Christopher Masterjohn
Christopher Masterjohn
http://www.westonaprice.org/moderndiseases/beyond-cholesterol/#
Beyond Cholesterol
Posted on January 20, 2014 by Christopher Masterjohn • 1 Comment
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Article Summary
• Between 1928 and 1945, Weston Price measured the fat-soluble vitamin content of over
twenty thousand samples of butterfat from many different regions. He found that abundant
sunshine and rainfall, together with high-quality soil, was associated with high concentrations
of vitamins within the butter and fewer deaths from heart disease.
• Modern science has shown that vitamins A, D, and K cooperate to prevent the calcification
of arterial plaque, which in turn prevents heart disease. This confirms Price’s conclusions that
fat-soluble vitamins protect against heart disease.
• We can maximize our fat-soluble vitamin status by consuming a diet rich in organ meats,
animal fats, fatty fish, cod liver oil, and fermented foods, supplemented with leafy greens and
other colorful vegetables; by spending lots of time out in the fresh air and sunshine; and by
using traditional fats and oils while avoiding modern vegetable oils.
• Vitamin D can be a double-edged sword: adequate vitamin D prevents heart disease, but too
much vitamin D promotes heart disease. The available evidence suggests that the lowest risk
of heart disease occurs when vitamin D status is between 20 and 40 ng/mL.
• Trying to determine optimal vitamin D status is very problematic. Rather than trying to
achieve an optimal vitamin D status with vitamin D supplementation, most people should
focus more on optimizing the nutrient density and nutrient balance of the diet.
Fat-Soluble Vitamins in the Prevention of Heart Disease
In the second edition of Nutrition and Physical Degeneration, Weston Price published data
suggesting that fat-soluble vitamins from animal fats might protect against heart disease.
Between 1928 and 1945, Price collected over twenty thousand samples of butterfat to analyze
for fat-soluble vitamins, from many regions across the United States, northwestern Canada,
Australia, Brazil and New Zealand.
His data suggested that abundant sunshine, rainfall and high-quality soil led to an abundance
of rapidly growing, lush, richly green grass, butterfat rich in fat-soluble vitamins, and fewer
deaths from heart disease. Our understanding of heart disease has progressed immensely since
1
Price’s time, and now more than ever we can be confident that Price’s emphasis on the
protective power of fat-soluble vitamins was correct.
Food Sources of the Fat-Soluble Vitamins
Price placed special emphasis on vitamins A, D, and K. These vitamins are richest in butterfat
when cattle are raised in the open sunshine and consume richly green grass, leading to a
deeply yellow or even orange butterfat. Price also noted other important sources of fat-soluble
vitamins. He concluded from his studies of traditional peoples that while some groups
obtained fat-soluble vitamins primarily from dairy foods, others obtained them primarily from
organ meats and eggs, from the animal life of the sea, or from insects and other small animals.
In his own practice, he emphasized organ meats, cod liver oil, butterfat and fish,
supplemented by colorful vegetables, as sources of fat-soluble vitamins. What we know about
food sources of fat-soluble vitamins in our own era could be summarized as follows.
Vitamin A is found only in animal foods. Animals store vitamin A primarily in their livers. As
a result, the best sources of vitamin A are the livers of land animals or fish. Oil extracts of
these livers, such as cod liver oil, are similarly excellent sources of vitamin A. Although not
often used as food in modern diets, eyeballs contain even higher concentrations of the vitamin
because of its important role in vision, as does the tissue located behind the eyeballs.
Smaller amounts of vitamin A are found in the fatty tissue of animals. Because of its critical
role in growth and development, the fats most closely related to reproduction—butterfat,
meant to nourish a young animal, and egg yolks, meant to become a young animal—tend to
be richer in vitamin A than other animal fats.
Carotenoids from plant foods are often confused with vitamin A, but they are not the same
thing. There are over six hundred known carotenoids, roughly 10 percent of which are
precursors to vitamin A. Among these, the most important in our diets are beta-carotene,
alphacarotene and beta-cryptoxanthin. Carotenoids provide plants with red, orange and yellow
colors. Because they play an important role in photosynthesis, they are closely associated with
chlorophyll, which imparts a green color. Red, orange, yellow and green colors thus provide a
strong indication that a plant is rich in carotenoids, which we can potentially convert to
vitamin A.
Many factors affect the ability to convert carotenoids to vitamin A,1,2 making them a highly
variable and less reliable source of the vitamin than animal foods. The percentage of
carotenoids converted to vitamin A ranges from 3 to 25 percent for most plant foods. The
conversion is much higher from foods with simple matrices; as a result, it is highest from red
palm oil, intermediate for fruits, and lowest for vegetables. Cooking and puréeing fruits and
vegetables, however, increases the conversion. Fiber, parasites, toxic metals, oxidative stress
and deficiencies of iron, zinc, protein and thyroid hormone all decrease the conversion.
Conversely, fat, vitamin E and a deficiency of vitamin A increase the conversion. It is quite
easy to see how complex this issue can become. Someone who is deficient in vitamin A will
make more of it from plant foods, but what if that person is also deficient in iron and protein,
or suffers from hypothyroidism?
Even if all these factors are optimized, there is a strong effect of genetics. Almost half of
people with European ancestry have a genetic mutation that decreases their ability to make the
2
conversion at least twofold, and about a third have a second mutation that decreases their
ability to make the conversion fourfold.3 Thus, while many people may be able to extract
adequate vitamin A from plant foods, many may not. For the latter, even if they use red palm
oil, cook or purée their fruits and vegetables, eat those fruits and vegetables with fat,
minimize their exposure to toxins, and have healthy digestive systems and optimal hormonal
status, their genetics will prevent them from satisfying their need for this vitamin from plants
alone. The inclusion of colorful fruits and vegetables in the diet is an excellent way to
supplement more reliable sources of vitamin A, but the inclusion of nutrient-dense animal
foods in the diet is a critically important insurance policy against vitamin A deficiency and a
more reliable and robust way of optimizing vitamin A status.
We obtain vitamin D through exposure to sunshine and from consuming the bodies of fatty
fish, the livers and liver oils of fish, and in smaller amounts from other animal fats, especially
butterfat and egg yolks.
Vitamin K comes in two forms: vitamin K1 and vitamin K2. Vitamin K1 is most abundant in
leafy greens, while vitamin K2 is most abundant in animal fats and fermented foods. The
richest sources of vitamin K2 in modern diets are egg yolks and cheese, especially hard
cheeses. While much more data documenting the distribution of vitamin K2 in foods is
needed, current databases suggest that the richest sources of the vitamin are natto, a fermented
soy food common in Eastern Japan, and goose liver.
Vitamin K2 appears to be much more effective at preventing pathological calcification than
vitamin K1, but there is some overlap between the two, and humans have a limited ability to
convert K1 to K2. Emerging evidence also suggests that the form of vitamin K2 found in
animal foods has unique functions not possessed by the form found in fermented foods. The
wisest approach to vitamin K nutrition seems to be to cover all the bases by eating a diet rich
in leafy greens, animal fats and fermented foods.
When looking at nutritional databases, it is important to keep in mind that these databases
universally ignore the variation in nutrition between different foods. “Butter” is likely to have
a single value for each nutrient, but a major point of Price’s analysis of over twenty thousand
butter samples was the extreme variation in nutrient values. The factors responsible for this
variation are discussed in detail in the sidebar below.
It is also important to keep in mind that the context in which these foods are eaten determines
the availability of their nutrients. Fat, for example, is critical to the absorption of fatsoluble
vitamins. The absorption of carotenoids from salad with no added fat is close to zero, while
the addition of canola oil increases their absorption.4 The type of fat also matters. Compared
to safflower oil, beef tallow promotes better absorption of beta-carotene and better conversion
to vitamin A.5 Similarly, olive oil promotes better carotenoid absorption than corn oil.6 It
appears from the available evidence that traditional fats and oils emphasizing saturated and
monounsaturated fatty acids promote much better fat-soluble vitamin absorption when
compared to modern polyunsaturated vegetable oils.
Overall, then, we can maximize our intake of these vitamins by consuming liver, cod liver oil,
fatty fish, animal fats and fermented foods, and by getting plenty of fresh air and sunshine.
Fruits and vegetables displaying red, orange, yellow, and green colors help supplement our
intakes of these vitamins. Adding traditional fats and oils to the diet, while excluding modern
vegetable oils, helps maximize the biological activity of these vitamins.
3
Protection Against Calcification and Plaque Rupture
While there are likely many ways this fat-soluble trio protects against heart disease, this
article will focus on the most well established link: by protecting against the calcification of
arteries, these vitamins in turn protect against the rupture of atherosclerotic plaques. Plaque
rupture is the principal cause of the narrowing of coronary arteries and the formation of
deadly clots in these arteries, and thus plays a major role in heart attack and stroke (see
sidebar).
Until recently, most heart disease researchers considered the calcification of arterial plaque to
be a phenomenon that starts only after atherosclerosis has become severe. They questioned,
moreover, whether such calcification is truly harmful in and of itself or is simply a marker for
the overall severity of the disease.
In the past few years, however, it has become clear that calcification begins in the very
earliest stages of atherosclerosis.7 In hindsight, it is not too surprising that researchers
previously missed this: nearly all of the calcification in a plaque site—a full of 97 percent of
it, in fact—is so small that modern imaging equipment designed to visualize calcification in a
live human being is incapable of detecting it.8 These “microcalcifications” make a plaque up
to five times more likely to rupture under stress.8 Depending on the severity of the rupture,
this will lead either to greater narrowing of the artery or to a cardiovascular “event” such as a
heart attack or stroke (see sidebar).
