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To (Vitamin) D or Not to D - That Is the Question – Endocrinology conf. debate April 2013

From Medscape

Lisa Nainggolan, Apr 29, 2013

COPENHAGEN, Denmark — Two leading experts in the field of vitamin D agreed to disagree yesterday here at the 2013 European Congress on Endocrinology during a lighthearted debate on the subject of whether or not everyone needs more vitamin D.

But their arguments were backed up by some serious science, and they both concurred that there are certain groups of people in whom it is necessary to ensure that vitamin-D levels are sufficient, such as pregnant women and those at risk for or with osteoporosis. And they also agreed on one way people can obtain more vitamin D: by going out in the sun for 30 minutes per day.

Where they differed, however, was that the vitamin-D proponent, Chantal Mathieu, MD, from Catholic University, Leuven, Belgium, said the list of people who need sufficient vitamin D "is so long that it really just makes more sense to give everyone small doses."

In the opposite corner, however, Mark Cooper, MD, from University Hospital, Birmingham, United Kingdom, argued that it is really only necessary to supplement specific, at-risk groups of people. "I am an investigator in randomized clinical trials of vitamin D, and I have nothing personally against [it], and I use it in my patients. But I tend to give it to people who actually need it, and that doesn't really include most of us," he observed.

And Dr. Cooper — who noted that there is a huge sector of the scientific community that is "evangelical" in its pro–vitamin-D stance — warned that physicians have been here before, with many other nutrients that subsequently, in large intervention trials, turned out to have a null effect or even be harmful. In fact, there is already evidence of risks with supplements of vitamin D from randomized clinical trials, with no evidence of benefit, he argued.

"Vitamin D — we all need more? Most of us don't, and more could actually do more harm than good."

What Does Vitamin D Do, and How Is "Deficiency" Defined?

Dr. Mathieu said the key role of vitamin D "is to promote resorption of calcium via the gut. One big lesson from all of the literature is that vitamin-D deficiency is not only bad because it's vitamin-D deficiency, but it also creates a bad calcemic status."

Vitamin-D deficiency is generally defined as a level of less than 20 ng/mL (<50 nm/L), and there are correlations in large observational studies "indicating that if you are vitamin-D deficient you get more cancer, especially colon cancer, you get more cardiovascular diseases, your immune system doesn't function properly, and overall you have a higher risk of dying," she stressed.

Going out in the sun is one option to boost vitamin D, she explained, noting that "even the dermatologists in Australia have reversed their zero-tolerance stance on the sun" in the past 2 years and conceded that 15 to 30 minutes per day in the sun "is allowed because it gives benefits." Nevertheless, the benefits must be balanced with the risks, she added, noting that "it's exactly the same wavelength of UV that you need to make vitamin D that also causes skin damage, aging, and skin cancers. So go back to nature and expose yourself to the sun, but do it with caution."

And she noted that UV rays in Northern Hemisphere winters are not strong enough to produce adequate levels of vitamin D, regardless of how long is spent in the sun. In addition, darker-skinned people, particularly those who do not expose themselves to the sun or who cover themselves, are particularly at risk. "We still see rickets in my country, in dark-skinned children who are exclusively breast-fed and whose mothers avoid the sun or are covered," she observed.

"You can also take it from foods," she explained, but added that the "only really rich food source" of vitamin D is cod-liver oil. "Salmon and mackerel from the ocean is a good source"; however, most of this fish is now bred in farms, and farm-bred fish do not have a lot of vitamin D.

If our skin cannot make enough vitamin D under the UV, just give vitamin D, give the hormone. Dr. Chantal Mathieu

"So what do we do? We are endocrinologists. If the thyroid fails, we give thyroid-hormone substitution. If our skin cannot make enough vitamin D under the UV, just give vitamin D, give the hormone itself."

But the key, she said, is to use smaller doses of vitamin D than have previously been recommended. The US Endocrine Society guidance, for example, advises supplementation with up to 2000 IU per day, but this is overzealous, she said. "A more reasonable dose is 600 to 800 IU per day," she noted, adding that she is an author on a new guidance, soon to be published in the Journal of Clinical Endocrinology and Metabolism, which will state that 2000 IU per day "is not warranted."

