The IOM Miscalculated Its RDA For Vitamin D

Last year (2014) saw an unusual event. Two statisticians at the University of Edmonton in Canada (Paul Veugelers and JP Ekwaru) published a paper in the online journal Nutrients (6(10):4472-5) showing that the Institute of Medicine (IOM) had made a serious calculation error in its recommended dietary allowance (RDA) for vitamin D. Immediately, other statisticians checked the Canadians’ analyses and found that, indeed, they were right. Together with my colleagues at Grassroots Health, I went back to square one, starting with a different population entirely, and came to exactly the same conclusion. The true RDA for vitamin D was about 10 times higher than the IOM had said. Not a small error. To understand, how this might have happened and why this is important, some background may be helpful.

Background
An RDA is technically the amount of a nutrient every member of a population should ingest to ensure that 97.5% of its members would meet a specified criterion of nutritional adequacy. For vitamin D, the IOM panel determined that the criterion for adequacy was a serum concentration of a particular vitamin D derivative (25-hydroxyvitamin D) of 20 ng/mL or higher, and that for adults up to age 70, 600 IU of vitamin D per day was the RDA.

Both of those figures provoked immediate and unprecedented dissent from a diverse group of nutritional scientists, but the disagreement centered mostly around the IOM panel’s reading and interpretation of the evidence, rather than its calculation of the RDA. The Edmonton statisticians took the dissent a step further, showing that the actual calculation was itself wrong. Here’s what seems to have happened.

What Happened
Not everyone gets the same response to a given intake of any particular nutrient, i.e., some require more than others to reach the specified target, and while the average response to a certain dose of vitamin D may be above the target level, a substantial fraction of a population can still be below it. Thus, the RDA will always be higher than the average requirement, and for some nutrients, substantially so. As a consequence, ensuring that every member of a population receives the RDA guarantees that 97.5% of that population will be getting at least enough, while many will be getting more than they actually need.

The IOM panel identified a number of published studies showing the 25-hydroxyvitamin D response to various vitamin D doses. They plotted the average response in each of those studies against dose, thereby generating what is termed a “dose response curve”, i.e., a way to estimate how much of a response would be predicted for any given vitamin D intake. But, to make a long story short, because it used average responses, that curve tells us nothing about the intake requirement for the individual members of a population, and particularly those whose response to a given dose falls in the bottom 2.5 percentiles. The IOM panel surely knew that the average intake required to meet or exceed 20 ng/mL was not the same as the RDA, as it would be inadequate for all those with below average responses (about half the population). So, to catch the “weak” responders, they calculated the 95% probability range around their dose response curve, designating as the RDA the point where the bottom end of that probability range exceeded 20 ng/mL. While this might seem to have been the right approach, it was not. The panel appears to have overlooked the fact that the 95% probability range for their curve is for the average values that would be expected from similar studies at any particular dose. The dispersion of averages of several studies is, as every beginning student of statistics knows, much more narrow than dispersion of individual values within a study around its own average. And it’s the 2.5th percentile individual values from those studies, not the study averages, that should have been used to create the relevant dose response curve.

It’s this latter approach that the Canadian statisticians used. They took precisely the same studies as the IOM had used and demonstrated that the requirement to ensure that 97.5% of the population would have a value of at least 20 ng/mL, was 8,895 IU per day. Recall that the IOM figure was less than 1/10 that, i.e. 600 IU per day up to age 70 (and 800 IU per day thereafter). When my colleagues and I analyzed the large GrassrootsHealth dataset, we calculated a value closer to 7,000 IU per day, still a full order of magnitude higher than the estimate of the IOM, and not substantially different from the estimate of Veugelers and Ekwaru.

Why This Is A Problem
This is an important mistake, not simply because it shouldn’t have been allowed in a major policy document, but because IOM recommendations have important effects on a wide array of government programs. These include nutritional standards for US military, for school lunch programs, for WIC and many others, both in the United States and in Canada.

