75 replies to this topic

[davidd]

Here is the original paper that was the source of the U-shaped all-cause mortality curve. I'm not sure exactly what to make of the fact that the CVD and cancer models weren't statistically significant. I presume the causes of death at the higher end of the curve are cancer and CVD given the data source, but would like to hear the author's interpretation of the role of vitamin D in those deaths. Anyone have access to the full text of the paper?

Arch Intern Med. 2008 Aug 11;168(15):1629-37. Link to Full Text, Not Free.
25-hydroxyvitamin D levels and the risk of mortality in the general population.

Melamed ML, Michos ED, Post W, Astor B.

Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Ullmann 615, Bronx, NY 10461, USA. mmelamed@aecom.yu.edu

BACKGROUND: In patients undergoing dialysis, therapy with calcitriol or paricalcitol or other vitamin D agents is associated with reduced mortality. Observational data suggests that low 25-hydroxyvitamin D levels (25[OH]D) are associated with diabetes mellitus, hypertension, and cancers. However, whether low serum 25(OH)D levels are associated with mortality in the general population is unknown. METHODS: We tested the association of low 25(OH)D levels with all-cause, cancer, and cardiovascular disease (CVD) mortality in 13 331 nationally representative adults 20 years or older from the Third National Health and Nutrition Examination Survey (NHANES III) linked mortality files. Participant vitamin D levels were collected from 1988 through 1994, and individuals were passively followed for mortality through 2000. RESULTS: In cross-sectional multivariate analyses, increasing age, female sex, nonwhite race/ethnicity, diabetes, current smoking, and higher body mass index were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D level, <17.8 ng/mL [to convert to nanomoles per liter, multiply by 2.496]), while greater physical activity, vitamin D supplementation, and nonwinter season were inversely associated. During a median 8.7 years of follow-up, there were 1806 deaths, including 777 from CVD. In multivariate models (adjusted for baseline demographics, season, and traditional and novel CVD risk factors), compared with the highest quartile, being in the lowest quartile (25[OH]D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08-1.46) and a population attributable risk of 3.1%. The adjusted models of CVD and cancer mortality revealed a higher risk, which was not statistically significant. CONCLUSION: The lowest quartile of 25(OH)D level (<17.8 ng/mL) is independently associated with all-cause mortality in the general population.

PMID: 18695076

I'm not understanding what exactly they are stating in that synopisis. What exactly do they mean about the adjusted models of CVD and cancer mortality not being statistically significant?? Does that mean people died of many things and some of those things were CVD and cancer, but when those were taking into account, the vitamin D level was still the root cause??

David

[davidd]

Anyone have access to the full text of the paper?

Yes, I want that paper too, it's the one I can't access. Davidd, Holick for instance notes that sunbathers and lifeguards reach not 60ng/mL, but up to 100ng/mL without evidence of toxicity and no hardwired limit at 60ng. Cannell emphasises that toxicity starts only at 150ng/mL (rarely there are reports of tox. at >=80ng/mL). Any issues with >50ng/mL must be subtle and I am wondering why Cannell's target is >50ng/mL and Holick's >30ng/mL? I can't find the paper where Cannell mentioned that ~50ng/mL are necessary for optimal bone health...

Hmm....so surfers reach a limit of 60, but others can go much higher. Maybe there was a genetic difference in the participants? Maybe the surfers had different skin pigmentation and/or other differences that cut it off sooner? So many variables.

Yeah, why are they picking 50 or 30 if the toxicity doesn't start until much much higher in their research? Why not 90? Why not 100?

David

[kismet]

Hmm....so surfers reach a limit of 60, but others can go much higher. Maybe there was a genetic difference in the participants? Maybe the surfers had different skin pigmentation and/or other differences that cut it off sooner? So many variables.

Yeah, why are they picking 50 or 30 if the toxicity doesn't start until much much higher in their research? Why not 90? Why not 100?

David

Different people may have different cut-offs, yes, I believe skin pigmentation may be one reason, some reach 60, I've seen 70 reported somewhere else and Holick mentions that up to 100ng/mL can be reached by sun exposure.
I guess Holick is more conservative, going only by strong evidence (that way he may have better chances to get his message across - which did not yet happen in the US - and maybe he changed his mind in some of the newer papers, I've only read the one freely available from 2003/4), whereas Cannell seems to extrapolate more, but as I've shown there is certainly evidence to support his opinion too. If giving health advice to public, being conservative is fine - a target between 35-40ng/mL seems like a good compromise to me.
As always the IOM* seems to wait for big scale interventional trials, no matter how good the evidence from epidemiology and smaller trials is. However, there may be other issues involved: "vitamin D's potential is a formidable threat to the profits of big‑pharma, a fact they are fully aware of" (Dr. Cannell)

Whatever their stance, they failed miserably and are responsible for thousands of deaths and an epidemic of morbidity.

*I think the IOM is the US authority devising the RDAs, right?

Edited by kismet, 02 February 2009 - 06:00 PM.

