by Chris
Masterjohn
Presented with
permission from the Weston A. Price Foundation,
www.westonaprice.org
where this article originally appeared.
Table of Contents
One of the many commonalities
that Dr. Weston A. Price observed among the diets
of the so-called "primitive" populations
whom he described in Nutrition and Physical
Degeneration, to which he attributed their
resistance to dental caries and their superb skeletal
structure, was a richness in the fat-soluble vitamins,
including vitamin A. In fact, Dr. Price noted that
primitive diets were "at least ten times"
higher in the fat-soluble vitamins than was the
American diet, even assuming Americans were meeting
the official recommendations of the day.1
Yet in recent years, some researchers have hypothesized
that the osteoporosis seen among the elderly in
modern civilizations, which manifests itself as
reduced bone density and increased risk of fracture,2
is attributable to an excess of vitamin A. Many
attendees of the Weston A. Price Foundation's recent
Wise Traditions 2005 conference were surprised
and confused to hear Dr. Noel Solomons, director
of the Guatemala-based CeSSIAM International Nutrition
Foundation, a heroic program to improve vitamin
A nutrition in third world countries, recommend
a mere 800 international units (IU) per day of preformed
vitamin A from animal foods - scientifically called
"retinol" - and warn that, based on recent
findings from the Nurses' Health Study, intakes
as low as 1500 IU per day are harmful to skeletal
health.3
More recently, Dr. John Cannel, president of the
Vitamin D Council and also a speaker at the Weston
A Price Foundation's 2005 conference, recommended
in a newsletter that vitamin D supplements not contain
any preformed vitamin A because it interferes with
the function of vitamin D, and warned that "if
you just have to take" cod liver oil, "don't
take more than a teaspoon a day." Dr. Cannel
suggested ß-carotene, a precursor to vitamin
A (retinol) that is found in plant foods, is a safe
alternative to the preformed retinol found in cod
liver oil.4
Although the vitamin supplement industry claims
that the research is conflicting and inconclusive,5
there is actually an impressive body of evidence
suggesting that, in certain circumstances, an "excess"
of vitamin A is contributing to an increased risk
of osteoporosis in certain populations even at relatively
low levels.
At first glance, the research seems to stand in
stark contrast to Price's consistent observation
of very high levels of vitamin A in primitive diets
accompanying the superior skeletal health of those
same groups. A more careful consideration of the
research suggests, however, that what is at issue
is not an excess of vitamin A, but an imbalance
between vitamin A and other nutrients in the diet,
especially vitamin D. Human and animal evidence
strongly suggests that vitamin A can only exert
harm against the backdrop of vitamin D deficiency,
that sufficient levels of vitamin A are even higher
than once thought, and that supplementing with carotenes
is neither an adequate nor a safe way to achieve
these optimal levels - all of which are consistent
with and supportive of Price's timeless findings.
Vitamin A, Bone Mineral
Density, and Hip Fracture: The Epidemiological Evidence
Just twelve years after vitamin A was discovered
as a constituent of cod liver oil and butterfat,
a team of researchers led by Takahashi established
in 1925 that it produced toxic symptoms (now called
"hypervitaminosis A") in rats when fed
as a natural fish oil concentrate at 10,000 times
the required amount. In 1933, these researchers
showed that this vitamin A-rich concentrate was
toxic to bone in extreme doses, resulting in spontaneous
fractures, and in 1945 Moore and Wang confirmed
that these effects were attributable to vitamin
A by inducing them with purified retinyl acetate,
which is, like retinol, a type of preformed vitamin
A. Researchers have since reported skeletal lesions
in response to extreme doses of vitamin A in dogs,
pigs, rabbits and chickens. In humans, an increase
in blood levels of calcium (caused by the leaching
of calcium from bone), bone pain, and other bone-related
symptoms sometimes accompany hypervitaminosis A.6
Yet it is not such toxic, wildly excessive doses
of vitamin A to which modern researchers are attributing
osteoporosis, but normal, even relatively low, non-toxic
intakes of vitamin A common in modern societies
- intakes far below those of the tribesmen and villagers
whom Weston Price found to have superb skeletal
health.
Summary of the Epidemiological
Evidence
In 1998, a group of Swedish researchers led by
Hakan Melhus observed that hip fracture rates vary
seven-fold across Europe and are highest in Northern
Europe, Sweden, and Norway - where northern latitudes
preclude the UV-induced synthesis of vitamin D in
human skin for much of the year, and where vitamin
D intakes are frequently well below the paltry recommended
minimums,6 which they failed to note - and where
intake of preformed retinol is six-fold higher than
elsewhere in Europe, which they noted duly. The
group studied women from Uppsala, a county of Sweden,
and published the first study on vitamin A intake,
bone mineral density (BMD) and hip fracture risk
that distinguished between preformed retinol, found
in animal foods, and its precursors, carotenes,
found in plant foods. They found that, compared
to an intake of retinol below 1,700 IU per day,
intakes of retinol exceeding 5,000 IU per day were
associated with a six percent decrease in total
body BMD, a 10 percent decrease in BMD at the site
of the hip, and a doubling of the risk of hip fracture.7
Several groups of researchers have published conflicting
studies since 1998, using different methods of estimating
vitamin A intake. Among them:
- Ballew and others published a study in 2001
finding no relationship between blood levels of
vitamin A and bone mineral density in Americans
in the Third National Health and Nutrition Examination
Survey (NHANES-III).8
- In 2002, Feskanich and others published findings
from among American nurses who participated in
the Nurses' Health Study showing that intakes
of preformed retinol, but not carotenes, were
associated with the risk of hip fracture among
postmenopausal women who were not taking hormone
replacement therapy (HRT). An intake above 1,700
IU per day was associated with a somewhat inconsistent
increased risk of fracture, while an intake above
6,700 IU per day was associated with a much sharper
and more consistent increased risk of fracture.9
- The same year, Promislow and others reported
a U-shaped curve between retinol intake and BMD
among Southern Californian elderly women and men
in the Rancho Bernardo study, in which an ideal
intake of preformed retinol amounting to 2000-2800
IU per day was associated with the greatest BMD,
while either an increase or decrease from this
amount was associated with a lower BMD. The trend
was more consistent and stronger among the postmenopausal
women and less pronounced among men.10
- In 2003, a study by Michaelsson, Melhus, and
others found a similar U-shaped curve for blood
levels of vitamin A and the risk of fracture in
elderly men of Uppsala, Sweden. Compared to the
middle quintile, the highest quintile of retinol
levels had a 64 percent increased risk of any
fracture and a 147 percent increased risk of hip
fracture. Compared to the same middle quintile,
men with retinol levels above 3.5 micromoles per
liter (µM, which is a measure of a specific
number of vitamin A molecules per liter of blood)
had seven times as many fractures. The
researchers concluded that risk is primarily associated
with levels above 3 µM. Although to a lesser
extent, risk of fracture increased in the lower
quintiles of serum retinol as well.11
- In 2004, a team led by Opotowsky published a
study of American women that established a much
cleaner U-shaped curve associating blood levels
of vitamin A with hip fracture risk than the curve
established by Michaelsson's team. The middle
quintile, which grouped those with blood levels
of vitamin A between 1.9 and 2.13 µM, had
the lowest risk of fracture. Compared to this
quintile, the lowest and highest quintiles both
carried approximately double the risk of fracture.12
- The same year, Lim and others published a study
drawing from data representing over 41,000 postmenopausal
women from the Iowa Women's Health Study, which
found no association between the dietary intake
of preformed retinol and the risk of hip fracture.