Canada, which paid one third the cost of generating the IOM report, is in a particularly difficult situation. Its First Nations peoples, living near the Arctic Circle, do not get any vitamin D from the sun, as do those of us living at more temperate latitudes. They are totally dependent upon food and supplement sources. Their ancestral diets, based largely on seals and whales, constituted a rich source of vitamin D.  They are much less commonly consumed today, in part because of the ready availability of low nutrient density foods flown in from the south, and in part because environmental pollution has made seal and whale products a source of dangerous toxins (as well as necessary nutrients).  The Canadian government, responsible for the health of all of its citizens, can turn only to the existing IOM recommendation (600 IU per day) to set standards for the people living in its northern territories. But, as the Edmonton statisticians noted, that number is woefully inadequate.

There is almost no public awareness of this error or its implications in the United States, but that is not true for Canada. A large nutritional health foundation located in Calgary (Pure North S’Energy Foundation) has taken out a series of half page advertisements in Canada’s national newspaper (Globe and Mail), alerting Canadians to the fact that the error was made and that they need more vitamin D than current policy indicates (http://www.purenorth.ca/?page_id=1356).  The IOM, Health Canada, and the Canadian Ministry of Health have all been formally alerted to this problem. The Health Ministry has agreed to undertake an independent reanalysis of the calculation of the RDA, but the results are not yet available and the shape of the ministry’s action is still uncertain.

How It May Have Happened
It’s one thing to know how the mistake was made, and quite another to know how it could have happened. Here, one can only speculate, as the IOM processes are shrouded in secrecy. The IOM report was a massive document and it is likely that much of the background work, such as the literature search, the drafting of the report, and the statistical calculations, were done by IOM staff members who may not, themselves, have been sufficiently expert in the vitamin D field to recognize discrepancies that might have popped up. (It is noteworthy that several of the dissenting letters submitted to scientific publications following release of the IOM report had specifically cited the fact that 600 IU per day was not sufficient to guarantee a level of 20 ng/mL.) It would then have been up to the expert panel to review and adjust this staff work. To be fair to the panel, it is important to understand that the scientific members of IOM panels are not compensated for their time and effort. They do it as a public service, and they are all busy scientists with work of their own. Still, it was their job, and one must wonder how they failed to see an error that was apparent to other equally knowledgeable, but outside, scientists.

Comment
There may be a moral here. It is widely recognized that many of the panel members, before coming together to review the evidence, had already staked out a position to the effect that, while the previous (1997) recommendation for vitamin D (200 IU per day) was probably inadequate, the actual RDA was almost certainly below 1000 IU per day. Accordingly, when the statistical calculations produced a number that matched their own expectations, they may not have been inclined to question its derivation.

There is a generally held belief that science is objective, data-driven. And to a substantial extent that is so. But science and scientists are not identical. Scientists often have strongly held opinions and, like people in general, find ways to construe the evidence to support their beliefs. When those beliefs are wrong, science, as a field, ultimately abandons them. I am confident that this IOM error will be corrected sooner or later. This is partly because it is demonstrably erroneous, and partly because the related set of IOM recommendations for vitamin D has not elicited a consensus in the field of vitamin D research.  If the Dietary Reference Intakes produced by the IOM are important, then it is important that they be right. I can only hope that not too much human damage will occur as we wait for the needed correction to happen.

[Author’s note: if readers are aware of factual inaccuracies in what I have written here, I would be grateful if you would call them to my attention at , so that I can correct this post.]

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The Paradox of Osteoporosis Irreversibility

Over 30 years ago I gave a paper at an osteoporosis meeting in Jerusalem titled “The Paradox of Irreversibility of Age-Related Bone Loss.” By  ”irreversibility” I meant that once the bone was lost there was not much that could be done to restore it.