[davidd]

Other interesting notes, Vitamin A toxicity, possibly through Vitamin D antagonism (important if supplementing Vitamin A but not enough D, like with any cheap multi). http://www.vitamindc...-december.shtml

I mentioned the Vitamin A connection briefly in my post in the cancer forums and even more briefly earlier in this thread. Thanks for finding that write-up -- a very interesting read.

That page references another study that I've looked at before, showing that increased vitamin A, beta-carotene and Vitamin E consumption can increase mortality.

...
When the different antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality by vitamin A (RR 1.16, 95% CI 1.10 to 1.24), beta-carotene (RR 1.07, 95% CI 1.02 to 1.11), and vitamin E (RR 1.04, 95% CI 1.01 to 1.07), but no significant detrimental effect of vitamin C (RR 1.06, 95% CI 0.94 to 1.20).
...

Your page points out that the increased Vitamin A may add to mortality by countering the benefits of Vitamin D. Seems logical. And an increase of 16% mortality is rather large in my opinion.

I can see the logic in wanting to maintain a level that results in starting to store Vitamin D in fat. That would seem to indicate that mother nature knows you have enough in your blood at that point. It still isn't clear how that relates to longevity, however, and I think we still need to keep that U-shaped graph in mind.

I think you posted the wrong link for the athletic performance. I believe it should have been: http://www.vitamindc.../2007-mar.shtml. I read the link you did post and it was a good read too. The part about which labs have the best tests was good information. I haven't gotten all the way through the athletic performance page, but I am enjoying it as well. Lots of good information, all around.

I checked my bookmarks and see that this is the test I was planning on getting. It is through some sort of special deal between The Vitamin D Council and ZRT Labs. $65, which is a $10 discount off their normal price. I'm guessing they must use the technique that LabCorp uses in order for the Vitamin D Council to partner with them. Do you know of a cheaper test that anyone offers?

http://www.zrtlab.co.....aminD Council

David

Edited by Michael, 12 February 2009 - 03:08 PM.

[nameless]

I checked my bookmarks and see that this is the test I was planning on getting. It is through some sort of special deal between The Vitamin D Council and ZRT Labs. $65, which is a $10 discount off their normal price. I'm guessing they must use the technique that LabCorp uses in order for the Vitamin D Council to partner with them. Do you know of a cheaper test that anyone offers?

http://www.zrtlab.co.....aminD Council

David

I think LEF offers vitamin D testing for about $63 for non-members and $47 for members. I've read that Diasorin is considered the best for D testing, which is what Labcorp uses. I'm afraid I don't know which lab ZRT or LEF uses for its D testing, though.

[davidd]

I checked my bookmarks and see that this is the test I was planning on getting. It is through some sort of special deal between The Vitamin D Council and ZRT Labs. $65, which is a $10 discount off their normal price. I'm guessing they must use the technique that LabCorp uses in order for the Vitamin D Council to partner with them. Do you know of a cheaper test that anyone offers?

http://www.zrtlab.co.....aminD Council

David

I think LEF offers vitamin D testing for about $63 for non-members and $47 for members. I've read that Diasorin is considered the best for D testing, which is what Labcorp uses. I'm afraid I don't know which lab ZRT or LEF uses for its D testing, though.

I believe LEF uses LabCorp. I just looked a bit closer at the ZRT test and see that they use the method that The Vitamin D Council does *not* recommend (mass spectrometry). Hmm...I might have to write to them about that.

David

[nowayout]

• Glucosamine sulfate 500mg + Chondroitin sulfate 300mg + MSM 75 mg

So you are ingesting a substance at a dose with exactly zero positive data on it? 1500mg or 0mg glucosamine, there is no compromise which makes sense.

Do you mean the glucosamine or the dose? I have been able to find a number of positive studies on glucosamine on pubmed and elsewhere, and only one or two that were neutral. For example, several studies found that long-term glucosamine seems to retard or stop joint narrowing in OA. I do not have RA or OA, and therefore do not intend to take the therapeutic dosages tested for these conditions, but both parents have developed some arthritis in their sixties, and it does not seem too out of the question that a lower dose might be prophylactic in the long term.

[nowayout]

Then, there is obviously a big difference in degree of damage between getting a lot of exposure on a small area (on which some of the recommendations for vitamin D production I have read were based) and getting just a little exposure on a large area.

No, not according to the accepted linear no-threshold model (LNT), which says that any radiation is damaging and the response is linear.

Okay, but doesn't this imply that the amount of damage per square centimeter of skin would be less in the latter case (little exposure over a large area) than in the former (lot of exposure over a small area).

[kismet]

If we assume the damage is completely stochastic it should be irrelevant as long as it does not cause frank radiation poisoning (or reach some other threshold).
Area*Intensity of exposure, be it 2*1 or 1*2, the result should be a damage of ~2. Maybe at some point the repair mechanism would be overwhelmed e.g. potentially reversible pyrmidine dimers would no longer be repaired because there are simply too many; or maybe at some point structural damage further exacerbates genetic damage. Other than that the chance of getting irreversible and potentially cancerous damage should be the same (2*1=1*2). That's my understanding at least.

