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The Many Forms of Vitamin K

The names “vitamin K₁” and “vitamin K₂” are artifacts of history (Suttie, 2014). The first form of vitamin K was found in alfalfa, so it was named K₁. The second form was found in rotten fish, so it was named K₂. As shown in the figure below, they both have the same ring structure, but different tail structures. The tail structures are known formally as side chains. Vitamin K₁, now known as phylloquinone, has a mostly saturated tail. Vitamin K₂, now known as menaquinone, has an unsaturated tail. Menaquinones are actually a class of compounds with varying tail lengths, designated MK-n, where “n” indicates the number of repeating units in the tail. The specific form of vitamin K₂ found in rotten fish was MK-7. When later MKs were discovered, they all had unsaturated tails, so scientists classified them as subforms of vitamin K₂.

We now know that this is overly simplistic (Shearer, 2014). Some bacteria, such as those used to make Jarlsberg cheese, produce partially saturated menaquinones wherein some of the repeating subunits have double bonds and others don’t. For example, Jarlsberg is very rich in tetrahydromenaquinone-9, which is similar in structure to MK-9 except the second and third units of the tail are saturated. As Shearer (2014) pointed out, even phylloquinone has a double bond in the first unit of its tail and could be seen as a partially saturated form of MK-4. Thus, rather than forming two categories of K vitamins, it makes more sense to say that vitamin K comes in a wide diversity of forms that are distinguished by the length and saturation of their tails.

Side Chain Length and Saturation Determines Tissue Distribution

While the ring structure is what allows vitamin K to support the vitamin K carboxylase, the enzyme that activates vitamin K-dependent proteins, the tail structure determines how different forms of vitamin K reach different tissues in the body. This all begins with how they are incorporated into lipoproteins soon after we absorb them from food.

When we digest fat and fat-soluble nutrients, our intestines package them into lipoproteins known as chylomicrons, which take them through the lymph and into the bloodstream. This event critically distinguishes how water-soluble and fat-soluble nutrients are distributed through the body: water-soluble nutrients travel directly to the liver through the portal vein, while fat-soluble nutrients travel through the lymph in chylomicrons to bypass the liver and nourish the other tissues first.

Chylomicrons, like all other lipoproteins, have to transport fat-soluble things through the water-based environment of the blood. Therefore, they are fat-soluble on the inside and water-soluble on the outside.

While all K vitamins are fat-soluble, they are not all equally soluble in fat. Those with longer tails are more fat-soluble than those with shorter tails; for tails of equal length, saturated tails are more fat-soluble than unsaturated tails. K vitamins that are more fat-soluble are carried deeper in the core of chylomicrons, while those that are less fat-soluble are carried more toward the edges. Let’s take the three forms most commonly found in supplements as examples: K₁, MK-4, and MK-7. We would expect to find MK-7 in the center of the chylomicron, MK-4 closer to the edges, and K₁ in between the two (Schurgers and Vermeer, 2002).

Chylomicrons move in and out of the bloodstream rapidly, with a half-life of 15-20 minutes (César, 2006). This means that once we eat a meal, 95% of the chylomicrons that enter our blood are fully cleared in the first hour. Very few tissues actually take up the whole chylomicron. Instead, most tissues use the enzyme lipoprotein lipase (LPL) to siphon off its nutrients bit by bit. While LPL is best known for feeding the heart, skeletal muscle, and adipose tissue, it also feeds other tissues such as the lungs, kidneys, mammary glands, and brain (Kersten, 2014). LPL spreads across the capillary beds that feed our great diversity of tissues, allowing widespread access to the fat-soluble nutrients we ingest in a meal. Presumably, these tissues all have greater access to the nutrients carried closer to the edges of the chylomicrons, such as MK-4.

As these many tissues feast on the chylomicrons, the chylomicrons get smaller and smaller until they become chylomicron remnants. A small handful of tissues donate apolipoprotein E (ApoE) to the chylomicron remnants, and then use the LDL receptor and other related receptors to bind to the ApoE and take up the whole remnant. This allows them to score everything left in the particle right down to its chewy center. In this sense, ApoE is like the bait on a fishing line, and the receptor is like the hook. While the liver is best known for fishing out chylomicron remnants in this manner, our bones and spleen do as well. Our bones primarily derive nutrients through the uptake of whole lipoprotein particles, and take up about a fifth as many chylomicron remnants as our liver (Shearer, 2008). Thus, we should expect bone and liver to primarily have access to nutrients carried in the center of chylomicrons, including K₁, but especially the MKs with longer tails, such as MK-7.

This whole stream of events takes place largely in the first hour after a meal. The liver then repackages the lipids it took in from chylomicron remnants into other lipoproteins, primarily VLDL, which are sent back out into the blood. Tissues continue to siphon off nutrients using LPL. Just like chylomicrons had been digested into chylomicron remnants, VLDL particles are then digested into LDL particles until our tissues take up the LDL particles themselves. Unlike the rapid clearance of chylomicrons, clearance of LDL particles takes place slowly over the course of two weeks (Langer, 1972). Although the liver is the main tissue that takes up LDL, bone is also important; in fact, bone takes up vitamin K more effectively from LDL than from any other lipoprotein (Shearer, 2012). Thus, K vitamins that get packaged into LDL particles will have a second opportunity to nourish bone.

Schurgers and Vermeer (2002) investigated how different K vitamins are transported using K₁, MK-4, and MK-9. They fed six healthy males a mixture of one milligram of each form and took repeated blood measurements over four days, beginning at the two-hour mark. MK-4 had already peaked by the time the first blood draw was taken, when much of it was found in HDL, and disappeared most rapidly from the blood out of all the forms. K₁ peaked at the four-hour mark, was mostly gone by eight hours, and disappeared by the end of the study. K₁ was found almost exclusively in VLDL rather than in LDL or HDL. MK-9 peaked at the four-hour mark as well, but persisted in the blood for several days while carried in LDL particles.

The authors suggested that MK-4 was taken up so quickly because it was carried toward the edges of the chylomicrons, making it easily accessible for LPL-mediated extraction, with the excess spilling over into HDL particles. Notably, we should expect the extended circulation of MK-9 in LDL to provide better nourishment to bone.

Schurgers later collaborated with Sato (2012) to compare the bioavailability of MK-4 and MK-7 in healthy women. Compared to the 2002 study, they used less than half the dose of each vitamin and fed them separately rather than combined so that the total dose of vitamin K given at each point was over six times lower. Similar to the 2002 study, they took their first blood sample at two hours. They didn’t find MK-4 in the blood at any time point, whereas MK-7 remained elevated for two days.

MK-4 vs. MK-7: What Do We Really Know?