The calcification of atherosclerotic plaque occurs in parallel with the accumulation of a
defective, inactive form of matrix Gla protein (MGP).7 This fact provides a strong hint about
the role of the fat-soluble trio: as has been known for quite some time, vitamins A and D
cooperate together to control how much MGP our cells produce; once produced, vitamin K
activates the protein, thereby enabling it to control the distribution of calcium.9
Indeed, mice with a genetic defect preventing them from producing MGP fail to accumulate
calcium in their bones, suffer from osteopenia and spontaneous fractures, and yet die within
two months of birth from the rupture of heavily calcified arteries.10 It is primarily vitamin K2,
found in animal fats and fermented foods, that activates MGP, which likely explains why
people with the highest intakes of vitamin K2—primarily from egg yolks and cheese—have
much lower rates of arterial calcification and coronary heart disease.11
Vitami n D: A Double-Edged Sword?
While vitamin K, especially vitamin K2, seems to be straightforwardly protective, the story of
vitamins A and D is more complex. When vitamins A and D are both provided abundantly,
they maximize the protective effect of vitamin K, but when vitamin D is provided in great
excess of vitamin A, it actually promotes abnormal, pathological calcification of soft tissues,
including arteries.12,13,14 This finding suggests that vitamin D may be a double-edged sword,
with the ability to either prevent or promote heart disease, depending on the dietary context in
which it is provided.
Indeed, both severe deficiencies of vitamin D15 and hefty excesses of the vitamin16 promote
atherosclerosis in animal experiments. Observational studies in humans show that the risk of
heart disease declines as vitamin D status increases. This relationship plateaus at about 24
4
ng/mL, and there is very little data exploring higher levels (see Figure 1). However, a recently
published study suggested that having vitamin D status higher than 40 ng/mL is just as
dangerous as having vitamin D status lower than 12 ng/ mL (see Figure 2). When viewed
together, the evidence in animals and humans suggests that vitamin D protects against heart
disease at the right dose, but that too much vitamin D actually contributes to heart disease.
Figure 1: The Risk of Cardiovascular Disease Declines with Increasing 25(OH)D Up to 24
ng/mL
This figure is adapted from Figure 3 as originally published in reference 27. The horizontal
axis has been converted from nmol/L to ng/mL so that the units correspond to those used by
clinical laboratories in the United States. The figure depicts data pooled from sixteen
independent studies measuring serum 25(OH)D and subsequent risk of cardiovascular disease.
25(OH) D is a metabolic product of vitamin D that is often used as a measure of vitamin D
status, though there are problems with this. Each circle represents an independent risk
estimate for a given category of 25(OH)D from an individual study. The size of the circle
represents the statistical power of the study, driven in part by low variation but mostly by
large sample size. Circles further to the right represent higher concentrations of 25(OH)D and
those higher up represent higher risks of cardiovascular disease. The shaded area represents
the confidence interval. The more narrow the shaded area, the higher our confidence in the
estimates; the wider the shaded area, the more uncertainty we have.
5
The risk of cardiovascular disease declines with increasing 25(OH)D up to 24 ng/mL but
appears to plateau thereafter. There are only two data points with poor statistical power at
concentrations higher than 32 ng/mL and there are no data points at concentrations higher
than about 45 ng/mL. The paucity of the data in these regions makes the uncertainty
surrounding the risk estimate very high, represented by the increasingly wide shaded area.
Figure 2: The Risk of Cardiovascular Events is Lowest between 20-40 ng/mL among Cardiac
Surgery Patients
This figure is adapted from the data in reference 28. The researchers measured serum
25(OH)D in just under 4,500 cardiac surgery patients, in whom the risk of future
cardiovascular events was very high. Over the following year, 11.5 percent of the patients
suffered a major event. The risk decreased with increasing concentrations of 25(OH)D up to
40 ng/mL, but increased thereafter. Those with 20-40 ng/mL had the lowest risk, but those
with concentrations greater than 40 ng/mL had just as high a risk as those with less than 12
ng/mL.
6
Many readers may be surprised that people with vitamin D status higher than 40 ng/mL have
a higher risk of heart disease when so many advocates of vitamin D supplementation
recommend levels much higher than this. Part of the reason many people recommend higher
levels is because they view the evidence within the framework of the very influential but very
problematic “naked ape” hypothesis of optimal vitamin D status (see sidebar).
We should keep in mind, however, that none of these studies takes into account the
interactions between vitamins A, D and K. It may be that vitamin D status higher than 40
ng/mL protects against heart disease in the context of a diet that provides liberal amounts of
organ meats, animal fats and fermented foods. It may also be that a simple cause-and-effect
relationship between vitamin D exposure and serum 25(OH)D, or between serum 25(OH)D
and disease risk, greatly oversimplifies the issue (see sidebar). The uncertainty over these
questions underlines the need to pay more attention to optimizing the nutrient density and
nutrient balance of the diet rather than overemphasizing the usefulness and importance of
optimizing blood levels of vitamin D.
An Old Solution to a New Problem
The successful traditionally living groups that Price studied placed special emphasis on
procuring foods rich in fat-soluble vitamins, supporting the health of their animals, and taking
great care to preserve the health of their soil. The causes of the twentieth century emergence
of heart disease are debatable, but Price’s suggestion that the fat-soluble vitamins provide
powerful protection against the disease has gained validation through decades of further
scientific inquiry. There is little doubt that the emergence of refined foods, the replacement of
butter with substitutes based on vegetable oils, the demonization of eggs, the loss of traditions
centered on the use of liver and cod liver oil, the dilution of the nutritional value of animal
products through industrial farming, and the campaign against animal fats have all greatly
diminished our ability to prevent and reverse this disease. The pervasive view that the foods
richest in fat-soluble vitamins are the very causes of heart disease because of their saturated
fat and cholesterol is particularly ironic and especially harmful. Returning to the traditional
emphasis on foods rich in fat-soluble vitamins may not be the whole answer but it is a critical
piece of the puzzle and an essential tool in our kit as we work toward a world where we
prevent the inevitable and cure the incurable.
Sidebars
Price’s Analysis of Butter Samples: A Closer Look
Price collected samples of butterfat every two to four weeks from many different regions.
This allowed him to trace the fat-soluble vitamin content of the butter through the year in each
region. He also assembled data provided by other researchers showing how sunshine, rainfall
and mortality from heart disease and pneumonia varied through the year in the same regions.
7
Price presented the mortality data for both diseases combined. This makes the graphs cleaner
and more readable but precludes us from analyzing the trends for heart disease and
pneumonia separately. In all likelihood, the fat-soluble vitamins found in the butterfat
protected against both diseases. Clinical trials over the preceding two decades had clearly
demonstrated the power of vitamins A and D—and cod liver oil, which contains a rich supply
of both vitamins—to protect against many different infectious diseases.17,18 The main text of
this article focuses on the evidence supporting the power of these vitamins and their
synergistic partner, vitamin K, to protect against heart disease.
Although this article focuses on vitamins A, D, and K as a synergistic trio, Price only used
two chemical tests to look for fat-soluble vitamins. His test for vitamin A used toxic reagents
and lacked perfect specificity—it picked up carotenoids, for example, which are also present
in butter—but it was a good test, dominant through the 1970s, and is still used in some
laboratories today. Price’s second test, however, has a more complicated story behind it.
From Price’s time through our own, scientists have primarily used the test to detect lipid
peroxides, which are formed when delicate polyunsaturated fatty acids suffer oxidative
damage. Based on research suggesting a correlation between an oil’s potential to oxidize and
its vitamin D content, Price initially used the test as an imperfect way to measure vitamin D. It
soon became clear, however, that isolated vitamin D caused soft tissue calcification. Butterfat
scoring high on the test, by contrast, seemed to safely and effectively promote the
calcification of bones and teeth, especially when combined with cod liver oil, and seemed to
have broader activities that no one had yet ascribed to vitamin D. Price therefore dropped the
term “vitamin D” from his butterfat analysis and began using the term “activator X.”
Researchers publishing in Russian- and German-language literature, unbeknownst to Price
and many others writing in English, had been using the same test to detect the synthetic
chemical benzoquinone, which belongs to a class of chemicals known as quinones. Decades
later, researchers publishing in English showed that the test detects biological quinones such
as coenzyme Q10. Vitamin K is another such quinone, and appears to be the compound Price
was trying to measure. It exists in two forms: K1 and K2. Cows obtain vitamin K1 from grass
and convert a portion of it to vitamin K2. Both forms of the vitamin are present in the butterfat
and presumably registered as “activator X” in Price’s test. Vitamin K2, moreover, has all the
biological characteristics Price attributed to activator X. A comprehensive argument
identifying activator X as vitamin K2 can be found in my Spring 2007 Wise Traditions article,
“On the Trail of the Elusive X-Factor: A Sixty-Two-Year-Old Mystery Finally Solved.”9
Price wrote in Nutrition and Physical Degeneration that the vitamin A and activator X
content of butterfat was related more to rainfall than sunshine, depended most closely on the
rapid growth of lush, green grass, and peaked at much greater concentrations in regions where
the soil remained most intact. There is a simple explanation for these findings. When grass
rapidly grows, it ramps up its photosynthetic activity. Photosynthesis uses energy from
sunlight and electrons from water to convert carbon dioxide to sugar, which is needed to fuel
growth. Essential components of the photosynthetic machinery include chlorophyll, betacarotene and vitamin K1.19 Chlorophyll imparts a deep green color to the grass. Cattle convert
a portion of beta-carotene to vitamin A and a portion of vitamin K1 to vitamin K2. All four
nutrients are present in the butterfat, and the beta-carotene imparts a yellow or even deeply
orange color to it.
8
The photosynthetic machinery also depends critically on minerals from the soil, including
iron, sulfur, calcium and magnesium.19 A deficiency of any other essential soil mineral can
also limit the ability of a plant to ramp up photosynthesis. Boron, for example, is not directly
involved in the photosynthetic machinery, but its deficiency compromises photosynthesis and
depletes chlorophyll and beta-carotene.20 Lack of available boron could be caused by lack of
boron itself or by factors that compromise its bioavailability such as high soil pH or low
concentrations of organic matter. We can conclude from all this that the recipe for high
vitamin A and activator X concentrations in butterfat is adequate water, sunshine and soil
health, which together support the rapid growth of grass.