Edited by kismet, 11 February 2009 - 05:31 PM.

[nowayout]

If we assume the damage is completely stochastic it should be irrelevant as long as it does not cause frank radiation poisoning (or reach some other threshold).
Area*Intensity of exposure, be it 2*1 or 1*2, the result should be a damage of ~2. Maybe at some point the repair mechanism would be overwhelmed e.g. potentially reversible pyrmidine dimers would no longer be repaired because there are simply too many; or maybe at some point structural damage further exacerbates genetic damage. Other than that the chance of getting irreversible and potentially cancerous damage should be the same (2*1=1*2). That's my understanding at least.

At least as far as wrinkling is concerned, it is most likely proportional to the local exposure per square centimeter (just time), not the overall exposure (area * time). For argument's sake, no matter how much you expose your big toe, your face will not wrinkle as a result. Furthermore, I find it unlikely that your face would wrinkle more than otherwise from any exposure it did get because your simultaneous chronic big toe exposure overwhelmed your repair mechanisms. It seems unlikely, but I have nothing to back this up with.

As for skin cancer, it might or might not work like wrinkling, and you may well be right.

[kismet]

At least as far as wrinkling is concerned, it is most likely proportional to the local exposure per square centimeter (just time), not the overall exposure (area * time).

I think that's what linear actually means, both time and intensity will play a key role, but I don't think most wrinkling is caused by genetical changes, is it? I think collagen and elastin is directly damaged and expression of degrading enzymes is increased.

As for skin cancer, it might or might not work like wrinkling, and you may well be right.

The systemic cancer risk of your toe and face exposure should very well be additive. The local damage (e.g. premature skin aging) it causes should be lower if the area exposed increases, but the intensity decreases (time=const), even though the cancer risk (and amount of vitamin D produced) stays the same.

So yes "little exposure over a large area" could be safer (I should have mentioned that thought in my post), but not when it comes to cancer I believe.

Edited by kismet, 11 February 2009 - 11:13 PM.

[kismet]

The study is available for download in the member section (well or PM me). 
Influence on CVD and cancer mortality was not significant when it was adjusted for confounders.
My interpretation of the study (which I only skimmed): "figure 2 shows a further decrease in [average and adjusted] mortality with blood levels of 40-49ng/ml. Other good news are that the 'association of low 25(OH)D levels with mortality was strongest in those without CVD, without hypertension, and without diabetes mellitus, arguing against low vitamin D levels being only a marker of poor general health.' High physical activity and lower BMI also seem to strengthen the association!"
I guess adjusting for confounders is rather difficult if low vitamin D levels are causative (in one model for instance they adjust for CRP, but AFAIK vitamin D is known to lower CRP, so low vitamin D ~ high CRP.. if you adjust for CRP it could attenuate the vitamin D effect).

[davidd]

I didn't realize I was posting in the paper forum. It really belongs here in this discussion:

...
Yes, thanks for posting the paper, Shepard!

Niner - I haven't had a chance to read the paper yet, but what is it that points toward dataset issues?

Edit: I just looked at figure 2. That's confusing to me. Why is figure 2 showing a decrease in mortality between 40-49 and figure 1 showing an increase? Additionally, why is it showing an increase, for men, from 30-39 vs 20-29/40-49? Also note that it shows >50 as being deadlier than <20???

What am I missing about the data used for Figure 1 vs Figure 2? Is it different in some way?

I did find where they briefly referenced the U-shaped nature: "As shown in Figure 2, in women, having both low (<20 ng/mL) and high (>50 ng/mL) 25(OH)D levels was associated with an increased rate of mortality." I haven't found where they try to explain this outcome, however. They seem totally focussed on the lowest quartile mortality.

David
...

[kismet]

What am I missing about the data used for Figure 1 vs Figure 2? Is it different in some way?

I think it's an issue with the model used to represent their data (a "restricted cubic spline"), a spline is already interpolated per definition and the mortality increase at >50ng/ml is huge, so it totally skews the graph.
I am not sure what may explain the high mortality at >50ng/ml, if we knew the values for 40-45, 45-50ng/ml we could hazard a guess if it's due to vitamin D overdose or external factors, but then again I believe the study is too small to give us such exact datapoints.
My guess is that there were simply too few people with blood levels of >50ng/ml and those who achieved them may supplement high doses of vitamin D because they're sick or get too much sun exposure and are at risk of cancer (adjusting may or may not solve such problems). I think the mortality may indeed start to rise at higher levels, but not as much as the study implies.

Edited by kismet, 18 February 2009 - 10:44 PM.

[davidd]

What am I missing about the data used for Figure 1 vs Figure 2? Is it different in some way?

I think it's an issue with the model used to represent their data (a "restricted cubic spline"), a spline is already interpolated per definition and the mortality increase at >50ng/ml is huge, so it totally skews the graph.
I am not sure what may explain the high mortality at >50ng/ml, if we knew the values for 40-45, 45-50ng/ml we could hazard a guess if it's due to vitamin D overdose or external factors, but then again I believe the study is too small to give us such exact datapoints.
My guess is that there were simply too few people with blood levels of >50ng/ml and those who achieved them may supplement high doses of vitamin D because they're sick or get too much sun exposure and are at risk of cancer. I think the mortality may indeed start to rise at higher levels, but not as much as the study implies.