If we compare the results of the 2012 study to the earlier 2002 study, we can surmise that the dose of MK-4 in the 2012 study was low enough that the initial LPL feast in the first hour fully distributed it to a variety of tissues so that it was all gone by two hours, and that MK-7 circulated for such a long time because, like MK-9, it was redistributed in LDL particles. We should expect from this that MK-4 is good at nourishing most tissues, but not very good at nourishing liver or bone. By contrast, we should expect that MK-7 is good at nourishing the liver and even better at nourishing bone.

At the present time, there is no direct support for this, but there are hints that it may be the case. Sato (2012) cited a Japanese paper as finding that 1.5 milligrams of MK-4, but not 500 μg, improved the carboxylation of osteocalcin. Not even the abstract seems to be available in English, so it is difficult to evaluate the study. Later, Nakamura (2014) showed that only 600 μg of MK-4 is needed, but in this study the researchers simply gave the same people higher and higher doses each week and waited for osteocalcin carboxylation to improve. For all we know, their lowest dose, 300 μg, would have worked if they had given it longer than a week. In seeming contrast to MK-4, MK-7 improves osteocalcin carboxylation with as little as 100 μg (Knapen, 2012; Inaba, 2015).

Placing these studies side by side, they seem to suggest that improvements in osteocalcin carboxylation require much lower doses of MK-7 than of MK-4. However, the studies had different designs and were conducted in different populations that may have had different nutritional needs and different responses to vitamin K supplementation. In fact, Inaba (2015) fed MK-7 for four weeks while Nakamura (2014) only fed each dose of MK-4 for one week. This alone could explain the difference. To date, no one has compared the osteocalcin response to MK-4 and MK-7 head-to-head.

On the other hand, MK-7 has been compared to K₁. At equal doses, MK-7 is three times more potent than K₁ at carboxylating osteocalcin (Schurgers, 2007). Osteocalcin is made in bone, so its carboxylation reflects vitamin K status in that tissue. Presumably, MK-7 is better than K₁ because its recirculation in LDL particles for days after it is first taken up by the liver gives it much more opportunity to nourish bone. Since MK-4 likely has even less opportunity to reach bone than K₁, MK-7 is probably superior to MK-4 for this purpose as well.

What about other tissues? Unfortunately, we know even less about those. We know that large pharmacological doses of MK-4 given to rats (Konishi, 1973) or dogs (Sano, 1997) reach the lungs, liver, kidney, pancreas, spleen, adrenal gland, and bone very rapidly. Such large doses are also excreted into the feces in large amounts. More moderate nutritional doses could behave very differently, however, so it is difficult to form any conclusions from these studies. Until we have well designed trials comparing the ability of different MKs to support different health outcomes in humans, it makes sense to rely on what we know generally about how lipoproteins transport nutrients. This suggests K₁ would best reach the liver, MKs 7-9 would best reach liver and bone, and MK-4 would best reach most other tissues.

MK-7 Supports Blood Clotting Better Than K₁

MK-7 is not just three times better than K₁ at reaching bone; it’s also five times better at supporting blood clotting (Schurgers, 2007). This may be because the greater fat-solubility of MK-7 makes it hold on more tightly to the membranes within liver cells, making it stay active in the liver much longer rather than being released and broken down (Shearer, 2008). The liver is where clotting proteins are made, so more extended activity in the liver would explain why MK-7 could better support blood clotting. If this is correct, other long-chain MKs such as MK-8 and MK-9 probably share this property as well.

MK-4 Plays a Unique Role in Gene Expression

MK-4 is unique among the K vitamins in its regulation of gene expression. It increases the expression of genes that regulate cell growth in osteoblasts (the cells responsible for bone growth), but MK-7 and K₁ do not (Ichikawa, 2007). MK-4 increases testosterone production when fed to male rats. Cellular experiments show that MK-4, but not K₁, increases testosterone  by increasing the expression of the enzyme that converts cholesterol to pregnenolone, which is the first step in sex hormone synthesis (Ito, 2011).

MK-4 also inhibits the growth of various cancers of the liver, gut, and bone (Shearer, 2008). Remarkably, the gene that is now known to code for the enzyme that converts other K vitamins to MK-4, Ubiad1, was known years earlier as a tumor-suppressor gene (Shearer, 2014). Scientists observed that Ubiad1 was often silenced in tumors of the bladder, prostate, and kidney. Conversely, experimental overexpression of Ubiad1 inhibited the growth of prostate cancer cells. Since the enzyme that Ubiad1 codes for converts other K vitamins to MK-4, these results underscore that the anticancer properties of vitamin K belong specifically to MK-4.

Can We Rely on the Conversion of Other K Vitamins to MK-4?

When we consume any form of vitamin K, our intestinal cells break the side chains off of a small portion to yield the pure ring structure, known as menadione (Thijssen, 2006). Menadione then disperses through the body to many tissues that convert it to MK-4 for their own use by adding  MK-4’s characteristic four-unit unsaturated side chain (Hirota, 2013).

We have known that animals synthesize MK-4 from other K vitamins for over a half century. It has been clear throughout that time, however, that the conversion varies widely. Early experiments, for example, showed that birds made the conversion better than rats and pigeons made it better than other birds (Billeter, 1960). Among rats, Wistar rats (Thijssen, 1994) seem to make the conversion better than Lewis rats (Ronden, 1998). Since the conversion varies between and within species, we should not assume that we as humans can make the conversion efficiently and consistently enough to meet our needs.

And just how good are we at this conversion? We really don’t know, but it stands to reason that it varies from person to person. Rare genetic defects in Ubiad1 have been identified (Yellore, 2007), and cancer is associated with epigenetic silencing of Ubiad1 (Woolston, 2015). Other genes involved in the conversion likely vary from person to person as well, but we don’t yet know what they are. One of them may be vitamin K epoxide oxidoreductase (VKOR), the target of warfarin. The normal role of VKOR is to reduce vitamin K that has been oxidized, and we know that menadione must be in a reduced state to undergo conversion to MK-4. Indeed, warfarin prevents the conversion of K₁ to MK-4 in rats (Spronk, 2003). Genetic polymorphisms in VKOR are common (Shearer, 2012), and could hypothetically contribute to variation in MK-4 synthesis. We still do not know what enzyme is responsible for cleaving the side chain within our intestinal cells, and that could be polymorphic as well.

However good or bad humans may naturally be at the conversion, many people are taking medications that inhibit it (Hirota, 2015). Lipophilic statins such as lovastatin and simvastatin (and presumably atorvastatin, branded as Lipitor) inhibit the conversion. So do nitrogen-containing bisphosphonates such as alendronate (Fosamax) and zolendronate (Zometa), and presumably other nitrogenous bisphosphates as well. Ubiad1 expression depends on zinc (Funahashi, 2015) and its enzymatic activity depends on magnesium (Hirota, 2015), suggesting that deficiencies of either of these minerals could also compromise the conversion.

