Is low Vitamin D just a marker of disease - March 2023

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Low vitamin D is a marker for poor health and increased risk for disease: But causality is still unclear in most cases – Oct 2022

Journal of Internal Medicine https://doi.org/10.1111/joim.13582C
Peter Bergman Editorial

It is almost 100 years since Adolf Windaus received the Nobel Prize in chemistry in 1928 for his studies’ on the constitution of sterols and their connection with vitamins’, including vitamin D and its role to prevent rickets [1]. The role of vitamin D to protect the bone has been well known since and has a central role in all medical textbooks. This part of vitamin D metabolism is generally known as the endocrine system, where the liver produces the storage form 25-hydroxyvitamin D (25OHD) and the kidney carries out the conversion into bioactive 1,25-dihydroxyvitamin D (1,25OHD), which mainly regulates calcium balance. In addition, the proform 25OHD can be activated locally in many different cell types, including monocytes, epithelial cells and even in neurons [2, 3]. Local production of the active form of vitamin D (1,25OHD) leads to activation of the vitamin D receptor and subsequent transcription of several hundreds of genes, depending on the cell type and physiological context [4]. This part of vitamin D metabolism is called the paracrine system and has been the focus of intense research during recent years [5]. In parallel with the molecular discoveries of vitamin D metabolism, there has been a rapid increase in observational studies that have found associations between low vitamin D levels and increased risk of many common diseases, including cancer, cardiovascular diseases, respiratory tract infections and Alzheimer's disease as well as all-cause mortality [6-9]. Combined, there has been a solid rationale to perform randomised controlled trials (RCTs) in many of these areas since there is a potential mechanism for beneficial effects and data from observational studies show an increased risk for disease with lower vitamin D levels in plasma. Randomised and placebo-controlled clinical trials of vitamin D supplementation in cancer, cardiovascular diseases and respiratory tract infections have shown both beneficial effects as well as null results [10, 11]. Interestingly, meta-analyses, where results from many RCTs are combined, have shown beneficial effects of vitamin D supplementation on cancer mortality and total mortality as well as reduced risk for respiratory tract infections [12-14]. In addition, Mendelian randomisation studies have shown an inverse association between genetically predicted 25OHD levels and all-cause mortality [15].

It is against this background that Sha et al. set out to obtain further information on the role of vitamin D in reduction of mortality from cancer and other causes, including cardiovascular and respiratory diseases [16]. They used data from the UK Biobank (n = 445,601 participants), including data on the use of vitamin D supplements (over-the-counter drugs or as part of a multivitamin product) and 25OHD levels defined as deficiency (<30 nmol/L) or insufficiency (30 to <50 nmol/L). The outcomes were all-cause and cause-specific mortality, with a focus on mortality due to cardiovascular disease, cancer and respiratory disease. Several covariates were also collected for the adjustment analyses, including demographic and socio-economic factors, which potentially could influence the outcome. The mean age of the cohort was 56.5 years, and a majority were overweight or obese. Interestingly, 21% of the cohort had vitamin D deficiency (<30 nmol/L) and 34.3% had insufficiency (<50 nmol/L). Only 4.3% reported a regular intake of vitamin D supplements, whereas 20.4% reported using multivitamin supplements on a regular basis. Consequently, users of vitamin D or multivitamin supplements had a higher level of 25OHD than nonusers.

Next, the authors analysed determinants associated with vitamin D deficiency. In general, worse health concomitant diseases, obesity, higher blood pressure, poor general health and the latitude of the test centre were factors associated with vitamin D deficiency or insufficiency, whereas the use of vitamin D or multivitamin supplements often had the reverse association, that is, healthier people had a higher tendency to take supplements.

The authors found that both vitamin D deficiency and insufficiency were associated with all-cause mortality and mortality due to cancer, cardiovascular disease (CVD) and respiratory diseases. Five different adjustment models were employed, and the hazard ratios were attenuated with increasing adjustment. The excess mortality was most prominent for CVD, followed by respiratory disease mortality and cancer mortality.

