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Vitamin D: The Evidence for Higher Doses

Vitamin D: The evidence for higher doses with Dr Michael Holick

For more than a century, scientists have recognised that Vitamin D3 is involved in bone health. The latest research, however, shows that Vitamin D3 deficiency is linked to a range of other health conditions such as depression, back pain, cancer, both insulin resistance and pre-eclampsia during pregnancy, impaired immunity and macular degeneration.

While it is clear that a large percentage of individuals are deficient, what is also becoming apparent is that our previous understanding of adequate dosing is way off the mark.

In this FX Medicine podcast Professor Michael Holick is interviewed on the latest evidence in support of higher dosing of vitamin D and the most recently identified health implications for deficiency.

Covered in this episode

[00:16] Welcoming back Michael Holick
[01:00] Serum vitamin D levels
[07:02] Asthma in infants and vitamin D
[08:54] Vitamin D and glucose metabolism
[11:45] Vitamin D in children
[18:18] Dosing in patients with liver or kidney issues
[20:45] Vitamin D and myalgia
[22:46] Vitamin D and myasthenia gravis
[23:40] Vitamin D and migraines
[24:56] Using other nutrients alongside vitamin D supplementation
[27:08] Vitamin D deficiency and other chronic diseases
[30:38] Screening for vitamin D in Australia


Andrew: This is FX Radio, and I am Andrew Whitfield-Cook. And with me on the line today is none other than the esteemed professor Michael Holick from Boston University. Now Michael is the Professor of Medicine, Physiology, and Biophysics, Director of the General Clinical Research Unit, Director of the Bone Health Care Clinic, and Director of the Heliotherapy, Light, and Skin Research Center at Boston University, and I've often said he's basically the professor of everything. But also interestingly, Professor Michael Holick was recently listed by Thomson Reuters as one of the most influential minds of the last decade. And I'd like to welcome Michael Holick once again to FX Radio.

Michael: Thank you, Andrew. It's a pleasure to be on with you.

Andrew: Always a pleasure to chat with you, Michael, and I can chat with you for hours because I just get so caught up in what you've got to say and we've got some very interesting topics to go through today. And the first one is a very interesting recent paper, which is a meta-analysis of all-cause mortality according to serum vitamin D levels. Can you comment on that paper, please?

Michael: Sure. This is Cedric Garland, and he's been kind of the pioneer in appreciating back in the 1980s that people who live at higher latitudes are more likely to develop prostate, breast, and colon cancer. And began to introduce the concept that vitamin D was really important for reducing risk for chronic diseases. But recently, as you're probably aware that there has been a lot of controversy about how much vitamin D one should be taking…

Andrew: Yeah.

Michael: …because, possibly, if you increase your vitamin D intake, as the Institute of Medicine had suggested, that yes, it's true, if you're vitamin D deficient, you increase risk for mortality. But if you now get to that magical number of about 75 to 80 nanomoles per litre for 25-hydroxy vitamin D, all of a sudden there was this little uptick in mortality…

Andrew: Yep.

Michael: …suggesting the possibility that, hey, wait a minute, you can't take too much because it's going to increase risk. So, Cedric Garland went through a large number of papers and did a very careful meta-analysis and found, just like the Institute of Medicine, that yes, that if you are vitamin D deficient, you're more likely to die. And that if you improve your vitamin D status, you reduce your risk for dying. And what he also found was that that slope continues to drop, that line continues to drop not only when you get to 75 nanomoles per litre, but it's sustained out to about 250 nanomoles per litre.

Andrew: Wow. That’s very interesting.

Michael: And that's important because it really can give us a level of comfort that improving people's vitamin D status is good for their overall health and well being and reduces risk for mortality, period.

Andrew: And this was backed up by another recent study, or paper, by Marshall, David Marshall, and the group. Looking at 4,000 IU per day for one year results in a decrease what's called positive cause, with repeat biopsy with prostate cancer.

Michael: Correct. And there is also some additional evidence to suggest that if you do have prostate cancer and you do improve your vitamin D status, that you may be able to improve disease outcome, as well.

Andrew: So, this is very interesting that there appears to be no J-curve. Is that what they're saying? Or is it that this J-curve is associated with other factors?

