Perhaps more than any other nutrient, the vitamin D world has been the focus of much controversy
over the last decade, with an intense debate between those saying we should be recommending
much higher doses and taking steps to educate the public on the importance of this nutrient,
and those urging caution and that we need to wait for definitive proof of efficacy from randomised
controlled trials before we can risk exposing people to higher and potentially toxic levels.
Today, I will be exploring some of the new science that has emerged over the last few years that will
hopefully bring about the beginning of the end of the vitamin D controversy. How are ye doing guys,
ye're very welcome back to the vitamin D series. Last time out we examined the many possible
reasons why vitamin D human interventional trials have failed - why despite the impressive health
benefits of vitamin D suggested by other forms of evidence such as observational and lab studies,
we tend not to realise these same results when we actually give vitamin D to people experimentally
in an attempt to improve their health, and why this might be as a result of the limitations of
the application of the randomised controlled trial to vitamin D rather than the nutrient not being
efficacious. Regardless, an impasse has been reached where governmental guidelines will not
recommend a dose to achieve the higher level of vitamin D required for these extra-skeletal health
benefits until they can be definitively proven with RCTs - a standard of evidence which may never
be met because of these limitations, and also because of additional problems with aggregating
and comparing the data from multiple RCTs. The debate between the two opposing sides has become
quite polemical at times, with those in favour of higher doses highlighting the methodological
issues and mathematical mistakes in the US Institute of Medicine's conservative report,
suggesting they have presented the data in a misleading fashion that does not align
with the actual facts and some even levelling accusations of an industry conspiracy, while some
in the conservative camp have claimed that those advocating for a higher level draw conclusions
that are too strong from the available science, even to go as far as suggesting they have been
selective with the studies they decide to include in their guidelines and that their approach has
not been systematic or evidence-based, or that investigators have been tied to industry or even
religious beliefs about vitamin D. The debate has been so intense that it has spawned not one,
not two, but three international conferences on controversies in vitamin D!
Despite all of this, most practical applications of the contrasting vitamin D recommendations
seem to be settling on an "insufficiency" serum level, which is unusual for nutrients, to define
this grey area between cut-off recommendations - specifically 50-75 nmol/L or 20-30 ng/dL.
This is an area where there is at least potential for further health benefits, even if not yet fully
proven, but importantly with minimal risk of extra toxicity. For example, you might recall from part
2 of this series that when we do not have enough vitamin D to meet our calcium needs from the diet,
the hormone PTH rises and we liberate calcium from the bones instead, making them weaker.
On a population level PTH does not seem to definitely be at it's lowest level until we pass
75 nmol/L vitamin D, so theoretically we would need to achieve this level to make our bones as
strong as possible. Observed bone mineral density does seem to continue to improve with these higher
levels as well, presumably making them less prone to fracture. However, the health effects have
only been definitively proven to be maximised at the lower level of 50 nmol/L - there has
been a paucity of appropriately-conducted human interventional trials to lend enough evidence to
go higher as we saw in the last video - a point that is made carefully and repeatedly in the most
important set of guidelines advocating for the higher level issued by the Endocrine Society. As
time has gone on however, more and more groups, specifically non-governmental medical societies
concerned with clinical practice rather than public health, have adopted guidelines more
aligned with the higher serum level viewpoint of the Endocrine Society, leaning towards preventing
insufficiency as well as outright deficiency in the hope of getting a return on these potential
extra health benefits. As I have discussed before, this is an important distinction to make - part of
the disagreement comes from the fact that it is the guidelines concerned with clinical practice
that tend to recommend higher doses, where it is implied that things like face-to-face care,
clinical interpretation, specific disease states and testing will be a part of the equation - all
luxuries that those giving recommendations for public health policy do not have,
where broad generalisations have to be made and where the implications of recommending too much
are more serious. Long-term efficacy and safety data are more important in this case when we are
dealing with large groups of healthy people, in whom it could be argued more is at stake and we
need greater proof of benefit. This group is also going to live for a lot longer and
accumulate orders of magnitude more patient-years of taking the advice issued, so the considerations
are very different, but this distinction has not made it down as far as the consumer level,
resulting in confusion about how much we should be taking and what levels we should be shooting for.
