all things vitamin D

[jimmylegs]

Does the environment influence multiple sclerosis pathogenesis via UVB light and/or induction of vitamin D? (2019)
https://www.sciencedirect.com/science/a ... 2817304782

Highlights
• Low Vitamin D levels are associated with MS susceptibility and –progression.
• UVB light is involved in MS etiology and progression independent from Vitamin D.
• Clinical aspects of UVB light and Vitamin D in epidemiological and clinical studies.
• α-MSH as an environmental mimetic for the development of novel MS therapeutics.

"Interestingly, genetic variation in Vit D binding protein (SNP rs4588 or its proxy rs2282679) has further been found to result in a smaller serum Vit D increase after vitamin D3 supplementation as compared to individuals without the SNP (Nimitphong et al., 2013), demonstrating some pharmacokinetic implications in potential supplementation regimens. In this line, the responsiveness to Vit D supplementation seems to also be impaired in MS patients: a recent study investigating whether Vit D supplementation results in similar increase in serum Vit D levels in healthy controls and MS patients showed that people with MS had a lower increase in Vit D levels following oral vitamin D supplementation as compared to healthy controls (Bhargava et al., 2016). These findings might support assumptions that are the basis of the so-called “Coimbra protocol” claiming that MS patients (and other autoimmune diseases) need higher doses of Vit D to reach adequate levels due to a genetically caused hypovitaminosis D (Finamor et al., 2013). As there are no peer reviewed study results available for the effects of the “Coimbra protocol” (doses of Vit D up to 400.000 IU!), it is currently unclear if ultrahigh doses of Vit D really have the desired disease-modifying effect, nor if the higher risk of side effects from ultra-high doses is worth the benefit"

oh genetics, you say? and what might fire up SNP rs4588, i wonder??

Therapeutic perspectives of epigenetically active nutrients (2015)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439873/
"So far, only magnesium has been linked to epigenetics (Takaya et al., 2011)."

all right we'll wait and see. in the meantime, recalling this one posted a year ago and recently revisited above:

Role of Magnesium in Vitamin D Activation and Function (2018)
https://www.ncbi.nlm.nih.gov/pubmed/29480918

"Vitamin D is transported in blood bound to the carrier proteins, and the major carrier is vitamin D–binding protein. Importantly, the activity of vitamin D–binding protein is also a magnesium-dependent process (Figure 2).62,63"

test day tomorrow - doing d3 and mag together, followed by any corrective action that may be needed, then a retest. can somebody please arrange to scale this solo effort up...!?!

[jimmylegs]

and returning to the recently-discussed d3 study using psychiatric inpatients and their caregivers, which provided low quality / anecdotal support for megadose d3 safety in terms of calcium interactions only, i am pleased to see this contribution to the literature:

• Serum Vitamin D and Magnesium levels in a psychiatric cohort (2019)
  https://www.ncbi.nlm.nih.gov/pubmed/31488730
  
  ...
  SUBJECTS AND METHODS:
  A single site audit of serum Vitamin D and magnesium levels in patients at an Acute Day Treatment Unit was carried out. Blood tests were performed on admission and analysed in house. Data were collected between April - June 2019 and was analysed subsequently, as described below (n=73).
  
  RESULTS:
  Our data show that our psychiatric day treatment unit cohort (n=73) had a higher proportion of vitamin D deficiency (52%) than the general population (40%), although due to the limited sample size this was not significant (p=0.22, Chi-squared test). The percentage of patients who were magnesium deficient was 78.6% (n=22/28). However, the F60 subgroup of patients with personality disorders showed a high prevalence of vit D deficiency (p=0.07), highlighting a trend towards significance despite the limited size of this subgroup.
  ...

note that levels were only obtained for 28 individuals. more data needed!

i'm amazed to see the relatively high cutoff used to define magnesium deficiency. i would have liked to see more on the case made for that number in particular.

