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Vitamin D, part 3 – The Evidence

296 points| usefulcat | 5 years ago |devaboone.com | reply

205 comments

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[+] staticassertion|5 years ago|reply
It seems interesting that Vitamin D may be so much more prone to false correlations due to the fact that it's tied to going out in the sun, and going out in the sun is what healthy people do. Since so many illnesses and conditions, from psychological to physical, can keep you indoors, one could conclude that vitamin D is really a miracle pill.

I take 1k iu a day, since I barely go outside anymore, but I'd probably cut that in half if life were normal again. I think of most vitamins as a "cover my bases in cases I eat like shit today", not as a "this is going to keep me from getting cancer".

I also found the commentary on metanalyses interesting - they're touted as being very high quality, but of course there's always the garbage in garbage out.

[+] bad_user|5 years ago|reply
RCTs are high quality, because they are done in a controlled setting, testing against a control group, testing the null hypothesis. RCTs are able to show causality. The problem with RCTs is that they are very expensive, since it involves keeping people in a clinic, so usually RCTs are short term and can only afford to look at surrogate markers.

However most often than not, surrogate markers are enough. Also RCTs tend to coroborate the findings from observational studies in about 70% of the cases. Also for really hot topics, like diabetes management, we do have year-long RCTs too.

And drawing conclusions from systematic reviews and meta analyses of RCTs, well, that's basically the best we can do.

For assessing the strength of available evidence, I recommend reading the following: https://examine.news/how-to-read-a-study

[+] baccheion|5 years ago|reply
400 IU is the RDA. On the other hand, the RDA assumes 20% will come from food and the other 80% from sunlight. That is, 2000 IU/day is actually what's expected from all sources. Enough to get 25(OH)D in range is the more generalizable rule.

Such an approach as you mention may work well enough if growth is finished (ie, plates fused) and there's a movement away from calcium to magnesium. That is, get more magnesium than phosphorus and then 1/3rd-1/2 as much calcium. For example, 1.5g phosphorus + 1.5g magnesium + 500-750 mg calcium.

As much calcium isn't needed after growth and I am assuming all RDAs are being met (with just a variety of whole quality foods before adding supplements). Especially enough potassium to ensure a negative PRAL score to further lessen stress reactions.

At such a low amount, you could try the sun/S.A.D. or red lamp therapy.

[+] nradov|5 years ago|reply
Why do you barely go outside?
[+] TacticalCoder|5 years ago|reply
What about the study in Spain from a few days ago (I'm in Spain atm and it's kinda big news over here), at the Reina Sofia University Hospital in Córdoba, where they just announced the results of the randomized blind controlled trial and the results are incredible: 1 person out of 50 who got huge doses of vitamin D for a few days after arriving at the hospital with Covid-19 symptoms ended up in the ICU, where 13 out of 26 who didn't get any vitamin D ended up in the ICU? It's "only" 76 people but it's 2% vs 50%.

It was a blind study (AFAICT): patients had no idea whether they got vit D or not and patients got randomly selected.

Here's a doctor's analysis of that study:

https://youtu.be/V8Ks9fUh2k8

[+] devaboone|5 years ago|reply
There is a lot of excitement about this study, but the details in it matter. It was randomized - but when you look at the two groups (treatment vs. control), they had some key differences. The control group (who didn't receive Vitamin D) had more men (69% vs 54%), more people with hypertension (57% vs 24%) and diabetes (19% vs 6%). So the groups were not the same. If you just compare the numbers of those who went into the ICU vs. not, then the results look amazing. But once you correct for hypertension and diabetes, it was not so impressive - it was not statistically significant in the study. (It is in the study but most people breeze right over that.)
[+] m12k|5 years ago|reply
So Vitamin D deficiency is linked to cancer, heart disease, respiratory infection, stroke, diabetes, and death. But taking it as a supplement helps with none of the above. What is a reasonable hypothesis then? That having an active lifestyle that brings you outside in the sun both causes your Vitamin D to go up, and is correlated with better physical health in general?
[+] gwd|5 years ago|reply
From TFA:

> How can we reconcile promising early observational studies linking Vitamin D to most major causes of death with our current results? One thing that seems increasingly clear is that in most cases low Vitamin D (truly low Vitamin D) is a marker of poor health rather than a cause. Vitamin D is made in the skin after exposure to sunlight. A chronically ill, frail individual may leave the house less often, leading to lower Vitamin D levels. Fixing the Vitamin D will not fix the chronic illness.