If Price was correct that the difference in peak vitamin content between different regions was
primarily a result of soil quality, then it is clear from his data that soil health is often the
limiting factor: regions with long histories of soil depletion had low levels of fat-soluble
vitamins year-round. Price dismissed the role of sunshine and suggested rainfall was more
dominant, probably because peak rainfall tends to occur when sunshine is already adequate
and rainfall is more often the weakest of the two links in the chain. Had Price been able to
resolve the conundrum presented by the “activator X” test, however, he would likely have
recognized a greater role for sunshine. Cattle obtain vitamin D from the sun, not from grass.
Price did not have access to a reliable chemical test for vitamin D, but other researchers at the
time tested the vitamin D content of butterfat by measuring its ability to prevent rickets in
experimental animals. These studies showed that the vitamin D content of butter correlates
closely with the exposure of the cattle to sunshine.21 Indeed, if we analyze Price’s data
closely, it seems that both sunshine and the vitamin content of butterfat are associated with
fewer deaths from heart disease and pneumonia. This is probably because during periods of
greater sun exposure, people made more of their own vitamin D and obtained more vitamin D
from butterfat; when the grass was growing most rapidly, the butterfat also provided abundant
amounts of vitamins A and K, enabling maximal synergy between the three vitamins.
Plaque Rupture and Coronary Heart Disease
An up-to-date review of the best evidence available today suggests that the current view of
heart attacks—that most are caused by the occlusion of coronary arteries by blood clots
known as thrombi or less often by severe narrowing of the coronary arteries—is largely
correct.
The role of thrombi in heart attacks was highly controversial during the mid-twentieth century
through the 1970s.22 Some studies found coronary thrombi in fewer than 10 percent of cases,
while others found them in over 90 percent of cases. Some research even showed that clots
were more often found when people had died at least twenty-four hours after the onset of a
heart attack and were rarely found when they died within an hour of the heart attack,
suggesting that clots may be a consequence rather than a cause of heart attacks, forming in the
distant aftermath of a fatal event. Researchers tried to determine whether clots form before or
after heart attacks by injecting people with radiolabeled fibrin soon after a heart attack to see
whether the clots contained the radiolabel, but the results were conflicting and difficult to
interpret.
In 1979, a team of English researchers made a compelling argument that several
methodological and interpretive problems were at the root of the controversy.22 Even within
the same hospital, some analysts were much more likely than others to find thrombi after
heart attacks, largely because of variations in the methods used. Similarly, studies using more
careful methods were more likely to find thrombi. Sudden death was often lumped together
9
with heart attacks, even though there is no way to know that a sudden death is actually due to
a heart attack. During a true heart attack, cells of the heart die and spill out certain enzymes
into the blood. If the person lives, a doctor can verify a heart attack by finding these enzymes
in the blood. If the person dies, a doctor can verify a heart attack by finding these enzymes
missing from the heart tissue. To run this test at autopsy, however, the person must have died
at least six hours after the heart attack, and the most accurate results are found when the
person died at least twelve to twenty-four hours after. Thus, not finding coronary thrombi in
someone who died within an hour of a heart attack could just be an indication that the person
did not die of a heart attack at all. Most studies of the time didn’t adequately differentiate
between different types of heart attacks. Heart attacks where the cell death is spread diffusely
through the heart tissue are rarely associated with coronary thrombi but are frequently
associated with severe narrowing of all three coronary arteries. Heart attacks where the cell
death afflicts a very specific region of the heart are much more common and are almost
always associated with coronary thrombi. Finally, the most carefully conducted and analyzed
studies using radiolabeled fibrin suggested that coronary thrombi begin to form before a heart
attack occurs, and after the heart attack they continue to grow and then eventually dissolve.
In 1980, angiography allowed researchers to look for the first time for coronary thrombi in
live people suffering from heart attacks.23 Coronary thrombi were almost always present in
the first six hours after the onset of symptoms. Between six and twenty-four hours after the
onset of symptoms, thrombi were found less often, being present in 80-85 percent of cases
and completely occluding a coronary artery in 65-70 percent of cases. This study contradicted
the suggestion of earlier research that clots are more likely to form twenty-four hours after a
heart attack occurs. Instead, it suggested that clots are almost universally present in the
earliest hours and begin dissolving after six hours. This strengthened the alternative
interpretation of earlier research, which held that thrombi were not found when people died a
short time after their putative heart attack because they had suffered from misclassified cases
of sudden death and in fact had not suffered from a heart attack at all.
Taken together, the evidence suggests that coronary thrombi are responsible for the more
common regional heart attacks and that severe narrowing of the coronary arteries contributes
to the less common diffuse heart attacks. Both of these factors reduce the supply of blood and
the oxygen it carries, making cells vulnerable to death. None of this suggests that other factors
are not important. Indeed, there may be many factors that make some cells vulnerable to
damage during transient deprivation of oxygen and make others less vulnerable. There may
also be other acute events involved that transiently deprive cells of oxygen or otherwise
impair their metabolism, particularly in the less common diffuse heart attacks.
The principal cause both of coronary thrombi and coronary narrowing is plaque rupture. In the
case of thrombi, rupture allows the inflammatory contents of the plaque to spill out into the
blood and cause the sudden formation of a clot.24 The case of narrowing may seem less
intuitive. When atherosclerotic plaque accumulates, it does not grow inward into the blood
vessel like grease clogging a pipe. It actually accumulates inside the blood vessel wall,
pushing the wall outward, allowing an equivalent or even larger space for blood to flow
within the vessel.25 When the plaque environment becomes sufficiently inflammatory, plaque
rupture ensues. If the aftermath of the rupture is mild, the plaque will heal itself. This healing
process results in successive plaques overlaying each other, with each healed rupture
intruding more and more into the inside of the artery.26 Thus, severely inflammatory ruptures
contribute to an occlusive thrombus that may result in an immediate heart attack, while mild
10
ruptures lead to progressive narrowing of the arteries, which impedes blood flow and could
eventually contribute to a heart attack.
What causes plaques to rupture? As plaque develops, it forms a highly protective fibrous cap
that is rich in collagen. The accumulation of oxidized lipids leads to an inflammatory
environment that degrades collagen and prevents its synthesis.24 Lack of nutrients needed to
synthesize collagen, such as vitamin C and copper, could play a role, as could infiltration of
the plaque by infectious microbes. Plaques that are richest in oxidized lipids and poorest in
collagen are most likely to rupture. As discussed in the main text, though, even when these
factors are held constant, small deposits of calcium in the fibrous cap greatly increase its
vulnerability to stress and make it far more likely to rupture. The fat-soluble trio—vitamins A,
D and K—forms our principal defense against this calcification.
Problems With the “Naked Ape” Hypothesis of Optimal Serum 25(OH)D
Concentrations
One of the most widely influential perspectives about 25(OH )D that appears in the scientific
literature and pervades the alternative health literature is the “naked ape” hypothesis of
optimal serum 25(OH )D. This hypothesis holds that humans evolved as “naked apes” in the
tropical savannahs of Africa where they were exposed to maximal sunshine and when the
requirement for 25(OH )D was indelibly fixed into our genome. Now that we have invented
modern clothing, indoor living, and migrated far from the tropics, most of us have far lower
25(OH )D than we had “back when we evolved,” as shown by the much higher levels of
25(OH )D found in lifeguards working in Missouri and Israel. Reinhold Vieth promoted this
view in a popular 1999 article.29 At the time of this writing, Google Scholar reports that this
article has been cited 1,159 times.
While it may seem compelling on the surface, the argument is deeply problematic. The
hypothesis assumes that at some point between the loss of body hair and the gain of clothing
we existed as naked sunbathers, and it was at just this very point where the requirement for
serum 25(OH )D was indelibly fixed into our genome. If we take “molecular clock” estimates
at face value, the loss of body hair and the gain of dark skin pigmention both occurred 1.2
million years ago,30,31 indicating we were never truly “naked” since both hair and pigment
protect the skin from ultraviolet light. Evidence for hide scrapers likely used to make leather,
either for clothing or some other form of shelter from the sun such as housing, goes back
almost eight hundred thousand years.30 Clothing was certainly in widespread use by the time
clothing lice diverged from head lice, which scientists estimate occurred some one hundred
seventy thousand years ago.30 Colored pigments appear in the African archeological record
over a quarter million years ago and remain a constant feature of African culture through the
present.32 These may have been used to paint the skin, as commonly occurs in Africa today.
Weston Price wrote in Nutrition and Physical Degeneration that it was a universal tradition in
the Pacific Islands to use coconut oil as a sunscreen, and there is no particular reason to doubt
the premise that prehistoric humans used botanical sunscreens as well. African primates and
traditionally living African humans seek shade from the hot sun at mid-day.33,34 Prehistoric
humans living in the African savannah were thus likely to be neither “naked” nor sunbathers.
Most of prehistoric human life was dominated by glacial periods in which the earth was
substantially colder and aerosolized dust and salt were much higher.35 The lower exposure of
the earth to solar radiation and the higher aerosols during these times probably made the
average UV-B exposure considerably lower, suggesting that no living human beings provide a
11
proxy for prehistoric 25(OH )D levels. The worst example we could possibly use for such a
purpose, however, are modern lifeguards. The Israeli lifeguards whose high 25(OH )D Vieth
cited in his 1999 paper as the closest approximation to the vitamin D status of our “naked
ape” ancestors had evidence of sun damage and twenty times the risk of kidney stones as the
general population. The lifeguards had a mean 25(OH )D higher than 50 ng/mL, and their
increased risk of soft tissue calcification is consistent with the increased risk of cardiovascular
disease that occurs above 40 ng/mL (see Figure 2).
Additionally, certain populations seem adapted to a lower “normal” 25(OH )D. Greenland
Inuit on their traditional diet have a mean serum 25(OH )D of only 20 ng/mL, but appear to
convert 25(OH )D to the more active 1,25(OH )2D at a higher rate.36 Similarly, African
Americans have lower 25(OH )D than white Americans, but higher 1,25(OH )2D and higher
bone density.37 It seems that these groups have lower 25(OH )D but higher total biological
activity of vitamin D, creating the illusion of a “deficiency” that does not actually exist. If
different groups are adapted to different optimal levels of 25(OH )D, moreover, this suggests
that the requirement for 25(OH )D has continued to evolve over time and was never indelibly
fixed into the human genome at any point, certainly not in some fictitious era of the “naked
ape.”