Michael: Right. So, at least from his study, demonstrated there was no J-curve. And as we've had the conversation before, and at a recent NIH conference that I attended in December of last year, I challenged the Institute of Medicine and the concept of their J-curve that a lot of others had begun reporting about, for the following reason. Typically this J-curve begins to uptick at around 100 nanomoles to 150 nanomoles per litre. So, the first question you have to ask is, who is maintaining a blood level of 150 nanomoles per litre? This likely is a person that maybe is being treated for vitamin D deficiency. So, if that was true, then they would have had whatever chronic illness was associated with vitamin D deficiency. And to suggest that because they have now been treated for vitamin D deficiency and they still have the risk for the chronic illness, for example, prostate cancer is a good example, pancreatic cancer. That indeed they have the risk because they were vitamin D deficient for a long period of time.

Andrew: Yeah, that's right.

Michael: We actually did a study and it's going to get published in PLOS One, probably within the next couple of weeks. Where we asked a question, and the U.S. population of over 3 million samples measuring 25-hydroxy vitamin D, and asking the question, who is above about 150 to 200 nanomoles per litre? And we have some good evidence that in fact, more than 50% were likely being treated for vitamin D deficiency.

Andrew: The other group of people that have very high vitamin D levels, of course, are the Maasai warriors, which you've previously been associated with. Indeed, I understand that you were inducted into their tribe. Is that right?

Michael: There you go. I actually was out in Kenya and visited with them. And we've now done another study in African children and found the same thing that was reported by Luxwolda, where he found that Maasai warriors and other African natives that live in the bush, their levels, on average, were about a 100 to 150 nanomoles per litre for 25-hydroxy vitamin D. And we have some data now in African children who are outside all the time, levels about 40 to 50 nanomoles per litre, even though many of them have nutritional deficiencies, but their exposure to sunlight has helped to preserve their vitamin D status.

Andrew: So, what level of vitamin D were you finding in children, in African populations?

Michael: The same as they found in the Maasai warriors, at around a 100 to 150 nanomoles per litre.

Andrew: So, that's very interesting because I'm just looking at a paper here regarding pregnancy and vitamin D, looking at asthma. It's an Australian study by Jones, and Prescott, and the group. And what they found is that infants who had levels above 75 nanomoles per litre, were at decreased risk of asthma, is that correct?

Michael: That's correct. And that's a really, you know, very nice study. It's well done. And, you know, they looked at innate immune responses during the first six months of life. And, you know, very nicely demonstrated that improvement in vitamin D status can definitely have a significant health benefit.

Andrew: So, this is really interesting because it's looking at the, basically the immune imprinting or the immune priming of the infant immune system.

Michael: Exactly. And so, yeah, they looked at a variety of factors and showed very nicely that one of the interleukins, like interleukin 13, for example, which is associated with increased risk for asthma, that there's an inverse correlation with blood levels of 25-hydroxy vitamin D. And so, the bottom line was that they felt that the higher blood levels of 25-hydroxy vitamin D at six months was associated with increased responses for these, what are called toll-like receptors, which play an important role in innate immunity.

Andrew: So, with the vitamin D, that's affecting what's called the FOXP3, is that correct? And that's interacting with the retinoid X receptor, to sort of cause a balance?

Michael: Yeah. There's a whole variety of fundamental genes that it appears that vitamin D is having some role to play in controlling them.

Andrew: It's really interesting stuff, isn't it?

Michael: It's amazing. And, we'll talk in a minute about a recent study that was published in a Journal of Biological Chemistry, where they have now looked at the active form of vitamin D regulating glucose metabolism in fat cells.

Andrew: Well, let's talk about that, because previously Dr Jenny Gunton at Westmead Hospital found that there was real issues with diabetic women, a huge deficiency of vitamin D3, and so she supplemented in that group. Tell me about this new paper.

Michael: So, what this new paper is suggesting is that it's been suggested that vitamin D supplementation will help lower glycemia in diabetes. But the explanation for it, you know, still remains elusive. And that this study that was performed by Jain, J-A-I-N and colleagues showed that 1,25-dihydroxy vitamin D, the active form of vitamin D, upregulates glucose transporter activity by improving translocation and glucose utilisation in adipocytes, so, in fat cells. And that, of course, is very important because often patients who are obese and develop insulin resistance, that it could be that vitamin D can help to fight that. And that's consistent with what the literature has suggested.

