As differences in opinion have developed over how to interpret the science,
a great deal of controversy has emerged over the optimal levels and doses of vitamin D. Never was
this debate more intense than after the release of the most influential report on vitamin D ever
published - and the discovery of several mistakes contained within it - which we are going to take a
look at today in this next part of the series on this enigmatic nutrient. How are ye doing guys,
and welcome back to the vitamin D series. Last time out we explored the main arguments put
forward by conservative authors for their sticking with recommending a lower dose of vitamin D that
is just enough to support bone health, and not the extra required to optimise the extra-skeletal
health benefits on things like cancer and diabetes we learned about in part 2. We saw how this lower
level was determined way back in the early 20th century not long after vitamin D itself had
been discovered, and some of the reasons it has persisted from guideline to guideline since then.
We finished up by looking at what is perhaps the strongest argument for not recommending higher
doses - concerns about toxicity - and why this might not be as much of a problem as you would
think. I will return to toxicity before we finish out the series, but today we will be
examining some of the mistakes made in the most influential set of guidelines to date on vitamin
D - and how if they were not made, perhaps their recommendations would have been higher.
Just a quick reminder on units - you may have seen vitamin D doses reported both in terms of
micrograms and IU, short for International Units, and your vitamin D supplement may
be labelled with either. To convert from the former to the latter, simply multiply by 40.
Similarly, you will see serum levels reported in both nanograms per millilitre and micromoles per
litre. To convert from the former to the latter simply multiply by 2.5. There is much disagreement
in the area of vitamin D and a huge variation in the doses various commentators recommend, but
in a way, and definitely as a starting point for systematically studying the topic and arriving at
your own informed conclusion, the whole debate can be distilled down into a dichotomy - shooting for
a serum level of 50 nmol/L, vs. 75 nmol/L or more. This divergence in opinion is best embodied by
the sometimes polemical debate between by far the two biggest proponents of each level - the former
argued for by the Institute of Medicine, and the Endocrine Society in support of the latter. The
Institute of Medicine, or IOM published their dietary reference intake guidelines in 2010.
The purpose of these guidelines was to inform the US and Canadian governments on the latest science
on vitamin D, and arrive at dietary reference values with a view to guiding everything from
public health policy to food fortification programmes, but over time they have come to
be used for guiding clinical practice, which was not their original intention. In parts 3 and 4 of
this series I discussed how guidelines issued by governmental bodies tend to be more conservative,
favouring recommending less of a nutrient to ensure doing no harm through toxicity,
at the expense of potentially missing out on some extra benefits that higher levels would provide,
if those benefits cannot be definitively proven. In contrast, the purpose of the guidelines issued
by the Endocrine Society in the same year was to guide clinical practice decisions by
doctors directly caring for patients. Clinical practice guidelines tend to accept other forms
of evidence and are not as dependent on data from randomised controlled trials,
with the overall hope of providing the maximal possible benefit for individual patients - but
they also have the luxury of things like 1:1 care and testing if deemed necessary, which of course
those with the responsibility of the health of the public do not have. The Institute of Medicine's
guideline is the most important and influential document relating to vitamin D dietary reference
values ever released. Prior to it's release the most recent major vitamin D guideline update was
from 1997, which proponents of a higher dose could easily dismiss since the recommendations were so
old and it was thought that the science had moved on enough to recommend significantly more. But it
came as a surprise to many that the IOM stuck very closely with these 1997 recommendations following
their review of the science since then, finding what in their view was insufficient evidence of
causality to recommend the higher level of vitamin D to reap the extra-skeletal health benefits. It
was released to a hugely negative reception from groups advocating for a higher intake of vitamin D.
As we saw in part 4, this report can trace it's roots all the way back to the early finding that
a teaspoon of cod liver oil was enough to prevent rickets. Randomised controlled trials later proved
cause and effect for this relationship, with a little more being required to optimise bone
health in other areas, coming out to around 600 units per day to achieve a serum level of 20 ng/mL
or 50 nmol/L by their calculations. In their opinion, the data from RCTs at the time of
publishing testing higher levels against the extra-skeletal effects of vitamin D had not
reached the threshold required to recommend these higher levels to realise these health benefits.
And so, the IOM recommends the lower level to the public. However, despite the thorough independent
systematic reviews of RCTs they independently commissioned, laudable absence of advocacy that
other important nutrition guidelines would do very well to follow, and pioneering implementation of
the use of a risk-assessment framework for derivation of nutrient reference intakes as
well as upper limits, it is well-documented that the IOM committee made several mistakes in their
analysis of the vitamin D literature, even inside of their only recommending doses for bone health.