Thanks for the analysis kismet. When we only had access to the first graph, I thought maybe the fitted line was just not fitted properly. I assumed (maybe wrongly) that the light blue shading represented the min/max mortality values. If so, then I don't understand how the >50 group shows higher mortality than the <20 group in figure 2, since the shading shows smaller values *and* the weighted line shows smaller values for >50 in figure 1.

Anyway, I too wondered about some of the things you mentioned. Hard to make conclusions without knowing the raw data. How many old people were in the >50 group, etc. Although I'd assume the scientists would have normalized for these things? Maybe they just weren't that interested in the top end vs the bottom end.

The question is....given this study, do we feel more comfortable with 30-39, 40-49, or 50-70? If we go by graph 1, alone, we'd probably pick 30-39. If we went by graph 2 alone, we'd probably pick 40-49. And then there are a number of experts recommending 50-70.

Comments?

David

[kismet]

The question is....given this study, do we feel more comfortable with 30-39, 40-49, or 50-70? If we go by graph 1, alone, we'd probably pick 30-39. If we went by graph 2 alone, we'd probably pick 40-49. And then there are a number of experts recommending 50-70.

Judging by this study the safest and most effective range would be 40-45ng/ml. When I have more time to look into the study I may email Dr. Cannell and some other viamin D experts to ask what they think. I prefer to contact Cannell, because he is the most vocal proponent of very high vitamin D doses and likes to answer emails (I think Holick still recommends >32ng/ml, but his upper bound is pretty much in the "huge mortality increase"-range of this study nonetheless).

Edited by kismet, 19 February 2009 - 11:58 AM.

[nowayout]

I prefer to contact Cannell, because he is the most vocal proponent of very high vitamin D doses ...

It sounds as if you are saying that you prefer to choose your expert opinion based on the answer you prefer to hear. But maybe I am hearing you wrong...

Edited by andre, 19 February 2009 - 01:05 PM.

[kismet]

I prefer to contact Cannell, because he is the most vocal proponent of very high vitamin D doses ...

It sounds as if you are saying that you prefer to choose your expert opinion based on the answer you prefer to hear. But maybe I am hearing you wrong...

Yes, I am biased towards high dose vitamin D, but my interpretation of the data is never one-sided and always cautious. Who else could (should) defend high doses of vitamin D if not the guy who recommends high doses? This study shows mortality to be in between Holick's and Cannell's minimum, so neither can be that wrong.
I fear Holick's arguments may be rather simple, because >32ng/ml is supported by most data and his designated maximum seems to be just below the possible toxicity range, I am not sure if Dr. Holick really looked at optimal mortality, but Dr. Cannell is always good for some crazy insight (Did you read his blood irradiation and athletic performance articles? Just theories, but marvellous they are for sure).

Edited by kismet, 19 February 2009 - 03:20 PM.

[davidd]

The question is....given this study, do we feel more comfortable with 30-39, 40-49, or 50-70? If we go by graph 1, alone, we'd probably pick 30-39. If we went by graph 2 alone, we'd probably pick 40-49. And then there are a number of experts recommending 50-70.

Judging by this study the safest and most effective range would be 40-45ng/ml. When I have more time to look into the study I may email Dr. Cannell and some other viamin D experts to ask what they think. I prefer to contact Cannell, because he is the most vocal proponent of very high vitamin D doses and likes to answer emails (I think Holick still recommends >32ng/ml, but his upper bound is pretty much in the "huge mortality increase"-range of this study nonetheless).

I emailed him on 02/11/2009. I asked him about 3 things:

a) He recommends LabCorp for testing, because of the method they use (Liaison) being more accurate for high volume tests. The method some other labs use (mass spectrometry), he believes, results in incorrect values (usually higher than the real value). However, The Vitamin D Council has partnered with ZRT Laboratory on a take-home test. That test uses mass spectrometry. I asked him if there was something unique about the ZRT Laboratory test even though it is mass spectrometry.

b) I asked him what his take is on how much calcium, magnesium and zinc should be taken if vitamin D is increased, as they are all interrelated. I should have asked him about potassium too, but I forgot. I'm still trying to work out my best guess at the ratios and don't have any good answers yet.

c) I asked him what his take is on our u-shaped graph, given that he recommends more than the amount that appears to minimize mortality.

I haven't heard back from him yet. Of course, he has a regular job. The website is just an after-hours thing for him, so I may never get a reply. I'm sure he gets a ton of emails.