• "Overall, 78.6% (n=22/28) of patients were magnesium deficient (<0.9 mmol/L) as defined by serum magnesium. The median serum magnesium level was 0.85 mmol/L."

i'm still curious to see what the stats would have been if they'd established some insufficiency and sufficiency numbers, 0.95 or 1.0 or 1.1 mmol/l say. or, for that matter, if they'd used a more typical deficiency cutoff like 0.7 or 0.65 mmol/l ... :S i'd also like to see studies more frequently clarifying what real serum magnesium excess looks like, so people can be clear on how far we are from that point when we talk about this tight range of more 'usual' numbers.

• "We recommend larger studies to gain better understanding of numerous factors that interact (from the molecular to clinical level) to show somewhat consistent link between low Vitamin D and magnesium levels and various psychiatric disorders."

agree

[jimmylegs]

• Response to Vitamin D of Magnesium Deficient Rats (1967)
  https://journals.sagepub.com/doi/abs/10 ... -125-32123
  
  These studies indicate that magnesium deficient rats are less responsive to physiologic amounts of vitamin D than control rats.

then the 70s called... with a case study...

• Magnesium-Induced Reversal Of Vitamin-D Resistance In Hypoparathyroidism (1973)
  https://www.thelancet.com/journals/lanc ... 8/fulltext
  
  A 13-year-old girl had hypoparathyroidism which was refractory to therapy with high doses of vitamin D2 (given orally and intramuscularly), dihydrotachysterol (' A.T. 10 ') treatment, and up to 8 g. per day of calcium-salt supplement. The patient responded convincingly when 25 meq. of magnesium per day was given in addition to moderate oral doses of vitamin D2.

boo. i only have full text access from 1995 onward. i want to know which mag form was used, starting and ending serum mag levels, starting and ending d3 levels.

science? got any replication? anything scaled up? i'll keep looking....

[jimmylegs]

about cows, but still interesting..

• Influence of Mg supply on toxicity of cholecalciferol in cattle (1970)
  Einfluss der Magnesiumversorgung auf die Toxizitat von Vitamin D3 beim Rind.
  https://www.cabdirect.org/cabdirect/abs ... 9711406943
  
  Abstract : Groups of 5 yearlings or cattle 2 years old were fed in stalls on a diet poor in Mg, 0.22 g per kg, of potato starch, casein, molasses, cellulose and urea with mineral and vitamin mixture; it was given without or with 1.8 or 17 g MgO per 100 kg liveweight until mean serum Mg values were 0.70, 2.04 and 3.00 mg%.
  At that time each animal was given an injection of cholecalciferol, 4 million IU per 100 kg (6 million for 2 cattle); the diet supplied 5000 IU per kg feed.
  Ten days after the injection serum Mg had fallen by on average 0.07, 0.30 and 0.66 mg% and Ca had risen by 1.4, 1.8 and 2.5 mg%. About 12 days after the injection the Mg-deficient diet was replaced by an ordinary diet of hay and concentrates, the Mg supplements being continued until the cattle were killed 25 to 30 days after the injection.
  There were calcified lesions in the aorta in all groups and in all cattle except one in the group given most Mg. In cattle given insufficient Mg the lesions were more extensive and occurred also in other major arteries and veins, lungs and heart. In the group given no Mg supplement 4 cattle had subepicardial calcification in one or both auricles and all had lesions of endocardium and valves
  It was concluded that in hypomagnesaemia treatment with vitamin D is contraindicated.

genau! mehr Humanstudien bitte..

[jimmylegs]

The effect of zinc on vitamin D3-induced cardiac necrosis (1985)
https://www.sciencedirect.com/science/a ... 2885800146

Multifocal heart muscle necrotic lesions in rats were induced with high oral doses of vitamin D3 (300,000 iu/rat in three daily doses 100 000 iu each). The calcium content increased over 100 fold in the hearts of rats receiving vitamin D3. Parenteral pre-treatment with zinc sulphate (50 or 200 mg/rat in ten daily doses) resulted either in a reduction or in the total prevention of myocardial lesions on macroscopic, light and electron microscopic examination. The effect of zinc was dose-dependent. The administration of various doses of zinc sulphate resulted in a gradual normalisation of heart calcium content.