Those who used vitamin A supplements, as a group,
had a 17 percent increased risk of hip fracture
compared to those who did not, but there was no
relationship between the amount of vitamin A taken
and the risk of hip fracture.13
- Barker and others published a study in 2005,
this one also failing to find a positive association
between vitamin A and fracture risk. In this study,
researchers measured the blood levels of vitamin
A among British women over the age of 75. Over
the following four years, the researchers actually
found a 15 percent decrease in the risk
of osteoporotic fracture among the highest
quintile of vitamin A levels. About 40 percent
of the subjects were using cod liver oil or a
multivitamin, but no information was provided
to differentiate between the two. This was the
first of these studies to mention cod liver oil
specifically as a source of vitamin A supplementation.14
Stronger Studies Show an Association
Although those of us who would like to feel reassured
of the safety and benefit of a high vitamin A intake
without giving the subject careful thought may be
tempted to brush off this research as conflicting
and therefore inconclusive, studies that do not
find an association between vitamin A and BMD or
fracture risk generally suffer from some inadequacy,
being bettered by their counterparts that do find
an association.
For example, the Ballew study analyzed the data
in such a way as to reveal a linear relationship
between blood levels of vitamin A and BMD, where
an increase from one vitamin A level to another
would consistently yield a decrease of BMD. It did
not, however, look for a U-shaped curve, where both
a decrease or an increase from an ideal level of
vitamin A could lower BMD.8 When the
Opotowski team analyzed its data in the same way,
it found a relative risk of 1.0 for blood levels
of vitamin A, meaning that fracture risk appeared
to be distributed perfectly evenly among all vitamin
A levels, yielding no relationship. Yet when the
Opotowski team analyzed the same data looking for
a U-shaped curve, it found high and low serum vitamin
A levels both to carry double the risk of fracture
as did optimal levels - something the Ballew team
couldn't have found because of the way the group
analyzed the data.12
Although the Lim team found no relationship between
dietary intake of preformed retinol and fracture
risk, it only used one one-week food frequency questionnaire
(FFQ),13 whereas the 1998 Melhus study
used four one-week FFQs,7 and the Nurses'
Health Study used five one-week FFQs. In fact, when
the Feskanich group analyzed the Nurses' Health
Study using only the data from the first FFQ, the
association between the fifth and first quintiles
of retinol intake fell from a statistically significant
(meaning consistent and unlikely to be due to chance)
89 percent increased risk to a non-statistically
significant (meaning inconsistent, with a high probability
of being due to chance) 17 percent increased risk.9
This suggests that one one-week FFQ does not measure
retinol intake with sufficient accuracy to detect
an association, and that, had the intake data more
accurately estimated real intake of retinol, the
Lim team might have found such an association.
Synthetic Versus Natural:
Does it Matter?
So far, things are looking bleak for vitamin A.
To those of us familiar with the long-established
findings of Dr. Price that associate diets very
rich in vitamin A with vibrant skeletal health,
the modern research that shows much lower amounts
of vitamin A to contribute to osteoporosis paints
a picture of vitamin A that appears not only bleak,
but also confusing. Many of us may be tempted to
argue that it is not natural vitamin A-rich food
that contributes to osteoporosis, but the synthetic
preparations of vitamin A found in multivitamins
and used to fortify foods like breakfast cereals,
margarine, and low-fat milk. Yet under closer scrutiny,
this familiar intellectual weapon in our arsenal
proves impotent, and the answer must lie elsewhere.
At first glance, two pieces of evidence seem to
suggest synthetic vitamin A is exclusively the culprit.
Indeed, a full 94 percent of the variance in retinol
intakes between the highest and lowest quintiles
in the Nurses' Health Study was attributable to
supplemental retinol, while only six percent of
the variance between these quintiles was attributable
to food retinol.9 Seemingly even more
powerful, the Rancho Bernardo study found that those
taking supplemental vitamin A had a dose-dependent
decrease in bone mineral density (BMD)
as they consumed more retinol, while those obtaining
retinol from food alone had a dose-dependent increase
in BMD as they consumed more retinol.10
Close examination shows, as the researchers noted,
that the apparent difference between supplement
users and supplement non-users in the Rancho Bernardo
study is an illusion created by the difference in
total vitamin A intakes between the two groups.
Those who obtained their retinol from food alone
had low intakes of retinol, while those who obtained
their retinol from both supplements and food together
had high intakes of retinol, with only a small portion
of overlap between the intakes of the two groups.10
Figure 1
Reproduced from J Bone Miner Res
2002;17:1349-1358 with permission of the American
Society for Bone and Mineral Research.
The lines punctuated by squares (left) represent
subjects who obtained retinol from food only; the
solid lines (right) represent subjects who obtained
retinol from food and supplements; the dotted curves
represent the two combined. As a line moves upward,
bone mineral density increases. As a line moves
rightward, retinol intake increases. The "X"
where the two lines cross represents the points
for which the two groups were consuming the same
amount of retinol. Even when consuming the same
amounts of retinol, bone mineral density increases
with increasing retinol intake for those not taking
supplements and decreases with increasing retinol
intake for those taking supplements. However, if
one imagines the square-punctuated line shifted
to the left to account for supplemental retinol
being utilized at a higher rate, a U-shaped curve
emerges for all retinol intakes.
Still one puzzle remains: In the graph in Figure
1, the line on the left, representing the BMD
of subjects who obtained retinol from food alone,
crosses the line on the right, which represents
those who obtained retinol from supplements, yet
even in this overlap, food retinol remains protective,
while supplemental retinol remains destructive -
something the researchers didn't explain. The answer
is likely found in the fact that fat-soluble retinol
found in food and some forms of supplements results
in lower peak plasma values (levels in the blood),
lower liver stores, and higher fecal loss than the
water-soluble, emulsified, and solidified forms
of vitamin A found in most supplements.15
Additionally, although the type of vitamin A found
in supplements, all-trans retinol, is the
most common type found in food, foods also contain
a variety of other forms of vitamin A, all of which
have lower levels of activity than all-trans
retinol.16
In other words, a given amount of retinol from food
is effectively a lower dose of retinol
than the same amount from most forms of supplements.