He's also been busy lately dealing with Medicare's proposed policy change of not paying for vitamin D testing. (http://foodconsumer.org/7777/8888/C_onsumer_A_ffair_26/021207582009_Medicare_s_idiocy_printer.shtml) I wrote to Medicare using the email address given in the letter as well as sending that letter to my congressperson, using the link given for that. I explained why I thought their decision was being based on a faulty premise -- that vitamin D deficiency can be managed by simply taking a fixed amount of vitamin D (once size fits all). I also explained that they are not considering the long-term risks of non-severe vitamin D deficiency, with "severe" being used to describe deficiencies to the levels that cause rickets, etc. I explained that the long term costs of cancer, heart disease, etc., etc., should greatly outweigh the relatively small cost of vitamin D screening.

I'll continue to try to find my own answers to the best ratios of vitamin D, magnesium, calcium, zinc and potassium (and others). If I don't hear back from him on the blood test, I'll probably go with the ZRT Laboratory test, only because it is a take-home test, so it is more practical for testing my wife and kids than having them go in for a blood draw. I want to get us tested in the dead of our Minnesota winter to see what our lowest values look like. The plan is to get more testing done in a couple months, before the sun kicks in, and see what supplementation has done. After the sun kicks in, supplementation will stop (gradually, over a couple weeks, to reduce the possibility of certain issues that can happen with a sudden reduction) and another test will be done in the middle of summer. It sure would be nice if the test was $10 instead of $55 (the cost, each, if you buy 4 kits), but I'm willing to pay, given all the science backing up the importance of this vital hormone.

David

[kismet]

b) I asked him what his take is on how much calcium, magnesium and zinc should be taken if vitamin D is increased, as they are all interrelated. I should have asked him about potassium too, but I forgot. I'm still trying to work out my best guess at the ratios and don't have any good answers yet.

I don't know if anyone can answer your question. As you can see we have a difficult time defining the optimal dose of vitamin D in isolation, because interventional studies are lacking (and only few well done epidemiological studies are available). If anything you can get a mechanistical (i.e. biochemically sound?) answer to your question, but most probably not from Cannell (an MD). There's simply not enough data to give meaningful advice in most cases.
Talking about mechanistcal (in this case even interventional) explanations of vitamin synergies. Did you know that (I am quoting from [1]) ”Fraser, et al. have shown that the MGP promotor contains a vitamin D response element that is responsible for a 2-3 fold enhancement of MGP expression after vitamin D binding”. Thus the pioneer's of vitamin K research did a study of vitamin D and vitamin K1 (1mg). [1] Unfortunately they used only 400IU, which may be the reason why the vitamin D only group was not different from placebo (but interestingly all the markers showed a trend towards improvement). Decline of vascular function was almost completely abolished in the combined group, while the placebo group declined constantly.

c) I asked him what his take is on our u-shaped graph, given that he recommends more than the amount that appears to minimize mortality.

I hope you noted that this graph is not all there is to that study? (i.e. figure 2 we've been talking about is probably more important).

[1] Thromb Haemost. 2004 Feb;91(2):373-80.
Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study.
Braam LA, Hoeks AP, Brouns F, Hamulyák K, Gerichhausen MJ, Vermeer C.

Edited by kismet, 21 February 2009 - 02:07 AM.

[davidd]

I just replied to this and then noticed that my post went missing. I hate when that happens. There should be some sort of auto-save option to go back to old drafts. I'll try to recreate my reply.

b) I asked him what his take is on how much calcium, magnesium and zinc should be taken if vitamin D is increased, as they are all interrelated. I should have asked him about potassium too, but I forgot. I'm still trying to work out my best guess at the ratios and don't have any good answers yet.

I don't know if anyone can answer your question. As you can see we have a difficult time defining the optimal dose of vitamin D in isolation, because interventional studies are lacking (and only few well done epidemiological studies are available). If anything you can get a mechanistical (i.e. biochemically sound?) answer to your question, but most probably not from Cannell (an MD). There's simply not enough data to give meaningful advice in most cases.
Talking about mechanistcal (in this case even interventional) explanations of vitamin synergies. Did you know that (I am quoting from [1]) "Fraser, et al. have shown that the MGP promotor contains a vitamin D response element that is responsible for a 2-3 fold enhancement of MGP expression after vitamin D binding". Thus the pioneer's of vitamin K research did a study of vitamin D and vitamin K1 (1mg). [1] Unfortunately they used only 400IU, which may be the reason why the vitamin D only group was not different from placebo (but interestingly all the markers showed a trend towards improvement). Decline of vascular function was almost completely abolished in the combined group, while the placebo group declined constantly.

I guess you are saying I should add vitamin K1 to my list? I vaguely remember reading that study, I *think*. I wonder if K1 is just boosting the availability of the relatively low dose (400 IU) of vitamin D? *If* that were the case, then it wouldn't be critical to take them together if the D is being given in higher doses. I guess a person could test this out by keeping vitamin D dose constant (at maybe a dose of 5000 IU) and then start ramping up the vitamin K1, getting a vitamin D test done at each change (or rather, shortly after each change, to allow time for delayed reactions).

c) I asked him what his take is on our u-shaped graph, given that he recommends more than the amount that appears to minimize mortality.

I hope you noted that this graph is not all there is to that study? (i.e. figure 2 we've been talking about is probably more important).

