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Issues with "Vitamin D3" research and calcium metabolism


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Initial post: Nov 3, 2012 3:43:32 PM PDT
Last edited by the author on Nov 3, 2012 3:45:16 PM PDT
Ryan says:
Okay, so there's something that's bugging me about a lot of studies related to "Vitamin D" and these forums seem to attract some really smart folks. (Hopefully this post will still get responses even though it doesn't involve religion or intelligent design.) So I'm posting here to see if anyone can help. So I can appreciate that some people have low levels of calcidiol (25,D3) and it's low levels of this stuff which is used as a marker of deficiency. Low levels of calcidiol correlate with all sorts of problems. One of those problems is arterial calcification and heart disease. And that's what's odd. Because arterial calcification seems more likely to be caused by over-conversion of 25 D3 to 1,25D3 and activation of the hormone D receptor (resulting in the destruction of the 1,25D3.)

Over-activation of the hormone D receptor, and not underproduction of 25-D3, seems a far more likely explanation for arterial calcification since activation of that receptor is involved in calcium absorption from the gut and also because activation of that receptor is involved in putting calcium into the blood from the bones.

This over-conversion of 25D3 to 1,25D3 could be caused by chronic inflammation.

This seems to be a much better explanation for why low 25D3 is linked to heart disease. But I have difficulty believing that I can see something so simple and the medical community has just missed it. So can someone prove me wrong using peer reviewed studies?

Much thanks.

In reply to an earlier post on Nov 3, 2012 4:28:04 PM PDT
Ryan Wise wrote:

"This over-conversion of 25D3 to 1,25D3 could be caused by chronic inflammation. "
===================================
Let us start by the physiologic actions of vitamin D.

Vitamin D inhibits cytokine release, adhesion molecule release, and proliferation and migration of vascular smooth muscle cells.

That means vitamin D reduces inflammatory reaction, not the other way around.

When vitamin D is reduced by kidney or liver disease, vascular and soft tissue calcification ensue.

Mohamed F. El-Hewie

Posted on Nov 3, 2012 6:13:09 PM PDT
Last edited by the author on Nov 3, 2012 6:15:46 PM PDT
Ryan says:
"Vitamin D inhibits cytokine release, adhesion molecule release, and proliferation and migration of vascular smooth muscle cells."

1. Okay, but this isn't addressing calcification, at least not directly. I can find a good study supporting cytokine release and controlling for VDR activation. So I'll agree there.
http://www.ncbi.nlm.nih.gov/pubmed/21592820

2. "When vitamin D is reduced by kidney or liver disease, vascular and soft tissue calcification ensue. "

And liver and kidney disease don't correlate with inflammation? I can see how such disease might reduce the production of cholesterol, conversion of cholesterol to D3, etc.

3. "not the other way around."

If x can cause y, that's not evidence, much less proof that y does not cause x. But let me be more specific. 1,25D3, which activates the hormone D receptor, is immunomodulatory.
"The sterol inhibits lymphocyte proliferation and immunoglobulin production in a dose-dependent fashion."
http://www.ncbi.nlm.nih.gov/pubmed/1644850

Activation of D3 also upregulates anti-microbial peptides.

I'll agree with all of that.

However inflammation triggers the Toll Like Receptors, which upregulates the creation of CYP27B1. This is the portion of the cytochrome system which catalyzes the conversion of calcidiol into calcitriol.
http://www.ncbi.nlm.nih.gov/pubmed/21424825

What I'd REALLY like is a study showing vascular and soft tissue calcification occurring while controlling for the activation of the hormone D receptor in some fashion. I don't know if that's available.

So I appreciate your response, Mohamed, but I don't think it addresses my point unless you were laying the groundwork for some other argument. (And peer reviewed sources would help, much thanks.)

In reply to an earlier post on Nov 3, 2012 6:24:36 PM PDT
noman says:
Low Calcidiol Levels and Coronary Artery Calcification: True, True, and Related?
Michal L. Melamed* and Ravi Thadhani†

+
Author Affiliations
*Departments of Medicine and Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York; and
†Department of Medicine and Renal Unit, Massachusetts General Hospital, Boston, Massachusetts
Correspondence:
Dr. Ravi Thadhani, Bullfinch 127, Massachusetts General Hospital, Boston, MA 02114. Phone: 617-724-1207; Fax: 617-726-2340; E-mail: thadhani.r@mgh.harvard.edu

