Re: Vitamin D / cancer study

[Guest guest]

Mmmmmmmmmmmmmmmkay, a risk ratio of 0.232 ... in other words a 4x

reduction in total cancer rates... now they's a benefit you cain't

hide under a thimble, cousin... I mean it's like don't call me if it's

0.865 with p < 0.03 but DO call me if it's 0.232 with p < 0.005, you

know what I'm sayin?... they mentioned that adjustment of booting out

the first year, on the radio... I don't know the " incubation times "

for cancers but that sounds like a defensible move... could be some

issue of Bonferroni / cherry picking / informed choice / whatever...

but they seem to have a p val that could survive a dent, and

apparantly it's consonant with some other work (which I also haven't

read or looked for disconfirmation of, myself).

> The difference from previous studies is that this one was an

> intervention study, double-blind, placebo-controlled, with a

> large number of patients.

>

> http://www.ajcn.org/cgi/content/full/85/6/1586

[Guest guest]

What do you make of their statement:

" The needed quantities of calcitriol are synthesized intracellularly

from 25(OH)D, tissue by tissue. However, the 1--hydroxylase

expressed in most tissues operates well below its is

constant, which means that the amount of calcitriol that a cell can

produce for itself in response to various stimuli is dependent on

the serum concentration of 25(OH)D. "

Some cells, at least, regulate the local concentration of calcitriol

in part by calcitriol-induced upregulation of CYP24, which

inactivates calcitriol--i.e., feedback inhibition. I like this

paper mechanistically for other reasons, but can you really push 25-

D through CYP27b1 by mass action without in turn inducing CYP24? In

other words, are tissues really unable to maintain the desired

amount of local calcitriol when calcidiol drops, say, twofold? This

has been my hangup over D3 supplementation. This is the first paper

I've read that addresses the issue bluntly.

CYP24 is, by the way, an oncogene (e.g., PMID: 10835626) not that I

think that actually suggests anything about therapeutic D3

supplementation, unless the cancer needs to inactivate calcidiol as

well as calcitriol. I just mention it since it's a cool finding.

>

> Mmmmmmmmmmmmmmmkay, a risk ratio of 0.232 ... in other words a 4x

> reduction in total cancer rates... now they's a benefit you cain't

> hide under a thimble, cousin... I mean it's like don't call me if

it's

> 0.865 with p < 0.03 but DO call me if it's 0.232 with p < 0.005,

you

> know what I'm sayin?... they mentioned that adjustment of booting

out

> the first year, on the radio... I don't know the " incubation times "

> for cancers but that sounds like a defensible move... could be some

> issue of Bonferroni / cherry picking / informed choice /

whatever...

> but they seem to have a p val that could survive a dent, and

> apparantly it's consonant with some other work (which I also

haven't

> read or looked for disconfirmation of, myself).

>

>

>

> > The difference from previous studies is that this one was an

> > intervention study, double-blind, placebo-controlled, with a

> > large number of patients.

> >

> > http://www.ajcn.org/cgi/content/full/85/6/1586

>

[Guest guest]

To answer my own question, perhaps the Vidal et al paper (PMID:

11909970) that cited long ago provides an answer. It claims

that IFNg blocks the ability of calcitriol to upregulate CYP24 in

macrophages. Perhaps, then, when a would-be tumor cell is near

macrophages and IFNg, local levels of calcitriol become a function

of calcidiol concentrations.

>

> What do you make of their statement:

>

> " The needed quantities of calcitriol are synthesized

intracellularly

> from 25(OH)D, tissue by tissue. However, the 1--hydroxylase

> expressed in most tissues operates well below its is

> constant, which means that the amount of calcitriol that a cell

can

> produce for itself in response to various stimuli is dependent on

> the serum concentration of 25(OH)D. "

>

>

> Some cells, at least, regulate the local concentration of

calcitriol

> in part by calcitriol-induced upregulation of CYP24, which

> inactivates calcitriol--i.e., feedback inhibition. I like this

> paper mechanistically for other reasons, but can you really push

25-

> D through CYP27b1 by mass action without in turn inducing CYP24?

In

> other words, are tissues really unable to maintain the desired

> amount of local calcitriol when calcidiol drops, say, twofold?

This

> has been my hangup over D3 supplementation. This is the first

paper

> I've read that addresses the issue bluntly.

>

> CYP24 is, by the way, an oncogene (e.g., PMID: 10835626) not that

I

> think that actually suggests anything about therapeutic D3

> supplementation, unless the cancer needs to inactivate calcidiol

as

> well as calcitriol. I just mention it since it's a cool finding.

>

[Guest guest]

> can you really push 25-

> D through CYP27b1 by mass action without in turn inducing CYP24? In

> other words, are tissues really unable to maintain the desired

> amount of local calcitriol when calcidiol drops, say, twofold? This

> has been my hangup over D3 supplementation. This is the first paper

> I've read that addresses the issue bluntly.