Despite rejecting evidence that does not come from human interventional trials in their justification
for not recommending the higher level, the IOM used supportive evidence for the lower level
from this cohort study on cadaveric samples from accidental deaths comparing various markers of
osteomalacia on the y-axis with vitamin D level on the x-axis, with anyone falling above the orange
line having weak enough bones to meet the criteria for osteomalacia. The most obvious thing at a
glance at these graphs is that as vitamin D level goes up, less people have markers of osteomalacia,
which of course makes sense. This study itself is not without it's limitations, such as some
arguing that the orange line should be higher in any case, but basically the IOM used it to support
it's position that a serum concentration of over 50 nmol/L is enough to prevent osteomalacia in
over 97.5% of the population, which is the cut-off these guidelines shoot for. Looking at osteoid
volume, they reasoned that once a concentration of 50 was achieved, 7 people were found to have
weakened bones. 7 divided by the 675 people in the study is only around 1%, so in their view this was
supportive evidence for 50 nmol/L being enough to cover the needs of 97.5% of people. Sounds
pretty good, right? The problem is that this is an incorrect analysis - they should have divided
these 7 people only by the 82 with a level over 50, in which case the conditional probability of
a patient having osteomalacia above this level of vitamin D actually becomes 7 divided by 82,
or around 8.5%, and thus only 91.5% of people would not have osteomalacia - which misses the
IOM's target of 97.5% and does not support their position. You have to compare like with like.
Interestingly, no individual had any marker of osteomlacia present on autopsy when their serum
level was over 75 nmol/L. Another mistake was made in determining the dose required
to achieve their desired level in over 97.5% of the population. Regardless of whether or not you
agree with a serum level of 50 nmol/L being enough to meet the needs of most people, once they had
decided on this level, the committee constructed a dose-response curve based on 32 dose-finding trial
arms. This method is already fraught with pitfalls as I will discuss later on, but it is the only
method we have of deriving an appropriate dose from a desired serum level. Confidence intervals
are applied to allow for uncertainty in the data and differences between the studies, between
which there is a 97.5% chance the aggregates from the included trial arms actually lies.
Thus the IOM used the lower confidence interval of the aggregates of these studies to estimate
the requirements of over 97.5% of the population, overshooting the desired level slightly to add in
a margin for error. But this analysis is incorrect - this method only gives us the lower predicition
limit of the averages of the studies - not the individual people that took part in those studies.
Intrepid researchers looked again at the study arms included by the IOM, and calculated
the lower confidence interval of the individual participant data from each arm where available,
and as would be expected it turned out to be much lower than that of the aggregates of the studies.
Based on this more correct analysis, it would actually take a lot more vitamin D to achieve
a level of 50 in 97.5% of the population given the now considerably wider confidence intervals.
The IOM's recommendation of 600 units per day would only get 97.5% of the population above
26.8 nmol/L by this analysis. This underestimation has also been realised in real-world results from
studies using the IOM's recommended dose, in which it has been found that much more
than 2.5% of participants miss the target serum level taking this dose - potentially resulting
in serious public health implications. These mistakes were thought to be so influential
that an external report on their impact on the recommendations was commissioned.
The authors of this report found that it was likely that these mistakes,
especially the second one, would have made a difference in the calculation of the RDAs,
but given the approach the committee took which allowed a certain amount of expert interpretation,
it was concluded that it is likely this would not have affected their final determinations,
essentially because there was no clear evidence of benefit in their view to doses over 600-800 units;
thus were again only really using the dose-response curve as supporting evidence.
However, given that nutrition guidelines always implement some element of professional opinion
in the interpretation of the data, the report did acknowledge that there was no way of knowing
if this correct interpretation of the curve would have been enough to change their minds.
But as we shall see in part 7 of this series, had the panel access to some of the new science
we have seen since, in my opinion these final determinations would have been very different,
an idea that this recent 2017 report into these errors also acknowledges. Note as well that
this report was not meant to appraise the methods of the IOM in determining their recommendations
and they were careful to say that the recommended levels would only stay the same according
to the methods the IOM used. This report also examined the two major governmental guidelines
issued since then to see if their findings corroborate the findings of the IOM report,
but they ran into the same problem we have seen over and over again in our investigation of vitamin D so
far - these latter recommendations built heavily on the work of the IOM report and only closely
examined evidence that emerged since 2010, which means the IOM's errors are in-built into these
newer guidelines and thus their agreement cannot be used to exonerate these mistakes because they
are implicity a part of these reports as well, and we will never know how strongly the IOM
recommendations influenced subsequent authors of guidelines - and the current world of vitamin D.
