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Effect of High-Dose Vitamin D on Volumetric Bone Density and Bone Strength (jamanetwork.com)
131 points by bookofjoe 7 days ago | hide | past | web | favorite | 71 comments

I thought you needed both vitamin D and vitamin K2 - D to mobilize the calcium and K2 to put it into the right place.


In my mind that’s what makes this kind of a garbage study.

Alongside focus on just osteoporosis, lack of control for calcium levels (other than blind supplementing with low dietary intake), phosphate levels.

Some people may be responding poorly to the supplement, especially at high doses and low calcium. Direct blood test for status would help.

CAC tests are a good indication if D3+K2+mag is mobilizing calcium. That is of course if your current CAC score is above 0 which it should not be.

I wonder if taking mega-doses of vitamin D without K2 would drain the subject's stored supply of K2, leaving none for other processes in which K2 plays a role (?)

Also... Magnesium!

And... Strontium!


In other words, a lack of Vitamin D reduces bone strength but getting more than necessary doesn't increase bone strength any further.

Makes sense. This is often how the body works. You should get enough of <nutrient> but having more than needed doesn't turn you into a superhero (but it can be poisonous).

To preface here, what I'm to share goes beyond what's in the article. That said, I worked for years in a clinical "bone lab" (and at a notable university hospital with respect to this area of research) investigating bone wasting diseases; namely, idiopathic hypercalciuria, and osteopenia & osteoporosis.

Not say that lends me too much authority on the matter, but many of the biological effects of D3 are pretty poorly understood, still. Simplifying a bit, this can be chalked up to the fact that it's roles in molecular networks across the systems are myriad, and of these, many of its (downstream) effects seem -- and, if not, are -- contradictory. (To the initial point, in it's bioactive form, it's classified as a hormone.)

At high dosages, typically what's found it many OTC supplements (5-10K IUs vs 500 IU daily allowance), there is evidence that it facilitates significant bone resorption.

So not only does it not strengthen bones, D3 actively makes it more brittle. Typically, this is linked to inadequate calcium & phosphate minerals to match the excess D3 (and these minerals in excess introduce additional problems of their own).

I didn't cite literature here but it is readily available & abundant (But I can pull some if anyone would like). And, within it, there is a glaring lack of consensus. And hence, why my language is couched in so many conditionals.

One of the big asterisks with most D3 bone density studies(and is applicable to this one) is that they are studying older adults specifically, vs, say, athletes. There are bodybuilders, for example, who swear by high-dose D3.

If you exceed calcium and phosphates intake by an amount sufficient to compensate for the excess D3, does that "do the trick" or is that a bad hack? I've seen certain 9 pills a day multivitamin formulations who deliver much much higher than the daily dose of everything, I think Life Extension sells them, and I'm wondering if they are hip to these facts.... I used to buy their vitamins. Now I just take the ones that are one a day pill instead of 9, and those never exceed the daily IUs.

Another question for you, does supplementation work as intended when our diet is insufficient, or is it just a gimmick? I've always wondered about this. By work, I mean, if you were to have a blood test in two parallel trials, one where you supplemented but had a crappy diet and another where you ate the "perfect" diet that supplied the daily IU needs, would the blood work show equal amount of each mineral/vitamin/etc in both cases?

Wiki on bone resorption says the opposite, not sure at what intake levels though:

>Vitamin D increases absorption of calcium and phosphate in the intestinal tract, leading to elevated levels of plasma calcium,[4] and thus lower bone resorption.

Why are there so many studies looking at vitamin D and bone health? Vitamin D levels affect expression of over 400 genes in the human body, make a difference in cancer survival and are strongly inversely correlated with all cause mortality (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103214/ https://www.mdedge.com/psychiatry/article/66349/depression/v... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201256/). Does the lay person really only associate vitamin D with bones?

Assessment of single specific claims has merits.

Essential vitamins are clearly important to multiple health and fitness pathways. But identifying which specific pathways, results, and mechanics has value.

Bones and SAD.


Time to start taking vitamin D

You would probably benefit more from being out in the sun than from taking vitamin D supplements.

Yeah, and possibly die of malignant melanoma. At the same time, no sun exposure is also a risk of melanoma - not sure if due to vitamin D or more possibly - due to the hormetic effect of mild skin DNA damage.

A little daily sun exposure won't significantly increase your risk of melanoma (unless you have a rare genetic disorder).

True, but you get enough vitamin D - especially not during the winter.

The only supplement that the NHS recommends is taken by the bulk of healthy adults in the UK - especially during winter months.

Being a dialysis patient, I have to deal with a lot of the issues of my kidneys not functioning. There is a complex interplay of vitamin D, PTH (from parathroid), phosphorus, calcium levels and bone loss. So I have to take vitamin D, calcitriol and phosphrous binder and dietary restrictions to balance it all. Going too far one way or the other is not good. Every month I get blood tests for all these things and my doses adjusted. Vitamin D is the least of my concern in this process.

Dialysis sucks. It takes away so many of life’s little pleasures. My best to you, brave person.