If we imagine the line to the left in Figure
1 to be shifted leftward to compensate for this
difference in availability, the picture that emerges,
then, is a clean U-shaped curve similar to that
found by the Opotowsky team with blood levels of
vitamin A. The implication of this important fact
is that larger amounts of natural vitamin A will
have the same effect on bone mineral density as
smaller amounts of supplemental vitamin A.
The results of the Nurses' Health Study are particularly
damning to the idea that it is synthetic, but not
natural, vitamin A that contributes to osteoporosis.
The Feskanich group reported the proportion of various
dietary sources of vitamin A in this study in great
detail and differentiated between supplemental and
food retinol with impressive rigor. When the figures
were adjusted for age only, the highest intake of
retinol from food and supplements combined carried
a 27 percent increased risk over the lowest quintile
of intake. The researchers performed a second analysis
that excluded all persons who consumed any form
of supplemental vitamin A. For those obtaining retinol
from food alone, the highest quintile of intake
carried a 67 percent increase in risk!9
The researchers then performed a multivariate analysis,
which adjusted for intake of vitamins D and K, protein,
calcium, alcohol, and caffeine, as well as smoking,
use of certain drugs and hormone replacement therapy,
body mass index and other factors in addition to
age. In this analysis, intake of retinol from food
and supplements combined yielded an 89 percent increased
risk among the highest quintile of intake compared
to the lowest, while those obtaining retinol from
food alone had a somewhat lower 67 percent increased
risk in the highest quintile compared to the lowest.
The authors duly noted that even those not using
supplemental vitamin A were obtaining vitamin A
from fortified foods in addition to naturally occurring
vitamin A, and performed a third analysis for that
reason: those who consumed liver at least once a
week had a 69 percent increased risk of fracture
compared to those who never ate liver.9
Although there are a variety of reasons to obtain
vitamin A from foods rather than supplements, avoiding
the risks of so-called "excessive" intakes
of vitamin A with respect to osteoporosis is not
one of them. The research clearly suggests that
the amount of vitamin A is the operative
factor rather than the form of vitamin
A.
At this point, the evidence against vitamin A appears
on the surface to be inescapably incriminating.
There is, however, much more to the story.
Vitamin D: The Missing Link
Most studies investigating the link between vitamin
A and osteoporosis view vitamin A "excess"
in a vacuum, as if the only factor determining what
constitutes an excess of vitamin A for a given body
weight is the amount of vitamin A itself. Indeed,
the toxicity of vitamins in general is often determined
by using large doses of a single vitamin.
This may help us attribute toxic effects to a particular
vitamin, but it also precludes our understanding
which effects are due to the absolute amount
of that vitamin, and which effects are due to an
imbalance between that vitamin and other
vitamins.
Vitamin D Protects Against
the Toxicity of Vitamin A
Research that examines the feeding of high doses
of more than one vitamin simultaneously reveals
that toxicity is dependent on reactions between
different nutrients. For example, studies in rats,
turkeys, and chickens have demonstrated that vitamin
A both decreases the toxicity of and increases the
dietary need for vitamin D, while vitamin D both
reduces the toxicity of and increases the dietary
need for vitamin A.6
In 2003, Myhre and other researchers examined all
291 cases of hypervitaminosis A in humans reported
in the medical literature between 1944 and 2000.
Of these, the Myhre team identified 81 reports that
provided information about the patient's vitamin
D supplementation, and found that concomitant supplementation
with vitamin D radically increased the dose of vitamin
A needed to cause toxicity. Unfortunately, the researchers
only mentioned whether vitamin D was supplemented
at all and did not discuss the specific amount of
vitamin D being supplemented. Nevertheless, they
found that the median dose reported for vitamin
A toxicity was over 2,300 IU per kilogram (kg) of
body weight per day higher when vitamin D was also
supplemented. For a hypothetical 75-kg person representing
the median, vitamin D supplementation would have
allowed an additional 175,000 IU per day
(the amount in five tablespoons of high-vitamin
cod liver oil) before toxicity symptoms were likely
to be reported!15
Vitamin D Requirements
in the Vitamin D Winter
It is difficult to resist the observation that
Scandinavian countries, which have the highest fracture
rates in Europe, not only have higher average intakes
of retinol but also exist at far northern latitudes,
where "vitamin D winters" - periods of
time during which vitamin D cannot be produced by
the action of sunlight upon the skin - are longer
and less vitamin D is available from the sun in
the months during which it is available at all.
The ideal way to obtain vitamin D is by exposure
to sunlight. Sunshine in the ultraviolet-B (UV-B)
spectrum strikes the skin, converting a cholesterol
precursor called 7-dehydrocholesterol into vitamin
D3, which is also called cholecalciferol, as well
as a variety of similar chemicals, including the
activated form of vitamin D, calcitriol. When atmospheric
conditions are ideal and skies are clear, 30 minutes
of whole-body exposure of pale skin to sunlight
without clothing or sunscreen can result in the
synthesis of between 10,000 and 20,000 IU of vitamin
D. These quantities of vitamin D are large, and
therefore capable of supplying the body's full needs.
At the same time, the body has two mechanisms to
prevent an excess of vitamin D from developing:
first, further irradiation converts excess vitamin
D in the skin to a variety of inactive metabolites;
second, the pigment melanin begins to accumulate
in skin tissues after the first exposure of the
season, which decreases the production of vitamin
D.17
The availability of UV-B rays, however, depends
on the angle at which sunshine strikes the earth,
making vitamin D synthesis impossible for most people
at most latitudes during parts of the year called
the "vitamin D winter." Outside the vitamin
D winter, sufficient UV-B rays for full vitamin
D synthesis do not suddenly become available: the
window of time during each day in which vitamin
D synthesis can occur gradually expands as the season
progresses, as does the amount of UV-B radiation
available within that window. In 1988, Webb and
other researchers established that some degree of
vitamin D winter occurs above 34 degrees latitude,
and that in Boston, at 42.2 degrees north, the vitamin
D winter extends for four months from November through
February, while in Edmonton at 52 degrees north,
it extends across six months from October through
March.18
In 2005, Engelsen and colleagues published a study
that suggests the Webb team may have overestimated
the true vitamin D winter for clear skies in Boston,
probably by mistaking scattered clouds, which are
almost always present even when the sky appears
clear, for cloudlessness. Using a more precise model,
the Engelsen team accounted for the following factors:
natural variations in the density of the ozone layer
can cause the length of the vitamin D winter to
increase or decrease by up to two months; clouds
can eliminate up to 99% of UV-B radiation; aerosols
and the presence of buildings decrease exposure
to UV-B; finally, increased altitude and reflective
surfaces such as snow increase exposure to UV-B.