Even outside of the mistakes they made, there have been some strong accusations of confirmation bias
in the IOM report and exclusion of expert authors who were known to be in favour of higher doses.
The point has also been made that any systematic review of RCTs on vitamin D will inherently bias
towards lower doses since they neglect natural synthesis from the sun, but I think this is
actually one of the IOM report's strengths and they actually did a very good job of controlling
for this by only including trials done above a latitude of 49.5 degrees North and in Winter,
a combination that by our current science results in negligible endogenous vitamin D systhesis.
This is in contrast to other governmental guidelines that do suffer from this error by
including trials known to have a non-negligible input from sun exposure by being less strict
with their latitude cut-off and definition of Winter, such as for example the EFSA's, which
would enhance the bias towards underestimating vitamin D requirement, though notably even the
IOM's selection criteria were not perfect in this regard either. These mistakes were unfortunate,
since they take credibility away from what was otherwise an excellently-conducted synthesis of
the literature into practical recommendations, and shouldn't be used as an excuse to discount
the whole thing. This was an unenviable task given that the committee were charged with
developing the first governmental guideline since 1997 and had to consider the explosion in vitamin
D research done since then - perhaps an imperfect report was to be expected. The IOM report is by
far the most comprehensive literature review of vitamin D we have, and this is the first,
among many other reasons I will outline over the rest of this series, that I think it is time vitamin D was
examined closely again in a similar fashion to the original 2011 IOM report in their otherwise
excellent approach, and taking into account some very important recent developments in the field
of vitamin D. Since these landmark guidelines were released, and given that the work was otherwise so
comprehensive and ground-breaking, other authors have tended to just build on the IOM report and
only look at studies done since the report and not the totality of evidence, as stated here by
the EFSA in their guidelines. Unfortunately this has compounded the IOM's original mistakes, with
anyone using the IOM report as a starting point automatically also including the report's flaws.
The premise of rejecting the non-RCT evidence to form recommendations in and of itself has also
been challenged. As we saw in the last video, public health policy has often been determined
in the absence of evidence from RCTs, probably most famously for the link between smoking and
lung cancer. And in the video before that we saw how the Bradford Hill criteria have been applied
to justify higher doses of vitamin D even in the absence of positive results from RCTs.
The paucity of appropriate and relevant RCT data is a challenge faced by any group setting
vitamin D intake recommendations and even the IOM used non-interventional data in the form of the
cadaveric study and other cross-sectional data to establish it's recommendations.
In modern medicine the randomised controlled trial is the gold standard of evidence, but it has been
argued that while this makes sense for drugs and other exocompounds that have the potential
to do harm and are under much more threat from the corrupting influence of vested interests,
it is not as appropriate for guiding public health policy on naturally-occurring nutrients that cannot
be patented like vitamin D. We must always remember that evidence-based medicine does not
equal randomised controlled trials, but assessment of the best-available evidence from all sources -
something I have tried to do in this video series and by now have hopefully laid the foundations for
the case of my recommending more than the official governmental guidelines. But there are many
reasons why vitamin D specifically is ill-suited to the randomised controlled trial - and here with
this, finally, we will be moving on to the crux of the matter for me and the most important point I
will make for why I think it is better to target the higher level of vitamin D, and that this is
the way the wind is blowing. Why vitamin D has failed in human interventional trials. So be sure
to join me for part 6 when we will be diving into the human interventional data, and the reasons
why it might have been seen to fail all this time. Stick with me guys, we're nearly there!
In summary, the IOM report from 2010 is the most influential publication on vitamin D
ever released. In what was a surprise to many, it continued to recommend the conservative dose
calculated in the last major update from 1997, despite what many thought was plenty
of non-interventional evidence that had emerged since then to support recommending much more.
The report has been criticised both in it's methodology and in some of the mistakes the
committee made, but despite these shortcomings it has formed the basis for all major governmental
guidelines published since then. However, the report should not be dismissed by those
advocating higher doses of vitamin D since it forms the basis of an excellent approach
to setting reference intakes, and if updated with new science may come closer than ever
before to resolving this controversy in vitamin D. Make sure you join me for part
6 when we will be exploring perhaps one of the biggest fuels of this controversy - the
failure of the human interventional trials. Talk to ye soon guys, sláinte!