There is increasing interest in the role of vitamin D in health and disease. From early articles showing associations between use of activated vitamin D and improved survival on dialysis1 to more recent analyses showing that low 25-hydroxyvitamin D (calcidiol) and 1,25-dihydroxyvitamin D (calcitriol) levels are associated with mortality in dialysis patients,2 the observational findings have been, for the most part, consistent. The associations between calcitriol use and survival have been extended to the predialysis chronic kidney disease (CKD) population,3 as have associations between low calcidiol levels and mortality.4 It is true that patients with renal disease represent an extreme population with profound deficiencies of both calcidiol and calcitriol. Low calcidiol levels associate with all-cause mortality in the general population.5 The elevated mortality risk is perhaps due to an increased hazard for cardiovascular events. Low calcidiol levels link with incident cardiovascular disease (CVD)6 and myocardial infarctions.7 Studies of vitamin D deficiency and outcomes in the general population require larger sample sizes than studies of patients with renal disease because less profound deficiency is found in the former population...
http://jasn.asnjournals.org/content/20/8/1663.full

In reply to an earlier post on Nov 3, 2012 8:20:09 PM PDT
Ryan says:
@Noman;

Thanks, but this paper has

1. Administered calcitriol and improved survival on dialysis ( not calcification.)
2. correlation between calcidiol and calcitriol levels and mortality for dialysis patients (not calcification.)
3. Correlation between low calcidiol levels and arterial calcification (which I'm not disputing), with no evidence regarding the actual mechanism linking the two.

In reply to an earlier post on Nov 3, 2012 9:00:04 PM PDT
Ryan Wise wrote:
"Okay, but this isn't addressing calcification, at least not directly."
"And liver and kidney disease don't correlate with inflammation? "
======================================

The mere fact that vitamin D level drops in plasma implies that Calcium release rate from bones increases, its clearance rate decreases, and its deposition rate increases.

Excess plasma calcium, on chronic scale, inevitably leads to calcification regardless of vitamin D receptor density or activation.

Excess plasma calcium increases the turbulence in vasculature, as the smooth muscles contraction increases with excess calcium.

Kidney and liver disease cause major systemic pathology that cannot be studied by correlation analysis, unless you specify each disease that inflicts each of the liver and the kidney.

Nothing works normal in the body when either of the two vital organs; liver and kidney, is being bothered with an insult.

Mohamed F. El-Hewie

In reply to an earlier post on Nov 3, 2012 9:33:47 PM PDT
Astrocat says:
Very interesting, Ryan, because my Naturopath just told me about the connection between arterial calcification and ingesting too much calcium. (Makes sense, but I never thought of it before). My "D" level is very high for the area in which I live (it's 53, and I live in the Pacific Northwest), and my calcium levels are acceptable, but she had me cut back from 1500 mg a day to 1000 of the Calcium Lactate I've been taking, and instead take 300 mg of Citramin II, a mineral compound. So, while it's not cutting back drastically, she thinks the change will diminish the chance of the calcification problem.

Your scientific explanation is a little over my head, but I did think it interesting in light of my recent conversation with my doctor.

In reply to an earlier post on Nov 3, 2012 9:57:42 PM PDT
Last edited by the author on Nov 3, 2012 10:06:59 PM PDT
Ryan says:
@Nancy, for what it's worth one aspect of calcium metabolism which should probably be considered for anyone supplementing with calcium is whether a person has adequate vitamin K intake, and particularly adequate vitamin K2 intake.

A recent study (EPIC-Heidelberg) suggested that calcium supplementation from artificial sources was associated with increased risk of heart attack, while increased intake of calcium from dietary sources was not.

http://www.ncbi.nlm.nih.gov/pubmed/22626900

That might be what your naturopath was looking at.

While those producing the analysis had vitamin K2 intake as part of their dataset, IIRC, for some reason they most unfortunately decided not to control for that variable.

Vitamin K, and especially vitamin K2, may be required to put calcium into the bones.

To oversimplify a bit, Vitamin D3 is involved in the process of getting calcium into the blood either from your bones or your intestines. There are essentially two sources for calcium; your bones and the food you eat. If you put calcium into your blood without putting it into your bones (or removing it), you can get arterial calcification. What causes that is a matter for debate, but in my personal opinion I suspect inflammation may play a role. The question is whether inflammation can cause a low level of 25D or whether a low level of 25D3 causes inflammation or both. My bets are on both.

This is because an infection can (theoretically) cause low levels of 25D3 and low levels of 25D3 can also allow an infection (since D3 is a critical immunomodulator.) But the research focuses almost exclusively on the 'deficiency' interpretation. That interpretation has merit but I suspect it may be somewhat over-applied. At least, that's the notion that I'm exploring.

