Do you live away from the tropics, work indoors, have darker skin, or even - Heaven forbid
- wear clothes? If so, there is a good chance you're a part of the severe public health
problem of vitamin D deficiency. But how much should you take to ensure adequacy? Watch
on to find out! How are ye doing guys, and welcome back to the vitamin D series. I wasn't
joking about the extent of vitamin D deficiency and insufficiency in the intro there - because
of the conditions of our modern world like where and how we live, as many as one third
of the Earth's population is deficient in vitamin D as per the generally-accepted
cut-off, and even worse than that in Europe, which according to the WHO makes it a severe
public health problem in some regions. We finished up last time by defining what I recommend
as the highest safe intake of vitamin D not to be exceeded without medical supervision.
We also discussed how it is not possible at present to define the upper toxic limit of
serum level of vitamin D, and we had to just stick with a catch-all toxic dose. However,
I have argued strongly throughout this series for what I believe should be the lower limit
of serum level of vitamin D - 75 nmol/L - and how this is at odds with the most important
vitamin D guidelines in existence at the moment. I believe that there is a rapidly emerging chain
of causation from the observation that people with a higher level are healthier, to the
biological plausibility for this lent by pre-clinical research, to the many biological processes
apparently affected by vitamin D, to the emerging positive results from human interventional
trials brought about by some recent developments in the field, and exploring all of this first
is why it has taken me eight whole videos just to get to this stage where I can now finally recommend
a dose, since I have first had to justify my position on level, and we sure have had
a lot to explore on the benefits of this higher level of vitamin D! I believe that just like
what we saw for the connection between high saturated fat and cholesterol intake and high
serum cholesterol, and the connection between this latter and coronary artery disease, it
is just a matter of time before we develop a chain of causation between higher vitamin
D levels with better outcomes in disease outside the skeleton as well as the classical skeletal
effects, and this higher level of vitamin D becomes accepted as the new normal. And
just to show I practice what I preach, here are my own last two vitamin D blood tests, both
of which were over 75, despite most certainly fitting into a certain at-risk cohort that
rarely sees the light of day! If you take this level as the cut-off for deficiency below
which the chance of adverse health effects increases, the epidemiological situation becomes
even worse, with studies of some regions suggesting over 90% of people do not meet this threshold
of 75. By now in this series the heavy lifting has been done and I hope I have convinced
you that it is worth shooting for that extra little bit of vitamin D circulating around
in your blood for the many health benefits it seems to provide. But if I have, the next
obvious question you might have is how much do I need to take to achieve a serum level
this high? As usual in my Nutrients of Concern series, we will only be discussing otherwise
healthy adults looking to maintain a normal level - treatment of severe deficiency or
use of vitamin D in disease states or special stages of life will be excluded and should
only be managed on an individual basis. The most influential guidelines ever released
on the topic by the IOM puts forward 600 units of vitamin D per day to achieve a serum level
of 50 nmol/L. If I have convinced you and you do want to shoot for a higher level than
this, could one simply just take 50% more vitamin D to achieve a serum level 50% higher
- in other words, would 900 units per day be enough to achieve a serum level of 75 nmol/L?
Unfortunately, incremental dose-response is rarely this simple for any nutrient or drug,
and indeed as we have seen throughout this series vitamin D has the most confusing dose-response
relationship of any nutrient. This is the reason why the IOM's own recommendation of
600 units doesn't even achieve their own conservative desired serum level of 50 in over 97.5% of
people following on from some mistakes they made in their analysis as we saw in part 5
of this series. But we're going to attempt to do just that today - extract an appropriate
dose from what is known about the vitamin D dose-response relationship to achieve a
level of at least 75 nmol/L. I know this is what you've all been waiting for guys, so
smash that 'Like' button if you're hyped to finally get some numbers! We saw in that video
that the correct analysis is to use the data from individual participants in studies to
build our dose-response curve, as shown here on the right, rather than the aggregated data
from each study, shown here on the left for comparison. When we do this, we include the
variation between individuals in response to vitamin D represented by the grey shaded
area in which 95% of people will fall, and we can minimise experimental variation by
using similarly-designed studies using standardised assays only, as was done here. And if we use
the lower confidence interval of the curve, we can estimate the amount of vitamin D required
to ensure over 97.5% of the population exceeds our desired vitamin D serum level. As we saw
in that video, the amount needed to ensure most people exceed 50 nmol/L is actually around 1000 units
per day according to this study, and not the 600 recommended by the IOM. But what about if we want to shoot
for 75 nmol/L? Can we just use this same graph to predict how much we need to take to achieve
75 instead of 50? No, unfortunately again we cannot do that. Note how few participants
in this particular synthesis took in more than 1200 units per day of vitamin D, or how
many achieved a level of over 75 - for example only .3% of participants were taking more
than 1400 units per day. We would be relying way too much on extrapolation and not actual
data. And indeed, as acknowledged by the authors of this paper, this would be a false extrapolation
- above intakes of around 1400 units per day it is recognised that the response to increasing
doses begins to plateau, and graphs produced by authors taking into account higher intakes
and levels have found that a curvilinear graph better represents the data. So even beyond
the extrapolation problem this data cannot be used to define intake requirements for
these higher levels of vitamin D since it used a linear rather than curvilinear regression
which better represented this data set of comparatively low intakes. Unfortunately,
at present there is no analysis of vitamin D intake to serum level dose-response that
meets the rigor of this study and includes only standardised individual participant data
from similarly-designed studies that also features the higher doses and serum levels
we are interested in as well as the sheer amount of studies that is required to formulate
recommendations for the public, so we will have to use the next best thing. The European
Food Safety Authority used the standard method of meta-regression of aggregate results from
vitamin D dose-finding RCTs irrespective of the analytical method used rather than the superior
individual-level standardised data method, but could then include many more studies - which
is essential when recommending to the public since we need a much more representative sample.