Does 1,25 really go up high when you provide a lot of 25, as Vieth

seems to say in some passages of his that I've read? I don't know. I

once glanced at this paper:

http://www.annals.org/cgi/content/full/122/7/511

which says otherwise. It studied people who took accidental overdoses

of D. But it also cites another paper that found the opposite of what

it found (ie, the other paper found what Vieth suggests, and this one

apparantly didn't; in this paper the people with the D3 overdoses

didn't have their serum 1,25d change very much at all).

And then, finally, you wonder if the above measurement is the relevant

measurement. After all, the 1,25-d we are concerned with is not that

found in the bloodstream, necessarily. Not all 1,25-d produced reaches

the bloodstream. But even without doing so, it might activate the VDR

in cells outside the blood.

And some people think other metabolites can come in to play (not just

1,25-d and 25-d). !!! Yuck. Eucaryote signaling sure hasn't been

selected for elegance.

[Guest guest]

Also interesting is the evolutionary perspective I discussed here,

though I haven't actually read the )#($ J Human Ev paper yet:

http://www.cpnhelp.org/vitamin_d_improves_athlet#comment-16241

[Guest guest]

, I don't know what passages of Vieth you have read, but he has

always adamantly affirmed that there is no correlation between 25D

levels and 1,25D levels.

The study on the overdose is interesting. The total levels of 1,25D

did not increase, but the levels of free 1,25D increased

significantly. Clearly the 25D was at such high levels that they

were binding with most of the VDR's, leaving the 1,25D free

(unbound). Since 25D disables the VDR, the effect of 25D overdose is

almost the same as not having any vitamin D at all. The VDR, and all

it controls or influences, is shut down.

Ken

> Does 1,25 really go up high when you provide a lot of 25, as Vieth

> seems to say in some passages of his that I've read? I don't know.

I

> once glanced at this paper:

>

> http://www.annals.org/cgi/content/full/122/7/511

>

> which says otherwise. It studied people who took accidental

overdoses

> of D. But it also cites another paper that found the opposite of

what

> it found (ie, the other paper found what Vieth suggests, and this

one

> apparantly didn't; in this paper the people with the D3 overdoses

> didn't have their serum 1,25d change very much at all).

>

> And then, finally, you wonder if the above measurement is the

relevant

> measurement. After all, the 1,25-d we are concerned with is not

that

> found in the bloodstream, necessarily. Not all 1,25-d produced

reaches

> the bloodstream. But even without doing so, it might activate the

VDR

> in cells outside the blood.

>

> And some people think other metabolites can come in to play (not

just

> 1,25-d and 25-d). !!! Yuck. Eucaryote signaling sure hasn't been

> selected for elegance.

>

[Guest guest]

> Some cells, at least, regulate the local concentration of calcitriol

> in part by calcitriol-induced upregulation of CYP24, which

> inactivates calcitriol--i.e., feedback inhibition.

I think you will also find that CYP24 also eliminates 25D (calcidiol),

although only 1,25D (not 25D) will upregulate CYP24. Since the CYP24

will indiscriminitly remove both, and 25D is in far greater

concentrations, then much more 25D will be removed than 1,25D.

So lets say someone has a chronic infection. The activated macrophages

are producing 1,25D, and CYP24 is upregulated. After a time (weeks,

months?) you would expect some rough equilibrium to be reached. 1,25D

would be in normal range although in a very dynamic state (a balance

beween macrophage production and CYP24 eliminatin). 25D would be

reduced due to elimination by the increased CYP24. This is exactly

what is found in nearly all chronic illnesses and the " autoimmune "

diseases.

Now what happens if you supplement 25D in this situation? Increased

25D does not increase CYP24. So once intake exceeds removal, the level

of 25D will rise. Increased 25D level will increase binding with the

VDR. 25D is antagonistic to the VDR. I said above that 1,25D increases

CYP24 but that is overly simplified. 1,25D increases the creation of

the VDR and CYP24 is a response to increased activated VDR. When the

artificially increased 25D levels inactivate the VDR, CYP24 production

will drop. This then allows significant increase in 1,25D. At this

point the vitamin D system, with all its myriad feedback loops and

self-regulation, is totally out of control. This is found in a great

many who have been ill for many years.

Studies which show people with low vitamin D (25D) levels to be at

greater risk for many diseases are assuming that correlation=causality

(very bad science). I see those results and say yes, the ones with

reduced D and normal vitamin D intake or sun exposure are obviously

already fighting an infection. They are just not yet symptomatic.

As for that cancer study.... What would happen if they ran the same 4

year study using prednisone or another steroid? If you shut down the

immune system you reduce inflammation which precedes and drives cancer

growth. High levels of 25D shut the immune system down. Well, reduce

it significantly.