While the Engelsen team found that the vitamin D
winter would be shorter than estimated by the Webb
team under truly "clear" skies, it also
found that the aforementioned factors can extend
the vitamin D winter so dramatically that such a
winter can sometimes occur even at the equator.19
The county of Uppsala, Sweden, where Michaelsson,
Melhus, and others had associated retinol intake
with reduced BMD and increased risk of fracture
in 1998, 7 and likewise had associated
serum retinol levels with the risk of fracture five
years later,11 is located at the northern
latitude of 59.97 degrees.20 Using an
online model provided by the Engelsen team21
and assuming typical atmospheric conditions and
complete cloudlessness - an idealized and rarely
occurring phenomenon - I estimate that Uppsala's
vitamin D winter would extend for a minimum of about
four months, from late October to late February.
However, dense ozone and overcast skies could cause
the vitamin D winter to extend for more than ten
months from mid-July, to the end of May. The typical
vitamin D winter probably lies somewhere between
the two.
In order to maximize calcium absorption, blood
levels of 25 (OH) D - the form of vitamin D that
the body stores in its reserves - must be maintained
at 30 ng/mL (nanograms per milliliter - a nanogram
is a billionth of a gram), which, in the absence
of UV-B light, would require roughly 2600 IU per
day of vitamin D to maintain. However, fracture
risk continues to decline at even higher levels
of 25 (OH) D because people actually fall less
often, suggesting that these higher vitamin
D levels enhance neuromuscular coordination. Higher
vitamin D levels also confer benefits that are unrelated
to the skeletal system: serum levels as high as
46 ng/mL, for example, appear to maximize the body's
ability to regulate blood sugar. Dark-skinned agricultural
workers in the tropics tend to have 25 (OH) D levels
of about 60 ng/mL, suggesting that the optimal level
of vitamin D is nearer to this figure.22
According to Dr. John Cannel of the Vitamin D Council,
to maintain serum levels of 25 (OH) D at the suggested
optimal range of 50 ng/mL during a vitamin D winter,
one must consume 4000 IU of vitamin D per day.23
By contrast, the groups studied by Melhus and Michaelsson
were consuming much less.
Low Vitamin D Levels in
Epidemiological Studies of Vitamin A and Osteoporosis
Although Michaelsson and Melhus did not report
the vitamin D intake of the Uppsala men and women
whom they studied in either of their two reports
associating vitamin A with osteoporosis, they authored
another report on a different subject, studying
women of Uppsala and the adjacent county, Vastmanland,
in which they reported vitamin D intakes organized
by quintile of calcium intake. The women in the
lowest quintile of calcium intake consumed an average
of only 97 IU of vitamin D per day, while the women
in the highest quintile of calcium intake consumed
an average of only 185 IU of vitamin D per day.24
Thus, at a latitude that spends the preponderance
of the year covered under the dusk of a vitamin
D winter, the residents of Uppsala are consuming
between one twentieth and one fortieth of
what is required to maintain optimal serum levels
of vitamin D.
The majority of epidemiological studies investigating
the hypothesized link between vitamin A and osteoporosis
have not reported vitamin D levels. What little
data we can glean from the few that have, however,
suggests that the relative amounts of vitamins A
and D may be more important than the amount of vitamin
A alone.
In the Nurses' Health Study, which found a positive
association between retinol intake and fracture
risk, intake of vitamin D increased as intake of
retinol increased, but at a much lower rate. The
net effect was that the retinol-to-vitamin D ratio
increased from 9.7 in the lowest quintile of retinol
intake, which had the lowest risk of fracture, to
19.34 in the highest quintile of retinol intake,
which had the highest risk of fracture. The researchers
found vitamin D intake to be protective, and multivariate
analysis that adjusted for many variables including
vitamin D intake caused the association with vitamin
A to become much more pronounced and consistent.9
That the effect of vitamin A became more pronounced
when vitamin D was controlled for shows that the
net effect of a higher vitamin A intake depends
not only on the amount of vitamin A consumed, but
also on the amount of vitamin D consumed with it.
Since vitamin D is produced in the skin by sunlight
but only vitamin D consumed in the diet, and not
blood levels, was reported, we can't know for sure
the true vitamin D status of the participants in
the Nurses' Health Study, but to the extent that
they relied on dietary vitamin D, the evidence suggests
that the increase in hip fractures may be due not
simply to an increase in vitamin A intake itself,
but to an increase in vitamin A considerably out
of proportion to the paltry increases in the very
low intakes of vitamin D.
By contrast, in the Barker study, which found a
negative association between serum retinol levels
and fracture risk, serum vitamin D increased as
serum retinol increased, but at a higher rate. Unfortunately,
the researchers made no differentiation between
a multivitamin and cod liver oil for the 40 percent
of study participants who took one or the other.
Nevertheless, the explicit mention of cod liver
oil as a source of vitamin A supplementation suggests
that its use was substantial. Those not using a
supplement had mean serum retinol levels of 1.95
µM and mean serum 25 (OH) D levels of 15.24
ng/mL, while those using a multivitamin or cod liver
oil had mean serum retinol levels of 2.07 µM
and mean serum 25 (OH) D levels of 18.88 ng/mL.
This represents an increase in serum retinol levels
of 6.15 percent, and an increase in serum vitamin
D levels of 23.9 percent. In this study, the highest
quartile of serum retinol carried a 15 percent decrease
in fracture risk, while using a multivitamin or
cod liver oil, which increased serum D levels at
nearly four times the rate at which it increased
serum retinol levels, carried an even greater 24
percent decreased risk of fracture.14
When taken together, these two studies demonstrate
that a higher intake or blood level of vitamin A
does not necessarily, by itself, lead to an increase
or decrease in fracture risk; instead, an increase
in vitamin A can be harmful if not accompanied by
a sufficient increase in vitamin D, or healthful
when accompanied by such an increase.
One study that does not support this view is the
Lim group's analysis of the Iowa Women's Health
Study. Although ratios of retinol intake to vitamin
D intake doubled between the lowest and highest
quintile, no association of any kind was found between
vitamin A intake and fracture risk. While use of
a vitamin A supplement decreased the ratio
of retinol intake to vitamin D intake, it also resulted
in a increased risk of fracture; since
there was no relationship between the amount supplemented
and the decrease of risk, however, the significance
of the finding is questionable.13 As
noted earlier, this study suffers from a major deficit:
the researchers used only one FFQ, a practice which
produced similarly null results in the Nurses' Health
Study, in contrast to the positive results produced
from the Nurses' Health Study when the same researchers
used all five FFQs.