However, in an effort to make up for the known limitations of this approach, in addition
to the 95% confidence intervals, which are represented by the yellow region in their
dose-response curve, the EFSA also provided 95% prediction intervals as an approximation
of the variability in true individual responses, represented here by the green region. As you
can see, they also included plenty of data in the higher range of levels and intakes,
so this curve is much more instructive for this range. From this graph, we can actually
start drawing some firm conclusions. The EFSA used it to conclude that 600 units per day
would get most people over around 50 nmol/L, but our goal is a little more ambitious than
that - we want to have over a 97.5% chance of exceeding 75 nmol/L. In this case, the
graph would predict somewhere in the region of 75 micrograms or 3000 units per day would
be required. The graph also tells us that 97.5% of people would be predicted to have
a level of less than 105 nmol/L at this level of intake, which gives a lot of reassurance
as regards toxicity. As we learned in the last video, toxicity for vitamin D is best
defined not by level but by intake at present, and I concluded from the limited data we have
that an intake of greater than 4000 units per day should not be exceeded without medical
supervision and this is the cut-off beyond which the risk of toxicity increases. Also,
I defined my own personal upper limit level as 150. So 3000 units per day passes on both
counts! There are a couple of caveats to this method. Obviously we are relying on extrapolation
of the graph, but we simply have no choice since these higher levels and intakes have
been so neglected in the research. Also, the EFSA adjusted the data for a number of factors
to try to ensure that the variation in response that resulted better represented variation
between individuals rather than for example between assays or due to heterogeneity between
studies. Of course, in this case there is always the potential that the data is over-adjusted.
But even using their unadjusted curve, 3000 units per day would be predicted to get over
95% of people to fall between 72 and 130 nmol/L. And perhaps even more reassuringly, the upper
limit dose of 4000 units per day would result in those 95% falling between 80 and 109 nmol/L
as predicted by the adjusted curve, or between 78 and 136 as per the unadjusted curve - still
well within safe levels for the great majority of people. By the curvilinear nature of these
graphs it quickly becomes clear why to achieve the modestly higher level of vitamin D I am
advocating will require more than a concurrent modest increase in dose - we need more and
more vitamin D to go from 50 to 75 than we would need to go from 25 to 50, for example.
And this is also why there is such a seemingly huge range in doses of daily vitamin D supplements,
from anywhere around a couple of hundred units to several thousand units - the amount of
vitamin D they provide varies by orders of magnitude, but the serum levels they achieve
vary much less dramatically because of this plateau effect. This however also gives us
a much bigger margin for error in dose when targeting a serum level of for example between
75 and 125 versus between 25 and 75. Now guys, some of you may have been thinking in this
video and the last few videos, that this seems to be a very crude and blunt instrument - determining
a recommended dose based on that which will ensure over 97.5% of people achieve our desired
serum level. And I would agree with you! In this case, most people will exceed this level
and some by a great margin, and the higher the level we want to achieve the more we risk
exposing those at the upper end of responders and those outside of the prediction intervals
to uncomfortably high levels. I believe we are safe up until at the very earliest around
150 nmol/L which gives us a lot more wiggle room than the old IOM upper limit of 125 which
certainly would have made recommending a target level of 75 hard to justify since the dose
required would push the EFSA's upper prediction interval up to 130 on their unadjusted graph,
for example - but the point remains, lots of people will end up with a much higher level
than that which is necessary with this dose, and let's not forget the 2.5% that will fall beyond
our upper prediction interval owing to for example polymorphisms in the enzyme that breaks
down vitamin D leading to symptomatic hypercalcaemia with doses as low as 4000 units per day in
children. The way I see it, there are three practical levels of finesse when it comes
to determining a vitamin D dose. The crudest we have just elucidated - work back from the
desired level to a dose that will ensure most people will achieve it. The best way would
be totally individualised - in other words titrating dose on an individual basis according
to results from vitamin D blood tests. This would take into account all the factors playing
into the dose-response for that individual rather than just going with a blanket dose
suitable for the population - but of course not everyone has access to this option. But
there is another way. The confidence intervals tell us where 95% of people will end up at
any given dose. This variation in response is due to variation between individuals, which
itself consists of both knowable and unknowable factors. These are what cause some people
to end up at 75 whilst others end up with 105 from taking the same dose. The unknowable
factors are things like enzyme polymorphisms and absorption issues that can only be fully
accounted for by actually measuring an individual's level. But there are also knowable factors
that affect the response to any given dose of vitamin D; things like BMI, ethnicity and
time of year. This being the case, there is the potential that we could use the average response
on the dose response curve rather than the confidence intervals, starting off with a
much lower dose and then adjust from there as per these knowable factors to get a slightly
more tailored dose than the simple 97.5% rule. Of course, this method doesn't take into account
the unknowable factors like genetics and so it is not as good as testing and titrating,
but could potentially be a little more personalised than the blanket recommendations and 97.5%
rule, and perhaps save some people from high levels or unnecessarily high doses. Likewise,
there is also the possibility that 3000 or even 4000 units per day won't be enough of
a maintenance dose for some people such as those with a high BMI or with absorption issues,
and don't forget about the 2.5% outside of the range of the lower prediction interval
that will not hit 75 nmol/L even with 3000 units or more! I have looked online but couldn't
find a dosing calculator that takes into account all the relevant variables, so I am thinking
of creating a smartphone application myself that takes into account adjustments like these
to calculate a more personalised dose on inputting some of these individual knowable factors.
