Originally published on April 30, 2009.
In the spring of 2007, Wise Traditions carried my article, “On the Trail of the Elusive X Factor,” in which I argued that the vitamin-like compound that Weston Price dubbed “Activator X” in the 1945 edition of Nutrition and Physical Degeneration was the very same nutrient researchers now call “vitamin K2.” Vitamin K2 is abundant in grass-fed animal fats and fermented foods, and promotes broad facial structure, healthy bones and teeth, a properly functioning nervous system, and robust cardiovascular health.
An accumulating body of research suggests that vitamin K2 may also protect against cancer.
A 2004 study published in the Journal of the American Medical Association showed that 45 milligrams per day (mg/day) of vitamin K2 in the MK-4 form could reduce the risk of liver cancer by 80 percent in twenty women with viral cirrhosis compared to twenty controls who received no treatment. Statistical adjustments for other factors that could affect the risk of cancer suggested that vitamin K2 could reduce this risk by just under 90 percent.
The women were randomly allotted to a treatment or control group, but the study was neither placebo-controlled nor double-blind, and it used a dose of vitamin K2 that is impossible to get from food. It therefore left open the question of whether vitamin K2-rich foods such as grass-fed liver, butter, cheese, and egg yolks could reduce the risk of cancer.
New research from the Heidelberg cohort of the European Prospective Investigation Into Cancer and Nutrition (EPIC-Heidelberg) suggests that vitamin K2 in amounts obtainable from natural foods does in fact protect against cancer. Analyses conducted in the Dutch PROSPECT cohort of this study expanded earlier findings of The Rotterdam Study by showing that vitamin K2, but not vitamin K1, is associated with a reduced risk of coronary calcification and heart disease. Analyses conducted in the German Heidelberg cohort of the study similarly found that vitamin K2, but not vitamin K1, is associated with a reduced risk of advanced prostate cancer. People who consumed more than 46 micrograms per day (mcg/day) at the beginning of the study were only half as likely to develop advanced prostate cancer over the following nine years as people who consumed less than 26 mcg/day.
The investigators also examined the relationship between undercarboxylated osteocalcin and the risk of adavanced prostate cancer. Osteocalcin is a protein made by bone, a small portion of which slips out into the blood. Vitamin K is required to “carboxylate” the protein, which is a form of activation that gives the protein the ability to bind calcium. When the vitamin K level of bone decreases, the amount of deformed, inactive, “undercarboxylated” osteocalcin in the blood increases. The percentage of serum osteocalcin that is in its activated state, then, is an indicator of the vitamin K status of bone and probably the extra-hepatic (non-liver) tissues in general. This is influenced to some degree by vitamin K1 status, but is influenced to a much greater extent by vitamin K2 status.
In the EPIC-Heidelberg cohort, in which the percentage of osteocalcin that is in its active form ranged from 80 to 89 percent, a 0.1-unit increase in the ratio of inactive to active osteocalcin was associated with a 38 percent increase in the risk of advanced prostate cancer.
There are three major insights we can obtain from the EPIC-Heidelberg data: first, vitamin K2 from foods may be much more powerful than synthetic vitamin K2 from supplements; second, vitamin K2 may protect against cancer through mechanisms that are independent from its classical role in protein carboxylation; and third, many segments of the population, especially growing children and postmenopausal women, are dangerously deficient in the all-important activator X.
Vitamin K2: Are Foods More Powerful Than Supplements?
In Japanese postmenopausal women, 1.5 milligrams per day (mg/day) of vitamin K2 in the MK-4 form is required to raise the percentage of serum osteocalcin that is in its active form from about 70 percent to just over 80 percent. This is a similar increase to the increase from 80 to 89 percent in the EPIC-Heidelberg cohort that was associated with about one-third lower risk of advanced prostate cancer, whereas a mere 20 mcg/day increase in vitamin K2 intake was associated with an even larger fifty percent decrease in risk. This 20 mcg/day dose is 75 times less than 1.5 mg/day.
Any attempt to explain this discrepancy is speculative. There are several reasons that could account for this difference. Postemenopausal women may have a higher vitamin K requirement than other members of the population. Supplemental MK-4 could be less effective at activating osteocalcin than other forms of vitamin K. The MK-7 form of vitamin K2 is three times more effective at activating serum osteocalcin than synthetic vitamin K1, but no one has yet compared either of these forms to MK-4. Any comparison between MK-7 and MK-4 would be confounded by the fact that MK-7 supplements are isolated from natural food sources while MK-4 supplements are synthetic. This brings us to the third possibility, that natural food sources of MK-4 are more powerful than synthetic MK-4 supplements. This is a possibility that cannot be ignored. Ultimately, we would like to see trials using K2-rich foods such as grass-fed liver, butter, cheese, egg yolks, and fermented foods such as natto, to increase the activation of osteocalcin or decrease the risk of prostate cancer.