[+] scott_s|5 years ago|reply
I would frame it in the opposite direction: having a serious illness is correlated with low levels of Vitamin D. People with a serious illness may stay inside more, and go outside less. It's possible that "low levels" of Vitamin D are still within the healthy range, and they merely are an indication of how much time the person has spent outside during the day.

In other words, it's possible that Vitamin D is pure symptom. It's not even necessarily the case that going outside is healthy, but that healthy people tend to go outside more.

[+] beagle3|5 years ago|reply
There are thousands of reasonable hypothesis, and it is extremely costly (and in some cases, nearly impossible) to test.

e.g. our bodies need sunlight and cholesterol in order to synthesize vitamin D; This process also apparently has some other outputs like NO which are much harder to measure since they get used quickly. It is possible that vitamin D is merely (mostly) a measure of the prevalence of this process, and it is the other (harder to measure) outputs are much more important; Or that it's the consumption of cholesterol that's more important than the production of vitamin D; Or that sunlight has other functions we don't measure that are the important ones. Or that it's all just a correlation to some other process we're not even aware of.

That said, my own experience and anecdotally other people I know (and gwern has some blind n=1 experiments on his site to back this up) is that taking vitamin D early in the morning improves sleep at night, and taking vitamin D in the afternoon/evening reduces sleep quality. For that reason alone, I take vitamin D in the morning, and anecdotally, I burn less when I'm in the sun without sunscreen as well.

[+] weezer|5 years ago|reply
Sun exposure (and even tanning beds) produces vitamin D, but it also causes other changes in the human body. It appears sun exposure OR tanning bed use (!!!) reduces all cause mortality.

"Avoidance of sun exposure is a risk factor for all-cause mortality: results from the Melanoma in Southern Sweden cohort" https://pubmed.ncbi.nlm.nih.gov/24697969/

I think there's some confounding factors in 'outdoorsy' people having other healthy lifestyle habits, but it also seems likely that there is some other mechanism, beneficial to human health, triggered by uv exposure.

[+] chownie|5 years ago|reply
It might just be that the production of vitamin D via sunlight has other effects on the body, perhaps vitamin D has been a proxy for those effects but for obvious reasons taking it as a supplement doesn't trigger the same outcome.

It's unfortunate that exposure to UV is so harmful, I'm left wondering if trials using UV lightboxes to stimulate vitamin D production would change the kinds of outcomes (cancer, heart disease, depression...) we're expecting it to .

[+] wukerplank|5 years ago|reply
I read (maybe here on HN comments) that Vitamin D could only be the indicator. People who live a certain lifestyle have low risk of the mentioned diseases AND have good Vitamin D levels. But you have to live that lifestyle, not just take supplements.
[+] tboyd47|5 years ago|reply
Perhaps it's just more complicated than the prevailing paradigm of "have problem -> take drug -> problem go away." It could be that Vitamin D deficiency is itself a symptom of an array of underlying problems, or that it is one factor among many leading to a pathology, or that various levels of Vitamin D have various effects among different patients, or all of the above.
[+] devaboone|5 years ago|reply
That is a reasonable hypothesis. Also, people who are very ill are less likely to get outside and get enough sun, so they will develop low Vitamin D. Vitamin D is likely a marker of poor health. (Once the Vitamin D gets low enough, we do see direct harmful effects from it (think rickets in children), and this may contribute to poor health at that point.)
[+] glofish|5 years ago|reply
There is a fundamental difference between vitamin D generated in your skin versus vitamin D placed in your gut. The mechanisms by which it acts and the effects it has on you are probably radically different.

We are more than just a pile of various materials.

[+] kebman|5 years ago|reply
It's a classic case of correlation does not imply causation. As implied in the article, people who are sick, stay indoors. So naturally, when they don't get enough sun from staying indoors, they also get lower levels of Vitamin D. And so that is the correlation. It doesn't mean that a lack of Vitamin D causes illness, or that taking Vitamin D supplements will magically cure those illnesses.
[+] dcolkitt|5 years ago|reply
> What is a reasonable hypothesis then?

