25(OH)D concentration, with 4% of the predicted 6% total reduction in CVD risk occurring below 20 ng/mL ^[6]. That group has also published an MR study regarding all-cause mortality rate and 25(OH)D ^[7] as well as a review of their work and that of others ^[8]. The importance of such work is that is provides the support to now use observational studies as the basis for estimating the effect of raising serum 25(OH)D concentrations, as noted in a recent review ^[4].

The role of vitamin D in reducing risk of and death from cancer continues to be a hot topic. Unfortunately, it is not well understood not only by the general public but also by many vitamin D researchers. The main reason is that the medical systems in the world have come to rely on RCTs to "certify" that a drug, or in the case of vitamin D, a natural substance, has significant benefits and limited risk for adverse events. As discussed above, vitamin D RCTs for cancer have been poorly designed. In addition, even the observational studies relating cancer outcomes to serum 25(OH)D concentrations are subject to misinterpretation when follow-up time is not taken into account. In a review published in 2022 ^[9], the major types of vitamin D studies regarding cancer were discussed. The early history of such studies was dominated by use of geographical ecological studies. In such studies, populations are defined geographically and cancer incidence or mortality rates are averaged for each population (such as states), as are indices for cancer risk-modifying factors such as alcohol consumption, smoking, etc. As tabulated in Tables 2 and 3 in ^[9], ecological studies from China, Japan, and the U.S. have found that about 20 types of cancer have incidence and/or mortality rates inversely correlated with indices for solar UVB doses. These studies are also supported by a quasi-ecological study of cancer incidence using data on cancer standardized incidence ratios by sex and 54 occupation categories based on 1.4 million male and 1.36 million female cancer cases for 1961-2005 in the five Nordic countries ^[10]. Those with outdoor occupations had the lowest cancer rates for 15 types of cancer. No mechanism other than vitamin D production has been identified to explain how solar radiation can reduce risk of cancer.

Another review of the role of vitamin D in reducing risk of cancer emphasized vitamin D signaling ^[11]. Since rapidly growing immune and cancer cells both use the same pathways and genes for controlling their proliferation, differentiation and apoptosis, not surprisingly vitamin D signaling changes these processes also in neoplastic cells. Thus, anti-cancer effects of vitamin D may derive from managing growth and differentiation in immunity. This review provides an update on the molecular basis of vitamin D signaling, i.e., the effects of 1,25(OH)2D3 on the epigenome and transcriptome, and its relationship to cancer prevention and therapy.

This review also discusses the strengths and limitations of observational studies of cancer incidence with respect to serum 25(OH)D concentration. There are three types of observational studies in general use: prospective, case-control, and cross-sectional. In prospective studies, participants are enrolled in a cohort, a series of data including blood for later measurement of vitamin D are obtained, the individuals are followed for up to 20 years, and any disease events recorded. Matched controls are drawn from the cohort for each cancer case. In case-control studies, serum 25(OH)D concentration is measured near time of diagnosis. In cross-sectional studies, populations are surveyed, noting existing or previous diseases and data such as vitamin D level. The problem with long follow-up studies is that serum 25(OH)D concentrations change with time, both seasonally and over long times. As a result, the longer the follow-up time, the less well the serum 25(OH)D concentration at time of enrollment is related to cancer risk. In ^[9], a meta-analysis of colorectal cancer (CRC) cohort studies ^[12] was reanalyzed. In the original paper, it was reported that there was an inverse relationship between serum 25(OH)D concentration and incidence of CRC for women but not for men. When the odds ratio (OF) for CRC incidence was plotted vs. median years to diagnosis (1 to 12 years) (Figure 1 in ^[9]), it was found that the regression fit to the data for zero years for high vs. low 25(OH)D concentration was 0.74 for men and 0.77 for women. Also, that the slope was 0.031/year for men and 0.0081 for women. Thus, the effect of serum 25(OH)D concentration on risk of CRC was the same for men and women, although the change in OR with respect to follow-up time differed for men and women. It is noted that researchers associated with the consortium that published the CRC study published a similar analysis for breast cancer incidence with respect to serum 25(OH)D concentration in early 2023 ^[13], making the same mistakes in analysis as for CRC.

The VITamin D and OmegA-3 TriaL (VITAL) enrolled 25,871 participants and studied the effect of 2000 IU/d vitamin D and, separately, 1000 mg/day marine omega-3 fatty acid supplementation for a mean time of 4.5 years ^[14]. While significant reductions for vitamin D supplementation for cancer incidence were found only for those with BMI < 25 kg/m2, significant reductions were found for overall cancer mortality when the first 1 or 2 years of data were omitted. No effect of vitamin D supplementation was found for cardiovascular disease. In 2022 it was reported that vitamin D supplementation also reduced risk of autoimmune diseases ^[15]. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids had (HR=0.69, 0.49 to 0.96), 60 who received only vitamin D had (HR=0.68, 0.48 to 0.94). The strongest effects were found for rheumatoid arthritis.

The genomic effects of vitamin D are well known by now. However, the non-genomic effects such as those involving calcium entry into cells are less well known. Thus, a review of the non-genomic effects of vitamin D published in December 2022 ^[16] is a welcome addition to the journal literature. From the abstract: Vitamin D was also found to stimulate a release of secondary messengers and modulate several intracellular processes-including cell cycle, proliferation, or immune responses-through wingless (WNT), sonic hedgehog (SHH), STAT1-3, or NF-kappaB pathways. Megalin and its coreceptor, cubilin, facilitate the import of vitamin D complex with vitamin-D-binding protein (DBP), and its involvement in rapid membrane responses was suggested. Vitamin D also directly and indirectly influences mitochondrial function, including fusion-fission, energy production, mitochondrial membrane potential, activity of ion channels, and apoptosis.

A review published in 2022 discussed the 25(OH)D concentrations reported to be associated with optimal health ^[17]. From the abstract: The general finding is that optimal 25(OH)D concentrations to support health and wellbeing are above 30 ng/mL (75 nmol/L) for cardiovascular disease and all-cause mortality rate, whereas the thresholds for several other outcomes appear to range up to 40 or 50 ng/mL. The most efficient way to achieve these concentrations is through vitamin D supplementation. Although additional studies are warranted, raising serum 25(OH)D concentrations to optimal concentrations will result in a significant reduction in preventable illness and death.

(Dr. William Grant, with over 300 scientific publications, heads the Sunlight, Nutrition and Health Research Center (www.sunarc.org). He receives funding from Bio-Tech Pharmacal, Fayetteville, AR, USA. His email address is wbgrant@infionline.net ).