The kind of treatment I'm having isn't so bad. Its just the time it sucks up plus the inconvenience of travel. I haven't gone on an out of town vacation is ages because of all the equipment I have to drag along. The best I can pull of is weekend trips and stay-cations.


One of my favorite articles. Vitamin D supplementation has a very poor track record of doing anything positive. It’s very likely that most of the studies attributing benefits to vitamin D and correlations between serum vitamin D and health are because it is a surrogate marker for getting sunlight, which may be the real health improver. When we supplement with D in properly controlled studies, the health benefits disappear.

To those who only read the HackerNews title and not the title of the actual article, it does not say that Vitamin D does not strengthen bones, but rather higher does don't seem to strengthen more than lower doses, not compared to not taking any at all as one would probably interpret from the HackerNews title.

I don't think "compared to not taking any at all" is an accurate summary here. Even if you never touch a Vitamin D supplement, many people are already getting an amount comparable to the baseline used in this study from a typical diet, or from sun exposure.

Except, say, for 6-9 months every year if you're vegan and living in cold climates...

2/3 of Americans get the RDA of Vitamin D. Picking a specific outlier case for your control group wouldn't make a lot of sense for a scientific study (not to mention, as others have pointed out in this thread, would be difficult or unethical.) If you are a vegan living in a low-sunlight location, look into supplementation.

So you're saying 1/3 of Americans don't get the RDA of Vitamin D, yet calling 33% of cases "an outlier"

I'm not vegan and I actually take Vitamin D3 supplements, but wanted to point out the flaw in assuming that everyone is in the same bucket as me.

I'm saying that probably a very tiny percentage of Americans get 0 IU. Which makes 0 IU a very poor choice of a baseline. Since you need some concrete amount to use for your control group, what would you propose using?

> hree-year, double-blind, randomized clinical trial conducted in a single center in Calgary, Canada, from August 2013 to December 2017 ...

Generally speaking, interesting to consider that Calgary is a fairly northern city and they say more northern people get less natural VitaminD from sun exposure... So even in a generally vitaminD short populace the results are showing no stronger of bones. I say all this iirc, not from specific scientific sources...

D3 is converted to 1,25(OH)2-D3 which is the active form. The transformation is limited by 1α(OH)-ase which in turn is regulated by levels of calcium and PTH and degraded by renal 24-OH-ase, which previous work has shown is upregulated by high 1,25(OH)2-D3, and 25(OH)D (formed in the liver from the oral cholecalciferol), thereby providing a brake on the system. It has also been shown that the upregulation of 24(OH)ase can be enough to actually decrease 1,25(OH)2-D3 levels, thereby resulting in osteoclastic activity. PTH is also suppressed by high 1.25(OH)2-D3.

tl;dr there are homeostatic mechanisms in place in calcium metabolism that result in a "counterintuitive" reduction in the active metabolite with supraphysiologic supplementation. Also, this is actually in line with prior work, though the authors don't mention any of it until the discussion at the end, and then only two papers. In about 5 minutes of searching, I found papers going back to 1995 suggesting the same thing.

It isn't counterintuitive. Too much calcium (especially in the absence of mangesium) hurts your bones (and many other things)

I have osteomalacia, and I have suffered 4 bone fractures in the last 4 years, two spontaneously: one during my sleep, and one while twisting in my car to pick up something from the passenger seat.

I take Vitamin D, Calcium, and alendronate (Fosamax), and when the sun is out, I go out for a while without sunscreen.

My last DXA (2.8 years ago) had a Z-score of -2. I'm only in my 40's, so I don't have a T-score.

I don't really care about the validity of this study. I just know I have to take Vitamin D and Calcium supplements regularly, and Magnesium less often, but regularly.

Folks on reddit we’re saying this isn’t a useful study because they’re not considering the roles of vit K and magnesium.

I mean no one really expects vitamin d by itself to improve bone density. It’s but one step in the process.

The results confuse me. Taking 4000 or 10,000 IU results in lower bone mineral density than 400. Is lower BMD better? Otherwise it sounds like vitamin D is actually bad for you.

The study is saying that too much MIGHT be bad for you. 400IUs was the control (not 0). Some vitamins have adverse effects in high doses. Vitamin D might be one of them, but the study just posed the question, it didn't conclude that that was the case. It would take more studies to confirm that.

The reduction is very small, but the 400 group also had lower mean BMD.

Yes, it appears that too much vitamin D may decrease bone density.

A larger, longitudinal study would be awesome for establishing other Vitamin D claims (in particular, reduced MS incidence and reduced cancer incidences)

As with all Vitamin D studies, this one should discuss or acknowledge the differences in intake requirements for people of different ethnic groups. It doesn't, which means that for some of us, the findings balance somewhere between useless and dangerous.

Magnesium is also a part of this!

So high doses reduce mineral density but have no effect on strength? How is that possible? Is strength not a function of density?

Here are two possibilities:

1) It probably easier to measure density than strength. Additional measurement noise could mean the strength difference is not statistically significant while the density difference is.