[jimmylegs]

Randomized clinical trials of oral vitamin D supplementation in need of a paradigm change: The vitamin D autacoid paradigm (2020)
https://www.sciencedirect.com/science/a ... 7719309715

Epidemiological studies highlight the negative correlation between vitamin D levels and the incidence of many non-skeletal diseases including inflammatory diseases, cancer, and metabolic and neurological disorders. However, most randomized controlled trials (RCTs) with oral vitamin D supplementation give mixed results or are inconclusive. It has been said that “discovery commences with the awareness of anomaly”. The “anomaly” between our preclinical and clinical data provides the opportunity to propose an alternative paradigm to the vitamin D endocrine system: the vitamin D autacoid paradigm. In the vitamin D autacoid paradigm, the extra-skeletal effects of vitamin D depend on the tissue reserves of vitamin D metabolites. These vitamin D autacoid systems are inducible oscillatory ecosystems in which 1,25D is produced, acts and is inactivated locally. In the vitamin D autacoid paradigm, attaining adequacy of vitamin D in the systemic circulation is necessary but not sufficient; we must also ensure the repletion of the tissue stores. The co-existence of two different vitamin D systems, endocrine and autacoid, with different functions and regulations leads to “significant shifts in the criteria determining the legitimacy both of problems and of proposed solutions”. With respect to our clinical trials of vitamin D supplementation for unconventional effects, the proposed solution is administering and quantifying vitamin D metabolites directly to the target tissue.

[Petr75]

2019 Nov 12
From the Department of Neurology (R.H., J.S.,), Zuyderland Medical Centre Sittard, Maastricht University Medical Centre; Department of Neurology (J.S.), Canisius Wilhelmina Ziekenhuis, Nijmegen, the Netherlands
Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon β-1a
https://www.ncbi.nlm.nih.gov/pubmed/31594857

Abstract
OBJECTIVE:
In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS.
METHODS:
Eligible patients with RRMS treated with SC interferon-β-1a (IFN-β-1a) 44 μg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-β-1a plus placebo (n = 116) or SC IFN-β-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48.
RESULTS:
At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035).
CONCLUSIONS:
SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-β-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS.
CLINICALTRIALSGOV IDENTIFIER:
NCT01285401.
CLASSIFICATION OF EVIDENCE:
This study provides Class II evidence that for patients with RRMS treated with SC IFN-β-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.

[jimmylegs]

The Latest Evidence from Vitamin D Intervention Trials for Skeletal and Non-skeletal Outcomes (2019)
https://link.springer.com/article/10.10 ... 19-00616-y

Vitamin D has long been considered a central part of the treatment paradigm for osteoporosis. Initial studies in high-risk populations with widespread vitamin D deficiency found a reduction of both vertebral and non-vertebral fractures. Subsequent studies in the general population have yielded mixed but mostly disappointing results both for skeletal and especially non-skeletal outcomes. Recent sequential trial meta-analyses suggest that future studies are likely to be futile given the overall disappointing result. However, mega-trials are still in progress, and additional results have been released. This narrative review aims to evaluate new literature to determine if there has been any substantial change in the message. In conclusion, there is no longer a strong case for initiating vitamin D alone trials in the general adult population, irrespective of age and gender, for significant health outcomes such as fractures, cardiovascular disease and cancer. New studies should focus on risk groups and take directions from the Heaney criteria for evaluation of threshold nutrients. Indeed, real benefits may still be reaped by directing vitamin D supplementation to persons with proven or likely vitamin D deficiency. Further, the role of dietary calcium as a critical co-nutrient remains controversial and could contribute to the discrepancy between studies in terms of cancer outcomes and possibly falls and fractures.