The logical conclusion is that vitamin D, as we measure it, is proxying for another factor that we haven't yet detected. This X-factor is heavily influenced by sun exposure, but at most weakly influenced by vitamin D supplementation in its current form.

Analogously imagine that we had no concept of the health benefits of exercise. We detected that people with gym memberships were much healthier than those without. So, we try giving a bunch of people a free gym membership. Yet few of the recipients end up using it to do any exercise. In this case the supplement group would show nowhere near the health gains of the baseline gym members. The key issue is that gym membership is only proxying for the underlying X-factor of physical activity.

Michael Pollan makes a great critique of a type of thinking called "nutrionism". Basically that the determinants of health can be broken down into their isolated sub-components. "You need X amount of protein, Y amount of this vitamin, and Z amount of this mineral." The problem is that unless our understanding of biology is perfect, there's almost certainly going to be flaws in the decomposition. When we try to replicate a healthy diet with a synthetic mixture of vitamins and macronutrients, we still fall well short of natural food. A very famous example of this is when people on total parenteral nutrition kept dying, because the original formulations lacked chromium. Humans only need a microscopic amount, yet die without it. Nobody realized this because almost all natural foods have trace amounts that satisfy the requirement.

As for vitamin D specifically, I think there's three pretty good candidates for what the missing X-factor is. In order from least to most controversial:

1) Our current understanding of the sub-types of Vitamin D is not complete. It wasn't too long ago that we began to learn that Vitamin D3 is much more essential than Vitamin D2. It's possible that there are sub-types of Vitamin D3 that are made in the correct proportion in the skin, but aren't represented in supplements.

2) There are other micronutrients, not yet discovered, that are synthesized in the skin. This goes back to the chromium example. Sun-exposed people may have high levels of Vitamin D + Vitamin X. Yet we can only measure the former, so we over-attribute the importance of Vitamin D.

3) Sun exposure induces the same physiological adaptations as physical exercise. Consider what we know about the mechanism of how exercise induces its health benefits. Micro-traumas to the muscle fibers and metabolic stress leads to an acute stress response. That peak leads to a down regulation of the HPA axis with accompanying metabolic benefits. The muscles recover, with an adaptation against the stress.

Is it not possible that something similar happens when we sunbathe? Without a doubt UV exposure induces micro-traumas in the skin cells, that looks very similar to what's found in the muscle cells. There's also emerging evidence that sun exposure triggers the HPA stress response[1], in the same way that exercise does.

If this is the case, then trying to replicate the benefits of sun exposure with supplements is a fool's errand. It's the sun exposure itself, specifically the sun damage, that is directly responsible for the health benefits.

[1]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398592/

[+] hannob|5 years ago|reply
That's a reasonable hypothesis. Another one is that it's a reverse causality: Several diseases may inhibit Vitamin D uptake.

And don't forget: It can be multiple causes combined. (I.e. it may be a mix of a confounder like being outside and reverse causality.)

[+] andi999|5 years ago|reply
Its probably same reasonwhy there are some correlations with alcohol intake and health, real reason probably: sick people dont drink wine.
[+] hhas01|5 years ago|reply
Correlation confused for causation? Say it isn’t so!

/s #APillForEveryIll

--

“For every complex problem there is an answer that is clear, simple, and wrong.” H. L. Mencken

[+] gameswithgo|5 years ago|reply
Nobody knows yet, but sunlight exposure causes the body to produce other things than Vitamin D, like nitric oxide (or similar correct me if I'm wrong here). It also affects circadian rhythms, so maybe people who get out more sleep better, maybe they are in better health from being more active, etc etc.
[+] dcx|5 years ago|reply
This seems like it might be a little selective.

What about these [1] [2] randomised controlled trials that show vitamin D supplementation has an effect on IBS symptoms?

Or this [3] double-blinded trial showing supplementation improved sleep quality in people with sleep disorders?