Andrew: Is there any evidence to show that vitamin D can also help reduce the inflammatory blockade with regards to leptin?

Michael: Yeah, there is some evidence for that. We actually had published a paper a couple of years ago looking at pre-adipocytes and the adipocytes recovered from subcutaneous fat and omental fat from biopsies. And we could show that leptin, adiponectin, and several markers for inflammation seem to be regulated by the local production of the active form of vitamin D within the cells. You know, we've talked about this before…

Andrew: Yeah.

Michael: …in our last conversation, we talked about gestational diabetes and how important it is for pregnant women to be taking an adequate amount of vitamin D because gestational diabetes has been associated with vitamin D deficiency, as has been preeclampsia. So, I think, you know, that there continues to be very good evidence to suggest that improvement of your vitamin D status could reduce your risk for developing type two diabetes as well as gestational diabetes during pregnancy.

Andrew: So, I think also that previously we didn't know about how much to give. And we've shown with the work from Bruce Hollis, that 4,000 IU in pregnancy is shown to be safe. I think Jenny Gunton gave 5,000 IU. But also, now what we're seeing is that children may well require above 75 nanomoles per litre to have adequate immune priming, correct immune priming with vitamin D. So, we really need to be looking at the adjustment of the dose to pregnant women and potentially children up. Is that correct?

Michael: Yeah, that's correct. I mean, there's essentially very little known about how much vitamin D is required for children, for their maximum health. We're now underway studying this to some degree in older children. But it's very difficult to be able to do these studies in younger children. There's a major study underway in Boston that I'm participating in where they're giving school children 2000 units a day and looking at a wide variety of parameters, including their growth spurt, blood pressure, weight, and all kinds of other issues, and we're in the process of analysing that data now to give us a better insight as to how much vitamin D a child truly needs to satisfy their requirement.

Andrew: Tell me about growing pains and how you would suspect that there may be a vitamin D deficiency in children, because you've got a couple of really nice, handy hints.

Michael: Yeah, it turns out that osteomalacia, which is basically a mineralization defect of the skeleton, can cause throbbing, aching bone pain. And so, typically you think about vitamin D deficiency in children causing rickets, but that usually only occurs in the first few years of life before a child can put an adequate amount of calcium in the skeleton, so they don't have the influence of gravity causing any deformation of the bones. But a growing child is rapidly growing. If they're vitamin D deficient and they have osteomalacia, they very well could be having aches and pains in their bones and muscles, especially in their hip region. And we found that just increasing vitamin D intake in some children, that a lot of these so-called growing pains resolved.

Andrew: And so, talking about the hip region, what about when you've got those, you know, the achy shins and the achy knees at night in kids. I remember them as a child.

Michael: I think that, I mean, we know that vitamin D deficiency can cause what are known as pseudo fractures or what are called Looser zones. That's a classic sign where you have these splits in the cortical bone that is horizontal to the bone. And we can see that that can cause a lot of discomfort and pain, and often due to vitamin D deficiency. Shin splits, for example, where they have these microfractures can, in fact, be precipitated by vitamin D deficiency.

Andrew: Yeah. And so your treatment for that would be what? What level of vitamin D would you give, and sunlight exposure?

Michael: Yeah, I mean, the sunlight exposure, what you need to do is to be thoughtful about it. So, if you use the app dminder.info, it will tell you exactly how long to stay outside and then to go into the shade or to use a sun protection so you don't get a sun burn. I typically recommend, if you know you're going to get a mild sunburn after 30 minutes outside, that's arms, and legs, abdomen, and back when appropriate for about maybe 10 minutes, followed by good sun protection, but always protect your face. It's the most sun-exposed and most sun-damaged and doesn't provide you with very much vitamin D. 

Andrew: Yeah.

Michael: But we do recommend based on the Endocrine Practice Guidelines that children should be on at least 600 to 1000 units of vitamin D a day. And from my experience, I think that teenagers should be considered like adults, they should be on at least 1500 to 2000 units of vitamin D a day.

Andrew: And that's if they're not obese. If they're obese, then that blows out to three to five times that dose, correct?