[Petr75]

2019 Nov 22
Department of Basic Medical Sciences, College of Medicine, Member of QU Health, Qatar University, Doha, Qatar.
Institute of Obstetric Hematology, Perigenesis, Thessaloniki, Greece
Immunomodulatory Effects of Vitamin D in Pregnancy and Beyond.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883724/

Abstract

In addition to its role in calcium homeostasis and bone formation, a modulatory role of the active form of vitamin D on cells of the immune system, particularly T lymphocytes, has been described. The effects of vitamin D on the production and action of several cytokines has been intensively investigated in recent years. In this connection, deficiency of vitamin D has been associated with several autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Hashimoto Thyroiditis (HT), and multiple sclerosis (MS). In a successful pregnancy, the maternal immune response needs to adapt to accommodate the semiallogeneic fetus. Disturbances in maternal tolerance are implicated in infertility and pregnancy complications such as miscarriages (RM) and preeclampsia (PE). It is well-known that a subset of T lymphocytes, regulatory T cells (Tregs) exhibit potent suppressive activity, and have a crucial role in curtailing the destructive response of the immune system during pregnancy, and preventing autoimmune diseases. Interestingly, vitamin D deficiency is common in pregnant women, despite the widespread use of prenatal vitamins, and adverse pregnancy outcomes such as RM, PE, intrauterine growth restriction have been linked to hypovitaminosis D during pregnancy. Research has shown that autoimmune diseases have a significant prevalence within the female population, and women with autoimmune disorders are at higher risk for adverse pregnancy outcomes. Provocatively, dysregulation of T cells plays a crucial role in the pathogenesis of autoimmunity, and adverse pregnancy outcomes where these pathologies are also associated with vitamin D deficiency. This article reviews the immunomodulatory role of vitamin D in autoimmune diseases and pregnancy. In particular, we will describe the role of vitamin D from conception until delivery, including the health of the offspring. This review highlights an observational study where hypovitaminosis D was correlated with decreased fertility, increased disease activity, placental insufficiency, and preeclampsia in women with APS.

[Petr75]

2019 Dec 6
Department of Pharmacology and Clinical Neuroscience, Umeå University, Sweden
High serum concentration of vitamin D may protect against multiple sclerosis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900627/

Abstract
Background:
High 25-hydroxyvitamin D concentrations have been associated with a reduced risk of multiple sclerosis, with indications of a stronger effect among young individuals.
Objective:
Investigate the 25-hydroxyvitamin D association with multiple sclerosis and test if this association is age dependent.
Methods:
Prospectively drawn blood samples from individuals later developing relapsing-remitting multiple sclerosis and controls matched for biobank, sex, age and date of sampling, were analysed with liquid chromatography tandem mass spectrometry.
Results:
High levels of 25-hydroxyvitamin D (top quintile) were associated with a reduced multiple sclerosis risk (odds ratio 0.68, 95% confidence interval 0.50-0.93).
Conclusion:
These findings further support a role for vitamin D in MS aetiology.

[Petr75]

2019 Dec 17
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
Low sun exposure increases multiple sclerosis risk both directly and indirectly.
https://www.ncbi.nlm.nih.gov/pubmed/31844981

Abstract
OBJECTIVE:
We aimed to study (1) to what extent the influence of low sun exposure on multiple sclerosis (MS) risk is mediated by low vitamin D levels; (2) whether low sun exposure or vitamin D deficiency act synergistically with HLA-DRB1*15:01 and absence of HLA-A*02:01.
METHODS:
We used two population-based case-control studies (7069 cases, 6632 matched controls). Subjects with different HLA alleles, sun exposure habits and vitamin D status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Mediation analysis was used to identify the potential mediation effect of vitamin D on the relationship between low sun exposure and MS risk.
RESULTS:
Low sun exposure increased MS risk directly as well as indirectly, by affecting vitamin D status. The direct effect, expressed as OR, was 1.26 (95% CI 1.04-1.45) and the indirect effect, mediated by vitamin D deficiency, was 1.10 (95% CI 1.02-1.23). Of the total effect, nearly 30% was mediated by vitamin D deficiency. There was a significant interaction between low sun exposure and vitamin D deficiency (attributable proportion due to interaction 0.3, 95% CI 0.04-0.5) accounting for about 12% of the total effect. Further, both factors interacted with HLA-DRB1*15:01 to increase MS risk.
INTERPRETATION:
Our findings indicate that low sun exposure acts both directly on MS risk as well as indirectly, by leading to low vitamin D levels. The protective effect of sun exposure thus seems to involve both vitamin D and non-vitamin D pathways, which is of relevance for prevention, in particular for those with a genetic susceptibility to MS.