Or this [4] one showing improvements in depressive symptoms in overweight and obese subjects? The study cited in TFA is large but only uses participants aged 50 and above, with a relatively low dose of vitamin D.

Also, is it just me or is the line of argument used a little bit weak? You could use the same kind of argument to dismiss the need for dietary vitamin C, as follows: (a) vitamin C deficiency is associated with a bunch of other health conditions (as it's a marker of poor nutrition or socioeconomic status), so (b) let's look at the effects of supplementing vitamin C, which (c) naturally finds that supplementation does nothing for said conditions, and therefore (d) conclude that it is a pretty useless vitamin, while placing minimal focus on the things that it actually does fix, such as scurvy?

I am not an academic, so perhaps I am missing some context though.

[1] https://pubmed.ncbi.nlm.nih.gov/27154424/

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900470/

[3] https://tumj.tums.ac.ir/article-1-8272-en.html

[4] https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2796...

[+] ljhsiung|5 years ago|reply
Did you read the article?

> It is an essential hormone, definitely, but not a magical pill that will ward off disease. There are conditions that benefit from Vitamin D supplementation - for hypoparathyroidism, a condition that can cause dangerously low calcium levels, Vitamin D is lifesaving. For otherwise healthy adults, the benefit is less clear.

Takeaways: it's not clear what preventative benefits it has.

Even to use your vitamin C example, it's also widely touted to take vitamin C for general well being, such as helping colds. But its preventative benefits aren't clear [1]. Nobody has ever said vitamin C is useless, but it's just not a panacea (much like the article claims about vitamin D).

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1160577/

[+] devaboone|5 years ago|reply
I wrote the blog post. Unfortunately I was not able to include every study on Vitamin D, and had to pare it back to the largest and/or most significant studies. Most of the studies you mention are small and published in obscure journals.

As for my argument, I would never claim that Vitamin D is "a pretty useless vitamin". It is extremely useful, and is lifesaving for people with hypoparathyroidism. But that doesn't mean we should all be taking it. Note that the studies you mention are looking at treating something, not preventing something. Many of the people supplementing are doing it because they believe it will keep them healthy - and this does not appear to be the case. That is more the point of my article. The articles you cite are interesting and hopefully will produce larger trials.

[+] fortenforge|5 years ago|reply
It's interesting that you mention Vitamin C! Do you know many people who take Vitamin C supplements? Did you know that Vitamin C had its own supplementation hype cycle in the 70s and 80s? It's out of fashion now, mostly because people understand now that it's not a miracle drug. I suspect the same thing will happen with Vitamin D.

TFA isn't saying that you don't need vitamin D, or that it can't be used to treat Ricketts or osteomalacia (which, like scurvy, are relatively rare conditions). It's simply saying that widespread supplementation on people who have normal levels or minor deficiencies isn't supported by the evidence.

[+] ramenmeal|5 years ago|reply
I think the article addresses those by saying they are the result of publication bias.
[+] mixmastamyk|5 years ago|reply
May be an unpopular take, but this one felt a bit too academic to me. It also, perhaps inadvertently, argues against several strawmen too.

We've long known D is an essential component of bone-health and the immune system, since it was noticed a century ago that tuberculosis patients that went outside in the sun had better outcomes. Known to prevents rickets too.

The fact that some have tried to apply it to heart disease or asthma, or random unrelated ailments and failed is immaterial, no?

The fact that the benefit of supplementation is strongest for those with the weakest levels is not particularly surprising either.

We also know that the body can make adjustments when nutrients are low in the short term, and that can mitigate some issues and pose unintuitive outcomes in such a time frame.

Bottom line, do we want to face Covid/Flu with an immune system at full strength, or one with one arm tied behind its back due to a deficiency?

Finally, given that a large majority of folks are D-deficient, and few can or will overdose, this push back (on HN and this piece) to warn folks that it is useless/dangerous (on the whole) does more harm than those recommending it, in my opinion.

Moderation continues to be the best path, and a number of studies linked here support benefits of supplementation for bone-health and immune system, but those things only. Don't overthink it.

[+] gambler|5 years ago|reply
This picture in the article is misleading:

https://static.wixstatic.com/media/3e0600_a25ba8bbf26b47a096...