Finally, if we converted other K vitamins to MK-4 on a “however much we need to” basis, then it shouldn’t matter what type of vitamin K we consume at all. All forms of vitamin K generate some menadione in the intestine that can be converted to MK-4 in other tissues. Whether the menadione comes from K₁, MK-4, MK-7, or any other form of vitamin K cannot make any difference in its tissue distribution. Humans accumulate MK-4 in multiple organs including the heart, lung, brain, liver, kidney, and pancreas (Thijssen, 1996). Thus, if there are no major limitations on the conversion besides our need for it, K₁ should be perfectly capable of supplying these tissues with all the MK-4 they need, especially in populations that have high K₁ intakes. Yet this does not seem to be what we find.

Consider the Dutch population, where this has been investigated most extensively. K₁ intakes are eight times higher than K₂ intakes, yet only K₂ intake is inversely correlated with heart disease (Geleijnse, 2004; Gast, 2009; Buelens, 2009; Zwakenberg, 2016). In Germany, K₁ intakes are about three times higher than K₂ intakes, yet only K₂ intake is inversely correlated with advanced prostate cancer (Nimptsch, 2008) and lung cancer (Nimptsch, 2010).

These observational studies don’t offer clear evidence of cause-and-effect relationships and they don’t show correlations with health endpoints that are specific to MK-4. However, they do add to the list of reasons to believe that our ability to synthesize MK-4 is limited by much more than our specific need for MK-4 itself, and by much more than our general need for vitamin K in the tissues that unconverted K₁ has a hard time reaching. In other words, many of us probably need more MK-4 than we can make on our own, and that’s a good reason to eat foods that provide it.

Altogether, the evidence suggests that the form of vitamin K we consume matters, and that we are best served by a diversity of K vitamins from leafy greens, animal foods, and fermented foods.

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Vitamin K₂: What is the Optimal Dose?

Another way to ask this question is as follows: what is the minimum effective dose to achieve the maximal desired effect? While there is no established toxicity for high doses, there are good reasons to be cautious before taking far more than we need (see below), hence the term “minimum effective dose.” At the same time, we don’t want to reap just some of the health benefit. We want to reap as much of the health benefit as we can in a safe and effective manner, hence the term “maximal desired effect.”

The only rigorous way to approach this is to look at dose-finding studies, which are studies where different doses were directly compared with one another. Ideally, the studies are randomized, controlled, long enough in duration to believe the dose was able to achieve its full effect, and conducted within a context where we would expect to see a benefit.

Pharmacological Doses of MK-4

A Japanese dose-finding study compared 15, 45, 90, and 135 milligrams per day (mg/d) of MK-4 to reduce fracture risk in postmenopausal women with osteoporosis and found 45 mg/d to be the minimal effective dose (Iwamoto, 2013). This is a pharmacological dose that is hundreds of times greater than what can be obtained from food. It probably works through mechanisms that are independent of the those seen for nutritional doses of vitamin K, such as overriding the body’s natural regulation of bone resorption. Thus, we should view MK-4 at these doses with the same type of cost-benefit analysis we would use for other osteoporosis drugs, like Fosamax, and we should not use these studies to determine the optimal nutritional dose of MK-4.

Nutritional Doses of MK-4

Unfortunately, there is a dearth of dose-response studies for nutritional doses of MK-4. Nakamura (2014) compared the effect of 0, 300, 600, 900, and 1500 micrograms per day (μg/d) on osteocalcin carboxylation, a marker of vitamin K status in bone. They fed everyone the same doses in the same order, increasing the dose from 0 one week at a time. The carboxylation status did not change with 300 μg/d, but improved with 600 μg/d. However, it is not at all clear that 300 μg/d would not have provided the same benefit if given for longer than one week. I do not consider this study to offer any clear insight about the optimal dose of MK-4.

MK-7 in Healthy Populations

Dalmeijer (2012) compared 180 and 360 μg/d MK-7 to a placebo given to healthy, non-obese men and postmenopausal women aged 40-65 years over the course of twelve weeks. The mean K₂ intake from food was 25 μg/d, so these treatments effectively compared total K₂ intakes of 25, 200, and 380 μg/d. Both treatment doses lowered desphospho-uncarboxylated MGP (dp-ucMGP), a marker of vitamin K deficiency in blood vessels, and improved the carboxylation status of osteocalcin. While 360 μg seemed to cause a slightly larger effect than 180 μg, the lion’s share of benefit came from 180 μg and the difference between the two doses was not statistically significant. Thus, the study hints at a possible benefit of doses higher than 200 μg that would have to be confirmed in future studies with greater statistical power, but provides rigorous evidence only that 200 μg is better than 25 μg.

Knapen (2012) reported a more extensive array of doses given to healthy men and premenopausal women aged 25-45 over the course of twelve weeks. The doses included 0, 10, 20, 45, 90, 180, and 360 μg/d MK-7 and the primary endpoint of interest reported was the carboxylation status of osteocalcin. Unfortunately, the sample size (n=42) was small for having so many groups, precluding a rigorous statistical analysis of the endpoints between each group. Additionally, while carboxylated osteocalcin levels were similar across groups at baseline, undercarboxylated osteocalcin levels were highly variable. The changes in undercarboxylated osteocalcin between baseline and the study’s end within any given group were generally about the same size as the difference in baseline values between groups. All of this makes it extremely difficult to know whether the the difference between groups for changes in undercarboxylated osteocalcin or its ratio to total osteocalcin are true biological differences or simply random variation resulting from noisy data.

Doses that were 90 μg/d or greater caused statistically significant decreases in undercarboxylated osteocalcin, but only the 180 μg and 360 μg doses increased the levels of carboxylated osteocalcin or improved the ratio. From among these measurements, the increase in carboxylated osteocalcin seen with the two higher doses is most convincing because the variation in baseline values for that measurement was so low. The ending values for this measurement were higher in the 180 and 360 μg groups than in any of the the others, but they were nearly identical between groups. K₂ intake from food was not reported, but presumably would have added at least 20 μg/d to the doses. I therefore consider this study to offer limited support to 200 μg/d as the optimum dose for improving vitamin K status at bone.

Inaba (2015) compared 0, 50, 100, and 200μg/d MK-7 in postmenopausal women aged 50 to 69 years over the course of four weeks. The primary endpoint of interest was the carboxylation status of osteocalcin, reported as the ratio of the carboxylated to the undercarboxylated form. The study was conducted in Hokkaido, Japan, where natto is popular. The subjects were required to avoid all MK-7-rich foods and to consume prepared meals that provided 65 μg/d of total vitamin K as a combination of K₁ and MK-4 in unspecified proportions. Whether intentional or not, this is effectively a study of how much MK-7 you need to preserve the carboxylation status of your osteocalcin when you stop eating natto. Indeed, the largest effect across all groups was for carboxylation status to significantly worsen in the 0 μg/d group. Carboxylation status was significantly different from that group in the 100 and 200 μg/d groups, but not in the 50 μg/d group. The authors did not report a statistical analysis for the difference between 100 and 200 μgd, but 200 μg/d was the only group in which carboxylation status actually improved over the course of the study. I therefore consider this study to offer limited support to 200 μg/d as the optimum dose for improving vitamin K status at bone.