Finally, the association between self-reported vitamin D intake and the outcomes was analysed. Notably, no effect was observed, but after considering concomitant diseases and general health status in the broadest adjustment model, users of vitamin D supplements had 10% lower all-cause mortality and 11% lower cancer mortality, whereas mortality for CVD did not reach statistical significance. The strongest effect was found for respiratory diseases, where self-reported vitamin D intake was associated with 29% decreased mortality.

How should these results be interpreted in the light of available evidence? First, there have been many studies before this one with a similar message, that is, low vitamin D levels are associated with many different diseases, including those discussed here. For example, there is evidence from a large European consortium that low vitamin D levels are associated with increased mortality [17]. We also know that vitamin D has several important functions in the body, apart from regulating calcium homeostasis. A recent example is from the covid area, where vitamin D was found to suppress inflammation in T cells, with potential implications for prevention and treatment of SARS CoV-2 infection [18]. However, despite ample evidence from experimental and observational studies, solid data from RCTs showing beneficial effects against any indication are scarce, with a few exceptions. For example, vitamin D did not prevent CVD or cancer in a large and well-designed RCT [19]. In contrast, in the field of respiratory tract infections, the team around Adrian Martineau has performed two large meta-analyses, one of which is an individual patient data meta-analysis, which found small but statistically significant effects of vitamin D supplementation against respiratory tract infections (RTIs) [13, 14]. However, two recent RCTs could not find any evidence of vitamin D supplementation (or cod liver oil supplementation) against covid-19 [20-22]. Thus, there is still a discrepancy between experimental and observational data on one side and data from RCTs on the other. Why is that? There are three models to consider at this point. The first of these implies that low levels of 25OHD are directly causing the disease. Supplementation would then be the solution and lead to reduced risk of the disease. The other explanation could be a reverse association, that is, that the disease causes low vitamin D levels; for example, if a chronic disease leads to immobilisation indoors without exposure to the sun. The final model is that there is a spurious or ‘false’ association where a third factor leads to both low vitamin D levels and increased risk for the disease. In the paper by Sha et al., for example, subjects with self-reported poor health status had 77% higher odds to have vitamin D deficiency and 19% lower odds of taking vitamin D supplements. Thus, there is a significant risk of the healthy user effect, that is, that healthier people tend to take more supplements, spend more time outdoors and simply avoid diseases to a higher extent than poor, fragile and sick people do. Sha et al. apply an ambitious adjustment approach to avoid this risk, but as the authors point out themselves, it is impossible to adjust for so-called hidden or residual confounders. This means that there could still be additional factors that we cannot adjust for, which could influence the observed associations. Thus, despite the impressive size of the study by Sha et al., we still cannot draw firm conclusions on causality and whether vitamin D supplementation can reduce mortality from CVD, cancer or respiratory diseases.

But which advice should we give to the public, physicians and policy makers about vitamin D deficiency and risk for disease? A pragmatic approach could be to focus on groups at the highest risk for vitamin D deficiency and supplement those <50 nmol/L with 1000–2000 IU/day. This would support the bone, improve immunity and potentially also reduce the risk of respiratory tract infections. Perhaps this strategy could also reduce mortality from CVD, cancer and respiratory disease, as suggested by Sha et al., but solid evidence from bona fide randomised and placebo-controlled clinical trials is still warranted.
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Regarding: Feb 2023

Journal of Internal Medicine https://doi.org/10.1111/joim.13621
William B. Grant, Barbara J. Boucher First published: 22 February 2023
To the Editor,

In a recent editorial, Peter Bergman stated that whether associations between low 25-hydroxyvitamin D [25(OH)D] concentrations and poor health are causally linked was unclear in most cases [1]. His statement was based on the consideration of vitamin D randomized controlled trials (RCTs). However, as discussed at length in a recent review, most vitamin D RCTs have been poorly designed, conducted, and analyzed [2], having been based on guidelines for pharmaceutical drugs rather than on nutrients. Heaney outlined guidelines for trials of nutrients such as vitamin D in 2014 [3]. These guidelines include, for vitamin D, that serum 25(OH)D concentrations of the proposed participants must be measured, and only subjects with low values should be included, that vitamin D doses used must raise 25(OH)D concentrations to values associated with reduced risk in observational studies, and that, therefore, achieved concentrations must be measured. However, most vitamin D RCTs have included many participants with relatively high 25(OH)D concentrations, have used too low vitamin D doses, and did not base their analyses on individual participant 25(OH)D concentrations.