Michael: That's correct. And in fact, there was a really nice study done out of Canada that helped to support this concept. The Endocrine Practice Guidelines had recommended this based on limited data. But there's a study being done now in Calgary by the Pure North group, and what they're doing is that they're giving large doses of vitamin D to the population at large in Calgary, and then they've been documenting how much vitamin D they're taking, and what was published in PLOS One late last year, and I co-authored the paper with Dr Veugelers and Ekwaru, showed that people could take up to 20,000 units of vitamin D a day and not raise their blood level above about 200 to 250 nanomoles per litre. There was no toxicity, and if you looked at body weight, there was 2.5 times more vitamin D to reach the same blood level of 25-hydroxy vitamin D.

Andrew: So, there's two things there. One is the issue of, obviously, obesity in our society, which is a separate issue, and vitamin D may indeed help in at least some of the...unlock some of the blockages in that, some of the inflammatory blockages in the signaling of obesity and hunger. The second one is obviously that the dose has been shown to be extremely safe because we can break down vitamin D the more we get, and particularly in issues where obesity, where we can't use it.

Michael: All correct. Yes. In fact, it's the, what's called the 24-hydroxylase that's present in most cells in your body that have a vitamin D receptor and then the major source is probably your kidneys, and so any excess active form of vitamin D or 25-hydroxy vitamin D can be rapidly destroyed by the 24-hydroxylase and it metabolises it basically to a water-soluble inactive metabolite.

Andrew: And so, can I just maybe ask for a caveat there. So, in those people that might have liver disease or kidney disease, then these elegant homeostatic mechanisms of vitamin D control might be out of whack. And so it's worthwhile in these populations to measure their vitamin D levels, correct?

Michael: For sure. I mean, patients with chronic liver failure have malabsorption, and so as a result, they don't absorb vitamin D very well, so they definitely should be followed. For patients that have severe liver dysfunction, they possibly can't adequately make 25-hydroxy vitamin D so that they need to be carefully followed as well. 

Andrew: Yeah.

Michael: But the major issue for liver disease is malabsorption of vitamin D. Regarding kidney disease it's different story because they can't activate vitamin D. But even the international kidney guidelines recommend that all patients, no matter what the level of chronic kidney disease, that they should maintain a blood level of 25-hydroxy vitamin D of greater than 75 nanomoles per litre.

Andrew: So, in the kidney patients, is it worthwhile supplementing with vitamin D if they can't activate it? Shouldn't they be receiving either the intermediate or indeed, the 1,25-dihydroxycholecalciferol?

Michael: That's what you would think. What we now recognise is that the parathyroid glands, for example, have the ability to convert 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D.

Andrew: Right.

Michael: So, if you raise the blood levels of 25-hydroxy vitamin D, me and others have shown that you can actually decrease the PTH levels independent of other therapies. So, the guidelines, both the national guidelines in the United States and the international guidelines for kidney doctors, they all recommend that all patients with kidney failure should be also receiving vitamin D, maintaining blood levels of at least 75 nanomoles per litre for 25-hydroxy vitamin D. And that if they have CKD 4 and 5 for example, where they can't make enough 1,25 dihydroxy vitamin D, they will benefit by receiving 1,25-dihydroxy vitamin D or one of its analogs, independent of them, definitely still receiving vitamin D.

Andrew: Michael, we've spoken about bone pain in children, but what about myalgia in adults? Muscle pain in adults related to low vitamin D levels? There's a very interesting paper by Moore and Levy, from Wayne State University. I think it was from 2014. Can you comment on that paper, please? And what's the pragmatic, or practice points, with regards to vitamin D in muscle pain?

Michael: Sure. I mean, basically, we've always known that vitamin D deficiency, increases risk of proximal muscle weakness. We also know that, especially in wintertime, people just feel achy, and they have these global myalgias and often they think that it's due to fibromyalgia, chronic fatigue syndrome, or the physician just throws up their hands because they just don't really know what's going on. And often these patients are suffering from vitamin D deficiency. And this paper, you know, documented very nicely that in their patient population that they had significant improvement in myalgic symptoms by correcting vitamin D deficiency.