Despite their rigid demand for evidence of causation in the relationship,
the trend overall in conservative guidelines has also been upwards. The IOM report did stick with
the original conservative recommendations for dose in 2010, but notably revised their
tolerable higher limit of dose upwards to reflect the gradual relaxation in concerns over toxicity.
And in their 2020 update, they acknowledged the growing body of research suggesting that vitamin
D might play some role in the prevention and treatment of these extra-skeletal
diseases, but they still held firm on their demand of evidence from RCTs before they would consider
changing their recommendations to reflect this. This debate is the hallmark of a vibrant field
though and has kept it energised and productive, and has sparked some new innovations that I hope
will go a long way towards settling the conflict in vitamin D once and for all. As we touched on
in the last video, perhaps the single biggest impediment towards achieving a consensus in
the field has been the fact that the tests for vitamin D have historically been very inaccurate.
This results in difficulties in comparing and aggregating data from human interventional
trials that use different assays, obscuring the more subtle effects on extra-skeletal health
and thus contributing in no small part to the apparent failure of vitamin D to show benefit
in these RCTs we learned about last time - and thus the persistence of conservative doses in
the guidelines of those depending on these RCTs to set their recommendations. Even intra-individual
variability in these assays exists, impeding the study and comparison of certain sub-groups,
and there have been major problems comparing trials and cohorts when different forms of vitamin
D are used in the studies. But over the last few years since the publication of the IOM report
some excellent work has been done in trying to standardise all these disparate vitamin D tests,
and labs participating in the international standardisation program have greatly improved
on this assay variability. But perhaps more importantly, in addition to improving the accuracy
and variability of assays used in practice, pioneering researchers have even developed
tools to go back over old bio-banked samples from previous studies, allowing us to look again at
the data using the new improved tests. This has resulted in some alarming findings. For example,
data from the NHANES surveys, which are used to set public health policy to reflect the trends
in health and nutritional status of adults and children in the US,
appeared to show a dramatic downward trend in population vitamin D levels between 1988 and 2006.
But when researchers went back and re-analysed the biobanked samples with modern standardised tests,
it became clear that this apparent downward trend was merely an artefact due to the variability in
assays used over the years, as becomes quite clear in this stark comparison of the data.
No wonder public health authorities have had such a hard time setting clear vitamin
D recommendations when they have had to deal with this kind of uncertainty!
This innovation has meant it is now possible for public health authorities to base their
vitamin D policy off accurate and precise estimates of current levels in the population,
rather than having to simply take their best guess, which will hopefully strengthen the
political case for further research on vitamin D which has been an issue in the past given the
known deficiencies of these surveys. This will in turn again help us to arrive at a consensus.
But to this end, what will be more important is the implementation of these new assay standards
in randomised controlled trials from now on, so we can properly aggregate the data
from them and find out once and for all how effective vitamin D actually is in humans.
Of course, all the other problems with vitamin D RCTs that we examined in the last video
will have to be addressed going forward as well, for example enrolling patients that are actually
vitamin D deficient to begin with. But we should not, and indeed cannot just ignore the RCTs done
in the past despite these methodological problems they were plagued with. Some of them have been
conducted very well and were largely free from these major problems - apart from the fact that
they have not used standardised tests which were of course not invented yet at the time.
There has been a huge amount of research done on vitamin D before assay standardisation came about,
and if we are to arrive at a consensus in a reasonable timeframe, it will be essential
to also go back over these old RCTs, identify the best trials that were free from most of
the other methodological problems and re-analyse the biobanked samples with the new standardised
assays. Perhaps a starting point might be to look at the studies included in a systematic fashion
by previous guidelines, such as those by the IOM and Endocrine Society, then re-analyse the samples
from these studies if they exist or repeat the trials with a standardised assay if they do not.
Some have even proposed going as far as recommending journals suspend the publication
of meta-analyses on vitamin D unless they only used standardised data, which I think makes
very good sense. Going back over old RCTs and re-analysing the bio-banked samples has already
been proven in concept by a pioneering research team based here in Ireland. In a similar fashion
to the NHANES data, the investigators re-analysed all the bio-banked samples from our equivalent
national survey with a standardised assay and found that the proportions of people falling
into each serum level range were again markedly different from the story the original data told.