Figure 2 was all I had at the time. This was before we had the fully paper available from Shepard. I'm not sure why figure 2 is *more* important, but if I would have had both available, I would have provided both and pointed out their conflicting results.


On a tangentially related item... I recently came across a page with a *lot* of information about vitamin A and vitamin D being taken together. Many vitamin D experts recommend sticking to the average amount of vitamin A that we get in our developed civilization diets, since we usually get enough to avoid deficiencies, and since they believe it may counter some of the good benefits of vitamin D. This page is in a different camp of thinking, stating that the ratio is important, and if you increase D, you should increase A as well, for maximum benefit.

http://www.westonapr...tml#ainterfered

And another page I found recently: http://www.greenpasture.org/node/115

Looks like we have a difference of opinion between The Vitamin D Council and The Weston A. Price Foundation, with the latter recommending certain brands/processing of cod liver oil that provide natural vitamin A as long as it is paired with enough natural vitamin D too. The former is less discriminating, recommending people stay away from cod liver oil, period.

I wonder if Dr. Cannell is just thinking that people will have a hard time finding the true, "good" cod liver oil, so better to not recommend taking any? Or would he be on board with it if there was enough vitamin D in it? He does often talk about cod liver oil in the past and how it had more vitamin D and how certain studies back then showed benefits, but those same benefits can't be had now due to the changes in processing of the substance.

Anyway, vitamin A is also on my list as I try to sort all this out.

David

[kismet]

I guess you are saying I should add vitamin K1 to my list? I vaguely remember reading that study, I *think*. I wonder if K1 is just boosting the availability of the relatively low dose (400 IU) of vitamin D? *If* that were the case, then it wouldn't be critical to take them together if the D is being given in higher doses. I guess a person could test this out by keeping vitamin D dose constant (at maybe a dose of 5000 IU) and then start ramping up the vitamin K1, getting a vitamin D test done at each change (or rather, shortly after each change, to allow time for delayed reactions).

Well, recent evidence (from the same group) suggests that vitamin K2 is superior anyway (MK-4, MK-7). Look up the rotterdam study. I think their influence on MGP is the only synergy between vitamin D and K discovered so far.

Figure 2 was all I had at the time. This was before we had the fully paper available from Shepard. I'm not sure why figure 2 is *more* important, but if I would have had both available, I would have provided both and pointed out their conflicting results.

Figure 1 is interpolated (I explained it in my post about splines), thus the mortality in the range 40-49ng/ml is incorrectly depicted.

I wonder if Dr. Cannell is just thinking that people will have a hard time finding the true, "good" cod liver oil, so better to not recommend taking any? Or would he be on board with it if there was enough vitamin D in it? He does often talk about cod liver oil in the past and how it had more vitamin D and how certain studies back then showed benefits, but those same benefits can't be had now due to the changes in processing of the substance.

Anyway, vitamin A is also on my list as I try to sort all this out.

David

I'm going to read the westonaprice articles as soon as I have time. I am, however, not going to supplement vitamin A, until I am completely sure why Cochrane found increased mortality from vitamin A supplementation and until I see some positive studies.

Edited by kismet, 22 February 2009 - 01:10 PM.

[davidd]

Well, recent evidence (from the same group) suggests that vitamin K2 is superior anyway (MK-4, MK-7). Look up the rotterdam study. I think their influence on MGP is the only synergy between vitamin D and K discovered so far.

Hmm...I was thinking K2 is produced by the body. I'll have to do more research.

Figure 2 was all I had at the time. This was before we had the fully paper available from Shepard. I'm not sure why figure 2 is *more* important, but if I would have had both available, I would have provided both and pointed out their conflicting results.

Figure 1 is interpolated (I explained it in my post about splines), thus the mortality in the range 40-49ng/ml is incorrectly depicted.

Figure 2 is a wave shaped graph. I still don't get the higher mortality at 30-39 and lower at 20-29 and 40-49 in figure 2.

I'm going to read the westonaprice articles as soon as I have time. I am, however, not going to supplement vitamin A, until I am completely sure why Cochrane found increased mortality from vitamin A supplementation and until I see some positive studies.

Yeah, if you are referring to the same study I read (did analysis on people taking antioxidants and found that A and E increased mortality), that too is what worries me. Would be good to know how much D they were taking.

d

[kismet]

Vitamin K2 is produced from K1 and by gut bacteria AFAIK, but it's probably not enough, because there's enough undercarboxylated osteocalcin in the blood present and higher exogenous K2 intakes showed further benefit (Rotterdam study).
Let's say both graphs are important, I don't remember which one was the spline...

[davidd]

Vitamin K2 is produced from K1 and by gut bacteria AFAIK, but it's probably not enough, because there's enough undercarboxylated osteocalcin in the blood present and higher exogenous K2 intakes showed further benefit (Rotterdam study).
Let's say both graphs are important, I don't remember which one was the spline...

I wonder what the effect would be of probiotics on the manufacture of K2? I mean, I wonder if this is part of the reason that health benefits are derived from use of probiotics?

The first graph was the spline. I suppose we could try contacting the study authors.