At the very leat, vitamin D does seem to prevent respiratory infections. The article even admits as much later on. There are several RCTs that verify this. So why put a red cross next to "prevention of respiratory infections"?

Also, worth reading:

"Why randomized controlled trials of calcium and vitamin D sometimes fail"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427206/

[+] dorenarode|5 years ago|reply
I read Dr. Boone's article and looked over each intervention in the study's she listed. I noticed that many researchers were dosing once a month (one was only once a year!) at levels I would not consider therapeutic. Yes, at non-therapeutic levels, I would expect vitamin D to not show much difference from Placebo. I am not a vitamin D expert, but am wondering why she selected to discuss research that didn't even match current vitamin D recommnedations. Her favorite research was VITAL which I was thrilled to learn was daily for 5 years. Unfortunately, it was at a level (2000IUs) that could leave many people at subnormal levels of vitamin D. 1000 IU will bring up blood levels 5 ng/mL. 30 ng/Ml is considered okay. Many people believe that levels between 60-100 ng/mL is better. I have a genetic defect that keeps me below 30ng/ml regardless of sun exposure. I supplement at 15000 IU per day. Which brings my levels up around 70-90ng/mL
[+] amai|5 years ago|reply
It's the magnesium, stupid!

Dai (2018): Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial https://pubmed.ncbi.nlm.nih.gov/30541089/ "Our findings suggest that optimal magnesium status may be important for optimizing 25(OH)D status. "

Coincidence?

"Vitamin D is currently the only Essential Vitamin or Mineral which appears to have deficiency rates at a similar level to Magnesium"

https://examine.com/supplements/magnesium/research/#nutrient...

[+] ComputerGuru|5 years ago|reply
I don’t want to be the contrarian that persists in the face of scientific evidences, but I will point out that none of the RCTs listed combined Vitamin D with supplementation of Vitamin K, which several studies suggest plays a synergistic role when it comes to the health benefits. This OSU link covers a number of such studies: https://lpi.oregonstate.edu/mic/vitamins/vitamin-K
[+] api|5 years ago|reply
The most obvious evidence to me has always been that Europeans are not black. A change like the loss of melanin requires selective pressure, which in this case was likely furnished by less vitamin D as we migrated away from the equator. The pressure must have been significant since being white carries a big downside: higher vulnerability to sunburn and skin cancer. When I lived in Cali I always envied my darker skinned friends who did not have to smear goo on themselves at the beach.

I gotta say though... the world would have far less race problems had that odd little quirk of photosynthesis of a key nutrient not existed.

[+] ComputerGuru|5 years ago|reply
> I gotta say though... the world would have far less race problems had that odd little quirk of photosynthesis of a key nutrient not existed.

Humans being humans, I’m sure nose shape, eye color (just ask Bran Sanderson), hair color/texture, or something else would readily suffice in the absence of a perceptible difference in skin tone.

[+] tchaffee|5 years ago|reply
> A change like the loss of melanin requires selective pressure

It does? What about genetic drift, random mutations, and artificial selection, where humans select based on qualities not necessarily conducive to survival?

There is also some evidence that this change in skin color was only widespread as recently as 8,000 years ago [1].

> which in this case was likely furnished by less vitamin D

How likely?

> The pressure must have been significant since being white carries a big downside: : higher vulnerability to sunburn and skin cancer.

Unless you are trying to hide from predators or your prey in snow? As far as skin cancer, as long as it doesn't kill you before you breed, it's not going to have a big impact on natural selection, right?

[1] https://www.smithsonianmag.com/smart-news/heres-how-european...

[+] meiraleal|5 years ago|reply
> I gotta say though... the world would have far less race problems had that odd little quirk of photosynthesis of a key nutrient not existed.

Not really, Europeans alone are capable of the same level of mess, before and after slavery.

[+] LinuxBender|5 years ago|reply
Perhaps I missed it, but I did not see the study including K2 MK-7 and magnesium with D3. The 3 work together and can not support all of the metabolic functions on their own in a silo. There are also enzymes and co-enzymes that are part of the picture and I did not see any mention of them. Is there a more detailed version of the study? Again, could be me, I may have overlooked a link.
[+] mola|5 years ago|reply
This is wonderful scientific writing; approachable without being condescending or over simplifying, without a trace of sensationalism. Really beautiful.
[+] oa335|5 years ago|reply
I would have loved to see some of her advice and information dis-aggregated by race.