The very concept of an optimal 25(OH )D may itself be flawed. The total biological activity
of vitamin D is determined by both 25(OH )D and the much more active 1,25(OH )2D. The
conversion of 25(OH )D to 1,25(OH )2D is, like many other steps in vitamin D metabolism,
partly determined by genetics.38 Many other factors can influence either the demand for or the
supply of 1,25(OH )2D. Calcium deficiency increases the demand for it and lowers 25(OH )D
status independently of vitamin D exposure.39 Vitamin A, by contrast, seems to increase the
supply of 25(OH )D to the kidney, making it easier to convert it to 1,25(OH )2D.40 Acute
inflammation41 and cancer42 also increase the conversion. If we only measure 25(OH )D and
it is low, we have no idea whether total biological activity of vitamin D is increased or
decreased, nor do we know why it is altered or whether this is a concern. The fact that crisis
states such as acute inflammation and disease states such as cancer can influence the
conversion raises an additional problem: are associations between 25(OH )D and disease risk
cause or effect? Until these questions are resolved, we should place much less emphasis on
using vitamin D supplements to achieve a desired 25(OH )D and much more emphasis on
improving the nutrient density and nutrient balance of the diet.
REFERENCES
1. Haskell MJ. The challenge to reach nutritional adequacy for vitamin A: [beta]-carotene
bioavailability and conversion – evidence in humans. Am J Clin Nutr. 2012;96(suppl):1193S203S.
2. Yamaguchi N, Suruga K. Triiodothyronine stimulates CMO1 gene expression in human
intestinal Caco-2 BBd cells. Life Sci. 2008;82(13-14):789-96.
3. Leung WC, Hessel S, Meplan C, Flint J, Oberhauser V, Tourniaire F, Hesketh JE, von
Lintig J, Lietz G. Two common single nucleotide polymorphisms in the gene encoding betacarotene 15,15’-monooxygenase alter beta-carotene metabolism in female volunteers. FASEB
J. 2009;23(4):1041-53.
12
4. Brown MJ, Ferruzzi MG, Nguyen ML, Cooper DA, Eldridge AL, Schwartz SJ, White WS.
Carotenoid bioavailability is higher from salads ingested with full-fat than with fat-reduced
salad dressings as measured with electrochemical detection. Am J Clin Nutr. 2004;80(2):396403.
5. Hu X, Jandacek RJ, White WS. Intestinal absorption of [beta]-carotene ingested with a
meal rich in sunflower oil or beef tallow: postprandial appearance I triacylglycerol- rich
lipoproteins in women. Am J Clin Nutr. 2000;71:1170-80.
6. Clark RM, Yao L, She L, Furr HC. A comparison of lycopene and astaxanthin absorption
from corn oil and olive oil emulsions. Lipids. 2000;35(7):803-6.
7. Roijers RB, Debernardi N, Cleutjens JP, Schurgers LJ, Mutsaers PH, van der Vusse GJ.
Microcalcifications in early intimal lesions of atherosclerotic humans coronary arteries. Am J
Pathol. 2011; 178(6):2879-87.
8. Maldonado N, Kelly-Arnold A, Vengrenyuk Y, Laudier D, Fallon JT, Virmani R, Cardoso
L, Weinbaum S. A mechanistic analysis of the role of micro calcifications in atherosclerotic
plaque: stability potential implications for plaque rupture. Am J Physiol Heart Circ Physiol.
2012;303(5):H619-28.
9. Masterjohn C. On the Trail of the Elusive X Factor: A Sixty-Two-Year-Old Mystery
Finally Solved. Wise Traditions. Spring, 2007.
10. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G.
Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein.
Nature. 1997;386(6620):78-81.
11. Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM,
Hofman A, Witteman JC. Dietary intake of menaquinone is associated with a reduced risk of
coronary heart disease: the Rotterdam Study. J Nutr. 2004;134(11):3100-5.
12. Masterjohn C. From Seafood to Sunshine: A New Understanding of Vitamin D Safety.
Wise Traditions. Fall, 2006.
13. Masterjohn C. Vitamin D toxicity redefined: vitamin K and the molecular mechanism.
Med Hypotheses. 2007;68(5):1026-34.
14. Masterjohn C. Thyroid Hormone and Vitamin A Protect Against Vitamin D Toxicity in
Cows. Mother Nature Obeyed. Published April 3, 2013.
http://www.westonaprice.org/blogs/cmasterjohn/2013/04/03/thyroid-hormone-and-vitamin-aprotect-against-vitamind- toxicity-in-cows/ Accessed November 21, 2013.
15. Schmidt N, Brandsch C, Kuhne H, Thiele A, Hirche F, Stangle GI. Vitamin D receptor
deficiency and low vitamin D diet stimulate aortic calcification and osteogenic key factor
expression in mice. PLoS One. 2012;7(4):e35316.
16. Taura S, Taura M, Kamio A, Kummerow FA. Vitamin D-induced coronary
atherosclerosis in normolipemic swine: comparison with human disease. Tohoku J Exp Med.
1979;129(1):9-16.
13
17. Semba RD. Vitamin A as “anti-infective therapy, 1920-1940. J Nutr. 1999;129(4):783-91.
18. Spiesman IG. Massive doses of vitamins A and D in the prevention of the common cold.
Arch Otolaryngol. 1941;34(4):787-91.
19. Chitnis PR. Photosystem I: Function and Physiology. Annu Rev Plant Phsyiol Plant Mol
Biol. 2001;51:593-626.
20. Han S, Chen LS, Jiang HX, Smith BR, Yang LT, Xie CY. Boron deficiency decreases
growth and photosynthesis, and increases starch and hexoses in leaves of citrus seedlings. J
Plant Physiol. 2008;165(13):1331-41.
21. Henry KM and Kon SK. The vitamin D content of English butter fat throughout the year.
Biochem J. 1942;36(5-6):456-9.
22. Davies MJ, Fulton WF, Robertson WB. The relation of coronary thrombosis to ischaemic
myocardial necrosis. J Pathol. 1979;127(2):99-110.
23. DeWood MA, Spres J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT.
Prevalence of total coronary occlusion during the early hours of transmural myocardial
infarction. N Engl J Med. 1980;303(16):897-902.
24. Libby P and Theroux P. Pathophysiology of Coronary Artery Disease. Circulation.
2005;111:3481-8.
25. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory
enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316(22):1371-5.
26. Burke AP, Kolodgie FD, Farb A, Weber DK, Malcom GT, Smialek J, Virmani R. Healed
plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in
plaque progression. Circulation. 2001;103(7):934-40.
27. Wang L, Song Y, Manson JE, Pilz S, Marz W, Michaelsson K, Lundgvist A, Jassal SK,
Barett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD. Circulating 25hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies.
Circ Cardiovasc Qual Outcomes. 2012;5(6):819-29.
28. Zittermann A, Kuhn J, Dreier J, Knabble C, Gummert JF, Borgermann J. Vitamin D status
and the risk of major adverse cardiac and cerebrovascular events in cardiac surgery. Eur
Heart J. 2013;34(18):1358-64.
29. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.
Am J Clin Nutr. 1999;69(5):842-56.
30. Toups MA, Kitchen A, Light JE, Reed DL. Origin of Clothing Lice Indicates Early
Clothing Use by Anatomically Modern Humans in Africa. Mol Biol. Evol. 2011;28(1):29-32.
31. Elias PM and Williams ML. Re-apparaisal of current theories for the development and
loss of epidermal pigmentation in hominids and modern humans. J Hum Evol. 2013;64:68792.
14
32. Barham LS. Systematic Pigment Use in the Middle Pleistocene of South-Central Africa.
Current Anthropology. 2002;43(1):181-90.
33. Wheeler PE. The thermoregulatory advantages of heat storage and shade-seeking behavior
to hominids foraging in equatorial savannah environments. Journal of Human Evolution.
1994;26:339-350.
34. Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DAJ, Muskiet FAJ. Traditionally
living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of
115 nmol/L. BJN. 2012;108(9):1557-61.
35. Petit JR, Jouzel J, Raynaud D, Barkov NI, Barnola JM, Basile M, Bender J, Chappellaz
M, Davis G, Delaygue G, Delmotte M, Kotlyakov VM, Legrand M, Lipenkov VY, Lorius C,
Ritz C, Saltzman E, Stievenard M. Climate and atmospheric history of the past 420,000 years
from the Vostok ice core, Antarctica. Nature. 1999;399:429-36.
36. Rejnmark L, Jorgensen ME, Pedersen MB, Hansen JC, Heickendorff L, Lauridsen AL,
Mulvad G, Siggard C, Skjoldborg H, Sorensen TB, Pedersen EB, Mosekilde L. Vitamin D
insufficiency in Greenlanders on a westernized fare: ethnic differences in calcitropic
hormones between Greenlanders and Danes. Calcif Tissue Int. 2004;74(3):255-63.
37. Weaver CM, McCabe LD, McCabe GP, Braun M, Martin BR, Dimeglio LA, Peacock M.
Vitamin D status and calcium metabolism in adolescent black and white girls on a range of
controlled calcium intakes. J Clin Endocrinol Metab. 2008;93(10):3907-14.
38. Signorello LB, Shi J, Cai Q, Zheng W, Williams SM, Long J, Cohen SS, Li G, Hollish
BW, Smith JR, Blot WJ. Common variation in vitamin D pathway genes predicts circulating
25-hydroxyvitamin D Levels among African Americans. PLoS One. 2011;6(12):e28623.
39. D’Amour P, Rousseau L, Hrnyak S, Yang Z, Cantor T. Influence of Secondary
Hyperparathyroidism Induced by Low Dietary Calcium, Vitamin D Deficiency, and Renal
Failure on Circulating Rat PTH Molecular Forms. Int J Endocrinol. 2011;469783.