Just as the higher quality studies demonstrate
a relationship between vitamin A and osteoporosis,
the higher quality studies among those that report
both vitamin A status and vitamin D status demonstrate
that whether vitamin A is harmful or healthful depends
on whether sufficient vitamin D is consumed with
it.
Steroid Hormone Deficiency
Mimics Vitamin D Deficiency
Finally, it should be reiterated that the Nurses'
Health Study found the association between vitamin
A and fracture risk to be concentrated among postmenopausal
women not using hormone replacement therapy (HRT).
When the researchers performed a separate analysis
of those using HRT and those not using HRT, there
was no consistent relationship between retinol intake
and fracture risk among those using HRT, while multivariate
analysis yielded a statistically significant 252
percent increased risk in the highest quintile of
vitamin A intake among women not using HRT .9
Estrogen and other sex steroids play some roles
in the body that are similar to roles played by
vitamin D. For example, estrogen is a primary inhibitor
of bone resorption in both men and women,26
while both estrogens and androgens increase intestinal
absorption and the retention of calcium,xii both
of which are also roles played by vitamin D.6
Estrogen, testosterone, and other androgens also
play roles in facilitating bone growth.25
It could be, then, that a decline in sex steroids
aggravates the effect of vitamin D deficiency, bringing
the total vitamin D-like activity to a low enough
level that a higher intake of vitamin A begins to
become harmful. It is enlightening that sex steroid
deficiency appears to "turn on" the otherwise
dormant association between vitamin A and fracture
risk: this should give us pause to consider whether
this same association can be "turned on"
by vitamin D deficiency and "turned off"
by vitamin D sufficiency in the same way - much
like the flip of a light switch.
Research Paradigms Must
Change to Consider the Relationships Between Vitamins
Although researchers in general have paid altogether
too little attention to the balance between
vitamins A and D when examining the relationship
between vitamin A and osteoporosis, one researcher,
Sara Johansson, a tutee of Hakan Melhus, has made
this relationship a central part of her hypothesis.
Johansson noted with Melhus in a 2001 paper that
vitamin D intakes in Scandinavia are often deficient
and sunlight is limited, concluding, "We hypothesize
that the high intake of vitamin A in Scandinavia
may aggravate further the effect of hypovitaminosis
D on calcium absorption."27
Similarly, Johansson concluded her 2004 PhD thesis
by writing, "I hypothesize that the high intake
of vitamin A in Scandinavia may further aggravate
the effect of hypovitaminosis D on calcium absorption
and, possibly, contribute to the high incidence
of osteoporosis . . . It would also be interesting
to see if the outcome of epidemiological studies
would be different if, in addition to the level
of vitamin A intake, consideration was taken to
the vitamin D status of the individuals." Unfortunately,
even Johansson went on to repeat the error of those
who, unlike her, see vitamin A "excess"
as a phenomenon operating in a vacuum rather than
a phenomenon dependent on balance with vitamin D,
with these final words: "It has become clear
that vitamins can not be considered magic pills
that bring only benefit to health, and that the
widespread misconception - ‘the more vitamins
the better' - is a fallacy."6
Certainly, the statement taken by itself is important
and true. Without doubt, there must be a point beyond
which the fat-soluble vitamins become harmful rather
than healthful, as do all substances. But to suggest
that this is the most powerful lesson to be concluded
from the research on vitamin A and osteoporosis
is to suggest that vitamin A intakes in modern society
are currently too high. Yet there are two other
possibilities: first, high vitamin A intakes might
be safe and beneficial when vitamin A is consumed
in the proper ratio to vitamin D; second, a wide
range of intakes and ratios between the two vitamins
might be acceptable if sufficient levels of both
are maintained.
Johansson's own research into the interactions
between vitamins A and D, and that conducted by
other researchers, suggests that the last two possibilities
are much more likely explanations than the first.
In fact some animal experiments have shown that
unthinkably massive doses of vitamin A are safe
when accompanied by equally massive doses of vitamin
D.
Before we review this fascinating research, let's
review some of the technical details of vitamin
A's role in bone metabolism, and how it interacts
with vitamin D.
Getting Technical with Vitamins
A and D: How They Interact to Regulate Bone Metabolism
An Introduction to Bone
Anatomy and Metabolism
Bone is a living tissue comprised mostly (90-95
percent) of a collagen matrix, an assortment of
other types of proteins, and deposited hydroxyapatite
crystals, which are made primarily of calcium and
phosphorus salts. Within bone are three types of
cells: osteocytes, which burrow canals
and blood vessels through bone to supply nutritive
support; osteoclasts, which secrete acids
and protein-digesting enzymes that dissolve bone;
and osteoblasts, which support the growth
of new bone by secreting the collagen-based matrix,
which itself attracts the deposition of mineral
salts. Precursors to osteoblasts and osteoclasts
lie on the surface of bone, each of which develops
into mature and active osteoblasts and osteoclasts,
respectively, when directed to do so by certain
signaling molecules. As osteoblasts secrete new
bone matrix, some of these cells become trapped
in their own matrix and develop into osteocytes.6
Bone resorption, performed by osteoclasts, and
bone growth, performed by osteoblasts, are complimentary
to one another, and together make up the process
called bone remodeling, which allows bones to optimize
their shape in response to environmental cues, to
adjust to the occurrence and repair of injury, and
to allow the body to tightly regulate calcium levels.
During childhood and adolescence, the balance between
the two favors bone growth, until peak bone mass
is reached between the ages of 25 and 30. Ideally,
the maintenance of evenly balanced bone remodeling
persists after this point, but typically in older
age an imbalance occurs in favor of bone resorption,
which contributes to decreased bone mineral density
(BMD) and therefore to osteoporosis.6
Osteoporosis is defined as "a skeletal disorder
characterized by a reduction in bone mass with accompanying
microarchitectural damage that increases bone fragility
and the risk for fracture."2 Low
BMD itself can only account for 28 percent of fractures.