In further support of this conclusion, Ikeda (2006) found that postmenopasual women who reported consuming enough natto to provide 200 μg/d K₂ or more (mostly as mostly MK-7) suffered less bone loss over the course of three years than women who consumed less. Since all lower intakes of natto were grouped together for the statistical analysis, it is not clear exactly where the line of maximal benefit lies, and it may be less than 200 μg/d. As an observational study, we should also be more cautious about inferring cause and effect. Nevertheless, the fact that it measured an actual health endpoint (bone loss) instead of just a surrogate marker (osteocalcin carboxylation), and the fact that it was three years long instead of four to twelve weeks, makes it very worthy of consideration.

MK-7 in Hemodialysis Patients

Westenfeld (2012) and Caluwé (2014) both conducted dose-finding studies in hemodialysis patients. Patients with kidney disease have high levels of vascular calcification, which is a major contributor to mortality in this population. Since MGP protects blood vessels from calcification, dp-ucMGP was the major endpoint in both studies. Lower dp-ucMGP suggests better vitamin K status in blood vessels and a better defense against pathological calcification.

Westenfeld compared 45, 135, and 360 μg/d MK-7 over six weeks. MK-7 dose-dependently decreased dc-ucMGP, with the effect almost doubling in size for each increase in the dose from 18% to 37% to 61%. However, change from baseline analysis is vulnerable to regression to the mean and it is more rigorous to compare the absolute levels of dc-ucMGP after treatment. When looked at this way, 135 and 360 μg/d had equal benefit over 45 μg/d.

Nevertheless, Caluwé later tested even higher doses and provided evidence of benefit for more than 300 μg/d. They fed the patients 360, 720, or 1080 μg MK-7 three times per week for eight weeks, which equates to average daily doses of 154, 309, and 463 μg. MK-7 dose-dependently decreased dp-ucMGP by 17%, 33%, and 46%. The ending dp-ucMGP values were lower in the 463 μg/d group than in the 309 μg/d group and were lower than Westenfeld found after feeding 360 μg/d, but they were still about four times higher than that found in healthy controls. The average K₂ intakes in the Caluwé paper were 16 μg/d, making the doses compared effectively 325 and and 479 μg/d. Future studies may clarify whether even higher doses can bring dp-ucMGP levels even closer to those found in healthy controls. Thus, there is strong evidence that the K₂ requirement for kidney patients is higher than 325 μg, possibly as high as 480 μg, and may well be much higher than that.

Conclusions

For healthy populations, there is no smoking gun, but several studies converge towards the conclusion that 200 μg/d is the optimal dose. Most of the benefit probably comes from the first 100 μg, and the evidence for the superiority of 200 μg is limited. There may be benefits to higher doses, but there is no convincing evidence of that at this time. Thus, there is a high likelihood that I will revise my recommendation as new data comes in, but I currently recommend at least 100 μg/d and preferably 200 μg/d.

For kidney disease patients, there is good reason to see 480 μg/d as better than lower doses. Since 480 μg/d almost slashes dp-ucMGP in half yet leaves it four times higher than in healthy controls, the optimal dose may well be much higher than this. I suspect it is at least 1 mg/d. Nevertheless, K₂ should only be used to augment treatment for kidney disease under medical supervision.

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Vitamin K₂ in Foods: A Closer Look

Vitamin K₂ in foods comes either from the conversion of other K vitamins to MK-4 in animals or from bacterial production of various MKs. A good example that ties these concepts together is cheese. A cow eats grass that contains K₁. The cow converts a portion of that K₁ to MK-4. Both K₁ and MK-4 are found in the milk. Humans take the milk and ferment it into cheese. During the fermentation process, bacteria proliferate that synthesize a variety of MKs, mainly MK-7 through MK-10, and especially MK-8 and MK-9.

A comparison of different cheeses illustrates the importance of the specific type of bacteria used in the fermentation. For example, in each 100 gram serving, Jarlsberg contains 74 μg while blue cheese contains 36, cheddar contains 21, Swiss contains 8, and mozzarella only contains 4. This variation can also be seen among fermented plant foods. For example, sauerkraut has only 5 μg, compared to nearly 1000 for natto.

Within a particular type of cheese, ripening has little effect. For example, gamalost increases from 38 to 51 in the first ten days of ripening, but this level remains mostly stable over the course of 20, 30, and 60 days. This is probably because the bacteria that produced the K₂ during the initial stage of fermentation die off during the ripening (Hojo, 2007).

The data for cheese also provide a window into the possibility that some of our current food data are gross underestimates. For example, most cheeses are made with lactic acid bacteria that produce mostly MK-8 and MK-9, but some cheeses are made with proprionibacteria that also produce tetrahydro-MK-9 (Hojo, 2007), which has a structure that is the same as MK-9 except it lacks some double bonds in its side chain. These include the Swiss cheeses Emmental and Gruyère, the French cheese Comté, and the Norwegian cheese Jarlsberg. Whether tetrahydro-MKs might be present in other foods is somewhat unclear because virtually all analyses of vitamin K in foods have ignored them. No analysis has yet evaluated both tetrahydro-MKs and all the regular MKs in any food at the same time, strongly suggesting that the total K₂ in foods that contain tetrahydro-MKs is grossly underestimated. To take Jarlsberg as an example, Hojo (2007) showed that, per 100 grams, it contains 8 μg MK-4 and 65 μg tetrahydro-MK-9, and cited evidence that it also contains another ~50 μg of MK-8 and MK-9. In our database, we only report values that were measured in a single scientific paper for any given sample, so our data for Jarlsberg reflects what was actually measured in the Hojo paper, 74 μg, but the true value may be over 130 μg.

Our own gut microbiota also synthesize K₂: Bacterioides synthesize MK-10 and MK-11, Enterobacteria synthesize MK-8, Veillonella synthesize MK-7, and Eubacterium lentum synthesizes MK-6 (Shearer, 2014). However, this probably makes little if any contribution to our own vitamin K status for two reasons: first, most of this occurs in the large intestine, which is well past the sites of vitamin K absorption in the small intestine, and all the K₂ is stuck in bacterial membranes that would have to be digested to release it.

MKs produced during the fermentation of foods such as cheese or natto are also bound in bacterial membranes, but when we eat them we digest those membranes to release the K₂ in the small intestine where it can be absorbed. Some animals eat their own feces, a practice known as coprophagia, and this allows the the microbiota-derived K₂ to be released and absorbed in the same way as when we eat cheese or natto. This may explain the recent finding that pork products are extremely rich in MK-10 and MK-11 (Fu, 2016). The meat was obtained from supermarkets in Eastern Massachusetts, so it presumably came from commercial farms. Perhaps pigs on those farms whether by instinct, necessity, or accident, consume feces.The only other possibility would seem to be that the pigs are fed rotten or fermented food.