40. Ternes SB, Rowling MJ. Vitamin D transport proteins megalin and disabled-2 are
expressed in prostate and colon epithelial cells and are induced and activated by all-transretinoic acid. Nutr Cancer. 2013;65(6):900-7.
41. Waldron JL, Ashby HL, Cornes MP, Bechervaise J, Razavi C, Thomas OL, Chugh S,
Deshpande S, Ford C, Gama R. Vitamin D: a negative acute phase reactant. J Clin Pathol.
2013;66(7):620-2.
42. Urbschat A, Paulus P, von Quernheim QF, Bruck P, Badenhoop K, Zeuzem S, RamosLopez E. Vitamin D hydroxylases CYP2R1, CYP27B1 and CYP24A1 in renal cell
carcinoma. Eur J Clin Invest. 2013;43(12):1282-90.
This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly
journal of the Weston A. Price Foundation, Winter 2013.
Christopher Masterjohn
15
One Response to Beyond Cholesterol
October 24, 2014 at 5:05 am
The number of data points above 40 in fig 1 make it impossible to make a call on Vit
D levels higher than 40 and there is no reference to sample sizes within fig 2 and the
high levels of vit D.
Resolving the Vitamin D Paradox — Chris
Masterjohn, Ph.D. (AHS14)
https://www.youtube.com/watch?v=9H7tbWVNrXQ
http://blog.cholesterol-and-health.com/search/label/Vitamins%20A%20D%20and%20K
http://www.westonaprice.org/blogs/cmasterjohn/undercarboxylated-osteocalcinmarker-of-vitamin-k-deficiency-or-booster-of-insulin-signaling-and-testosterone/
Undercarboxylated Osteocalcin: Marker of
Vitamin K Deficiency, or Booster of Insulin
Signaling and Testosterone?
Posted on July 17, 2013 by Christopher Masterjohn • 17 Comments
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Osteocalcin is a vitamin K-dependent protein that our bones produce. The job of vitamin K is
to activate this protein by adding carbon dioxide to it, which in scientific jargon we call
“carboxylation.” Vitamin K researchers widely regard the ratio of undercarboxylated to
16
carboxylated or total osteocalcin as a marker of inadequate vitamin K status. Evidence has
accumulated over the last half decade, however, that undercarboxylated osteocalcin may
stimulate the production of insulin and testosterone, while simultaneously enhancing insulin
sensitivity, and by doing so, make us lean and fertile.
Is undercarboxylated osteocalcin a good thing or a bad thing? Could this represent a downside
to getting enough vitamin K, particularly vitamin K2, the form that most effectively reaches
our bones? I’ll tackle these questions in this post as I critically review the literature on
undercarboxylated osteocalcin’s role as an insulin- and testosterone-boosting hormone.
Widespread Deficiency of Vitamin K2?
In my Spring, 2007 article, “On the Trail of the Elusive X-Factor: A Sixty-Two-Year-Old
Mystery Finally Solved,” I followed the convention of the vitamin K research community by
using the proportion of osteocalcin in its undercarboxylated form — which I then called
“inactive,” a term that now seems inappropriate — as a marker of inadequate vitamin K
status. More specifically, it indicates deficient vitamin K status of bone, and since vitamin K2
reaches bone more effectively than K1, it is in a certain sense more a marker of K2 deficiency.
I supported this by pointing out that people with the highest proportion of osteocalcin in this
form have a five-fold greater risk of fracture. Vitamin K2 supplementation, moreover,
improves the activation of osteocalcin, and in a series of Japanese trials it reduced fracture
risk by 80 percent. These data offer strong support for using undercarboxylated osteocalcin as
a marker of vitamin K deficiency in bone tissue.
In a 2010 blog post, I argued that “10-20 percent of serum osteocalcin in its inactive form
indicates a state of deficiency” on the basis that within this range small improvements in the
proportion of osteocalcin that is carboxylated are associated with large decreases in the risk of
advanced prostate cancer. I further argued that there is “widespread deficiency” of vitamin K2
in children, based on studies showing that the proportion of osteocalcin that is inactive is
remarkably high in children, considerably higher than 10-20 percent, and increases during
puberty, reaching in some children as high as 83 percent.
Our bone-building cells, osteoblasts, produce osteocalcin. As a result, we make more
osteocalcin when we are building more bone. Childhood is a period of rapid bone growth,
especially adolescence, during which bone mass approximately doubles (1). This would seem
to offer a very simple and elegant explanation of why the proportion of undercarboxylated
osteocalcin is so high during childhood and especially during puberty: when bones are
growing, the production of osteocalcin, and thus the demand for vitamin K, is very high; if the
intake of vitamin K, especially vitamin K2, is low, then a large proportion of this osteocalcin
will be undercarboxylated. According to this paradigm, undercarboxylated osteocalcin reflects
widespread deficiency of vitamin K2 in growing children.
17
Undercarboxylated Osteocalcin: A
Beneficial Insulin- and TestosteroneBoosting Hormone?
Beginning in 2007, however, a body of literature began to emerge suggesting that
undercarboxylated osteocalcin plays an important physiological role as an insulin-stimulating,
insulin-sensitizing, testosterone-boosting hormone — at least in mice, anyway. These
findings, if they can be generalized to humans, have the potential to throw a major monkey
wrench into the standard interpretation of undercarboxylated osteocalcin as a marker of
vitamin K deficiency.
Undercarboxylated Osteocalcin, Insulin, and Energy
Balance
In 2007, Lee and colleagues from the labs of Gerard Karsenty and Patricia Ducy at Columbia
University published a study (2) showing that mice engineered to lack the osteocalcin gene
were fat, had elevated blood glucose, burned energy at a lower rate, and were both deficient in
and insensitive to insulin.
Incubating fat cells with osteoblasts caused them to produce adiponectin, an insulinsensitizing hormone, and incubating pancreatic cells with osteoblasts caused them to produce
insulin itself. Osteoblasts were only effective, however, if they produced osteocalcin;
osteoblasts taken from the mice with a deletion in the gene had no effect. Actually, osteoblasts
themselves weren’t needed. Just incubating the cells with osteocalcin worked fine.
But here’s the catch: treating the osteoblasts with warfarin, which reduces the carboxylation
of osteocalcin by interfering with vitamin K metabolism, actually increased the effect. In fact,
when the investigators compared purely carboxylated osteocalcin to purely uncarboxylated
osteocalcin, only the uncarboxylated form was effective. Giving the live, osteocalcin-deficient
mice uncarboxylated osteocalcin, moreover, improved their glucose tolerance and insulin
secretion.
We should note here that the osteocalcin the investigators used wasn’t just
“undercarboxylated” as it tends to occur in humans and live animals (meaning it has some
carbon dioxide added to it, but less than it should), but totally “uncarboxylated” because they
genetically engineered bacteria to make it, and these bacteria were among the vast majority of
microorganisms that lack the vitamin K-dependent enzyme responsible for carboxylation.
The same group published a second study early the following year (3) showing that these
phenomena held true not just in genetically engineered mice but even in wild-type mice.
Subcutaneous infusion of uncarboxylated osteocalcin protected mice against the damaging
metabolic effects of both highly purified, industrial, high-fat rodent diets as well as damage to
the hypothalamus, a key part of the brain that contributes to the regulation of energy balance.*
18
Undercarboxylated Osteocalcin, Testosterone, and
Fertility
In 2011, the Karsenty and Ducy labs, along with several other collaborators, published a
landmark paper expanding their findings from energy metabolism to male fertility (4). In male
mice, experiments involving deletion of the osteocalcin gene or administration of
uncarboxylated osteocalcin showed that undercarboxylated or uncarboxylated osteocalcin
increases production of testosterone, the size and weight of testes, and both the frequency and
size of sired litters.
Mice lacking osteocalcin also had an excess of luteinizing hormone (LH), a pituitary hormone
responsible for increasing testosterone production. The excess of LH seems to be an attempt
to compensate for the lack of testosterone, but it obviously isn’t effective at restoring
testosterone to normal.
In female mice, by contrast, the protein had no effect on fertility or on production of estrogen
and progesterone. The paper makes no mention of female testosterone or male estrogen and
progesterone.
The investigators also identified a protein that may act as a receptor for undercarboxylated
osteocalcin, present in testes but not ovaries, which would explain why the effect seems to
apply to male mice but not females.
The Critical Role of Bone Resorption
Additional studies from the Karsenty lab and various collaborators showed that genetically
altering or pharmaceutically treating the mice to increase or decrease the rate of bone
resorption controlled the release of undercarboxylated osteocalcin into circulation and its
subsequent effects on energy balance and testosterone (5, 6).
Bone growth and bone resorption are both parts of normal, everyday, healthy bone
metabolism. Bone resorption is the acidic dissolution and digestion of mineralized bone
matrix. It plays important roles in regulating the levels of minerals in the blood, mainly
calcium and phosphorus, and in allowing bone matrix to reorganize as needed to best fulfill
the demands of the body and environment.
While the vitamin K-dependent addition of carbon dioxide allows osteocalcin to accumulate
in the bone matrix, bone resorption creates an acidic environment that removes some of the
carbon dioxide and allows release of undercarboxylated osteocalcin into the blood. Removal
of carbon dioxide is known as “decarboxylation.” According to the paradigm Karsenty and
his collaborators have been presenting, this process allows the activation of osteocalcin to its
hormone form.
These authors follow the exact opposite usage that I have over the past six or seven years and
refer to undercarboxylated osteocalcin as the “active” form. For clarity, I may refer to this
form as “hormonally active.”
19
Sarah Booth and her colleagues at Tufts University have pointed out that when human
osteoclasts are cultured on bovine bone, only a small amount of osteocalcin is released and
enzymes subsequently digest most of it into fragments that are unlikely to act as hormones
(7).