Let me know in the comments if that's something you would be interested in! But anyway, as
I'm sure you can see, there is no easy answer here. The problem with recommending higher
doses when using the 97.5% method is that you risk pushing more and more strong responders
into toxicity - even though the extent of this risk as a public health problem is not
known. What is known is that low levels definitely do result in worse health outcomes. So who
is to say that the poor responders should be the ones to suffer by recommending less rather
than the theoretical possibility of the occasional strong responder being worse off by recommending
more? In fact, the still unproven nature of toxicity at these relatively modest high doses
and levels is why many authors and guidelines do not recommend testing at all and that everyone
just takes vitamin D doses on the order of thousands of units per day without worrying
about toxicity - they remain unconvinced that it is a problem at all until exceptionally
high intakes and levels. Regardless, I myself think that there would be far more people
that would end up with health problems at the lower end of the range by recommending
a serum level of 50, than the amount of people that would end up with health problems at
the higher end of the range on recommending 75. This again has flavours of the primum
non nocere bias we discussed in part 4 of this series - it might be more justifiable
to have lots more disease that may have been contributed to by vitamin D deficiency without
being provable, rather than have toxicity that could only be due to vitamin D as a result
of overzealous public health recommendations - even if the former dwarfs the latter. Of
course, also because of this paradigm, the higher the level anyone recommends the more
pressure there is on them to concurrently recommend testing since you will be pushing
more and more of the strong responders into potentially toxic levels. I feel I have justified
my stance on not automatically recommending concurrent testing in this and the last video
in shooting for 75 nmol/L and 3000 units per day, but if one was to pursue numbers any
higher than this the case for testing really starts to go up. And of course, also remember
you could easily be one of those 2.5%, and even at this relatively modest dose you could
end up with a level far higher than most people. The only way to know for sure is to get tested
at least once so you know you are not a very strong responder. So there you have it guys,
my blanket daily dose recommendation for maintenance of healthy vitamin D levels in adults. But
we're not done yet! All the numbers we have discussed today assume minimal contribution
from natural synthesis from sun exposure - how would you combine the two sources if you were
a real-life person that gets plenty of sun on some days or for some parts of the year,
but not at other times? There is also plenty more to discuss on things like dosing frequency,
specific supplement recommendations, interactions with other nutrients and testing to name but
a few. I want this series to be as comprehensive a guide to vitamin D as possible, so we will
be covering many more aspects beyond just the optimal dose before we finish out the
series. I also promised in an earlier video to propose why I think vegans might actually
have an advantage when it comes to optimising vitamin D status - don't worry, I haven't
forgotten about it, that video is on it's way as well! In summary, I believe our target
for vitamin D level should be 75 nmol/L. To achieve this we must look to the efforts at
constructing a vitamin D dose-response curve, taking into account the limitations of different
methodologies, and working back from our desired serum level to a dose that ensures the majority
of people will achieve it by looking at the prediction intervals. Given the plateau effect
and curvilinear nature of the dose-response graph, we require a non-linear increase in
dose to achieve a linear increase in serum level. 3000 units daily will be enough for
almost everyone to achieve a serum level of 75 nmol/L, but many will require substantially
less than that. The best way of determining the optimal dose on an individual basis is
to test and titrate your dose to your desired serum level. And of course, all of this neglects
many knowable factors that can change the required dose, such as sun exposure. Join
me next time when I will be examining other pertinent factors relating to posology like
how often vitamin D should be taken and at what time of day. Talk to ye then guys, sláinte!