David

[kismet]

Hot off the presses (via Dr. Cannell's newsletter). The plot thickens. Vitamin D levels >30ng/ml provide additional protection from upper respiratory tract infection compared to levels between 10-30ng/ml as per the "Third National Health and Nutrition Examination Survey" (18 883 participants)
Once again a study in the Archives of Internal Medicine (which I can't access) and once again the question, did they check higher vitamin D levels? Where's the optimum? 2x, 3x, 4x or maybe 5x ng/ml?

"The median serum 25(OH)D level was 29 ng/mL (to convert to nanomoles per liter, multiply by 2.496) (interquartile range, 21-37 ng/mL), and 19% (95% confidence interval [CI], 18%-20%) of participants reported a recent URTI. Recent URTI was reported by 24% of participants with 25(OH)D levels less than 10 ng/mL, by 20% with levels of 10 to less than 30 ng/mL, and by 17% with levels of 30 ng/mL or more (P < .001). Even after adjusting for demographic and clinical characteristics, lower 25(OH)D levels were independently associated with recent URTI (compared with 25[OH]D levels of 30 ng/mL: odds ratio [OR], 1.36; 95% CI, 1.01-1.84 for <10 ng/mL and 1.24; 1.07-1.43 for 10 to <30 ng/mL). The association between 25(OH)D level and URTI seemed to be stronger in individuals with asthma and chronic obstructive pulmonary disease (OR, 5.67 and 2.26, respectively)."
http://archinte.ama-...tract/169/4/384

Edited by kismet, 25 February 2009 - 12:55 AM.

[krillin]

I try for 45-50 ng/ml. To my knowledge, the highest level needed to maximize a specific benefit is about 50 ng/ml, and that's based on the first two papers below. Anything higher has inadequate evidence to support it, and has the U-curve to argue against it. Also see this nutritionist's experience that levels above 55 ng/ml will be toxic for some individuals.

The third paper says to get > 368 mg/day magnesium and to keep Ca/Mg < 2.78.

J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):708-11.
Vitamin D and prevention of breast cancer: pooled analysis.
Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, Newmark H, Holick MF, Garland FC.
Department of Family and Preventive Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. cgarland@ucsd.edu

BACKGROUND: Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence and mortality rates of breast cancer in ecological and observational studies, but the dose-response relationship in individuals has not been adequately studied. METHODS: A literature search for all studies that reported risk by of breast cancer by quantiles of 25(OH)D identified two studies with 1760 individuals. Data were pooled to assess the dose-response association between serum 25(OH)D and risk of breast cancer. RESULTS: The medians of the pooled quintiles of serum 25(OH)D were 6, 18, 29, 37 and 48 ng/ml. Pooled odds ratios for breast cancer from lowest to highest quintile, were 1.00, 0.90, 0.70, 0.70 and 0.50 (p trend<0.001). According to the pooled analysis, individuals with serum 25(OH)D of approximately 52 ng/ml had 50% lower risk of breast cancer than those with serum <13 ng/ml. This serum level corresponds to intake of 4000 IU/day. This exceeds the National Academy of Sciences upper limit of 2000 IU/day. A 25(OH)D level of 52 ng/ml could be maintained by intake of 2000 IU/day and, when appropriate, about 12 min/day in the sun, equivalent to oral intake of 3000 IU of Vitamin D(3). CONCLUSIONS: Intake of 2000 IU/day of Vitamin D(3), and, when possible, very moderate exposure to sunlight, could raise serum 25(OH)D to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer, according to observational studies.

PMID: 17368188

Am J Clin Nutr. 2007 Nov;86(5):1420-5.
Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women.
Richards JB, Valdes AM, Gardner JP, Paximadas D, Kimura M, Nessa A, Lu X, Surdulescu GL, Swaminathan R, Spector TD, Aviv A.
Twin Research and Genetic Epidemiology, St Thomas' Hospital, King's College, London School of Medicine, London, United Kingdom. brent.richards@kcl.ac.uk

BACKGROUND: Vitamin D is a potent inhibitor of the proinflammatory response and thereby diminishes turnover of leukocytes. Leukocyte telomere length (LTL) is a predictor of aging-related disease and decreases with each cell cycle and increased inflammation. OBJECTIVE: The objective of the study was to examine whether vitamin D concentrations would attenuate the rate of telomere attrition in leukocytes, such that higher vitamin D concentrations would be associated with longer LTL. DESIGN: Serum vitamin D concentrations were measured in 2160 women aged 18-79 y (mean age: 49.4) from a large population-based cohort of twins. LTL was measured by using the Southern blot method. RESULTS: Age was negatively correlated with LTL (r = -0.40, P < 0.0001). Serum vitamin D concentrations were positively associated with LTL (r = 0.07, P = 0.0010), and this relation persisted after adjustment for age (r = 0.09, P < 0.0001) and other covariates (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity; P for trend across tertiles = 0.003). The difference in LTL between the highest and lowest tertiles of vitamin D was 107 base pairs (P = 0.0009), which is equivalent to 5.0 y of telomeric aging. This difference was further accentuated by increased concentrations of C-reactive protein, which is a measure of systemic inflammation. CONCLUSION: Our findings suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases.