Ken

[Guest guest]

> , I don't know what passages of Vieth you have read, but he has

> always adamantly affirmed that there is no correlation between 25D

> levels and 1,25D levels.

Ken you seem to be right. Looks like there are some mixed messages

here or Vieth has changed his mind, or perhaps was misquoted in this

post, which is what my statement was based on:

http://marshallprotocol.com/view_topic.php?id=6362 & forum_id=39 & jump_to=63688#p63\

688

I have not actually read many/any of Vieth's writings - just that

quotation. Another post, the Fri Jan 6th, 2006 14:18 post on this thread:

http://marshallprotocol.com/view_topic.php?id=5178 & forum_id=11 & highlight=vieth

claims the opposite about Vieth's views, or in other words, affirms

what you are saying. Thanks for pointing that out to me.

I guess only the data know the real truth... I'm not conversant with

those data and that probably won't change tonight. I will say, there

are two different meanings for the sentence " 1,25 varies with 25, " and

they should be distinguished. Meaning One is " your 1,25 goes up if you

eat 25. " Meaning Two is " measuring, in a zillion subjects, both 1,25

and 25, the two values should be correlated. " It seems to me that

Meaning One could still be true even if Meaning Two is false. As you

point out, chronic inflammation could raise 1,25 while eventually

tending to deplete 25 - in addition to the variations in dietary,

supplementary, and photolytic intake of 25, which will throw in their

own twists. Thus, it does seem unlikely that 25 is a valid surrogate

for 1,25. But that doesn't rule out the possibility that in a *given*

person, increased 25 will jack up the 1,25 (by an amount that will

depend on the person's 25 concentration at baseline, his chronic

inflammatory picture, if any, etc - in addition to, of course, maybe,

the " usual " biologic variables such as his genes, etc).

> The study on the overdose is interesting. The total levels of 1,25D

> did not increase, but the levels of free 1,25D increased

> significantly. Clearly the 25D was at such high levels that they

> were binding with most of the VDR's, leaving the 1,25D free

> (unbound).

I don't think VDR is involved here. This is a serum assay, and I don't

believe(?) VDR should be present in serum (perhaps it could get into

serum as a laboratory artifact - but if so I'm guessing someone would

have figured that out, though obviously that is far from certain).

What is present in serum is the D binding protein (DBP). I was not

aware of this protein until recent months, though if you think about

it or look into it, lots of steroid type hormones have binding

proteins in the serum. (I'd guess this is because steroids are

hydrophobic and would otherwise tend to get stuck in cell membranes

and thus remain near the site of synthesis).

If someone wants to find out how the free 1,25 assay is done, they

cite [12] and [13], which I don't have access to right now. But here

is what they say about what they think is happening to cause the

increased free 1,25:

" The presence of elevated free 1,25-(OH)2D levels despite normal total

1,25-(OH)2D levels suggests that 1,25-(OH)2D is displaced from DBP by

the micromolar concentrations of 25-OHD and other unmeasured

metabolites (such as 25-OHD-26,23 lactone; 24,25-[OH]2D; and

25,26-[OH]2D) [7]. Concentrations of DBP are approximately 5 x 10 (–6)

M, and the vitamin D metabolites appear to bind to DBP in a 1:1 molar

ratio and to compete for the same site. However, this hypothesis has

not been rigorously tested. Thus, as the vitamin D metabolite

concentrations approach those of DBP, the level of saturation of DBP

binding reaches a point where the percentage of bound metabolites

decreases in a clinically significant manner [13, 15]. "

It doesn't sound like they have the various binding affinities for the

bonds between DBP and the various D metabolites. If they had em they'd

cite em. However:

" The above hypothesis is supported in part by our in vitro studies.

When 25-OHD was added to normal serum in the same concentrations (800

nM) as those recorded in the patients, the percentage of free

1,25-(OH) (2D) increased by 78%. "

I'm not sure just how strong the support from this experiment is. *If*

there is no 25 >> 1,25 converting activity in the serum, and the serum

is free of VDR, then the support does seem pretty strong.

Most of these people had normal free 1,25. It's only the percent free

1,25 (free 1,25 over total 1,25) that is consistently out of bounds.

As has often been pointed out, it's not clear that serum 1,25 is

always a terrific measure of paracrine 1,25 - and there's really no

easy way to find out. Furthermore, even knowledge of paracrine 1,25 is

not the final answer. These are all surrogate measurements -

surrogates for VDR activity. It's actually VDR activity that we care

about. The concentration of VDR itself might be downshifted sometimes

(by, say, 1,25) - and that could matter.

> Since 25D disables the VDR, the effect of 25D overdose is

> almost the same as not having any vitamin D at all. The VDR, and all

> it controls or influences, is shut down.