[Petr75]

2019 Dec 26
Department of Immunology, School of Public Health, Tehran University of Medical Sciences(TUMS), Tehran, Iran
Association between vitamin D receptor (VDR) polymorphisms and the risk of multiple sclerosis (MS): an updated meta-analysis
https://www.ncbi.nlm.nih.gov/pubmed/31878897

Abstract
BACKGROUND:
The association between the Vitamin D Receptor (VDR) gene polymorphism and the risk of Multiple sclerosis (MS) has been evaluated in several researches. However, the findings were inconsistent and inconclusive. Therefore, we set out a meta-analysis of all eligible published case-control studies to obtain an exact evaluation of the association between VDR gene polymorphisms and MS.
METHOD:
All relevant studies reporting the association between the VDR gene FokI (rs2228570), or/and TaqI (rs731236) or/and BsmI (rs1544410) or/and ApaI (rs7975232) polymorphisms and susceptibility to MS published up to May, 2019 were identified by comprehensive systematic search in the electronic database of web of science, Scopus, and PubMed. After that, the strength of association between VDR gene polymorphisms and susceptibility to MS was evaluated by odds ratio (OR) and 95% confidence interval (CI).
RESULTS:
A total of 30 case-control studies were included in the meta-analysis. The overall results suggested a significant association between TaqI polymorphism and MS risk under heterozygote genetic model (OR = 1.27, 95%CI = 1.01-1.59, random effect). Moreover, the pooled results of subgroup analysis declined presence of significant association under all defined genetic model. In subgroup analysis, BsmI polymorphisms was associated with increased risk of MS under recessive model in Asian populations. On the other hand, ApaI polymorphism was associated with decreased risk of MS under recessive and aa vs. AA model in Asian populations.
CONCLUSION:
This meta-analysis suggested a significant association between TaqI polymorphism and MS susceptibility. Furthermore, BsmI polymorphism was associated with increased risk of MS in Asian populations. In contrast, ApaI polymorphism was associated with decreased risk of MS in Asian populations. Future large-scale studies on gene-environment and gene-gene interactions are required to estimate risk factors and assist early diagnosis of patients at high risk for MS.

[jimmylegs]

nice find, petr. i had missed this one earlier:

Acute Vitamin D Toxicity- Without Hypercalcemia (2016)
https://nijp.org/acute-vitamin-d-toxici ... rcalcemia/

maybe it's been off the radar for good reason...
https://nijp.org/about-journal/

[jimmylegs]

Excessive cholecalciferol supplementation increases kidney dysfunction associated with intrarenal artery calcification in obese insulin-resistant mice (2020)
fft: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952360/

"... In conclusion, this study unfolds novel mechanisms of progressive renal dysfunction in diabetes mellitus (DM) after VitD3 in vivo associated with increased intrarenal vascular calcification and highlights possible harmful effects of long-term supplementation of VitD3 in this population."

[jimmylegs]

new(ish) review, in which i note the following extensively-discussed interaction:

Important drug-micronutrient interactions: A selection for clinical practice (2020)
https://www.ncbi.nlm.nih.gov/pubmed/30580552

"Magnesium supplementation substantially reversed the resistance to vitamin D treatment (de Baaij, Hoenderop, and Bindels 2015; Gröber, Reichrath, and Holick 2015)."