Bone_HeaneyPerhaps “puzzle” would have been a better word than “paradox.”  From our experience with other similar situations, we would have expected that the lost bone would be restored.  The underlying facts are that during the postmenopausal period bone loss occurs rapidly as estrogen levels drop to low values.  Estrogen replacement therapy started at menopause prevents that loss, showing clearly that it is the estrogen deficiency that is responsible. Similarly, severe calcium deficiency also leads to bone loss, and maintaining a high calcium intake does slow that loss, and perhaps even prevent it.  And, as is generally recognized, low calcium intake and low estrogen status are common in contemporary women during the post-menopausal years. These factors are the principal reasons for age-related bone loss in women.

But neither estrogen, nor calcium, nor the combination of the two, will restore the lost bone after it is gone.  This seemed puzzling because with many other nutritional and hormonal deficiencies, restoring the lost hormone or nutrient does generally return the body to its pre-deficiency state.  Examples would be hypothyroidism, which responds to thyroid hormone replacement, and iron-deficiency anemia, which responds fully to replacement of the lost iron.

The explanations for this seeming irreversibility which I offered at the time were twofold.  1) bone building (or rebuilding) requires  weight-bearing or impact exercise, and physical activity generally declines after midlife; so a condition necessary for rebuilding was missing. 2) much of the lost bone is trabecular in character, i.e., the spongy latticework in the center of bones such as the vertebral bodies of the spine; once that lattice is lost, there is no longer a scaffolding or framework on which to rebuild.

I believe that both reasons are at least partially correct, but today they seem to me far from satisfactory explanations for this puzzling irreversibility. There is, I think, a better, more complete explanation, one that can be tested (and thus proved or disproved), and one that, if correct, could revolutionize the treatment and prevention of osteoporosis.

Bone is not just calcium. It is made up, first of all, of a protein matrix within which the calcium salts are embedded.  Soak a bone in acid and you remove the calcium.  But what’s left still looks like the bone you started with, except now it’s rubbery rather than hard. It’s now all protein and no mineral. The key point is that, while bone is the body’s reservoir of calcium, that calcium is tied up as part of a structure, the largest component of which is protein. When the body needs calcium and has to make withdrawals from the skeletal reserves, it does so not by leaching the calcium from this protein-mineral complex, but by physically tearing down microscopic units of bone and scavenging the calcium that is released in the process. Inevitably, therefore, the protein matrix – the structure – goes as well.

In order to profit fully from a high calcium intake, a patient who has lost bone needs to consume enough protein to allow the body to rebuild the lost structure. Otherwise all that a high calcium intake can do is to prevent the body’s further tearing down of bone to meet the calcium needs of other body systems and tissues. That’s a good thing to do, but it is not enough. Nevertheless, it is precisely to prevent that draining of the body’s calcium reserves that a high calcium intake (whether from food or supplements) is today a vital part of the standard of care for patients with osteoporosis. Even so, the failure of nutritional replacement to rebuild lost bone is what originally set the stage for the entry of pharmaceutical agents, some of which can produce substantial bone rebuilding.

That landscape began to change a few years ago when an insightful investigator at the Tufts Nutrition Research Center on Aging in Boston noticed that a high calcium intake did, in fact, lead to increased bone gain if the patient’s intake of protein was high. Bess Dawson-Hughes had previously published the results of a calcium and vitamin D supplementation trial, producing a better than 50 percent reduction in fracture risk in healthy elderly Bostonians with those two nutrients alone. But, like others before her, she noted that, while high calcium intakes reduced or stopped bone loss in her treated subjects, the two nutrients didn’t lead to bone gain. They didn’t, that is, in individuals consuming usual protein intakes. However, in a subset of her treated patients, who, it turns out, had protein intakes above 1.5 times the RDA (0.8 g/kg body weight), bone gain was dramatic (while it was zero in those with more usual – and usually thought “adequate” – protein intakes). The figure below shows the 3-year change in bone mineral density (BMD) at the hip in the calcium- and vitamin-supplemented participants in the Tufts study.  Only with the highest protein intakes was there appreciable bone gain.