Andrew: So wouldn't that also be relevant? I understand there's a few papers looking at vitamin D and... Sorry, forgive me, vitamin D deficiency in statin-induced myalgia. Correct?

Michael: Correct. And so, we and others have speculated, but there aren't really any good data out there yet that have clearly demonstrated that association. We're very suspicious that they're in some way associated. And I find in my patients that are on statins that I will treat them with vitamin D to see whether or not I can reduce their myalgic-like symptoms and in some cases, quite successfully. But not in all cases.

Andrew: Yeah. What if somebody had the suspected diagnosis of myasthenia gravis? Would you institute, along with other therapies, a vitamin D trial?

Michael: Yeah. I don't think there's any question that, you know, it's an autoimmune disease and we know that improving vitamin D status can improve your immune system. I mean, we had demonstrated that a year ago where we gave 2,000 units of vitamin D a day to healthy adults and showed that we could up or down-regulate about 291 genes in their white blood cells. So, we think that, indeed, improving vitamin D status for everyone, especially those with autoimmune diseases, can definitely be beneficial along with the appropriate medications to help in treating these particular disorders.

Andrew: With regards to vitamin D in migraine treatment, where are we now with the evidence? There were some pros and there was a couple of negative studies saying, oh, no, there isn't really an association. What's your stance on this? What do you find clinically?

Michael: Clinically, I mean, migraines, you know, are often, can be associated with, you know, significant muscle spasms, especially the muscles in the back of the neck, that can sometimes precipitate these. And we find that improving their vitamin D status can help give some muscle relaxation. So, they have decreased frequency for migraines as well as decrease in the intensity of the migraines.

Andrew: And do you tend to use other therapies with them, or do you stick to mainly drug therapy, or do you use other nutrients involved in that as well?

Michael: Right. So, I mean, you know, the standard therapy is...it works reasonably well. So, we definitely will use that along with treating them for the vitamin D deficiency.

Andrew: Michael, from an endocrinologist's perspective, and I understand that you are extremely tightly regulated in what you can and can't prescribe, but what do you say when patients want to use vitamins and minerals and nutrients in their therapy? Outside of vitamin D, for instance?

Michael: Yeah, I mean, I have a lot of patients that come in, you know, bringing in the latest and greatest nutrient information. I mean, clearly adequate calcium, adequate phosphate, adequate vitamin D, and you know, most of the multivitamins, they're all very important for your health. And so, I have no problem in recommending a multivitamin supplement. I mean, there is a lot of information out there now and hype about vitamin K2, and it's possible that vitamin K2, you know, may be of some benefit for both your bone health and cardiovascular health. I think more studies need to be done, you know, to be convincing of it. 

Andrew: Yep.

Michael: But my philosophy has been, to my patients, if there's no downside to doing it, and if they want to spend a little bit of money and there is the possibility that it may have some long term positive health benefit, then why not do it?

Andrew: Do you ever use magnesium at all, with migraines?

Michael: I don't. I mean, the problem is that most magnesium is inside your cells. So, measuring a blood magnesium level doesn't tell you very much about magnesium status. 

Andrew: No. That’s right.

Michael: What you have to do actually is load them with magnesium and get a 24-hour urine magnesium level to see if they're deficient, and that mainly occurs in alcoholics, because alcohol causes you to lose magnesium into your urine. But most people, if you're on a healthy diet, especially leafy vegetables, that's part of your diet, you're getting all the magnesium that you need. Elders may be more prone to magnesium deficiency, but otherwise, I don't think a big deal, and certainly no evidence that magnesium helps you absorb calcium. It's just not true.

Andrew: No. So, Michael, we've covered children, we've covered muscle pain. What about things like adrenal stress, or indeed, post-traumatic stress disorder and vitamin D? Is there actually a clinical link or is it just biochemical? Just an association?

Michael: At the moment, I think that it's mainly an association. I think we need a lot more information before we can link the two. I mean, vitamin D deficiency is so common and many of these syndromes are common in certain populations, that the fact that you see deficiency and you see the issue, does that mean the deficiency is causing it, or are they just related because vitamin D deficiency is very common? 

Andrew: Yeah.