2) The relationship between density and strength is probably not a simple 1:1 linear function. For example a 10% bone mass reduction may only result in a 1% strength reduction. Therefore one many be statistically significant while the other is.

Likely is is a combination of factors like this. Things are rarely simple in the lab.

Isn't that a pretty narrow age group?

"mean [SD] age, 62.2 [4.2] years"

It's actually good for the purposes of the study, as the highest risk populations for decreased bone mineral density are elderly populations. We know from multiple studies that women are at highest risk due to decreasing estrogen levels post-menopause, and around peak risk around age 65 (hence why it's recommended to get osteoporosis screening done at age 65). Men aren't quite as susceptible as our testosterone levels are relatively stable, and maybe including them isn't the best of ideas. However, proportion of gender is nearly equal in all treatment arms of the study, so it shouldn't skew the results.

I thought calcium had a bigger impact on bone density than Vitamin D?

Generally the greatest way to increase bone density is to lift "heavy" weights. Compared to that any other solution pales in comparison but doctors never seem to prescribe that.

Many things in the weight lifting world revolve around 3 things:

1. Stimulus: ie lifting heavy, nutrients to support hormonal response

2. Materials: ie Calcium / minerals

3. Rest: ie Sleep, recovery time etc.

I would expect any isolated intervention to find lackluster results despite considerable results in conjunction.

Many doctors will prescribe D megadoses for patients with at-risk bone density. I guess this is saying to not do that.

The study ensured that all participants had adequate calcium by supplements as needed.

There is no documented positive effect above 300mg/day.

300 milligrams!?!

Current advice is don't take more than 100 micrograms per day.

Calcium, not vitamin D.

Well yes, but Vitamin D is needed to absorb calcium. So both are needed in adequate quantities. One without the other will be ineffective.

Headline is imprecise. The study is saying that higher doses of vit D do not strengthen bone more than lower doses, not that they don't strengthen bone at all, which is suggested by this headline.

As usual, the headline ought to be taken from the publication. Bone strength was virtually unchanged for every group in the study; no participant had osteoporosis. Mean BMD went down a hair for all groups, but estimated failure load was considered statistically the same:

> At trial end[...]

> mean percent change in [radial] volumetric BMD of −1.2% (400 IU group), −2.4% (4000 IU group), and −3.5% (10 000 IU group).

> mean percent change [...in tibial volumetric BMD] of −0.4% (400 IU), −1.0% (4000 IU), and −1.7% (10 000 IU).

> There were no significant differences for changes in failure load (radius, P = .06; tibia, P = .12).

Agreed the differences look small but find a copy of the full article (I would link but I saw a hard copy). The time curve will convince you this effect is real. All participants start at the same place and you see the dose curves move apart over time and very consistently. What definitely isn’t clear is whether vitamin D supplementation is benefiting the participants at all, thanks to their lack of a proper control.

The bone density decreases may look minor on paper but look at it this way: it’s quite possible that a very large cohort of elderly and middle aged people concerned about their bone health (potentially because they were told they have reason to be concerned) have been paying a lot of money annually to actually worsen their situation. That sucks.

I'd trust EPIC series more, even though it's not RCD. They showed J-curve for all cause mortality and morbidity with best inflection point around 1500-2000 IU. The curve is somewhat flat above this.

One of the findings (there's a summary somewhere): https://epic.iarc.fr/highlights/vitamindcolorectal.php

It's not too imprecise, I initially interpreted it to mean the correct thing. If anything, it's a mistake, not an attempt to clickbait.

>Interventions: Daily doses of vitamin D3 for 3 years at 400 IU (n = 109), 4000 IU (n = 100), or 10 000 IU (n = 102). Calcium supplementation was provided to participants with dietary intake of less than 1200 mg per day.

>Main Outcomes and Measures: Co-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis.

>Conclusions and Relevance: Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful.

Headline is not imprecise according to above-cited Conclusions and Relevance.

> Headline is not imprecise according to above-cited Conclusions and Relevance.

No, aladoc99 is right, because the study doesn't compare against 0. So you don't know if 4000 and 10000 improve strength compared to 0, only that they don't compared to 400. It's not a hill that someone should die on, though.

Nobody has 0 intake, that is a useless control; nor would any IRB sign off on such a study, because it would be harmful to the subjects.

> Nobody has 0 intake

And thus we have ourselves a quandary, but truth isn't diminished by the practical limits of safe experimentation. We don't have to lie just because.

> it would be harmful to the subjects.

That doesn't make the title precise or the observation inapt.

The experiment itself may be useless control; most people get D vitamins from the sun. How do we know the cohorts got the same D from sun exposure?

Should use a blood tests for vitamin D status, probably calcium, phosphate and K too instead of relying on self reported diet.

If you avoid animal foods the only dietary vitamin D really is from fortified products. However we also synthesize it, albeit poorly as adults, particularly with lower exposure to the sun.

Plenty of people have 0 supplementation though.

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