"So my conclusion, yes, we all need more vitamin D, but we don't need crazy high doses."

In response, Dr. Cooper conceded: "Our natural state of vitamin D is much higher than we have today — we live indoors too much — and lower levels of vitamin D have been linked with cancer, heart disease, increases in diabetes, shortened life, the list goes on, and it's a very long list. In fact, you will do well to find a condition that isn't linked with too little vitamin D." But the problem, said Dr. Cooper, is that "the supposed benefits of vitamin D are exclusively reported in observational studies. We really need some robust evidence."

Vitamin-D Intervention Trials to Date "Mostly Negative"

Dr. Mathieu, Dr. Cooper said, had alluded to randomized trials in the future, "but we have got lots of randomized trials now," he argued, quoting a "typical" one, the RECORD trial from the United Kingdom.

This looked at vitamin-D supplementation and fractures in 5000 community-dwelling women and was reported in the Lancet in 2005. "What it showed was that if you took vitamin D from [a level of] 38 nm/L, the average in that population on placebo, and raised it to 62 nm/L, which is a very useful increase — what does it do? Absolutely nothing, [at least] to falls and fractures."

And there have been "lots" of other randomized controlled trials, he added, "and my view is that these are mostly negative. The Women's Health Initiative, with 36,000 people [taking vitamin D] combined with calcium, didn't show any effect whatsoever. It did show, however, that [vitamin D plus calcium] caused kidney stones, a 70% increase, which is not medically insignificant."

Vitamin D holds the record for the most number of meta-analyses for the fewest number of trials. Dr. Mark Cooper

He noted also that in the attempts to find some benefit, "Vitamin D holds the record for the most number of meta-analyses for the fewest number of trials," and the results generally "depend on who does the meta-analysis. Those who do not have a major ax to grind (eg, the Institute of Medicine [IOM]), tend to come up with negative results, whereas those who really believe in vitamin D seem to get positive results with their meta-analysis."

And then there are those who say "maybe we are not getting levels high enough, we need to get over a certain threshold of intake," he observed. "But there have been trials in recent years that have done this, too."

He cited one from JAMA (2010;303:1815-1822), performed in Australia in the winter in women, giving them very high doses. The women in the active-treatment group ended up with levels of vitamin D of 75 nm/L, "so it worked" in comparison with the placebo group, who had average levels of 50 nm/L. "But the result was vitamin D caused a significant excess of falls and fractures. One in 3 people had an extra fall due to the vitamin D. This is not good."

He then went on to discuss the editorial accompanying this study, "which gave the explanation that the reason falls increased was because vitamin D was too good, the people who got it felt so well, they came to harm because they were having such increased functional mobility. Clearly ridiculous, but it gives you a mind-set of how people think about vitamin D."

He went on to list a number of other, recent randomized clinical trials with vitamin D, for conditions such as cognition, muscle strength, cancer, osteoarthritis, TB, etc. "Different doses of vitamin D, different groups, all well-designed, all in major journals, and all negative." He added that at least 1 in 20 of these studies "should be positive" just by chance, "but we haven't seen that yet."

Does a Little Suboptimal Absorption of Calcium Matter?
In rebuttal, however, Dr. Matheiu said all of the intervention studies "struggle with compliance issues, we all know that if we need to take a pill every day for 1 year, we will start to forget.
So all the intervention studies you have seen give vitamin D in megadoses once every month, once every 2 months. That's not what I mean as 'we all need more.'

"Where we are now is a mean of 20 to 25 ng/mL, so if we want to analyze this objectively, half of our population is deficient. We all need more vitamin D than we are getting now. Saudi Arabia has a mean level of vitamin D that is below 20 ng/mL; should we wait to supplement people in Saudi? We know they are all vitamin-D deficient because it's too hot to get out in the sun.

Where we are now is a mean of 20 to 25 ng/mL; half of our population is deficient. Dr. Chantal Mathieu

"Vitamin-D deficiency in all of our association studies is clearly associated with impaired outcomes. We know that restoration of vitamin-D deficiency with small doses avoids adverse outcomes. I do not think we can afford to sit and wait for well-designed intervention studies," she stressed.