And in an important step towards practical application of retrospective standardisation,
it was also found that the protocols developed for taking a much smaller pool of the original
1000+ samples agreed very closely with the overall findings - which will make roll-out of
retrospecitve analyses on a widespread basis much more feasible. Some of these intrepid researchers
then took this concept a step further, and once more in the first work of it's kind attempted
to use standardised tests from individual trial participants to try to determine the intake levels
that would be required for any desired serum level - in other words, to create a dose-response curve.
They pooled the individual data from 7 RCTs all with the same design
and with strict adherence to conditions which would have resulted in negligible
endogenous synthesis of vitamin D so it is only the effect of supplementation we will be seeing.
In fact the trials even exceeded the inclusion criteria of the IOM report,
and indeed the 5 that existed at the time of that report were included in it.
Three of these studies required the investigators to go back and re-analyse the bio-banked samples
with a standardised assay, as described above. Without going too much into detail,
in a similar method to what the IOM did with their dose-response curve as we examined in part 5 of
this series, the researchers constructed a plot based on the achieved serum level
of vitamin D by the participants in these trials. But the key difference from the IOM method is that
the Irish team used the data from INDIVIDUALS shown here on the right, not the aggregated
levels from each of the trial arms, which they also included here on the left for comparison.
This allows us to capture the inter-individual variability, shown here by the grey shaded area,
and thus the needs of over 97.5% of the population with our recommended doses. You might also
remember from part 5 that researchers attempted to do just this with the IOM curve retrospectively,
by going back to the trials they included and constructing a new curve, shown here on the
bottom in red, based on the individual data where available instead of aggregated data. But during
this correct interpretation, the curve would predict a very high dose to ensure over 97.5%
of the population would exceed the desired serum level since there is so much uncertainty in the
actual location of the curve introduced by assay variability and heterogeneity in study design.
The curve constructed by the Irish research team does not suffer from these problems since
they used standardised data from trials uniform in design, which allowed them to estimate the
required doses much more closely. In this case the uncertainty represented by the grey shaded region
is more due to the inter-individual variability in response to vitamin D, rather than variability
in study design and assay accuracy. This is exactly what we want, because we want
to include variability between individuals when setting reference nutrient intake recommendations.
With the caveat that this was a proof-of-concept study with only a small number of included trials,
the result, as we would expect, is that we need a lot more vitamin D to ensure most
people achieve any given serum level than what was put forward by the IOM.
For example, they found that we would actually require over 1000 units of vitamin D per day to
achieve a serum level of over 50 in most people and not the 600 units recommended by the IOM.
Notably, the Irish researchers also analysed their own studies using the aggregated data as did the
IOM in their approach, which again produced the lower intake figure of around 600 units.
Please note though that the purpose of this work was not to determine which vitamin D
level we should be aiming for, but simply to propose a better way of working out how
much vitamin D we need to recommend once we have decided what serum level we should be going for.
With this in mind, these investigators were unable to calculate an intake level to achieve over 75
nmol/L since so few included participants in these 7 trials achieved this level and the figure would
have relied too much on extrapolation. This is again highlighting a perennial problem in vitamin
D research - since previous recommendations have been quite conservative with tolerable upper
limits, few trials have experimented with these higher doses and thus there is less certainty in
the dose-response relationship in this range. But there was one governmental guideline,
issued by the Scientific Advisory Committee on Nutrition in the UK, where their recommended dose
DID agree with that calculated by this Irish team. What's going on here? It turns out that these UK
guidelines actually did use the individual participant approach, and unsurprisingly
they calculated a value that agrees very closely with that calculated by the Irish research team.