The question arises whether MK-10 and MK-11 provide similar bioavailability to the MKs in other foods, which are generally much richer in MK-4 (animal foods), MK-7 (natto) or MK-8 and MK-9 (cheese) than in MK-10 or MK-11. In humans, MK-10 and MK-11 tend to predominate in the liver rather than in other tissues, and in the mitochondria rather than in the endoplasmic reticulum where vitamin K-dependent carboxylation takes place (Thijssen, 1996). Thus, we should be cautious before making a conclusion about how interchangeable the MKs in pork products are with the MKs in most other foods. Ultimately this can be resolved with studies comparing the abilities of the different MKs to support different biological functions of vitamin K.

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Vitamin K₂ Supplements: Quality, Convenience, and Price

Here is my comprehensive review of vitamin K₂ supplements. It doesn’t cover every single supplement on the market, but it covers the supplements that provide singular doses of about one milligram or less and are easily accessible through the major online retailers Amazon and iHerb. If you would like me to review a supplement that didn’t make the list, please let me know in the comments.

I have broken the list into five categories according to whether they provide a combination of MK-4 and MK-7, only MK-4, only synthetic MK-7, only natural MK-7 from chickpeas, or only natural MK-7 from natto. Within each category, I have listed them from least expensive to most expensive.

One concern for synthetic MK-7 supplements is whether they are bioidentical. Natural MK-7 is all-trans (Bentley, 1982). If synthetic MK-7 is not guaranteed to be bioidentical, it may contain cis forms. While it is difficult to find reliable information on the biological activity of cis MK-7, cis phylloquinone fails to support vitamin K-dependent carboxylation in the rat (Knauer, 1975). Therefore, I recommend avoiding synthetic MK-7 supplements that do not guarantee the all-trans configuration. Notably, many of the MK-7 supplements use one of two products made by MenaQ7, either synthetic or from fermented chickpeas, both guaranteed to be all-trans. This MK-7 has the advantage of having been used in scientific studies and shown to be effective.

The prices listed were retrieved between December 4 and December 7, 2016 and are subject to change. Where I link to more than one way of obtaining a supplement, the cents per capsule and cents per 200 μg calculations are based on the least expensive option. Additions were made to this review on December 29, 2016. They are catalogued here.

Mixed MK-4 and MK-7 Supplements

Life Extension Super K With Advanced K₂ Complex — 1 mg K₁, 1 mg MK-4, 200 μg mK-7, with an additional 10 mg ascorbic acid from 25 mg ascorbyl palmitate. Sold by iHerb ($22.50) but cheaper at Amazon ($17.93). Eligible for Prime and Amazon Fresh. 20 cents per capsule, 3 cents per day to average 200 μg/d. Beware of the subscription button when buying on Amazon. The vitamins are synthetic. According to Life Extension, the MK-7 is synthesized in China and is bioidentical, but they could not verify for me that it is 100% all-trans, which is the natural form. The reason I do not advocate this supplement is because the high dose of K₁ adds little value, and although there is no well characterized risk of high doses, it is possible that multiple milligrams per day of vitamin K (this supplement itself provides 2.2 mg per capsule) may unnecessarily tax the body’s antioxidant system.

Maxx Labs Vitamin K₂ Complex — 500 μg MK-4, 100 μg MK-7, 100 mg calcium from calcium citrate. 20 cents per capsule, 7 cents per day to average 200 μg/d. $17.98 on Amazon, where it is fulfilled by Amazon and eligible for Prime. Be careful to avoid the subscription setting if you only want to order one bottle. Free of GMOs and allergens.

Innovix Full-Spectrum K₂ — 500 μg MK-4, 100 μg MK-7. 24 cents per capsule, 8 cents per day to average 200 μg/d. $21.97 on Amazon, fulfilled by Amazon and eligible for Prime. Both forms of K₂ in this product appear to be synthetic but bioidentical. It contains caramel coloring derived from non-GMO corn, a potential source of allergens. I consider this the best choice for a mixed MK-4/MK-7 supplement.

Country Life Vegan K₂ Strawberry Smooth Melt — 500 μg total K₂. MK-4 and MK-7 in unidentified proportions. 19 cents per smooth melt, 8 cents per day to average 200 μg/d. Almost identical prices on Amazon ($16.65) and iHerb ($16.67). On Amazon, it is fulfilled by Amazon and eligible for Prime. It is not clear where the vitamins come from or whether the MK-7 is bioidentical. It is free of GMOs, soy, and other common allergens.

Pure Encapsulations Synergy K — 1,000 IU Vitamin D₃, 1 mg MK-4, 500 μg K1, 45 μg MK-7. 47 cents per capsule, 9 cents per day to average 200 μg/d. $56 on Amazon, where it is fulfilled by Amazon and eligible for Prime. Free of GMOs and allergens. Taken to yield an average close to 200 μg K₂, the amounts of vitamin D (200 IU) and MK-7 (9 μg) are rather low compared to the Innovix Full-Spectrum K₂ (20 μg MK-7) or the Thorne Research D/K₂ (1,000 IU vitamin D), but the unique combination of the three vitamins may be optimal for some people whose nutritional needs fit it just right.

MK-4 Supplements

Thorne Research Vitamin K₂ — 1 mg MK-4. 5 cents per drop, 1 cent per day to average 200 μg/d. Similarly priced at Amazon ($64.62) and iHerb ($64.65), and if ordered on Amazon it is fulfilled by Amazon and eligible for Prime. It is dissolved in a base of nothing but MCT oil and mixed tocopherolsd. This is the least expensive option in the list.

Thorne Research D/K₂— 1000 IU vitamin D and 200 μg MK-4. 4 cents per day to obtain 200 μg from each two-drop serving. Although available on Amazon from third party shippers at prices ranging from $36-$70, it is not eligible for Prime and it is much less expensive ($23.70) through iHerb. This is a great option for someone who also needs to improve their vitamin D status. When compared to the Thorne Vitamin K₂, it has the added benefit that the dose of MK-4 is smaller so it is easier to take a consistent dose of 200 μg every day. However, don’t be fooled by the price difference: the bottle costs less (hardly more than a third the price), but on a per 200 μg basis it is four times as expensive.

Superior Source Sublingual MK-4 Tablets — 500 μg MK-4. 29 cents per tablet and 12 cents per day to average 200 μg per day. Similar price from Amazon ($17.59), where it is shipped and sold by Amazon as well as eligible for Prime, and iHerb ($17.79). The company claims that the sublingual formulation offers superior absorption but I’m not aware of any specific evidence of this. It contains lactose, so should be avoided by people with lactose intolerance.