Fracture risk is also determined by the mechanical
quality and geometry of the joint. Another factor
in fracture risk is so obvious that it may go overlooked:
the propensity to fall.6 This might actually
be, to some degree, nutritionally determined: as
discussed above, one study associated high serum
vitamin D levels with decreased likelihood to take
a fall, interpreted by some to attribute a neuromuscular
benefit to high levels of vitamin D.22
Bone Resorption: A Positive
and Necessary Function Regulated by Vitamins A and
D
The activated forms of vitamins A and D, retinoic
acid and calcitriol respectively, are both hormones,
which are signals that cause changes in cells by
altering the expression of genes, or activating
one or another enzyme within the cell that carries
out some function. Retinoic acid activates bone
resorption by increasing the number and activity
of osteoclasts. It also decreases the growth of
osteoblasts. The oft-cited and conventionally understood
role of calcitriol is to inhibit bone resorption,6
but mice that have no vitamin D receptor have impaired
bone resorption, indicating that calcitriol also
plays a role in stimulating bone resorption.28
While bone resorption and bone growth are in a
sense "antagonistic," they really are
complimentary processes. Osteoblasts and osteoclasts
synergistically regulate each other. Although osteoclasts
perform bone resorption, it is osteoblasts
that initiate the process, by secreting
signals that cause osteoclast precursor cells to
develop into mature osteoclasts. As osteoclasts
erode bone, various growth factors are released
from the eroded bone that in turn stimulate the
maturation of osteoblasts. As osteoblasts mature,
they progressively make fewer osteoclast-activating
signals and more osteoclast-inhibiting signals,
so that bone resorption gradually slows and eventually
comes to a stop just before bone growth begins.6
Vitamin A's bone resorption-stimulating activity
is vitally important to bone health. The Opotowski
team, which found that low vitamin A levels had
as great an effect lowering BMD as did high vitamin
A levels, suggested that vitamin A deficiency may
contribute to increased fracture risk by allowing
bone matrix to grow faster than it can be mineralized.12
Indeed, although the net effect of vitamin A is
to stimulate osteoclasts and slow the growth of
osteoblasts, vitamin A also causes osteoblasts to
secrete a variety of enzymes and other proteins
that are important to bone mineralization, including
osteocalcin, which is a protein that plays a direct
role in attracting and binding calcium within the
bone matrix.6 By slowing the growth of
the matrix but increasing the rate at which it is
mineralized, adequate vitamin A helps to ensure
sufficient bone density.
Rickets, a vitamin D-deficiency disease that occurs
in developing children, is marked by a massive increase
in osteoid tissue (non-mineralized bone matrix),
an increase in the number of osteoblasts, and an
inability of osteoclasts to perform bone resorption.
Rickets is accompanied by a dramatic expansion of
a portion of the bone called the metaphyseal plate,
and total bone volume can actually increase. The
adult version of rickets, osteomalacia, a term also
used to refer to the unregulated osteoid growth
that occurs in childhood rickets, is also sometimes
accompanied by a decrease in the number of osteoclast
cells.28 Thus, bone resorption is a vitally
important process that both vitamins A and D play
a role in stimulating and regulating.
(See Appendix 1 for more
details on the regulation of bone remodeling by
vitamins A and D.)
Vitamins A and D Regulate
the Intestinal Absorption of Calcium and Phosphorus
Vitamin D's primary role in bone health is not
to act directly on bone cells, but to increase the
intestinal absorption of calcium. Mice that have
been modified to not possess the vitamin D receptor
(VDR) develop rickets and osteomalacia when fed
a diet that is one percent calcium and 0.67 percent
phosphorus. They have 30 times the osteoid tissue
of controls, suffer a seven-fold decrease in bone
stiffness, and experience a marked expansion of
the metaphyseal plate, a primary sign of rickets.
However, when the amount of calcium and phosphorus
in the diet is doubled, mice with no VDR develop
normally without any such changes.28
Vitamin D acts through the VDR to increase the
expression of various proteins in the intestines
that are involved in transporting calcium across
the intestinal border and through intestinal cells
into the blood, and by less-understood mechanisms
also increases the absorption of phosphorus. When
the calcium concentration of the diet is very high,
however, calcium passively diffuses across the border
of the intestines.29 Phosphorus, in turn,
must be consumed in the proper proportion to calcium
- which, in vitamin D-deficient rats is one to two30-
which explains why a diet high in calcium and phosphorus
would be able to bypass the effects of an absent
VDR.
Still, we can not rule out an effect of vitamin
D on calcium and phosphorus absorption even in these
experiments, since the mice that lacked a VDR still
consumed some vitamin D. In 2005, researchers identified
a mammalian protein they termed 1,25D3-MARRS
present in the outer membrane of intestinal cells
that induces a rapid response to vitamin D, enhancing
the transport of phosphorus31 and possibly
calcium32 into the cell, showing that
not all of vitamin D's actions occur through the
VDR.
In both the rat33, 34 and the human,27
vitamin A antagonizes the rise in serum calcium
that is induced by vitamin D. Johansson and Melhus
performed the first in vivo human intervention study
(an in vivo study is one that utilizes an intact
organism, rather than cells or chemicals dissociated
from the organism) measuring the interaction between
vitamins A and D, in which they found vitamin D
to raise serum calcium and vitamin A to lower serum
calcium. Since neither vitamin affected the rate
of bone resorption or the amount of calcium in the
urine, they concluded that the changes in serum
calcium resulted from changes in the rate of intestinal
calcium absorption. Since intake of vitamins A and
D simultaneously did not lower the amount of metabolites
of each vitamin in the blood compared to taking
one or the other alone, they concluded that vitamin
A probably antagonizes the effect of vitamin D by
some mechanism other than interfering with the absorption
of vitamin D.27 In the rat,33, 34
the decrease in serum calcium is accompanied by
an increase in serum phosphorus, but Johansson and
Melhus did not measure serum phosphorus levels in
humans.
Does Vitamin A "Interfere
With" Vitamin D?
Researchers have made several suggestions about
possible mechanisms by which vitamin A might interfere
with the function of vitamin D. For the ambitious
reader, a discussion of the molecular details of
these mechanisms is presented in Appendix
2.
Although the net effect of vitamin A is to promote
bone resorption and the net effect of vitamin D
is to inhibit bone resorption, each vitamin also
plays a role in the opposing process: mice that
have no vitamin D receptor lose their ability to
engage in bone resorption,28 and one
study showed vitamin A to inhibit bone resorption.6
Vitamin A also increases the body's production of
growth factors, some of which stimulate osteoblasts
and thus bone growth.12 Therefore, it
is overly simplistic to say that the two vitamins
are "antagonistic" in this respect.
Likewise, although it is true that when vitamins
A and D are administered together, D tends to lower
serum phosphorus and raise serum calcium, while
A tends to lower serum calcium and raise serum phosphorus,
the molecular mechanisms of this process are not
understood. Vitamin D is necessary for the absorption
of both minerals from the intestine,29
so it could be that vitamin A acts as a modulator
of vitamin D, controlling to what degree it enhances
the uptake of one mineral versus the other.