PMID: 17991655

Am J Clin Nutr. 2007 Sep;86(3):743-51.
The relation of magnesium and calcium intakes and a genetic polymorphism in the magnesium transporter to colorectal neoplasia risk.
Dai Q, Shrubsole MJ, Ness RM, Schlundt D, Cai Q, Smalley WE, Li M, Shyr Y, Zheng W.
Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN 37203-1738, USA. qi.dai@vanderbilt.edu

BACKGROUND: Mean magnesium intake in the US population does not differ from that in East Asian populations with traditionally low risks of colorectal cancer and other chronic diseases, but the ratio of calcium to magnesium (Ca:Mg) intake is much higher in the US population. Transient receptor potential melastatin 7 (TRPM7) is a newly found gene essential to magnesium absorption and homeostasis. OBJECTIVE: We aimed to test whether the association of colorectal polyps with intake of calcium, magnesium, or both and Thr1482Ile polymorphism in the TRPM7 gene is modified by the Ca:Mg intake. DESIGN: Included in the study were a total of 688 adenoma cases, 210 hyperplastic polyp cases, and 1306 polyp-free controls from the Tennessee Colorectal Polyp Study. RESULTS: We found that total magnesium consumption was linked to a significantly lower risk of colorectal adenoma, particularly in those subjects with a low Ca:Mg intake. An inverse association trend was found for hyperplastic polyps. We also found that the common Thr1482Ile polymorphism was associated with an elevated risk of both adenomatous and hyperplastic polyps. Moreover, this polymorphism significantly interacted with the Ca:Mg intake in relation to both adenomatous and hyperplastic polyps. The subjects who carried >or=1 1482Ile allele and who consumed diets with a high Ca:Mg intake were at a higher risk of adenoma (odds ratio: 1.60; 95% CI: 1.12, 2.29) and hyperplastic polyps (odds ratio: 1.85; 95% CI: 1.09, 3.14) than were the subjects who did not carry the polymorphism. CONCLUSION: These findings, if confirmed, may provide a new avenue for the personalized prevention of magnesium deficiency and, thus, colorectal cancer.

PMID: 17823441

[nowayout]

I am still rather worried about the long-term safety of oral D3 supplementation.

Serum levels are a very blunt instrument, and I fear people who megadose D orally to obtain specific serum levels may not be considering that the distribution of D in the various tissues may matter, and are probably quite different from the distribution obtained by photosynthesis. For example, given large dose oral supplementation, D3 will likely reach concentrations in the gastrointestinal tissues during digestion that are much larger than anything the relevant cell types have had to deal with during the course of evolution. The possible side effects of this over long periods worry me.

Edited by andre, 09 March 2009 - 02:00 PM.

[FunkOdyssey]

If you agree that there does exist an optimal range of 25OHD blood values (I think even the most skeptical do at this point), your only decision is between sunlight exposure and oral supplementation. Or phrased another way, a well-documented danger vs. purely theoretical risk. Actually the risk of oral supplementation is not even theoretical because that would imply you had worked out a proposed mechanism of harm.

Also bear in mind cholecalciferol is not the active form of D3. It is not even the precursor to the active form of D3. It is the precursor to the precursor of the active form, and basically inert. If cholecalciferol is worrisome, what about cholesterol? That turns into cholecalciferol, as well as many hormones including estrogen. Beware!

Edited by FunkOdyssey, 09 March 2009 - 03:12 PM.

[kismet]

Also bear in mind cholecalciferol is not the active form of D3. It is not even the precursor to the active form of D3. It is the precursor to the precursor of the active form, and basically inert. If cholecalciferol is worrisome, what about cholesterol? That turns into cholecalciferol, as well as many hormones including estrogen. Beware!

Touché, really nice response.
However, as I'm currently reading up on vitamin D, I'd like to make a slight correction to that statement: 25(OH)D actually has been found - and I was surprised to read it myself - to exert some effects on the VDR similarly to 1,25(OH)2D (calcitriol), but I believe cholecalciferol is in fact inert.

We don't know how much vitamin D is necessary for sure, but the evidence is overwhelming. Long term oral supplementation of 1000-2000IU is likely safe, as likely as eating fish is safe.
Staying deficient is not the answer. To obtain your vitamin D you can choose between long term exposure to a carcinogen (i.e. sunlight - I really wonder how well our bodies - and I remind you that only recently has the life expectancy increased from 20-30 years to almost 80 - are adapted to 80+ years of exposure to ionising radiation, any bets?) or long term exposure to a prehormone, which at the moment is believed to be completely (or relatively) inert.
The only meaningful questions are: 30ng or 45ng/ml 25(OH)D? Higher levels are associated with lower mortality, even if oral supplementation did negatively affect the gut it could be worth it.

Edit: Don't edit your post while I'm writing my response, that's confusing.

Edited by kismet, 09 March 2009 - 04:17 PM.