The Karsenty lab’s data, however, is quite convincing that bone resorption releases functional,
hormonally active osteocalcin in mice. As mentioned above, genetic or pharmaceutical
interventions to increase or decrease bone resorption not only controlled the release of
undercarboxylated osteocalcin, but also produced the expected effects on energy metabolism
and testosterone. When the researchers mimicked the process outside of a live animal,
moreover, they verified the hormonal activity of the osteocalcin that was released.
Roles for Insulin and Leptin
In the initial paper reporting that mice lacking the osteocalcin gene were fat and in metabolic
disarray, the investigators also uncovered a role for the Esp gene: deleting it increased the
amount of undercarboxylated osteocalcin circulating and had the exact opposite metabolic
effects as deleting the osteocalcin gene. Subsequent experiments published by the same group
(5) showed that the protein encoded by this gene neutralizes the insulin receptor once it has
been activated. Although this gene isn’t active in humans, we have a different enzyme known
as PTP1B that fulfills the same function.
In the same paper (5), the researchers reported that, although insulin signaling in osteoblasts
promotes bone growth and ultimately leads to stronger bones, it also promotes bone
resorption. Bone growth involves the production of osteocalcin, its vitamin K-dependent
carboxylation, and its accumulation in bone matrix; bone resorption involves its
decarboxylation and release into circulation as a hormone. Insulin signaling in osteoblasts is
therefore a key pathway that promotes the release of circulating hormonally active
osteocalcin.
This group had also published a separate paper (8) showing that leptin, a hormone secreted by
fat tissue, acts on the brain to increase signaling of the sympathetic nervous system to
osteoblasts, which increases the activity of the Esp gene. This antagonizes insulin signaling in
osteoblasts, decreases bone resorption, and thereby decreases the circulating amount of
hormonally active osteocalcin.
This paper remarkably showed that, in mice, fat tissue, bone tissue, and the brain all
communicate with each other to regulate energy metabolism and fertility.**
This evidence suggests that a higher insulin-to-leptin ratio may promote bone resorption and
thereby promote the release of hormonally active osteocalcin. We should exercise caution
when generalizing from these studies, however, since even if this hormonal axis works
similarly in humans, simply measuring the concentrations of these hormones in the blood
does not necessarily provide adequate information about their signaling activity at the cellular
level where they are fulfilling their functions.
20
Of Mice, Men , and a Little Protein In Need
of a Job
So far, all of the direct experimental evidence supporting the hormonal role of osteocalcin is
in mice. The Karsenty lab and its collaborators argued that it would be unprecedented for this
work to have no implications for humans, but also admitted the need for direct evidence (4):
. . . there is no example yet of a molecule being a hormone in the mouse that has abruptly lost
this attribute in humans. This is, nevertheless, an aspect of osteocalcin that will need further
investigation in the future.
Mouse Osteocalcin Could Hypothetically Be Unique
In a critical review referenced above (7), Sarah Booth and colleagues pointed out that the
sequence of the mouse osteocalcin gene has less similarity to that of the human gene
compared to many other species. The way the gene is organized on chromosomes differs and
the way vitamin D regulates its expression also differs between mice and humans. Rats are
actually closer to humans than mice in these respects. While these points hardly refute a
hormonal role for osteocalcin in humans, they do support, in a very limited way, the
possibility that the function of osteocalcin could vary between species, which further
emphasizes the need to generate direct evidence for its hormonal role in humans.
If Osteocalcin Isn’t a Hormone, What on Earth Does It
Do?
On the other hand, if these newly discovered hormonal roles of osteocalcin hold across
species, this would help disperse some of the fog of mystery that has enveloped for so many
years the question of just what it is this protein actually does. As I pointed out back in 2007,
mice that lack the osteocalcin gene have no problems mineralizing their bones, but the bone
matrix is organized somewhat differently. I concluded that “this could mean that osteocalcin
is important to the functional quality of bone and the ability to regulate its shape,” but “could
mean” is a critical phrase in that sentence.
It was the Karsenty lab that carried out these studies back in the 1990s, the same lab that has
been promoting the paradigm that osteocalcin acts as an insulin- and testosterone-boosting
hormone. One of their early studies (9) suggested that mice with no osteocalcin gene actually
have better bone strength than normal mice. Their subsequent analysis (10) of these mutant
mice indicated the bone matrix seemed less “mature,” but the functional benefit of osteocalcin
remained elusive.
To go beyond “could mean” when the only clearly demonstrated function of the protein was
to reorganize bone in a way that decreases its strength would have been a stretch. Indeed,
although osteocalcin must logically have some beneficial role in the body, the question of just
what that role actually is was at that time extremely puzzling.
21
In retrospect, the figure in my 2007 article depicting the role of osteocalcin as “organization
of minerals” over-interpreted the evidence available back in 2006 when I was researching the
article. I was assuming that, if this was osteocalcin’s only known function, it must be
beneficial in some way even if its benefit was far from obvious.
When we consider that these mice have no obvious bone defects yet are fat, infertile, and
metabolically damaged, it would seem that in the mouse the primary role of osteocalcin is to
regulate energy metabolism and fertility rather than to do anything particular to bone.
And since in mice osteocalcin affects the production or activity of numerous other hormones
that affect bone metabolism, such as insulin, adiponectin, and testosterone, there is no reason
to assume that osteocalcin’s modest yet quite puzzling effects on bone are directly a result of
its accumulation in bone matrix. Indeed, the changes in the bones of osteocalcin-deficient
mice could simply be a relatively minor side effect of the disturbances in these other
hormones.
If undercarboxylated osteocalcin is not a hormone that regulates energy balance and fertility
in humans, we are back to square one with little understanding of its function. These mouse
studies, then, provide us with hope that we may be making progress towards solving the
enigma.
Limited Support From Epidemiological Evidence
There is a considerable amount of epidemiological evidence associating total osteocalcin with
energy metabolism in humans, but this sheds little light on the matter because the studies do
not look at undercarboxylated osteocalcin specifically (for example, 11, 12). This could
simply reflect an association between bone growth and overall health.
There is a growing body of favorable epidemiological evidence looking at undercarboxylated
osteocalcin, but because of the complex interactions between the cells and hormones
involved, these studies are difficult to interpret. Here are some examples:




Among just under 300 men and postmenopausal women with type 2 diabetes,
undercarboxylated and total osteocalcin were inversely related to fat mass and
HbA1c, a marker of poor glucose metabolism (13). Puzzlingly, the ratio of
undercarboxylated to total osteocalcin had the opposite association with fat
mass in men but no association in women, and the associations between
undercarboxylated osteocalcin, fat mass, and glucose metabolism lost
statistical significance after adjustment for putative confounders in women, but
not in men.
Among just under 60 male subjects across a wide spectrum of body weights,
morbidly obese men had lower undercarboxylated osteocalcin than normalweight men, and a lower ratio of undercarboxylated to total osteocalcin (14).
Among all the obese subjects, undercarboxylated osteocalcin inversely
correlated with waist circumference and fasting glucose.
Among just over 60 overweight men, the ratio between undercarboxylated and
carboxylated osteocalcin, but not either individual form of the protein,
correlated with free testosterone, but not with total testosterone or other sex
hormone-related measures (15).
Among just over 50 healthy boys ranging in age from 7 to 21, both
undercarboxylated and total osteocalcin correlated with serum testosterone
22


after adjusting for “bone age,” an estimation of the maturity of a child’s
skeleton (16). These authors did not report correlations with the ratio between
the two forms of osteocalcin.
Among just under 70 men with severe type 2 diabetes, undercarboxylated
osteocalcin did not correlate with testosterone until the authors statistically
adjusted for markers of bone and glucose metabolism, gonadal hormones, age,
and body mass index (17). After adjustment, undercarboxylated osteocalcin
correlated positively with free testosterone and inversely with luteinizing
hormone. The ratio of undercarboxylated to total osteocalcin was similarly
correlated with testosterone, whereas total osteocalcin itself was not.
Among just under 250 healthy postmenopausal women, by contrast, Cees
Vermeer’s Netherlands-based vitamin K research team found very different
results: carboxylated osteocalcin was inversely related with body weight, body
mass index, hip and waist circumference, and body fatness, whereas the ratio
of undercarboxylated to carboxylated osteocalcin had smaller positive
associations with these parameters, and our putative hormone,
undercarboxylated osteocalcin, had no such associations (18).
These studies are difficult to interpret. The reasons are myriad:






Undercarboxylated osteocalcin could reflect the insufficient carboxylation of
the protein, or could reflect its decarboxylation during bone resorption.
Insufficient carboxylation of the protein could, in turn, reflect a high rate of its
production during bone growth, inadequate vitamin K status, or most likely
some combination thereof.
The ratio of undercarboxylated to total osteocalcin could reflect poor vitamin K
status, but it could also reflect a greater rate of bone resorption compared to
bone growth.
It is unclear whether the absolute amount of undercarboxylated osteocalcin or
its ratio to total osteocalcin would be the best measure of its hormonal activity
because no one to my knowledge has determined whether the carboxylated
form interferes with the hormonal activity of the undercarboxylated form.
Since all of the downstream targets of undercarboxylated osteocalcin, such as
insulin, adiponectin, and testosterone, affect bone metabolism, correlations
between these factors are riddled with chicken-and-egg questions.
To confuse matters further, some recent reports (14, 15) indicate that, in
addition to osteoblasts, pre-adipocytes in fat tissue produce osteocalcin,
including undercarboxylated osteocalcin. They produce more osteocalcin in
response to testosterone, but less osteocalcin as the fat tissue proliferates and
the pre-adipocytes turn into true fat cells. This adds another chicken-and-egg
question to correlations between osteocalcin and testosterone. It also adds a
further layer of confusion: lower undercarboxylated osteocalcin in obesity
could reflect not only a fat-burning effect of the putative hormone, but also a
lower production of it by adipose tissue in people with greater numbers of fat
cells.
Overall, then, I would say the epidemiological evidence is, although somewhat conflicting in
some respects, generally consistent with a fat-burning and testosterone-boosting effect of
undercarboxylated osteocalcin in humans, but I would be reticent to claim the evidence is
more than slightly supportive.