Synthetic MK-7 Supplements

Amazing Nutrition MenaQ7 — 100 μg MK-7. 12 cents per capsule, 25 cents per day for 200 μg . $14.99 on Amazon where it is fulfilled by Amazon and eligible for Prime free one-day shipping. Free of common allergens and bioidentical.

Young Life Research MenaQ7 and Organic Coconut Oil — 100 μg MK-7. 16 cents per capsule, 32 cents per day for 200 μg . $19.47 from Amazon, fulfilled by Amazon and eligible for Prime. Free of common allergens and bioidentical. Non-GMO. I consider this the best balance of quality and price from among the synthetic MK-7 supplements.

Superior Source Sublingual Vitamin K₂-MK7 — 100 μg MK-7. 25 cents per tablet, 50 cents per day for 200 μg . Less expensive from Amazon ($14.99) than from iHerb ($16.06). On Amazon, it is sold by Amazon and eligible for Prime,. The company claims that the sublingual formulation offers superior absorption but I’m not aware of any specific evidence of this. It contains lactose, so should be avoided by people with lactose intolerance. The company does not claim this is bioidentical.

Life Extension Low-Dose Vitamin K₂ (MK-7) — 45 μg MK-7. 14 cents per capsule, 56 cents per day for 180 μg and 69 cents per day for 225 μg . Less expensive from Amazon ($12.49) than from iHerb ($13.50). On Amazon, it is eligible for Prime free one-day shipping and Amazon Fresh. According to Life Extension, the MK-7 is manufactured in Poland, but any further information is proprietary. Presumably it is synthetic and not bioidentical.

K-Force — 5,000 IU vitamin D3, 180 μg MK-7. $1.13 per capsule, and $1.13 per day to yield 180 μg or $1.20 per day to yield an average of 200 μg/d. $67.95 on Amazon, where it can be obtained with free shipping but is not fulfilled by Amazon or eligible for Prime. The company lists the MK-7 as soy-free but does not clarify its origin. Presumably it is synthetic, but it may be derived from fermented chickpeas. This supplement is useful specifically to people who need to take 5,000 IU of vitamin D per day.

Natural MK-7 From Chickpeas

These all derive their MK-7 from MenaQ7.  Everything in this section is the fermented chickpea product.

Nested Naturals K₂ — 100 μg MK-7. 12 cents per capsule, 24 cents per day to take 200 μg. $21.95 on Amazon, where it is fulfilled by Amazon and eligible for free one-day shipping, but beware of the subscription button. Free of GMOs, soy, and other common allergens. This is the least expensive of the products derived from fermented chickpeas and remains the least expensive even when including those derived from natto.

Doctor’s Best Natural Vitamin K₂ — 100 μg MK-7. 18 cents per capsule, 37 cents per day to take 200 μg . Almost identical prices on Amazon ($11.06) and iHerb ($11.25). On Amazon, it is sold by Amazon and eligible for Prime free one-day shipping and Amazon Fresh delivery, but beware of the subscription button. Free of GMOs, soy, and other common allergens. They also sell a 45 μg dose, but it is much more expensive if trying to achieve 200 μg per day.

Sports Research Vitamin K₂ — 100 μg MK-7. 25 cents per capsule, 50 cents per day to take 200 μg . $14.95 on Amazon, where it is fulfilled by Amazon and eligible for free one-day shipping. The fermented chickpea product comes from MenaQ7, which distributes their MK-7 products under many names. Free of GMOs, soy, and other common allergens. It’s main special feature out of the fermented chickpea products is the snap-top that the company says maintains better freshness.

Dr. Mercola Vitamin K₂ — 150 μg MK-7. 79 cents per capsule: 79 cents per day to take 150 μg , $1.58 per day to take 300 μg , or $1.05 per day to take an average of 200μg per day. The cost is nearly identical between iHerb ($71.37) and Amazon ($71.97) but slightly less expensive on iHerb. On Amazon, it ships from a third party and is not eligible for Prime. Free of GMOs, soy, and other common allergens.

Natural MK-7 From Natto

Healthy Origins Vitamin K₂ as MK-7 — 100 μg MK-7. 14 cents per softgel, 28 cents per day to get 200 μg . Less expensive at iHerb ($24.99) than at Amazon ($29.50). On Amazon, it is sold by Amazon and eligible for Prime. Beware of the subscription button, and beware of the bottle containing 60 softgels rather than 180, which is much more expensive per softgel. The company says this product comes from natto but is free of soy. It contains non-GMO corn starch, a potential source of allergens. This is the least expensive option from among the natto-derived supplements.

Sonora Nutrition Vitamin K₂ Natural MK-7 — 100 μg MK-7. 18 cents per capsule, 36 cents per day to get 200 μg. Available on Amazon, where it is fulfilled by Amazon and eligible for Prime free one-day shipping. Presumably made from soy.

Natural Factors K₂ — 100 μg MK-7. 21 cents per capsule, 42 cents per day to achieve 200 μg. $12.57 from Amazon. Derived from non-GMO natto. The company has a unique farm-to-capsule model where it controls everything that goes into its supplements from the soil to the encapsulation.

Nature’s Plus Source of Life Garden Vitamin K₂ — 120 μg MK-7. 22 cents per capsule. 43 cents per day to obtain 240 μg , 37 cents per day to take an average of 200 μg . Less expensive on Amazon ($12.95) than iHerb ($15.13). On Amazon, fulfilled by Amazon and eligible for Prime. Contains a blend of plant, mushroom, and algae extracts. Certified organic, certified non-GMO, certified allergen-free.

Now Foods MK-7 Vitamin K₂ — 100 μg MK-7. 21 cents per capsule, 42 cents per day to get 200 μg . 19 cents per capsule, 38 cents per day to get 200 μg. Less expensive at Amazon ($11.46) than at iHerb ($12.73). On Amazon, it is sold by Amazon and eligible for Prime free one-day shipping and Amazon Fresh, but beware of the subscription button. From non-GMO natto. Contains soy. Does not contain other common allergens but processed in a facility where other allergens may be present.

Nutrigold Vitamin K₂ MK-7 Gold — 100 μg MK-7. 23 cents per capsule, 45 cents per day to get 200 μg. $27.99 from Amazon. Sold by Amazon and eligible for Prime, but beware of the subscription button. Non-GMO. Made from soybeans, but free of allergenic soy protein. Free of other common allergens as well, verified by third party testing.

Natural Factors D₃ & K₂ — 1000 IU vitamin D, 120 μg MK-7. 35 cents per softgel, 58 cents per day taken to average 200 μg/d, or 70 cents per day to yield 240 μg. Identical in price ($20.97) between Amazon and iHerb. MK-7 is derived from non-GMO natto. The company has an unusual farm-to-capsule model where it controls everything that goes into its supplements from the soil to the encapsulation. Taken to yield an average daily dose of 200 μg K₂/d, it yields 1,667 IU vitamin D; taken twice a day to yield 240 μg K₂, it yields 2000 IU of vitamin D, both of which are more than the 1,000 IU of vitamin D in Thorne Research D/K₂. However, the Thorne product contains MK-4 and this product contains MK-7. This is the only product that combines relatively high doses of vitamin D and MK-7.