Do the Unique Actions of MK-4 Protect Against Cancer?
Another reason the negative correlation between vitamin K2 intake and advanced prostate cancer may be stronger than the negative correlation with serum osteocalcin may be that the unique actions of MK-4 are responsible for the protective effect. Any vitamin K that reaches bone tissue will contribute to osteocalcin activation, but only a portion of the MK-7, K1, and other forms of vitamin K that reach the tissue will be converted to MK-4.
Recent experiments in isolated cells have shown that MK-4, but not MK-7 or vitamin K1, regulates gene expression like its partner vitamins A and D. By binding to its nuclear receptor, called the SXR, or by activating an enzyme called protein kinase A, MK-4 regulates the expression of dozens of genes, some of which are involved in regulating cellular growth and proliferation, two processes important in the development of cancer.
Both vitamin K1 and vitamin K2 in the MK-4 form inhibit the growth and proliferation of isolated cancer cells, but the concentrations required for K2 to be effective are five times lower than the concentrations required for K1 to be effective.
Since many animal cells can convert vitamin K1 to MK-4, this raises the possibility that any protective effect of vitamin K1 may be due to the portion of it that is converted to MK-4. Since vitamin K1 is preferentially delivered to the liver rather than to other tissues, this may be why vitamin K1 at doses found in the diet offers little if any protection against cancer.
The Widespread Deficiency of Activator X
Virtually everyone who does not supplement with vitamin K has at least some of their serum osteocalcin in the defective, undercarboxylated form. This suggests that most people have suboptimal vitamin K2 status, but it could always be argued that there is no need to have all of the osteocalcin activated.
The EPIC-Heidelberg study makes clear that 10-20 percent of serum osteocalcin in its inactive form indicates a state of deficiency.
Wisconsin adults have between 2 and 15 percent of their serum osteocalcin in its inactive form. The numbers for growing chilren, however, are much worse. Osteocalcin levels are much higher in children because the activty of growing bone is much higher. Consequently, the demand for vitamin K2 is much higher. In 11-year-old and 12-year-old Danish girls, undercarboxylated osteocalcin levels reach almost 60 percent. Over half the girls have levels over 20 percent. In children of ages 8 through 14 in Amsterdam, undercarboxylated osteocalcin ranged from 11 to 83 percent and increased during puberty. A small study in The Netherlands found average levels of 43 percent in adults and 67 percent in children, increasing during puberty from 64 percent to 73 percent.
Children are not at risk for most cancers, but the structure of our bodies becomes fixed in many ways during our growth and development, and the widespread severe deficiency of activator X during this period is likely to compromise long-term health for decades, even though demand for the vitamin will decline during adulthood.
Postmenopausal women, however, are at risk for developing cancer, and the numers are almost as frightening in this population as they are in children. In postmenopausal American women in the Framingham Offspring Study, for example, which did not account for whether anyone was supplementing with vitamin K, undercarboxylated osteocalcin ranged from zero to 91 percent, and averaged 17 percent.
One wonders whether vitamin K2 intake is associated with a reduced risk of breast cancer in the same way it is associated with a reduced risk of prostate cancer.
Interpreting Uncertainty Through the Lens of Traditional Diets
Correlation never implies causation. The mere fact that vitamin K2 intake and vitamin K status is associated with a reduced risk of prostate cancer does not in and of itself imply that vitamin K protects against prostate cancer. The fact that cell experiments and a human trial using large doses of vitamin K2 both show an anticarcinogenic effect of the vitamin, however, strengthens the hypothesis that foods rich in K2 do in fact protect against cancer.
Moreover, traditional diets were rich in vitamin K2 and appeared to afford protection against cancer. When Weston Price visited the Torres Strait Islands north of Austrailia, he spoke to a doctor who had suspected only one case of cancer and operated on none among more than 4,000 natives eating their traditional diet, but had operated on dozens of whites eating diets of refined foods living in the same area.
It should be humbling to us that these natives did not have any of the money, research methods, or medical equipment that we have, yet were far more successful at protecting themselves against cancer and other degenerative diseases than we are. What they did have was traditional wisdom accumulated over the ages — something to which our society offers little respect but nevertheless confirms over and over again with the tools of modern science. Those of us in the know can get ahead of the game by deferring to traditional wisdom here and now, and thus obtain protection from modern disease and support for longevity and vibrant health.
Read more about the author, Chris Masterjohn, PhD, here.