Human Genetic Evidence
23
The strongest and most direct evidence to date that undercarboxylated osteocalcin acts as a
hormone in humans comes from human patients with genetic defects in the putative
osteocalcin receptor (6). The Karsenty lab and their collaborators analyzed the genetics of just
under 60 men with primary testicular failure presenting with low sperm count and high
luteinizing hormone (LH), but without any increase in testosterone resulting from the high
LH. Two of them (3.4%) had genetic defects in the putative osteocalcin receptor.
Although this genetic defect is present in 1.2% of African Americans and 0.02% of Europeans
who submitted DNA to the NHLBI Grand Opportunity Exome Sequencing Project, none of
the more than 900 healthy controls recruited by the Karsenty team had the defect. This
provides strong preliminary evidence that the defect is associated with and perhaps causes
testicular dysfunction that resembles the infertility seen in mice lacking the osteocalcin gene.
The patients with this defect resembled these mice in other ways as well. One had a large
waist circumference and excess body fatness as well as glucose intolerance, while the other
had a history of high blood glucose that he kept under control with daily exercise and strict
caloric restriction.
I refer to this receptor as a “putative” osteocalcin receptor because in test tube experiments it
binds to a variety of different compounds. The only compound for which there is thus far
clear evidence of receptor activation in live animals is undercarboxylated osteocalcin. Thus,
the resemblance of men with defects in the receptor to mice with defects in the osteocalcin
gene suggests that undercarboxylated osteocalcin is hormonally active in humans, but the
evidence is not conclusive.
Looking at the Totality of the Evidence
Adding up a bunch of inconclusive studies can never yield a conclusive result, but when we
view the hints of the hormonal role of undercarboxylated osteocalcin in humans from
epidemiological and genetic evidence in the context of the conclusive evidence for its
hormonal role in mice and in the context of the lack of any other compelling explanation for
the function of this protein in any species, we arrive at very strong hints that this protein is, in
fact, a hormone in humans.
While the evidence is not yet conclusive, I would hedge my bets that future evidence, as it
improves both in quantity and quality and pushes us towards a conclusion, will support rather
than refute the hormonal role of undercarboxylated osteocalcin in humans and across many
species.
Should We All Get Deficient in Vitamin K?
If we accept the probability that undercarboxylated osteocalcin has positive hormonal roles in
humans, as I do, this naturally leads us to consider the implications for vitamin K intake.
Since the function of vitamin K is, in part, to carboxylate osteocalcin, and since it decreases
circulating amounts of undercarboxylated osteocalcin, could obtaining an abundance of
vitamin K from foods or supplements be harmful?
24
On the one hand, the experiments I cited above showed that osteoblasts or their secretions
could elicit hormonal responses more effectively when made vitamin K-deficient with
warfarin.
On the other hand, the Karsenty team and its collaborators have consistently argued, with
strong evidence, that bone resorption is the trigger for release of hormonally active
osteocalcin into the bloodstream. If this paradigm is correct, one could argue that adequate
vitamin K is needed to ensure that osteocalcin is fully carboxylated as it is produced, allowing
it to accumulate in bone matrix, so that the presence of the undercarboxylated form in the
bloodstream accurately reflects the degree of bone resorption.
Vitamin K, moreover, is involved in much more than osteocalcin metabolism. As I pointed
out back in 2007, it not only supports strong bones and teeth, adequate growth, and the health
of the kidneys, brain, and heart, but it appears to support energy metabolism and fertility as
well, since it accumulates in the pancreas and testes and activates a protein of unknown
function in sperm.
Rats on vitamin K-deficient diets develop poor glucose tolerance (19). There is some weak
indication, conversely, that vitamin K2 supplementation in humans with poor status improves
glucose and insulin metabolism (20). Vitamin K1 or K2 supplementation in rats, moreover,
lowers body fatness (21) and vitamin K2 supplementation increases testosterone (22).
Clearly, the research on the hormonal role of undercarboxylated osteocalcin does not suggest
in any way that the road toward leanness and virility is paved by vitamin K deficiency.
Undercarboxylated Osteocalcin: Why So
High in Growing Children?
This brings us back to the original question: why are blood levels of undercarboxylated
osteocalcin so high in growing children? Is it a marker of vitamin K deficiency, or part of a
developmental program to boost anabolic hormones?
I believe a consideration of the developmental endocrine program launched during puberty (1)
indicates that the original interpretation of this protein as a marker of vitamin K deficiency is,
in this case, correct. During adolescence, bone growth predominates over bone resorption,
making bone resorption a rather untenable explanation for the presence of undercarboxylated
osteocalcin in blood. Sex hormones and growth hormone increase the activation of vitamin D
to its hormone form, calcitriol, which increases the production of osteocalcin, alongside
massive increases in bone growth. If the supply of vitamin K to bone tissue is inadequate to
meet the demand to carboxylate all this extra osteocalcin, it will be released into the
circulation in its undercarboxylated form.
The incidence of fracture increases in boys and girls between the ages of 10 and 14, and in 14year-old boys it reaches the same magnitude as in 53-year-old women. The author of a recent
review (1) suggested that fracture risk increases during adolescence because bone volume and
soft tissue mass grow so rapidly during this period that the process of mineralization can’t
keep up:
25
Adolescence may be a period of life during which the bones are relatively “thin” in
comparison with the mass of soft body tissue. The inability of the mineralization process to
keep pace with the growth in length of the long bones may be an inevitable consequence of
the magnitude of the sex steroid-driven growth spurt. Indeed, bone modelling at the epiphyses
and metaphyses may be so active that skeletal volume is expanding at a faster rate than the
mineralization process.
Inevitable? Probably not. If the large increases in undercarboxylated osteocalcin indicate an
inadequate supply of vitamin K to bone, then they likely also indicate an inadequate supply of
vitamin K to the cells of cartilage and blood vessels, which make matrix Gla protein, one of
the most important proteins known to support bone mineralization (even if it may do so
indirectly).
Cees Vermeer’s group published an epidemiological study consistent with this concept (23).
Among over 300 children between the ages of 8 and 14, the ratio of undercarboxylated to
carboxylated osteocalcin was positively associated with testosterone in boys and estrogen in
girls, but inversely associated with bone mineral content.
The association with sex hormones is inconsistent with the mouse studies on the hormonal
role of osteocalcin: it produces testosterone in male mice but has no effect on estrogen in
female mice. Yet it is perfectly consistent with the hormonal program launched during
adolescence (1), wherein both testosterone and estrogen play roles in increasing bone growth
and osteocalcin production. The inverse association between undercarboxylated osteocalcin
and bone mineral content is consistent with a supply of vitamin K too scant to support the
mineralization process.
Conclusion? Back to Bone Resorption…
Is vitamin K completely off the hook? Not necessarily. Certain genetics, an excessively high
ratio of calcium to phosphorus in the diet, statins, osteoporosis drugs, and a variety of highdose nutritional supplements, possibly including vitamin K, could interfere with the process
of bone resorption. Such conditions could suppress the normal release of hormonally active
osteocalcin, and adding vitamin K into the mix could conceivably aggravate the situation.
In a future post, I’ll attempt to fill in the rest of this story by making sense of the hormonal
and nutritional regulation of bone resorption, and its role in regulating the circulation of
hormonally active osteocalcin.
I think the evidence is clear, however, that when all systems are otherwise working properly,
adequate vitamin K supports proper glucose metabolism, energy balance, and fertility. I
would feel very confident hedging my bets that more vitamin K for growing children would
mean better bone development and a lower risk of fracture.
This is consistent with Weston Price’s emphasis on the extraordinary skeletal and dental
health and the beautiful, broad, well developed faces of individuals consuming their
traditional ancestral diets, free of refined foods and rich in fat-soluble vitamins.
Read more about the author, Chris Masterjohn, PhD, here.
26
Notes
* Oddly enough, however, the experiments with fresh pancreatic islets and fat cells taken
from the mice suggested that the positive effects of uncarboxylated osteocalcin on insulin
only occurred at concentrations extremely low compared to those of undercarboxylated
osteocalcin normally present in mice, while the effects on adiponectin and energy expenditure
only occurred at normal to high concentrations. Similarly, in the later experiment concerning
fertility, only small doses of uncarboxylated osteocalcin enhanced testosterone production.
Larger doses abolished the effect.
I chose to relegate this to the “notes” section because some of the in vivo evidence from these
studies seems to indicate that osteocalcin has hormonal effects on all these parameters across
a wide range. For example, both increasing or decreasing the rate of bone resorption affects
energy balance and testosterone, apparently via undercarboxylated osteocalcin, showing that
departures from “normal” in both directions are effective, and thus that “normal” is within the
effective range. In general this is true for a variety of other loss-of-function and gain-offunction genetic experiments reported in these papers that alter the biochemical pathways
discussed. Overall, though, I think these findings related to dose need more attention in future
research. [Back to Main Text]
** Fat tissue produces another factor involved, adiponectin (24). While leptin levels increase
with body fatness, adiponectin levels decrease. Although adiponectin’s signaling pathways
are generally thought to be distinct from those of insulin, in this case it acts through the same
signaling pathway as insulin in both osteoblasts and in the brain. Paradoxically, its actions in
osteoblasts promote bone resorption while its actions in the brain decrease bone resorption.
The net effect of deleting the adiponectin gene in mice is to produce higher bone mass in
young mice and lower bone mass in older mice. It would thus seem that the short-term effect
of adiponectin is to promote bone resorption while its long-term effect is to inhibit bone
resorption, but ultimately the implications of these diametrically opposed roles are unclear.
[Back to Main Text]
References
1. Saggese G, Baroncelli GI, Bertelloni S. Puberty and bone development. Best Pract Res Clin
Endocrinol Metab. 2002;16(1):53-64.
2. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Me PJ, McKee
MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine
regulation of energy metabolism by the skeleton. Cell 2007;130(3):456-69.