Also overlooked in the editorial is that Mendelian randomization (MR) studies have now demonstrated the causality of vitamin D in reducing risk of several types of disease. In MR studies, data for alleles of genes involved in the vitamin D pathway are used to estimate genetic variations in serum 25(OH)D (genome-wide association studies) using perhaps 100,000 participants and have then examined health outcomes with those gene variants in large study populations. The assumption is that, because individuals are randomized into study groups by the genetic variants they carry, bias due to confounding and reverse causation is avoided [4]. The Hyppönen group, using MR analyses of findings stratified by baseline 25(OH)D concentration (i.e., non-linear analyses), has shown many significant effects of vitamin D in participants with low 25(OH)D concentrations. This methodology has already demonstrated causality for several health outcomes in their hands, including cardiovascular disease, dementia, and all-cause mortality rates, using data from the UK Biobank [4] as well as for hypertension, multiple sclerosis, and type 2 diabetes mellitus by others that they cite [4].

RCTs and MR studies have not supported the causality of vitamin D in the reducing risk of cancers. However, the evidence from observational studies and geographical ecological studies, as well as an understanding of the mechanisms involved, provides sufficient evidence for causality when considered by Hill's criteria for causality in a biological system [5, 6]. It should also be noted that the Vitamin D and Omega-3 Trial (VITAL) [7] had serious shortcomings including that the mean 25(OH)D concentration for those in the vitamin D treatment arm with 25(OH)D data was 30 ng/mL, that the vitamin D dose was 2000 IU/d but that all participants were permitted to take up to 600–800 IU/d vitamin D and to receive solar UVB, and that outcomes were not analyzed in terms of achieved 25(OH)D concentrations. Nevertheless, secondary analyses did find significant reductions for cancer incidence for those with a BMI <25 kg/m2 and overall reductions in the cancer mortality rate whe n the earliest years of data were omitted.
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Authors reply: March 2023

Journal of Internal Medicine https://doi.org/10.1111/joim.13622
Peter Bergman
Dear Editor,

I have read the letter by Dr Grant with great interest [1]. The question whether vitamin D can prevent common diseases, such as hypertension, diabetes and cardiovascular diseases is often debated. The field is somewhat polarised between hard-line sceptics and more positive “believers”. Both teams use a long line of evidence to support their respective views. In my editorial, I tried to shed light on some of the different views in the field and pointed out that there is still a lack of solid results from large, randomised and placebo-controlled clinical trials (RCTs) for most indications. One exception could be the effects on respiratory tract infections, where two large meta-analyses on RCTs have shown a small but statistically significant effects of about 8%–10% [2, 3]. However, two recent RCTs on vitamin D supplementation against COVID-19 failed to show any beneficial effect [4, 5]. These are just a few examples, but it is clear that we lack evidence from bona fide RCTs on the beneficial effects of vitamin D supplementation for most indications.
However, I do agree with Dr Grant that there are many other pieces of evidence that point in favour of vitamin D for many human diseases. For example, there is mechanistic evidence that vitamin D can modulate inflammation in T-cells from patients infected with SARS CoV-2 [6], vitamin D can directly induce antimicrobial peptides in human macrophages and fight tuberculosis [7] and – as an example, the vitamin D receptor is expressed in beta cells in the pancreas [8]. On top of these mechanistic leads, there are many observational studies that show that low vitamin D levels are associated with an increased risk for disease. And, more recently, several studies based on Mendelian randomisation analysis suggest that vitamin D levels can be linked to human disease. Up to this point, I agree with Dr Grant.

Nevertheless, the bar for certainty is higher than a plausible mechanism, observational evidence and Mendelian randomisation analyses and needs to be based on solid RCTs. It is always possible to find problems with available RCTs in the field and claim that they were not performed in the correct way. However, to be able to change paradigms and guidelines, we need solid evidence from RCTs and that is currently lacking for most indications, as I pointed out in my editorial. For medical doctors, including myself, it is important to follow guidelines and regulations. Thus, any clinical decision to start vitamin D supplementation has to be based on solid evidence. Dr Grant has a slightly different platform in this discussion, because he represents a company that produce and sell vitamin D supplements to the public. This difference might not be decisive for his standpoints but is nevertheless important to keep in mind as there could be a conflict of interest here.