Ca-Prot_for_blogFor me, it was an “Aha!” moment.  Why hadn’t we thought of that?  It was known that bone is 50 percent protein by volume (but only about 20 percent calcium by weight).  And it was known that when bone is torn down (as with estrogen or calcium deficiency), its protein is degraded in the process. So it made sense that, to rebuild the lost bone, you would need not just calcium but fresh protein as well.

When I first heard of this result, I immediately went to our own Creighton database on calcium metabolism in midlife women (the “Omaha Nuns Project) and looked to see whether protein intake (which we had recorded and measured) made a difference in the bone metabolism of our nuns. There it was, just as the Tufts investigator had shown. Our nuns with protein intakes below the median for the group could not retain calcium, no matter what the intake (i. e., they couldn’t build bone). By contrast, those with protein intakes above the median for the group retained extra calcium reasonably well.

So, here were two distinct data sets, two quite different investigations, exhibiting the same interdependence of calcium and protein. What we, and probably most clinical nutritionists, had failed to recognize, was that the adult RDA for protein is just barely enough to prevent muscle loss, and is not enough to support tissue building or rebuilding. But, as already noted, when calcium deficiency leads to bone loss, the bone protein is lost as well, and that has to be rebuilt to restore the lost bone.

This mutual dependence of calcium and protein provides a good illustration of two key (and often underappreciated) aspects of nutrition. The first is that nutrients almost always act together with other nutrients. The second feature is what Bruce Ames of the University of California, Berkeley, has called a “triage” system within nutrition. The body operates a triage mechanism, ensuring that the most vital functions receive the nutrients first and leaving the other tissues and systems of the body to get by on what is left over. It seems that this triage mechanism is at work with respect to adult bone rebuilding.  With limited protein intake, the body ensures that its most vital functions are served first.  Bone, in effect, gets the leftovers.  We need a high protein intake precisely to ensure that there will be something left for bone.

Two unplanned observations such as those of Dawson-Hughes and our own Creighton group, even if they make perfect sense, would not generally be considered enough to change public policy, particularly when it comes to nutrient intake recommendations.  So, if we are to be certain that supplementing both protein and calcium will permit rebuilding of lost bone, it will be necessary to mount one or more clinical trials testing that hypothesis.

Such a trial would likely be designed to start  with a group of probably several hundred postmenopausal women who had already lost bone and whose protein intakes were in the range of the current RDA, that is about 0.8 g/kg/day.  All would be supplemented with sufficient calcium to permit maximum bone building if the individuals concerned could, in fact, use the calcium efficiently. They would all also receive sufficient vitamin D to ensure a serum concentration of 25(OH)D of 40 ng/mL or higher.  Then half would be given a diet, probably involving a protein supplement, which would raise their protein intakes to above 1.2 g/kg/day.  [Some might argue that there should be a third group, one with protein intakes at the RDA, but without the substantial calcium and vitamin D supplementation envisioned above.]  In either case, trial duration would be about three to four years, and the endpoint would be the observed change in BMD over that treatment period. The predicted outcome would be that the lower protein group receiving calcium and vitamin D would have no appreciable change in BMD, while the higher protein group, also receiving extra calcium and vitamin D, would exhibit clinically significant bone gain.  As outlined here, such a trial could not be blinded, mainly because the diets would be perceptibly different.

Even if such a trial were to start today, it would probably be at least five years before the results would be clear and actions could be taken to change official recommendations and influence individual dietary behaviors.  What should one do in the meanwhile?

This is a matter for individual decision, but it is helpful to know that high protein intakes are safe. Their principal negative impact is on the wallet, not the body (as rich protein foods tend to cost somewhat more than foods high in added sugars, for example, or other types of empty calories).  For me the decision is easy; I’d opt for the high protein intake without a second thought (with, of course, adequate calcium and vitamin D, as well).  As a dividend, I should note that there is one food group that is both a very rich source of protein and at the same time the principal source of calcium in the diets of first world populations – dairy.  Moreover, if consumed as milk, its cost is less than the average cost of the other foods in your grocery cart.