Thus, the apparent "antagonistic" actions
of vitamins A and D are not clear examples of certain
antagonism, and the relevant mechanisms by which
vitamin A could be said to actively interfere with
the function of vitamin D are, as shown in Appendix
2, either undemonstrated or disproved.
How Much Vitamin A is
Too Much?
The Wrong Question to Ask
Now that we've established that vitamin A's role
in bone metabolism is a positive one and that its
interaction with vitamin D is of a complex character
that includes synergism rather than simply antagonism,
let's turn to the hard evidence: human and animal
experiments suggest that sufficient vitamin D -
something possessed by none of the groups studied
in the epidemiological reports that tie vitamin
A to osteoporosis - nullifies the effect of vitamin
A in promoting poor skeletal health. Put another
way, it isn't vitamin A in and of itself that contributes
to poor skeletal health; it is the combination of
comparatively high vitamin A and deficient vitamin
D.
Therefore, the question being asked by these epidemiological
studies - namely, "how much vitamin A is too
much?" - is entirely the wrong one.
There are three basic models we could use to assess
the effect of a given amount of vitamin A. The first
is to consider the absolute quantity. The second
would be a ratio model, wherein the importance of
the absolute quantity of vitamin A is subject to
the importance of the ratio between vitamins A and
D. The third is a threshold or "switch"
model, wherein the association between vitamin A
and osteoporosis could be "turned on"
by deficient vitamin D levels, and likewise "turned
off" by vitamin D levels meeting a certain
level of sufficiency, just like a light switch.
Several groups of researchers have published studies
investigating the effects of varying combinations
of vitamins A and D on the absorption of calcium
and phosphorus, serum levels of these minerals,
bone mineral density, other measures of skeletal
health, or some combination thereof, in animals
and humans, all of which support either a ratio
model or a switch model and none of which appear
to support a quantity model.
Human Evidence
As noted earlier, Myrhe and others conducted a
meta-analysis of all hypervitaminosis A case reports
that were published by the year 2000, which established
in humans the principle that the toxicity of vitamin
A depends not only on the intake of vitamin A, but
also on the intake of vitamin D. Although the analysis
clearly established this principle, it did not shed
any light on whether this interaction constitutes
a ratio or a switch model. The researchers found
that the median dose of vitamin A reported to be
toxic was 175,000 IU higher if vitamin
D was also being supplemented, but they did not
analyze the actual amount of vitamin D taken, thus
making it impossible to ascertain which of the above
models the data best supports. Moreover, although
46 percent of the toxicity cases involved elevated
blood calcium levels, likely due to an excess of
vitamin A-stimulated bone resorption (and thus an
efflux of calcium from bone to the blood), the effect
of vitamin D supplementation on neither this nor
any other criterion of toxicity specific to skeletal
health was studied.15
In 2001, Sara Johansson, who hypothesized in her
PhD thesis that excess vitamin A contributes to
osteoporosis by aggravating the effects vitamin
D deficiency,6 and her tutor, Hakan Melhus,
who published the first study associating vitamin
A intake with the risk of hip fracture,7
together published a double-blind crossover study
demonstrating that vitamins A and D have antagonistic
effects on serum calcium levels in humans. This
is, so far, the only controlled human intervention
study to my knowledge that has investigated the
interactive effects of vitamins A and D on the skeletal
system. Johansson and Melhus found that 50,000 IU
of vitamin A as retinyl palmitate decreased serum
calcium levels, while 2 µg (micrograms, or
millionths of a gram) of calcitriol, or activated
vitamin D, increased serum calcium levels.
(By weight, 2 µg of calcitriol is equivalent
to 6.66 IU of cholecalciferol, or non-activated
vitamin D, but since IU is a measure of physiological
effect and the physiological effect per unit of
weight of calcitriol is much more powerful than
that of cholecalciferol, we can't express the amount
calcitriol in terms of IU.)
Serum calcium levels rose when vitamins A and D
were administered together, but less than they did
when vitamin D was administered alone. Although
an increase in the rate of bone resorption would
have increased serum calcium, neither vitamin changed
the rate of bone resorption. Likewise, although
one vitamin could have exerted an antagonistic effect
on the other by blocking its absorption, neither
vitamin appeared to affect the absorption of the
other. Finally, although a decrease in the rate
of excretion of calcium from the blood into the
urine would raise serum calcium, neither vitamin
changed the amount of calcium in the urine. Johansson
and Melhus concluded, therefore, that the difference
in serum calcium concentrations produced by different
combinations of vitamins A and D is probably due
to changes that they produce in the intestinal absorption
of calcium.27
Figure 2
Reproduced from J Bone Miner Res 2002;17:1349-1358
with permission of the American Society for Bone
and Mineral Research
The lines with X's represent the effect of vitamin
D administered alone; the lines with diamonds represent
the effect vitamin A administered alone; the lines
with circles represent the effect of the placebo
control; the lines with triangles represent the
effect of vitamins D and A administered together.
Asterisks indicate that the effect is statistically
significantly different from the effect of the placebo;
a cross indicates that the effect is statistically
significantly different from the effect of vitamin
D alone. A. Vitamin A alone depresses serum calcium
relative to the placebo control, while vitamins
A and D administered together raise serum calcium
almost as much as vitamin D does alone. B. Vitamin
D lowers levels of parathyroid hormone (PTH), a
sign of vitamin D deficiency, relative to the control.
Vitamin A alone does not affect PTH levels, but
vitamins A and D administered together lower PTH
levels equally as well as does vitamin D alone.
Using the graph published by Johansson and Melhus
reproduced in Figure 2, I
estimate that serum calcium fell 0.77 percent compared
to the placebo group when vitamin A was administered
alone, rose 3.25 percent when activated vitamin
D was administered alone, and rose 2.87 percent
when vitamins A and D were administered together.
Since this study only tested one quantity of each
vitamin, it is impossible to know whether it fits
a ratio model or a switch model, but one thing is
clear: the absolute quantity of vitamin A is irrelevant.
In fact, the effect of vitamin A on serum calcium
levels was so dependent on the vitamin D status
of the individuals that it gave the appearance of
having the opposite effect when administered
alone, of lowering serum calcium, than it did when
administered together with vitamin D, of raising
serum calcium.
While comparing the effect of vitamins A and D
together to the effects of vitamins A and D alone
helps us distinguish the effects of each - something
that's interesting in an academic sense - those
of us eating a diet rich in all vitamins across
the board are interested in the more practical knowledge
of whether the vitamin A component of a nutrient-dense
diet is harmful. Clearly, as can be seen by the
graph in Figure 2, the lesson
of the Johansson and Melhus study is that vitamins
A and D together are very effective at raising serum
calcium levels. A look through the more extensive
animal evidence will reassure us further of the
safety and benefit of a nutrient-dense diet.