Michael: And I think we just don't know the answer to that. I mean, a good example, for me at least, is the issue of autism. You know, I mean, it's estimated like, what, 1 in 600 children may be affected to some degree with autism. And to kind of imply that, you know, in utero vitamin D deficiency or vitamin D deficiency in early childhood kind of precipitated autism, I think is a stretch because most children are vitamin D deficient, to begin with. 

Andrew: Yeah.

Michael: And autistic children would be indoors more, and less likely to be playing outside, less likely to be getting an adequate amount of sun exposure to improve their vitamin D status. So, there's no reason not to give autistic children vitamin D, but I'm not sure that vitamin D deficiency causes autism, or is a major cause of autism.

Andrew: Yeah. I think it's the old axiom of medicine and research is that association does not imply causality.

Michael: For sure. And of course, that's the major criticism that many have levelled for the vitamin D story. But one has to argue that there are, you know, literally thousands upon thousands of observations now linking vitamin D deficiency, inadequate sun exposure, low blood levels of 25-hydroxy vitamin D with many chronic illnesses, that I think we have to at least take pause to consider the possibility that the two, in fact, may be related and that there really isn't any reason or downside to be increasing your vitamin D intake for you and all family members, which is what I do for my family.

Andrew: I think the other side of it, as well is, when you've got an association with causality, that doesn't also imply that you can treat with vitamin D either, or anything, indeed. But, with regards to vitamin D, if you're vitamin D deficient and you are at increased risk of, let's say, atopic dermatitis, then can you then reverse atopic dermatitis by giving vitamin D? Can I ask for your comment on that one?

Michael: Yeah. I mean, there is, you know, a recent review on the subject to suggest that maybe you can help in reversing atopic dermatitis, but certainly, to think that you could treat atopic dermatitis with vitamin D if you're vitamin D deficient, I think is a stretch. And I think you definitely need appropriate other therapy along with correcting the vitamin D deficiency. I mean, it's possible that the vitamin D deficiency, you know, exacerbated the condition, but I don't believe that vitamin D deficiency caused the condition.

Andrew: So, Michael, just recently the Australian government, for reasons of cost-saving measures, restricted the testing of vitamin D. Can you comment on that, please? Because I know that you were involved in this.

Michael: That's correct. I mean, the Institute of Medicine and the Endocrine Practice Guidelines Committee, and I chaired that committee with many experts in vitamin D, and we both concluded that we should not do broad screening for 25-hydroxy vitamin D. And so, both of these organisations concur with the Australian Health Ministry that you should not be screening everyone, but rather you should be encouraging adequate sun exposure, vitamin D supplementation, and increasing food intake that contains vitamin D. And those three measures will more than guarantee that people can have an adequate vitamin D supply without needing to have an expensive test performed. 

Andrew: Now…

Michael: However, the Australian government and the Endocrine Society and the IOM all recognise that if you have fat malabsorption syndrome, for example, coeliac disease, or Crohn's disease, or cystic fibrosis, if you're obese, if you are on medications like glucocorticoids, antiseizure medications, AIDS medications that destroy vitamin D, all of these types of patients should be screened, and followed after they're being treated with vitamin D to be sure that you're correcting a vitamin D deficiency.

Andrew: What about those people that might be institutionalised or those people that for cultural reasons don't get enough vitamin D? Is there cause for screening in this population, or just supplement?

Michael: Yeah. Well, so, for example, in institutionalised patients, it was well documented, over 50 years ago now, that if they were on antiseizure medications, multiple antiseizure medications that they needed probably 5 to upwards of 10 times more vitamin D because the medication itself caused significant destruction of the vitamin D. 

Andrew: Yep.

Michael: Also institutionalised people are often not outside. They don't have a particularly great diet, and so, for sure they need to be supplemented and it's not unreasonable, especially if they're on a variety of medications, to be screened for vitamin D deficiency and appropriately treated.

Andrew: Some salient points with regards to immune regulation, with regards to pain, children, and lactation as well. Michael Holick, thank you so much for joining us once again. I know that next time we'll have, again, more papers to discuss, and I just thank you for your clinical insights as well.

Michael: My pleasure. Have a delightful day.

Andrew: Thanks, Michael. This is FX Radio, and I'm Andrew Whitfield-Cook.


 

 

Other podcasts with Prof Michael Holick include:


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Prof. Michael Holick