Low Vitamin D levels of are not evenly distributed among different ethic groups. e.g. "53%–76% of non-Hispanic blacks [ had low vitamin D levels, in the Southern U.S.] compared with 8%–33% of non-Hispanic whites [0]".

Thus the risk-reward considerations of taking vitamin D are likely different for dark-skinned individuals than for light skinned individuals.

I have to assume her advice at the end is targeted at light-skinned people. As a dark-skinned person myself, I'm irritated that she couldn't bother to at least mention the above issues.

[0] https://academic.oup.com/jn/article/136/4/1126/4664238

[+] jeffreyrogers|5 years ago|reply
Shouldn't they be looking at getting vitamin D via sun exposure, rather than supplementation? If the real benefit is sun exposure, which also increases vitamin D, then just supplementing vitamin D won't show any benefits.
[+] lprd|5 years ago|reply
I have a couple questions for any doctors out there.

How many times a year should one check his vitamin levels?

I live in Paris, and during the winter months we don't get that much sunlight. My doctor gave me a prescription for vitamin D3 (100,000 IU vial, once a month, for three months). Is this a good dose for the year (provided you get adequate sunlight during the summer months)? How long does vitamin D3 stay in the body until it uses/flushes excess out? Are you better off taking a high dose like this for 3 months, or adopting a more slow and steady method (i.e. supplementing daily).

[+] burgerquizz|5 years ago|reply
I've seen a well explained video about a study[1] saying vitamin D3 helps in reducing severity of COVID19. What's your argument(s) against it?

[1]https://www.youtube.com/watch?v=V8Ks9fUh2k8

[+] devaboone|5 years ago|reply
I didn't watch the whole video but I read the study. There is a lot of excitement about this study, but the details in it matter. It was randomized - but when you look at the two groups (treatment vs. control), they had some key differences. The control group (who didn't receive Vitamin D) had more men (69% vs 54%), more people with hypertension (57% vs 24%) and diabetes (19% vs 6%). These are all areas that increase the risk of severe disease. So the groups were not the same. If you just compare the numbers of those who went into the ICU vs. not, then the results look amazing. But once you correct for hypertension and diabetes, it was not so impressive - it was not statistically significant in the study. This does not mean that I think Vitamin D has no effect. There is some evidence for Vitamin D in respiratory illnesses. But the effect is not as dramatic as some of the headlines for this study would imply.
[+] jahlove|5 years ago|reply
OP's article does not address Vitamin D's effects on COVID.
[+] zzzeek|5 years ago|reply
correct me if I'm wrong (like that ever happens on HN...) but even mainstream SSRIs like Lexapro (which I am taking, I'm a lifelong depressive, thanks) probably get a big red X in "prevention of depression". trying to "prevent depression" is like trying to grab Jell-O.
[+] DoreenMichele|5 years ago|reply
A few thoughts:

Expecting vitamin D supplementation to be some cure-all is silly on the face of it. It's like saying "Your building has a brick deficiency" after some disaster does egregious harm to it and then ordering a bunch of bricks or starting a charity to give away free bricks to the entire community after a hurricane levels things.

Yes, bricks may well be a critical ingredient necessary to rebuild, but getting a giant pile of bricks dropped at your front door is the start of the rebuilding process, not the end of it. And then you will find that you may not able to do anything with your pile of bricks because there's no mortar to hold them together or there are no skilled brick layers available.

The body is a very complex machine. It really shouldn't surprise anyone that a simple solution -- like "needs more vitamin D" -- isn't going to miraculously get it working better across all categories of things that can go wrong, either due to a deficiency or in a way that will cause a deficiency.

[+] RL_Quine|5 years ago|reply
For other reasons I get tested for vitamin D every few months and managed to get my levels just above the normally recommended amount as per doctors advice. When people are saying they’re taking 25-100k UI a day I’m just stumped why they’d be doing that without medical advice, the amount to change my levels was nothing in comparison.