Animal Evidence: Rats
One group of researchers led by Cynthia Rhode investigated
the interaction of dietary vitamins A and D2 in
rats.33 Vitamin D2 is a type
of vitamin D that is synthesized from ergosterol,
a chemical found in plant fats, and is not normally
found in significant quantities in the diet. It
is worthless in birds because it has no affinity
for the protein that stores and carries vitamin
D in the blood; it effectively treats rickets and
severe vitamin D deficiency in mammals, including
humans, but it is up to 10 times less effective
than vitamin D3 at maintaining long-term
vitamin D status in humans, which is necessary for
a variety of other parameters of health.34a
The researchers fed 21-day-old rats a diet deficient
in phosphorus, designed to produce rickets. They
provided five doses of vitamin A ranging from 0
to about 29,000 IU per day, which is the bodyweight-adjusted
equivalent of a 75-kg human taking about 39,000,000
IU of vitamin A per day. They provided six doses
of vitamin D2 ranging from 0 to about 26 IU per
day, which is the bodyweight-adjusted equivalent
of a 75-kg human taking about 35,000 IU of vitamin
D per day. When no vitamin D2 was administered,
the lowest dose of vitamin A, equivalent to about
52,000 IU for a 75-kg human, increased bone mineralization,
while higher doses of vitamin A decreased bone mineralization.
For all other doses of vitamin D2, raising
the dose of vitamin A progressively lowered the
total amount of bone mineralization. Vitamin A also
progressively lowered the bone mineral density (which
is the amount of mineralization for a given volume
of bone, rather than the total amount of mineralization),
except at the level approaching the human equivalent
of 40 million IU per day, which caused a marked
reduction in growth, allowing bone mineral density
to stay constant as less minerals were deposited
into a smaller femur.
This study clearly refutes a model wherein the
absolute quantity of vitamin A is the only operative
factor. Whereas when vitamin D2 was held
constant, increasing vitamin A decreased bone mineralization,
I have assembled data in Table
1 showing that when vitamin D2 was
allowed to increase with vitamin A, increasing vitamin
A instead increased bone mineralization. Since this
study showed vitamin A to have an antagonistic effect
even at the highest level of vitamin D2,
however, it supports a ratio, rather than a switch,
model.
Table 1
Only a portion of the data is shown, simply
to elucidate the relative unimportance of absolute
quantities of vitamin A when analyzed alone. Vitamin
intakes are expressed as bodyweight-adjusted equivalents
for a 75-kg human.
| Vitamin D2 (IU/75 kg/day) |
Vitamin A (IU/75 kg/day) |
Total Femur Ash (mg) |
| 0 |
0 |
30.5 |
| 0 |
51,818 |
34.5 |
| 284 |
15,657,273 |
36.7 |
| 1418 |
39,145,909 |
46.5 |
By contrast, the same group of researchers published
a more elaborate and much more useful study last
year that supports a switch, rather than a ratio,
model. The researchers tested how different combinations
of vitamins A and D interact to affect serum calcium
and phosphorus concentrations. They used two forms
of vitamin A, retinyl acetate and the activated
hormone all-trans retinoic acid (ATRA),
and four forms of vitamin D: vitamin D2,
vitamin D3, the activated hormone calcitriol,
and a synthetic variant of calcitriol.34
Unlike in the first study, the researchers used
a diet with normal calcium and phosphorus concentrations
in this study, making it more relevant to the practical
question of how much vitamin A to include in a healthy
diet, rather than the academic question of how the
two vitamins interact within a disease-producing
diet.
When rats consumed an amount of vitamin D2
equivalent to a daily human dose of just under 500
IU, vitamin A as retinyl acetate decreased serum
calcium and increased serum phosphorus; yet at an
amount of vitamin D2 equivalent to a
daily human dose of just over 900 IU, even an amount
of vitamin A exceeding the daily human equivalent
of 5,000,000 IU could not lower serum calcium levels,
although vitamin A continued to raise serum phosphorus
levels. In fact, when the amount of vitamin D2
was equivalent to a human dose of about 1400 IU
per day, the amount of vitamin A equivalent to a
human dose of over 5,000,000 IU per day substantially
raised both serum calcium and serum phosphorus levels
(Table 3).
Likewise, activated retinoic acid was only able
to decrease serum calcium and increase serum phosphorus
at low doses of activated calcitriol. When rats
consumed higher doses of calcitriol, this ability
of retinoic acid was "turned off" like
a light switch.
Unfortunately, the researchers only tested one
dose of vitamin D3. When rats were fed an amount
of vitamin D3 equivalent to a daily human
dose of about 500 IU, amounts of vitamin A equivalent
to daily human doses of 2,600,000 IU and 5,000,000
IU both lowered serum calcium and raised serum phosphorus.
An amount of vitamin A equivalent to a daily human
dose of just over 17,000 IU, however, caused a small
(but not statistically significant) rise in serum
calcium, and actually caused a statistically significant
decrease in serum phosphorus levels.
Since vitamin D3 (shown in Table
2) was only administered at one dose that was
insufficient to "flip the switch," the
data first appear to support a ratio model. The
vitamin D2 data presented in Table
3, however, establish an unambiguous switch
model.
Table 2
When vitamin D3 was supplied at an amount below
the switch threshold of 938 IU, it exhibited a ratio
model, but if one compares the two values for 17,255
IU of vitamin A, it becomes clear that the absolute
amount of vitamin A is irrelevant. Vitamin intakes
are presented as bodyweight-adjusted equivalents
for a 75-kg human.
| Vitamin A (IU/75 kg/day) |
Vitamin D3 (IU/75 kg/day) |
Serum Calcium (mM) |
Serum Phosphorus (mM) |
| 17,255 |
0 |
1.10 |
3.35 |
| 0 |
454 |
2.15 |
3.06 |
| 17,255 |
454 |
2.30 |
2.41 |
| 2,603,455 |
454 |
2.08 |
2.84 |
| 5,146,364 |
454 |
1.73 |
3.23 |
Table 3
When vitamin D2 was supplied below the switch
threshold of 938 IU, vitamin A decreased serum calcium.
The very small decrease in the average serum calcium
that occurred when 938 IU of vitamin D2 was administered
was not statistically significant. Once the "switch"
was "flipped," vitamin A actually enhanced
the rise in serum calcium.
| Vitamin A (IU/75 kg/day) |
Vitamin D2 (IU/75 kg/day) |
Serum Calcium (mM) |
Serum Phosphorus (mM) |
| 17,255 |
0 |
1.23 |
3.74 |
| 0 |
469 |
1.95 |
2.65 |
| 5,206,909 |
469 |
1.40 |
4.58 |
| 0 |
938 |
2.33 |
2.87 |