And, she argues, "It's too expensive to go around and measure vitamin-D levels in everybody. My argument would be to stop measuring levels in everybody. It's nonsense. There is a very easy way to prevent all of this, and that is to give small doses of vitamin D to the whole population, and that's what the IOM says. They say in children below 1 year of age, 400 IU per day; in individuals older than 70 years of age, 800 IU per day; and all of the rest, all of us, 600 IU of vitamin D every day. So yes! We all need more."

She did concede, however, that here are a few potential exceptions, such as patients with kidney stones "in whom you need to be careful."

In his rebuttal, Dr. Cooper replied, "Clearly, we agree on many things. Those populations at risk of rickets or hypocalcemia need vitamin D. Pregnancy is a situation where, clearly, you want to make sure levels are adequate" — although he acknowledged there has recently been debate on this issue — "and having vitamin D in the treatment of osteoporosis is mandatory, because you don't want to risk someone having even a small deficiency. But for the rest of the population, what does a little bit of suboptimal absorption of calcium matter? Who cares?

All of the primary analyses of the intervention studies described previously bear out the fact that there is no evidence of any benefit with vitamin D for the most part, he stressed.

"You can get on-the-spot tests for vitamin D now. And we are doing loads of vitamin-D assays.
We are making everybody anxious. We [endocrinologists] ourselves are anxious.
We shouldn't worry everybody, we should have good, balanced nutrition, but the majority of people who are otherwise healthy and asymptomatic shouldn't go around taking supplements.

"Will having a higher vitamin-D level give you a healthier, longer life?
You can't do a randomized trial for 50 or 60 years, which is what you need to address this.
More work needs to be done, clearly, but it's a tricky area," he concluded.

Drs. Mathieu and Cooper have reported no relevant financial relationships.

2013 European Congress of Endocrinology. Debate 1, presented April 28, 2013.

See also VitaminDWiki for huge number of vitamin D deficiency diseases,
in addition to those diseases which Endocrinologists treat

Health ProblemPrev /
Reduction   Notes#
HypertensionT 149 to 142 RCT, mm Hg avg., 2400 IU * 1
Cardiovascular T 32 % Death after heart failure, 1000 IU2
Diabetes T1 P 85 % 12000 kids, 2000 IU3
Diabetes T2T 62 % RCT, CRP reduction, 4000 IU * 4
Back PainT 95 % 5000/10000 IU5
Influenza P 90 % RCT, 2000 IU6
Falls P 19 %RCT, 1000 IU 7
Hip Fractures P 30 %Meta-analysis 800 IU8
Rickets P 98 %Turkey, 400 IU9
Raynaud's SyndromeT 40 % RCT, visual scale, 20000 IU avg10
Menstrual painP 76 %RCT, 7000 IU avg11
Pregnancy risks P 50 % RCT, 4000 IU12
C-section, unplannedP 50 % RCT, 4000 IU, small study13
Low birth weightP 60 % Meta-analysis 1000 IU of D214
TBP 60 % RCT, 800 IU15
Breast Cancer P 60 % RCT, 1100 IU16
Rheumatoid Arthritis painT 40 %RCT, 500 IU, added to prescription17
Cystic FibrosisT 75 %RCT, pilot 4X fewer deaths 250,000 IU 18
Chronic KidneyT 90 to 70RCT, 3500 IU, PTH avg19
Respiratory Tract InfectionP 63 %RCT, 4000 IU 1 year20
LupusT No flaresLoading then 100,000 IU monthly21
Sickle Cell T Less painRCT, up to 100,000 IU/week22
Leg ulcer healingT 4X fasterRCT, 50,0000 IU/week, small study23
Traumatic Brain Injury T 2X RCT, 20,0000 IU/day with progesterone24
Parkenson's DiseaseT StabilizeRCT, 1200 IU/day25
Multiple SclerosisP 68%RCT, 7100 IU prevent pre-MS ==> MS26
Congestive Heart Failure T 90 % RCT, 1000 IU infants 27

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