Well, as far as I can guess, what you're implicitly citing there is

based on computer models. I don't think that's reliable at all. Many

of the commenters on Lowe's posts on models are more pro-model

than he is, but I don't see a single one of them suggesting that

models can be relied on in a given situation. Instead, the most

optimistic of them seem to feel that it gives info that may or may not

be even close to right, but is at least not random, and therefore is

of *some* use to them when they have 400 drug candidate molecules and

can only pick out 15 to do definitive bioassays on:

http://pipeline.corante.com/archives/in_silico/

I will say, I looked up 4 or 5 different bioassays for the binding

constant of tetracycline to bacterial ribosomes, and they were

painfully divergent (multiple orders of magnitude). Yuck! I hope the

situation with tetracycline is out of the ordinary. Even if not, real

bioassays are still going to have to be the gold standard for truth

and the standard by which computer models are appraised, because the

models are fairly crude.

[Guest guest]

> 25D is antagonistic to the VDR.

Here's a 1995 paper, which may not be free, which measured a 1.6 nM

binding constant for 1,25, and 100 nM for 25. So they think the

affinity ratio (1,25 affinity over 25 affinity) is ~40 ... whereas I

think you are thinking of computer models where it came out to around

3. I don't know if anyone has confirmed this value of 40, but even if

not I still think it trumps the computer model value of 3.

see " Table 1 "

http://endo.endojournals.org/cgi/reprint/136/1/20

So, if ingestion of 25 is going to antagonize VDR signaling - it's

going to have to jack up the free 25d concentration at least 40 times

more than it jacks up the free 1,25d concentration. (Because a

ligand's total receptor occupancy equals the ligand's concentration

times the ligand's affinity for the receptor.) Assuming the

concentration of VDR is fixed.

> Studies which show people with low vitamin D (25D) levels to be at

> greater risk for many diseases are assuming that

> correlation=causality (very bad science). I see those results and

> say yes, the ones with reduced D and normal vitamin D intake or sun

> exposure are obviously already fighting an infection. They are just

> not yet symptomatic.

Well, it's true that correlation != causation. But, that's why they

did this large randomized trial, ja? In a large randomized trial,

correlation does equal causation, because hidden co-variates of D

status (like subclinical inflammatory disease) should be as common in

the intervention group as they are in the control group, and should

thus result in no artifact.

If you are a reader cpnhelp, you'll see I administered 5 laziness

points to myself for not actually reading the paper, because it turns

out the subjects were all white postmenapausal women. That could be a

special biological set. So, if your overall point is that more large

randomized trials are needed to stringently ensure that this finding

applies to us boys, etc - I think you're right about that. However,

since this study (if replicated) shows that this particular

correlation does equal causation in white menopausal women in

Nebraska, that does make it significantly more *likely* that the same

correlation, when seen in other demographic groups, does represent

causation.

> As for that cancer study.... What would happen if they ran the same 4

> year study using prednisone or another steroid? If you shut down the

> immune system you reduce inflammation which precedes and drives cancer

> growth. High levels of 25D shut the immune system down. Well, reduce

> it significantly.

Well, most people think the immune system also kills many tumors

before they are ever detected (though I know absolutely nothing of the

subject firsthand).

Anyway, empirically, I think this effect would be likely to have been

detected if it existed. A lot of people with organ transplants or

immune diseases are on heavy immunosuppression, and I know there has

been some worry that these treatments could increase cancer. So I

*suspect* it's probably been quite well-studied, but obviously that's

not worth much.

Anyway anyway, thanks for raising a couple points about D that I

didn't know about. This lil field is certainly a jungle, eh. I'll tell

you why I'm interested - last January, due to my ongoing serious

relapse, I decided to eat a bunch of 25 (6000 IU /day) since I hadn't

taken any vitamins to speak of for a couple years. It was just for the

sake of doing something - I didn't feel certain it was a good idea,

and I really didn't expect anything to happen at all anyway. On day 5

or so I got really sick for 4 days with things like photophobia, total

anorexia, disgusting head malaise, etc, even though the weather was

quite clear (which usually makes me feel great). I was

(conservatively) 3.5x sicker than I had been on the worst occasions of

the relapse. Psychology played no role in my evaluation of the

experience, as the thought it was a herx did not cross my mind. I just

thought I was continuing to deteriorate (and I was scared shitless).

After the 4 days passed I had a ridiculous mania for a few days. After

that settled, I was still much improved. Only then did I find out that

multiple other people at cpnhelp had also experienced phenomena

consistent with herx.

What happened? I don't know, and whatever happened to me certainly is

not guaranteed to apply to other people. For whatever it's worth, if

some bandits put my feet to the fire and demanded a guess, I'd no

doubt guess that I herxed.