Jarrow Formulas MK-7 Vitamin K₂ — 90 μg MK-7. 20 cents per softgel. 42 cents per day to get 180 μg, 47 cents per day to average 200 μg. Less expensive at iHerb ($12.48) than at Amazon ($13.55). On Amazon, it is sold by Amazon and eligible for Prime free one-day shipping and Amazon Fresh, but beware of the subscription button. From non-GMO natto. Contains soy but free of most other common allergens.

Carlson Labs Vitamin K₂ MK-7 — 45 μg. 13 cents per capsule, 53 cents per day to get 180 μg, 67 cents per day to get 225 μg. Less expensive buying a 180-capsule bottle from iHerb ($24) than the 90-capsule bottle sold on Amazon ($15.23). On Amazon, sold by Amazon and eligible for Prime free one-day shipping and Amazon Fresh, but beware of the subscription button. Made from natto and contains soy, though their own web site suggests they may have switched to chickpea.

Bluebonnet Nutrition Vitamin K₂ — 100 μg. 32 cents per capsule, 64 cents per day to get 200 μg. Almost identical in price between Amazon ($32.39) and iHerb ($32.40). On Amazon, fulfilled by Amazon and eligible for Prime, but beware of the 2-bottle package that is more expensive and not eligible for Prime. Made from natto. Non-GMO, Kosher, contains soy but free of other common allergens.

Nature Made Vitamin K₂ Softgel — 100 μg. 52 cents per softgel, $1.03 per day to get 200 μg. $15.45 on Amazon, where it is sold by Amazon and eligible for Prime. Made from “natto organism,” and contains soy.

High-Dose MK-4

Supplements where the lowest dose contains 5 mg or more of MK-4 are included in this section. It is impractical to use these supplements to reach an average dose of 200 μg/d. They are primarily useful as a means of reaching the pharmacological dose of 45 mg/d that has been used to treat osteoporosis, to prevent the occurrence of hepatocellular carcinoma in women with viral cirrhosis, and to prevent the recurrence of the same disease in people who have already been treated for it. Although high-dose MK-4 supplements are available over-the-counter and have a low risk of side effects, these treatments are pharmacological rather than nutritional in nature. Therefore, I recommend using them under the supervision of the physician who is overseeing treatment for one of these conditions.

Advanced Orthomolecular Research Peak K2 — 15 mg MK-4. 35 cents per capsule and $1.04 per day to reach 45 mg. Less expensive on Amazon ($31.30) than iHerb ($34.56). On Amazon, fulfilled by Amazon and eligible for Prime. Free of common allergens.

Note: This company also makes a low-dose supplement, but it can't be ordered online and the company is not transparent about its price, so I am not including it in this review.

Relentless Improvement Vitamin K2 — 15 mg MK-4, 60 μg MK-7. 39 cents per capsule and $1.17 per day to reach 45 mg. $34.95 per bottle on Amazon, where it is fulfilled by Amazon and eligible for Prime free one-day shipping. Taken to provide 45 mg/d MK-4, it also provides 180 μg/d MK-7. While research suggests that MK-4 and MK-7 have different tissue distributions at low doses, it is unclear whether there is any benefit to adding a low dose of MK-7 to a far higher dose of MK-4. The vitamins are synthetic and the company guarantees a low percentage of inactive cis isomers.

Carlson Labs Vitamin K2  — 5 mg MK-4. 18 cents per capsule and $1.66 per day to reach 45 mg. Less expensive on Amazon than on iHerb. On Amazon, the 60-capsule bottle ($10.99) and 180-capsule bottle ($33.26) are both equivalent in price per capsule. Both are fulfilled by Amazon and eligible for Prime, and the larger one is eligible for Prime free one-day shipping. Be careful of the subscribe and save button on the smaller bottle. iHerb only sells the 60-capsule bottle ($14.94).

Food-Based Supplements

Supplements included in this section are those that isolate a food oil itself or a major fraction thereof rather than specifically isolating one or more forms of vitamin K₂. The nutrients in these supplements are less concentrated, but they are present in a broader network of synergists. While vitamin K₂ supplements are a great way to optimize vitamin K status in someone whose diet is otherwise good, food-based supplements are likely to be better ways of compensating for an otherwise suboptimal diet.

Walkabout Australian Emu Oil — 40 cents per gram as a liquid oil, 52 cents per gram as capsules. Each capsule contains one gram of total oil and 4 μg MK-4. This product is not available on Amazon or iHerb. Its price is identical between Radiant Life, where the liquid oil ($45) and capsules ($52) can be ordered on the same page, and Corganic, where the oil and capsules are available on separate pages. Additional shipping charges apply to both sellers. Shipping charges for RadiantLife would be $7.95 for the liquid oil, $9.95 for the capsules, and free for a total order over $125. Corganic shipping charges depend on your address. Reaching 200 μg K₂/d with this product would require 48 capsules or 3.5 tablespoons per day of the liquid oil and is obviously impractical. However, five capsules per day would yield 20 μg/d; added to a nutrient-poor diet containing only 15-20 μg/d on its own, this would double a person's K₂ intake. The oil also naturally contains a blend of essential fatty acids and other fat-soluble vitamins.

Green Pastures X-Factor Butter Oil — 43 cents per capsule, with each capsule containing 0.5 grams of oil. Less expensive on Amazon ($43.20) than on the Green Pastures web site ($60). On Amazon, fulfilled by Amazon and eligible for Prime free one-day shipping. However, the Green Pastures web site offers liquid oils as well as capsules and offers a greater diversity of flavors than available on Amazon. Each capsule contains 0.4 μg of K₂, mostly as MK-4. Reaching 200 μg/d would require 500 capsules per day and is obviously impractical. However, Green Pastures has in the past reported an unidentified set of quinones in the oil, which could upon further testing be shown to have additional vitamin K activity. For example, the fermentation of the oil could produce tetrahydromenaquinones, which are found in high concentrations in certain cheeses but have not been measured in the butter oil. The oil also naturally contains a blend of essential fatty acids and other fat-soluble vitamins.