3. Ferron M, Hinoi E, Karsenty G, Ducy P. Osteocalcin differentially regulates beta cell and
adipocyte gene expression and affects the development of metabolic diseases in wild-type
mice. Proc Natl Acad Sci USA. 2008;105(13):5266-70.
4. Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth
BL, Ducy P, Karsenty G. Endocrine regulation of male fertility by the skeleton. Cell.
2011;144(5):796-809.
27
5. Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G.
Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell.
2010;142(2):296-308.
6. Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, Srinivas P, Chamouni A,
Lugani F, Lejeune H, Kumar TR, Plotton I, Karsenty G. Osteocalcin regulates murine and
human fertility through a pancreas-bone-testis axis. J Clin Invest. 2013. [page numbers not yet
assigned at time of writing]
7. Booth SL, Centi A, Smith SR, Gundberg C. The role of osteocalcin in human glucose
metabolism: marker or mediator? Nat Rev Endocrinol. 2013;9(1):43-55.
8. Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers MG Jr, Chua SC Jr, Kim JK,
Kaestner KH, Karsenty G. The sympathetic tone mediates leptin’s inhibition of insulin
secretion by modulating osteocalcin bioactivity. J Cell Biol. 2008;183(7):1235-42.
9. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein
S, Gundberg C, Bradley A, Karsenty G. Increased bone formation in osteocalcin-deficient
mice. Nature. 1996;448-52.
10. Boskey AL, Gadaleta S, Gundberg C, Doty SB, Ducy P, Karsenty G. Fourier transform
infrared micro spectroscopic analysis of bones of osteocalcin-deficient mice provides insight
into the function of osteocalcin. Bone. 1998;23(3):187-96.
11. Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellstrom
D. Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish
men. J Bone Miner Res. 2009;24(5):785-91.
12. Saleem U, Mosley TH Jr, Kullo IJ. Serum osteocalcin is associated with measures of
insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler
Thromb Vasc Biol. 2010;30(7):1474-8.
13. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T.
Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and
fat mass in type 2 diabetes mellitus. Osteoporosis Int. 2011;22(1):187-94.
14. Foresta C, Strapazzon G, De Toni L, Gianesello L, Calcagno A, Pilon C, Plebani M,
Vettor R. Evidence for osteocalcin production by adipose tissue and its role in human
metabolism. J Clin Endocrinol Metab. 2010;95(7):3502-6.
15. Foresta C, Strapazzon G, De Toni L, Gianesello L, Bruttocao A, Scarda A, Plebani M,
Garolla A. Androgens modulate osteocalcin release by human visceral adipose tissue. Clin
Endocrinol (Oxf). 2011;75:64-69.
16. Kirmani S, Atkinson EJ, Melton LJ 3rd, Riggs BL, Amin S, Khosla S. Reltationship of
testosterone and osteocalcin levels during growth. J Bone Miner Res. 2011;26(9):2212-6.
17. Kanazawa I, Tanaka K, Ogawa N, Yamauchi M, Yamaguchi T, Sugimoto T.
Undercarboxylated osteocalcin is positively associated with free testosterone in male patients
with type 2 diabetes mellitus. Osteoporos Int. 2013;24(3):1115-9.
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18. Knapen MH, Schurgers LJ, Shearer MJ, Newman P, Theuwissen E, Vermeer C.
Association of vitamin K status with adiponectin and body composition in healthy subjects:
uncarboxylated osteocalcin is not associated with fat mass and body weight. Br J Nutr.
2012;108(6):1017-24.
19. Sakamoto N, Wakabayashi I, Sakamoto K. Low vitamin K intake effects on glucose
tolerance in rats. Int J Vitam Nutr. Res. 1999;69(1):27-31.
20. Sakamoto N, Nishiike T, Iguchi H, Sakamoto K. Possible effects of one week vitamin K
(menaquinone-4) tablets intake on glucose tolerance in healthy young male volunteers with
different descarboxy prothrombin levels. Clin Nutr. 2000;19(4):259-63.
21. Sogabe N, Maruyama R, Baba O, Hosoi T, Goseki-Sone M. Effects of long-term vitamin
K(1) (phylloquinone) or vitamin K(2) (menaquinone-4) supplementation on body composition
and serum parameters in rats. Bone. 2011;48(5):1036-42.
22. Ito A, Shirakawa H, Takumi N, Minegishi Y, Ohashi A, Howlader ZH, Ohsaki Y, Sato T,
Goto T, Komai M. Menaquinone-4 enhances testosterone production in rats and testis-derived
tumor cells. Lipids Health Dis. 2011;10:158.
23. van Summeren MJ, van Coeverden SC, Schurgers LJ, Braam LA, Noirt F, Uiterwaal CS,
Kuis W, Vermeer C. Vitamin K status is associated with childhood bone mineral content. Br J
Nutr. 2008;100(4):852-8.
24. Kajimura D, Lee HW, Riley KJ, Arteaga-Solis E, Ferron M, Zhou B, Clarke CJ, Hannun
YA, Depinho RA, Guo EX, Mann JJ, Karsenty G. Adiponectin Regulates Bone Mass via
Opposite Central and Peripheral Mechanisms through FoxO1. Cell Metab. 2013;17(6):90115.
Christopher Masterjohn
Filed Under: blogs, cmasterjohn
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17 Responses to Undercarboxylated Osteocalcin: Marker of Vitamin K
Deficiency, or Booster of Insulin Signaling and Testosterone?
1. George Henderson says:
July 17, 2013 at 10:50 pm
Interestingly, vitamin E elevated undercarboxlated prothrombin, but not osteocalcin,
in this human study http://www.ncbi.nlm.nih.gov/pubmed/15213041
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if tocopherol does protect undercarboxylated osteocalcin in rodents, this might explain
why it is a fertility factor.
There are no animal studies in Pubmed and just one other relevant human study:
http://www.ncbi.nlm.nih.gov/pubmed/12032162
Reply
2. Chris Heppner says:
July 18, 2013 at 6:14 pm
Chris, thanks for a very interesting, though deliberately inconclusive, study. I hope
that in the follow-up you will also deal with the issue of arterial and heart valve
calcification, since this process seems to be connected with bone mineralization, and
K2 has a history (maybe now being questioned) of assisting in directing calcium into
bones and keeping it out of arteries and valves.
There are documented cases of K2 supplementation reversing valvular calcification
(from Japan mostly, but William Davis also records a case history of aortic valve
stenosis much improved by addition of K2). I have a personal interest here–in 2004 I
was found to have a “severely stenotic and heavily calcified aortic valve,” which was
replaced by a bioprosthetic valve. As you know, these are also suject to calcification; I
have been supplementing K2 (as well as eating a diet rich in K1), and 9 years out my
valve is still functioning and looking (on echo) well. I won’t give up my K2 without
some more definitive evidence!
Thanks again, Chris Heppner
Reply
o
Chris Masterjohn says:
July 19, 2013 at 10:12 am
Hi Chris,
I think it’s clear that K2 protects against soft tissue calcification and promotes
bone mineralization. But that’s mainly the function of matrix Gla protein, not
osteocalcin.
Chris
Reply
3. rocks2stocks says:
July 18, 2013 at 10:01 pm
Chris,
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To what were you referring when you wrote:
“and a variety of high-dose nutritional supplements, …, could interfere with the
process of bone resorption.”
Reply
o
Chris Masterjohn says:
July 19, 2013 at 10:11 am
Hi Rocks2stocks,
There are a variety of nutrients that at high doses could inhibit bone resorption,
tocotrienols and K2 are among them, but I need to do more research before I
conclude anything about it. Coming in the next post!
Chris
Reply
4. Erella says:
July 19, 2013 at 10:28 am
It is great to see you reevaluating your older publications and updating it as new
information comes out. Your ability to get difficult and convoluted information across
to your reader in an organized fashion is without parallel. I am grateful to be a
recipient.
I was not sure in which venue to ask you this question, and I thought that your article
today relating to bone health/bone hormones is a good place to post this question.
Taken from “Why Broth is Beautiful: Essential Roles for Proline, Glycine and
Gelatin”- 18 June 2003 – by Kaayla T. Daniel, PhD, CCN
“You can use the stock as is, or chill to remove the fat that congeals on the top. (There
is nothing wrong with the fat, but culinary purists point out the clearest sauces are
achieved with stock from which the fat has been removed).”
Is there any nutritional value in the fat? Are any of the fat soluble vitamins( ?or other
nutrients) extracted from the marrow or other fat content of the simmered bones
preserved in the fat that congeals when the broth is put in the fridge? If the liquid part
of the bone broth does not become jellylike on refrigeration, does that mean that the
gelatin was not extracted properly (I cooked the broth for 72 hours)?
Since vitamins A/D/K are fat soluble vitamins( vs the unstored water-soluble
vitamins), would be giving your child liver once per week, as well as full fat
yogurt/cheese/sauerkraut regularly be enough, or would you suggest supplementing
(eg. with Thorne vitamin K2)? I understand that you don’t have the data, I am asking
for your best guess.
I thank you.
31
Reply
o
Chris Masterjohn says:
July 19, 2013 at 4:00 pm
Hi Erella,
Thank you for your kind words.
I don’t know the answers to any of these questions for sure, but my best
guesses are as follows:
1) All the fat-soluble nutrients in the marrow should be present in the fat. Some
of them may suffer some heat damage, however. Also, the fat itself could
suffer some heat damage, especially if it is from chickens, which tend to have
fat high in PUFAs (though not intrinsically so — see my blog post “Good
Lard, Bad Lard” on that topic).
2) Lack of gelling is probably from insufficient gelatin, or destruction of the
gelatin. It may be the case that cooking too short a time or using too few bones
or not using any more gelatinous materials like chicken feet is responsible for
inadequate gelatin, or that cooking too long a time breaks down the gelatin.
Try to find the happy medium.
3) Liver once a week and yogurt/cheese/fermented veggies should be good, but
for vitamin D make sure to get sunlight or use cod liver oil. Overall I think this
should be decent for most children without the need for supplementation but
there could be individual cases where supplementation is warranted.
Hope that helps,
Chris
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