Even if the trial were to be successful, It  would be naïve to think that would be the end of the story.  Recall that the pharmaceutical industry stepped into this field 25 years ago when it appeared that nutritional therapy was not up to the task (at least as it was conceived at the time).  If this protein hypothesis is correct, then better nutrition could be a much better form of prevention than pharmacotherapy.  However, I suspect that the pharmaceutical industry will not back out of the field as readily as it got into it.

To be fair, resistance from big Pharma should not be surprising. After all, they’ve invested billions of dollars in helping us solve a critical health problem for an aging population. Naturally, they (and our pension funds who are their stockholders) want to protect that investment. Still, if diet can do the job for us, few would choose a lifetime of pill taking or injections over better eating.

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Vitamin D and the nursing mother

Do infants receive enough vitamin D?

Do infants receive enough vitamin D?

Everyone seems to agree that vitamin D is important throughout life. This is certainly as true in the first year of life as it is later on. For it is during the first year that, in addition to its role in calcium metabolism, this critical nutrient reduces both the risk of current infections and the late-life development of such autoimmune diseases as multiple sclerosis and type 1 diabetes. Both the Institute of Medicine (IOM) and the American Academy of Pediatrics (AAP) agree that vitamin D intake during the first year of life should be 400 IU/d. My own estimation of the requirement (for different ages and body sizes) is 65–75 IU/kg body weight per day. For average body weights in infants during the first year of life that rule of thumb computes to somewhere between 300 and 500 IU/d for infants. So, while there is still contention with respect to the optimal intake for adults, there really is no disagreement about how much is needed for infants, either among various authoritative sources or arising from different approaches to the evidence. With respect to infants, 400 IU/d seems to be just about right.

The question is, how is the infant to get that vitamin D? Human milk, in most nursing mothers, contains very little vitamin D. Infant formulas, from various manufacturers, all contain some added vitamin D in amounts calculated to be sufficient to meet an infant’s needs. But extensive studies during the first year of life reveal that less than one-fifth of all infants ever get as much as the recommended 400 IU/d from any source, and fewer than one out of 10 breast-fed infants meet the requirement. As a result, the AAP urges that all infants, regardless of whether they are breast or formula fed, receive their 400 IU/d as pediatric drops. Unfortunately, this recommendation, while appropriate, is not often followed. Most babies are just not getting the vitamin D they need. The late-life consequences of this shortfall could be enormous.

It must seem strange that on the one hand we stress that human milk is the best source of nourishment for our babies, and on the other seem to ignore the fact that human milk doesn’t contain the vitamin D those babies need. The explanation, very simply, is that the disconnect is artificial. Nursing mothers have so little vitamin D in their own bodies that there is little or none left over to put into their milk. But it has not always been this way. We know that the vitamin D blood concentrations that are regularly found today in Africans living ancestral lifestyles are high enough to support putting into breast milk all the vitamin D an infant needs. But the bulk of the world’s population today is not living on the high equatorial plains of East Africa nor exposing much of its skin for most of the day.

Fortunately, we don’t have to return to East Africa. It turns out that, if we give nursing mothers enough vitamin D to bring their blood levels up to the likely ancestral levels, then they automatically put all of the vitamin D their baby needs into their own milk, thereby ensuring that the infant gets total nutrition without the need to resort to vitamin D drops.

How much vitamin D does the mother need so as to ensure an adequate amount in her milk? As with everything else related to vitamin D, there is a lot of individual variation, but it appears that the daily intake must be in the range of 5,000–6,000 IUs. As no surprise, that’s just about the amount needed to reproduce the vitamin D blood levels in persons living ancestral lifestyles today. And while 5,000–6,000 IU may initially seem high, it is important to remember how much the sun produces for us. A single 15 minute whole body exposure to sun at mid-day in summer produces well over 10,000 IU.

There is one important proviso for nursing mothers concerning the needed intake. Those who live in North America and have to rely on supplements should be certain that they take their supplements every day. While for other purposes it is possible to take vitamin D intermittently (e.g., once a week), that doesn’t work for putting vitamin D into human milk. The residence time of vitamin D in the blood is so short that, if the mother stops taking her vitamin D supplement for a day or two, vitamin D in her milk will be low (or absent altogether) on the days she skips.