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Vitamin K Absorption and Fat: A Closer Look

Dietary fat is important for the absorption of all fat-soluble vitamins partly because it helps dissolve the vitamins and partly because it helps stimulate the machinery involved in fat digestion, such as bile acids and lipases. Studies have generally suggested the following rule: the more fat you eat, the more fat-soluble vitamins you absorb. For example, 28 grams of fat allows better absorption of carotenoids from a salad than 6 grams of fat (Brown, 2004), and 30 grams of fat allows better absorption of vitamin E from a supplement than 11 grams of fat (Bruno, 2006). Studies have also shown that oils lower in polyunsaturated fatty acids (PUFAs) promote better absorption of fat-soluble vitamins than high-PUFA oils. For example, beef tallow allows better absorption of beta-carotene from a standardized test meal than safflower oil (Hu, 2000).

These rules appear to apply to vitamin K just the same. For example, 35 grams of fat allows better absorption of MK-4 than 20 grams of fat (Uematsu, 1996), and more K₁ is absorbed from spinach with 25 grams of butter than without butter (Gijsbers, 1996). More K₁ was absorbed from a “cosmopolitan” meal or an “animal-oriented” meal than from a “convenience meal,” with one possible explanation being the two-fold greater PUFA content of the convenience meal (Jones, 2009).

None of these studies showed a ceiling to the fat effect, and none of them tested more than 35 grams of fat. So, there may not be any ceiling to the effect. What we can say with confidence is that 30-35 grams of fat will provide for better absorption than lower amounts. Even still, absorption will probably never reach 0% or 100%, and for any given percent absorption one can always absorb a greater total amount of a vitamin by consuming more of it. Therefore, there is no sense in chasing after complete absorption and there is no intrinsic danger of a low-fat diet. If you have a good reason to eat less than 35 grams of fat per meal, it just becomes more important to spend the fat you do eat wisely by allocating it to K₂-rich foods. It is fine to be flexible about fat intake, but it is important to be aware that any given amount of K₂ in the diet will provide more nutrition to our bodies if consumed with a good dose of healthy fat.

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Tests for Vitamin K Status: A Closer Look

Vitamin K travels through the blood almost entirely as a means of being delivered to our other tissues, so blood levels of vitamin K only reflect recent intake rather than long-term nutritional status. Red blood cells lack the organelles in which vitamin K function is important (the endoplasmic reticulum, mitochondria, and nucleus). Lymphocyte vitamin K concentrations could, perhaps, reflect long-term vitamin K status, but practically nothing is known about what vitamin K does in lymphocytes in the context of human nutrition, and such tests have never been validated to show anything important.

The appropriate way to test vitamin K status is to look at the carboxylation status of vitamin K-dependent proteins. These tests can be validated by showing that they respond to vitamin K depletion or supplementation and that they correlate with known health outcomes that respond in the same way. For example, the ability of the blood to clot reflects vitamin K status in the liver, where clotting factors are made; the carboxylation status of osteocalcin reflects vitamin K status in bone, where osteocalcin is made; and the carboxylation status of matrix Gla protein (MGP) reflects vitamin K status in blood vessels, where MGP is made.

Clotting disorders are life threatening and we have known about the role of vitamin K in this process for almost a century. As a result, a whole battery of tests for the different vitamin K-dependent clotting factors are readily available (for example, Ohishi, 2014). Vitamin K₁ is perfectly good at supporting the production of clotting factors, and since hemorrhage can be life-threatening, clotting factors will always get priority over a limited pool of vitamin K. Thus, most people consume enough vitamin K for their clotting factors to be fully carboxylated and these tests are not useful measures of whether vitamin K status is adequate to support its other functions in other tissues.

The most common marker of vitamin K status in research studies is the carboxylation status of osteocalcin, which reflects vitamin K status in bone. This test is only useful if the proportion of osteocalcin in the carboxylated and undercarboxylated forms can be measured. Unfortunately, this is not available outside of research studies. Quest offers total osteocalcin, but doesn’t measure its carboxylation status; Genova offers undercarboxylated osteocalcin, but doesn’t measure the total. One could “hack” its carboxylation status by getting both, but this would require each “half” of the correct marker to be measured from separate blood samples analyzed by separate laboratories, making the interpretation highly questionable. Were it available, we would still have to interpret it with caution, because, independent of vitamin K status, bone resorption decarboxylates osteocalcin and releases the undercarboxylated form into the bloodstream where it has beneficial hormonal roles, so it isn’t a black-and-white marker of vitamin K status.

The most promising marker of vitamin K status on the horizon is desphospho-uncarboxylated matrix Gla protein (dc-ucMGP), which reflects vitamin K status in blood vessels and the risk of soft tissue calcification. It’s just a matter of time before it becomes available.

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Hypothetical Side Effects of High-Dose Vitamin K

There are several aspects of vitamin K’s biochemistry that suggest high doses could have adverse effects on our health:

• Vitamins E and K are broken down in similar pathways (Shearer, 2008). High doses of either one elicit an increase in these catabolic pathways by activating a common receptor known as the steroid and xenobiotic receptor (SXR) or the pregnane X receptor (PXR). As a result, high doses of one will elicit the destruction of the other. Thus, high-dose vitamin K could contribute to vitamin E deficiency.
• Second, a small portion of vitamin K is broken down to a compound known as menadione (Thijssen, 2006). Some of the menadione is used to synthesize MK-4, but high concentrations are toxic. We therefore conjugate a portion of the menadione to glutathione, the master antioxidant and detoxifier of the cell, and excrete the complex into our urine. High doses of vitamin K could therefore deplete glutathione. This would impair detoxification, and along with vitamin E depletion it would hurt antioxidant activity.
• High doses of vitamin K can inhibit bone resorption, which is probably the mechanistic basis by which 45 mg/day reduce fracture risk (Iwamoto, 2013). While bone resorption sounds like a bad thing, we need to use it every day to help our bones remodel themselves and adapt their structures to our lifestyles, and to keep blood levels of calcium within a precisely controlled range. We also use bone resorption to release osteocalcin into the blood, where it acts on multiple tissues to improve our metabolic and hormonal health (Ferron, 2007; Oury, 2013). Ironically, one of the benefits of vitamin K₂ is to support proper production of osteocalcin, but high doses of the vitamin could hypothetically prevent us from using it. That would be expected to hurt blood sugar control, insulin sensitivity, our metabolic rate, and, in males, testosterone production.

Japanese trials using 45 mg/day MK-4 to treat osteoporosis have not established any risk of severe side effects (Iwamoto, 2013). Most of them, however, had between 20 and 120 subjects per group. One very large two-year trial with over 2,000 subjects per group (Inoue, 2009) reported 23 percent more adverse drug reactions in the MK-4 group than in the control group. The report did not include any description of what those side effects were, but confirmed that there was no difference in “serious” adverse effects or deaths.

Such high doses are pharmacological in nature and not nutritional. We should look at their costs and benefits in the same way we look at other pharmaceutical drugs. In this light, high-dose MK-4 is remarkably safe and effective. We nevertheless have hints that negative side effects of some sort occur when using extended pharmacological doses and we have several biochemical rationales for why high doses would cause harm. This provides a basis for caution in using doses outside of the nutritional range.

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