In reply to an earlier post on Nov 3, 2012 10:10:03 PM PDT
Last edited by the author on Nov 3, 2012 10:25:48 PM PDT
Angel says:
Ryan Wise says:

Over-activation of the hormone D receptor, and not underproduction of 25-D3, seems a far more likely explanation for arterial calcification since activation of that receptor is involved in calcium absorption from the gut and also because activation of that receptor is involved in putting calcium into the blood from the bones.

This over-conversion of 25D3 to 1,25D3 could be caused by chronic inflammation.
This seems to be a much better explanation for why low 25D3 is linked to heart disease. But I have difficulty believing that I can see something so simple and the medical community has just missed it. So can someone prove me wrong using peer reviewed studies?

***I'm off the boards, but my belief is arterial calcification results from a magnesium deficiency. What's needed is Calcium, Vitamin D and Magnesium to prevent low levels of 25-D3.

Scientific study below:

"In the animal study researchers tested the effect of magnesium supplements on calcification of arteries. They found that magnesium relieved the degree of calcification with higher doses, offering better protection. They concluded that magnesium "plays a role in the pathogenesis of vascular calcification by reducing vascular calcification and decreasing vascular injury."

Magnesium is involved with many enzymes and other factors associated with cardiovascular function. Refined foods and magnesium depleted soils have placed the entire American population at risk of deficiency of this key mineral. It is nice to see that supplementing with magnesium can make such a difference."

http://www.wellnessresources.com/health/articles/magnesium_supplements_lower_blood_pressure_prevent_calcification/

Best,

Posted on Nov 3, 2012 10:19:59 PM PDT
Last edited by the author on Nov 3, 2012 10:20:22 PM PDT
Ryan says:
@Mohamed F. El-Hewie

"The mere fact that vitamin D level drops in plasma implies that Calcium release rate from bones increases, its clearance rate decreases, and its deposition rate increases. "

However this statement says nothing about the mechanism behind the correlation you're describing.

"Excess plasma calcium, on chronic scale, inevitably leads to calcification regardless of vitamin D receptor density or activation"

I'm not claiming that local VRD tissue density is an issue. If you have a study which controls for VDR activation, please post. Thanks.

In reply to an earlier post on Nov 3, 2012 10:20:19 PM PDT
Astrocat says:
I eat lots of spinach and other foods that are rich in Vitamin K. I'm wondering if that's enough.

In reply to an earlier post on Nov 3, 2012 10:23:36 PM PDT
Last edited by the author on Nov 4, 2012 10:49:36 AM PST
Ryan says:
@Nancy - You may want to consider K2 supplementation. Vegetables have only Phylloquinone (K1) which isn't the most active form. K2 is found either in meat or by the action of very particular bacteria. Some K2 is in dairy products like cheese. Japanese natto has the highest density of K2 that I'm aware of. Personally, I just take a supplement. It dissolves best in oil.

There's debate about whether MK4 (Menatetranone) or MK7 is better for you. The second stays in your system much longer and is taken in a much smaller dose.

In reply to an earlier post on Nov 3, 2012 10:30:27 PM PDT
Ryan says:
@Angel - Thanks for the info. I haven't properly explored the role of magnesium in arterial calcification yet, but I've heard people talking about the importance of magnesium-calcium balance. Green vegetables should supply magnesium, since it's in the center of the cholrin ring in chlorophyll, IIRC.

But that still leaves open why low 25D3 is a marker for calcification.

In reply to an earlier post on Nov 3, 2012 10:33:46 PM PDT
Astrocat says:
Yeah, the supplement sounds fine, since I can't stand the thought of natto.

In reply to an earlier post on Nov 4, 2012 4:59:27 AM PST
NHAtlatl says:
Ryan, You may have already seen this, but if not check out http://site.alvaro.com.br/pdf/vitaminad/Vitamin%20D%20the%20alternative%20hypothesis.pdf - Vitamin D: the Alternative Hypothesis.

The problem with most vitamin D studies is that they show correlation, not causation.

Anyone with calcium issues should have levels of calcitriol (1,25D3) monitored.

It is also important to treat vitamin D for what it is, not a vitamin but a powerful and highly regulated seco-steroid hormone.

In reply to an earlier post on Nov 4, 2012 5:46:02 AM PST
Last edited by the author on Nov 4, 2012 5:48:21 AM PST
K ??