There is a glaring disconnect here between these well-attested physiological facts and the official IOM recommendation for nursing mothers, i.e., only 400 IU/d – the same intake for her as IOM recommends for her baby (whose body weight is less than 10% of her own). The IOM, if it were to be explicit about its current recommendations, would be telling nursing mothers something like this:

“The evidence we analyzed indicates that your own body needs only 400 IU of vitamin D each day. Unfortunately, that won’t allow you to put any vitamin D into your breast milk. Sorry about that . . . So, if you want to ensure that your baby is adequately nourished, you are going to have to resort to giving your infant vitamin D drops.”

That would be a hard message to sell, and clearly, it makes little sense on its face. As I have already noted, women living ancestral lifestyles (whether or not they are nursing an infant) have far higher blood levels of vitamin D than contemporary urban Americans. Milk production (and its optimal composition) are simply two of the many functions that vitamin D supports in a healthy adult. This breast-feeding example is not a special case; it is just one of the many pieces of evidence that point to the fact that current vitamin D recommendations for adults are too low – way too low.

Vitamin D supplements – and in this case vitamin D drops – are literal lifesavers for infants today. But what about two or three generations back – before nutritional supplements come into existence, but long after migration out of Africa? Ninety years ago vitamin D had not yet been discovered, and there certainly were no vitamin D supplements that could have been used. How did we get by through those thousands of years? There are two answers. Most of us, living in temperate latitudes, got a lot more sun exposure than we do today, and of course there were no sunscreens, so there was no blocking of the solar radiation that produces vitamin D in our skin. Those of us living in far northern latitudes survived mostly by depending upon diets that were very high in seafood, which is naturally a rich source of vitamin D. And those of us who got vitamin D by neither route were at increased risk of a whole host of vitamin D-related disorders, most obvious and most easily recognized being rickets.

The bony deformities of rickets were common a century ago in Europe, North America, and East Asia, and were largely eradicated in growing children by use of cod liver oil and, in the US, by the introduction of vitamin D fortification of milk in the 1930s. Fortunately, growing children can repair some of the bone deformities of rickets if they are given vitamin D soon enough. But, repairing rickets, while a good and necessary thing to do, is not sufficient. It is too late, by the time we recognize the deformities of rickets, to ensure maximal protection against the autoimmune diseases (for example), for which susceptibility is mainly determined in the first year of life.

To sum up, we now better recognize the importance of vitamin D in the earliest stages of life. Furthermore, there is, as noted earlier, quite good agreement on how much an infant needs. Where we lack consensus is how to make certain that all of our babies get the amount they need. Why not rely on giving nursing infants vitamin D drops, as the AAP recommends? Two reasons: 1) It’s been tried and has failed; and, 2) When it does work in individual infants, it provides no benefit for the mother. By contrast, ensuring an adequate vitamin D input to the mother during pregnancy and lactation is almost certainly the best way to meet the needs of both individuals.

An “adequate” intake for nursing mothers, as noted earlier, is not the 400 IU/d the IOM recommends, but is instead in the range of 5,000–6,000 IU/d, taken daily. If they get that much, they will meet not only their own needs, but their infant’s as well. And they will have the satisfaction of knowing that they are supplying all their baby’s needs, the natural way.

Links for more exploration:

  1. Perrine CG, Sharma AJ, Jefferds MED, Serdula MK, Scanlon KS. Adherence to vitamin D recommendations among US infants. Pediatrics 2010;125:627-632.
  2. Hollis BW, Wagner CL. The role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab 2013;98:4619-4628.
  3. Luxwolda MF, Kuipers RS, Kema IP, van der Veer E, Dijck-Brouwer DAJ, Muskiet FAJ. Vitamin D status indicators in indigenous populations in East Africa. Eur J Nutr 2013;52:1115-1125.
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