To end in a more positive note, there is still a lot to discover in the field of vitamin D and the optimal RCT, which consider all possible confounders, has not yet been performed. Thus, there is more to learn and perhaps we will reach a more solid evidence base in this field in the future. Until then, I recommend a pragmatic approach where vitamin D supplementation should be directed towards risk-groups for vitamin D deficiency, such as the obese, pregnant women, and those with darker skin. A cut-off level of 50 nmol/L will work for most individuals and supplementation with 1000–2000 IU/day will support the bone, improve immunity, and potentially also reduce the risk for respiratory tract infections.
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Vitamin D is not just association - examples of RCTs finding that adding D fights diseases

• Proof that Vitamin D Works 93 health problems
• 48 Health problems fought by weekly 50K Vitamin D most were RCTs

Loading Dose

• Birth rates doubled with Vitamin D - 300,000 for infertile men – RCT Nov 2017
• COVID-19 defeated 3x faster by 420,000 IU Vitamin D nanoemulsion – RCT Nov 12, 2020
• Those getting an injection of 300,000 IU Vitamin D got out of the ICU a week sooner – RCT Dec 2020

Pregnancy

• 50,000 IU of Vitamin D every 2 weeks reduced gestational diabetes – RCT Feb 2015
• 300,000 IU injection loading dose of vitamin D3 stopped gestational diabetes in RCT – Oct 2011
• Risk of infant Asthma cut in half if mother supplemented Vitamin D to get more than 30 ng – RCT Oct 2017

Children

• 2.4 X fewer lower respiratory track infections in infants getting 400 IU of Vitamin D – May 2022
• Half the risk of Influenza -A in infants taking 1200 IU of vitamin D for 4 months – RCT Jan 2018
• Allergic Rhinitis in infants treated by 1,000 IU vitamin D daily – June 2019

Diabetes

• Diabetes prevented by 50,000 IU vitamin D monthly (Iran) – Jan 2022
• Prediabetes reduced by weekly 60,000 IU of Vitamin D – RCT Jan 2021
• Diabetic inflammation reduced by Vitamin D (30,000 IU weekly) – RCT July 2020
• Diabetics and prediabetics helped by 5,000 IU of Vitamin D for 6 months– RCT July 2019

Virus

• COVID in hospital fought by Vitamin D (25,000 IU daily for 4 days, then 25K weekly) - RCT – July 2022
• 4X less likely to get COVID following 4,000 IU daily for a month – RCT April 2022
• 21 fewer days in hospital with ARDS (COVID) if 10,000 IU of Vitamin D daily after enter hospital – RCT April, 2022
• Group achieving 30 ng (vs 26 ng) were 2X less likely to get COVID symptoms - RCT Jan 2022
• COVID-19 mortality reduced 4X (chart looks like 2X) by large, infrequent doses of Vitamin D in France – July 2021

Obesity

• Weight loss on low-calorie diet: 7 lbs more lost if got lots of Vitamin D – June 2021
• Obese lost more weight on diet if added 50,000 IU of vitamin D weekly – many RCTs

Multiple Sclerosis

• Multiple Sclerosis Relapsing-Remitting rate reduced 30 percent by addition of 14,000 IU vitamin D daily – RCT Nov 2016
• No multiple sclerosis relapses during pregnancy if 50,000 IU of Vitamin D weekly – RCT April 2015

Autoimmune

• Hay Fever treated by Vitamin D (50,000 IU weekly) – RCT July 2019
• [https://vitad.org/Chronic+Hives+treated+by+Vitamin+D+-+many+studies#Hives_treated_by_28_000_IU_of_Vitamin_D_weekly_RCT_Aug_2020 |Hives treated by 28,000 IU of Vitamin D weekly – RCT Aug 2020))

Better than Daily

• 44 percent of successful RCTs in Vitamin D Life used non-daily dosing - Nov 2020

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100 most-recently updated RCTs in Vitamin D Life - (from 900+)

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100 most-recently updated Meta-analyses in Vitamin D Life - (from 600+)

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