I heard you needed D to make the calcium work

simple info in plain english please
what does my doctor not know about all this that i could explain to him

he said my D was low
and has me taking 1000 D3 a day

In reply to an earlier post on Nov 4, 2012 6:17:36 AM PST
Ryan Wise says:
"If you have a study which controls for VDR activation, please post."
==================================

Deletion of VDR in mice started those lines of research. Those are few landmarks between 2003-2008:

===Quotes====

1- Japan 2003
Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors.

http://www.ncbi.nlm.nih.gov/pubmed/12959989

2- The Netherlands 2004
Addresses the VDR polymorphisms in understanding their potential clinical implications.

http://web.udl.es/usuaris/e4650869/Morella06/BB/Review_VDR_Polymorphism.pdf

3-Finland Tampere University (2005)
Partially deleted VRD effect on mice behavior

http://www.kaluefflab.com/pdfs/KalueffDocDisseration.pdf

4- UK Cambridge Research Institute (2007)
We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001483

5-Belgium 2008
http://edrv.endojournals.org/content/29/6/726.long

(a) VDR and 1α-hydroxylase null mice display severe hypocalcemia, rickets, and osteomalacia. These effects on calcium and bone homeostasis are largely mediated by 1,25-(OH)2D action on intestinal and renal calcium absorption because these processes are severely impaired in VDR-ablated mice

(b) Nearly all cell types express a functional VDR, and their growth is inhibited upon exposure to pharmacological doses of 1,25-(OH)2D, the active metabolite of vitamin D.

(c) The regulated presence in many immune cells of the key enzymes involved in the metabolism of 1,25-(OH)2D and the presence of VDR in almost all immune cells suggests a physiological role for the VDR-vitamin D endocrine system in immune homeostasis.

====== end of Quotes=============

Mohamed F. El-Hewie

In reply to an earlier post on Nov 4, 2012 9:13:26 AM PST
Ryan says:
@andthehorseirodeinontoo - I'll put this as simply as possible. D3 does not make the calcium work. D3 may help you move calcium from the food you eat into your body but you need other things to put it into the bone and keep it there once it gets there. If you are taking calcium supplements or D3 supplements, you should be taking K2 as well. K2 helps your body use calcium to make your bones stronger. The research on K2 is fairly new, so many people, even doctors and some researchers, seem to not be aware of it. There are two different kinds of K2 and no clear consensus on which is best, but both are probably good.

Some people have argued for adding magnesium as well to that mix. I haven't had a chance to look into that yet.

I hope this helps.

In reply to an earlier post on Nov 4, 2012 9:21:03 AM PST
andthehorseirodeinontoo? wrote:

"what does my doctor not know about all this that i could explain to him"
==============================================

That is backward, your doctor knows it all, but your doctor cannot make you do the right thing unless you were educated enough to avoid going to a doctor.

The time you take to educate your doctor is better invested in educating yourself to find better lifestyle.

Mohamed F. El-Hewie

In reply to an earlier post on Nov 4, 2012 9:57:32 AM PST
thanks

i need to look into K2

In reply to an earlier post on Nov 4, 2012 10:04:01 AM PST
Last edited by the author on Nov 4, 2012 10:05:23 AM PST
nutz

doctors are still learning

some of the older ones are obsolete
i had a good one who knew nothing about sports injuries
even then an orthopedist did not know enough to help

now such things are routine
but i would still look for one who specialised in that body part

all of them take classes to keep up to date
but none of them know everything

and some areas are too specialised for them to know enough

In reply to an earlier post on Nov 4, 2012 10:07:22 AM PST
andthehorseirodeinontoo? wrote: "doctors are still learning"
=================================

Why not worry about you own lack of ability to learn, since doctors cannot help lazy, ignorant patients?

Mohamed F. El-Hewie

In reply to an earlier post on Nov 4, 2012 10:09:26 AM PST
i have a superb ability to learn
and do so constantly

may a thousand capacitors blow up when you power on your next project

In reply to an earlier post on Nov 4, 2012 10:22:07 AM PST
Last edited by the author on Nov 4, 2012 10:22:27 AM PST
andthehorseirodeinontoo? wrote:

'i have a superb ability to learn
and do so constantly

may a thousand capacitors blow up when you power on your next project '
======================
You cannot even capitalize letters or spell check or correct punctuation.

Capacitors are not causing me problems, my main board has five shorted varistors caused by malfunctioning fuse.

Mohamed F. El-Hewie

In reply to an earlier post on Nov 4, 2012 10:29:59 AM PST
the only fuse shorting out seems to be in your logic circuits
and i am not talking electronics or hardware
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Discussion in:  Science forum
Participants:  8
Total posts:  56
Initial post:  Nov 3, 2012
Latest post:  Nov 8, 2012

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