The problem is, they used a target serum level far lower even than other conservative governmental
guidelines of 25 nmol/L with the goal of merely preventing the severest manifestations of bone
disease that has been widely criticised and claimed to be without evidence base,
seemingly tracing it's roots all the way back to a 1976 paper with 9 cases of rickets,
with no justification of the recommendation and unclear assay performance characteristics
let alone standardisation, but that has unfortunately stuck since it was used
originally to define the cut-point on 25 nmol/L. So using individual participant data has even been
road-tested in official government guidelines - albeit with a highly debatable chosen serum
level target. But to that very end, remember the reason that proponents of the higher level
do want to shoot for over 75 nmol/L in the first place is to reap those extra-skeletal benefits.
As we have explored throughout this series, all the evidence is in favour of vitamin D providing
health benefits outside of the skeleton EXCEPT FOR the human interventional trials. I have put
forward in the last video why that might be due to the limitations of the application of
the RCT to the study of vitamin D rather than lack of efficacy, but nevertheless,
the point remains that vitamin D has not been proven in human interventional trials.
Until...NOW! When we standardise the assay used in an RCT and include the individual participant's
data from these RCTs in meta-analyses instead of just the aggregated data, the beneficial
effects of vitamin D do, finally, emerge in human interventional trials. For example, in this IPD
meta-analysis of RCTs using standardised tests, vitamin D supplementation was found to reduce the
risk of respiratory tract infection by 12% among all participants, with an even more impressive
effect seen in those receiving regular vitamin D without an additional large bolus dose which
as we saw in part 6 may not be a healthy practice - as high as a 70% risk reduction in those very
deficient at baseline, and a still very impressive risk reduction of 25% in those not so deficient!
We have also seen earlier in the series that some but not all older meta-analyses suggested
a decrease in mortality risk, but the first one performed using standardised individual
participant data revealed a clear increase in mortality beginning from somewhere in the region
of 50 nmol/L and downwards where both confidence intervals have crossed the x-axis. Again,
the researchers in this case were unable to draw firm conclusions about the higher end of serum
levels since so few people attained a level this high and hence the wide confidence intervals, but
did state that there was no clear indication of toxicity leading to reduced survival even over 125
nmol/L. These new research techniques are still very much in their infancy and the researchers
were unable to detect any meaningful variation of all-cause mortality risk between levels of 50
and 125 nmol/L as can be seen by the confidence intervals never crossing the x-axis after 50,
and likewise the authors of the respiratory infection paper could not distinguish if there
was any additional benefit in going from 50 to 75 nmol/L. But if we can marry the prospective and
retrospective use of standardised tests with the powerful individual participant data approach used
by the UK SACN and of course include much larger study populations and many more patient-years,
I believe that it will now be possible to get a much greater resolution in this range and it
will be soon time to look once again at vitamin D and combine the best of the methods used by all
these different guidelines, and hopefully very soon we will be able to achieve a consensus and
see the end of the controversy in vitamin D with the help of these two powerful new innovations.
Given the current pandemic-striken World we now live in, the promising emerging data of the
effects of vitamin D on respiratory infections might even be enough on it's own to move the
dial and encourage decision-makers to once again take a look at this nutrient. But what should we
do until then? Stick around for the next two parts of the series, when I will finally be
getting into detail on my own recommendations based on my reading of the current science.
In summary, the controversy in vitamin D has sparked much debate and innovation over the
last decade. Many practical applications of vitamin D science have recently settled
on defining an "insufficienct" range for the nutrient of between 50 and 75 nmol/L,
reflecting the potential at least for futher health benefits in going above this range.
But these benefits could not be definitively proven until the emergence of two innovations
in the study of vitamin D over the last 10 years. Firstly, the recent pioneering work
of standardising vitamin D assays will take away one of the greatest barriers towards allowing us
to identify the subtle extra-skeletal health benefits in RCTs that may be the most we will
ever see given all the other limitations of vitamin D interventional studies. And secondly,
the other major breakthrough of using individual participant data from these RCTs in meta-analyses
will allow us to much more accurately calculate the vitamin D needs of the population at large,
as well as define what level we should be aiming for in the population and individuals in the first
place. But as of yet, these innovations have not been established long enough for guideline-makers
to put into use. Hopefully over the next few years we will see these tools used to redefine
vitamin D reference nutrient intakes, but until then you're going to have to wait for the next
couple of videos in my series on vitamin D to find out what I recommend. See ye then guys, sláinte!