Vitamin K2

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There is strong new evidence supporting Vitamin K2, making it an ingredient with untapped potential with applications in bone and cardivascular health. Also supporting evidence of its antioxidant properties:

Vitamin K2 provides major protection from osteoporosis, cardiovascular blockages and pathological calcification.

Vitamin K's job is to put calcium in the right places and keep it from being deposited in the wrong places. The right places are bones and blood, and the wrong places include calcification of the vessels, bone spurs and calcification of soft tissues.

Vitamin K: Its Relationship to the Optimal Tissue Distribution and Function of Calcium

It has been shown that calcium has a ubiquitous role in health, impacting on essentially all the Syndrome X conditions and diseases, which include obesity, blood pressure disorders, cardiovascular disease, diabetes, and malfunctioning of cell signaling. Calcification of the arteries is a major known consequence of aging, as is the calcification of soft tissues and the accumulation of calcium intracellularly (within the cells).

Optimum calcium nutrition depends on the interplay of a number of related compounds, such as magnesium, vitamin D3, and vitamin K. Just recently, the importance of vitamin K in regulating the healthy function of calcium has been recognized. It has been shown that vitamin K2 can be supplemented in very high doses, as used in Japan. It has been found to be safe even at 45 mg or more per day - up to a thousand times greater than generally occurring in the daily diet. Even small amounts of vitamins K1 & K2, as we will see, can have a great impact on overall health.

Vitamin K1 and more importantly, vitamin K2, play critical roles in preventing arterial calcification, which is a risk factor in coronary artery disease, as well as other calcification conditions associated with aging.

Vitamin K is actually a group name for related compounds, which all have a similar molecular structure (methylated naphthoquinone ring structure).

Vitamin K was discovered in the 1920's as a fat-soluble factor important in blood coagulation ("K" for koagulation). Vitamin K1 is found in plants and vitamin K2 is found in animals and bacteria, including beneficial probiotic bacteria, aka "good bacteria," from the GI tract. The body can store about a one-month supply of the vitamin. Antibiotics interfere with the growth of healthy intestinal bacteria and as a result, impair vitamin K production. The prescription anticoagulant Warfarin also interferes with the metabolism and function of vitamin K by inhibiting critical enzymes that are involved with the production of coagulation factors. Without these coagulation factors, excessive bleeding can occur.

How this vitamin is involved in blood coagulation eluded scientists until 1974, when a requirement for vitamin K was shown for the formation of numerous proteins in the body known as gamma-carboxy glutamic acid (GCGA) proteins. These proteins, when modified, specifically bind to calcium which is important for blood coagulation, as well as other critical processes, and through which calcium regulation affects cartilage, bone, protein in blood, and very importantly, regulates the calcium in the cardiovascular system. It appears that the extra carboxyl group binds calcium so that it can be moved around.

What Are GCGA Proteins?

Vitamin K works by acting as a cofactor in the carboxylation (adding of a carboxyl group C02) via an enzyme (gamma glutamyl carboxylase), of glutamic acid (a specific amino acid) to form a modification of that amino acid (gamma carboxyglutamic acid) in a variety of critical plasma proteins. Without this step, these plasma proteins will not function in their role of the regulation of calcium concentrations in various tissues.

There are several different types of GCGA proteins including: osteocalcin (OC), which is the most abundant GCGA protein in humans and is synthesized in bone; the GCGA protein containing blood coagulation factors are synthesized in the liver; the matrix GCGA proteins (MGP) are synthesized in the cartilage and in the vessel walls of arteries. 1

According to the Food and Nutrition Board of the National Academy of Sciences National Research Council, the requirements of vitamin K in micrograms (mcg) ranges from 5 micrograms for infants and up to 80 mcg for adult males and 65 mcg for adult females. 2

When vitamin K is in short supply in the body, these proteins are formed without
the GCGA component and are inactive for their intended functions - which play
important roles in four different tissue types including: 1) liver; 2) bone; 3)
cartilage; and 4) arterial vessel walls.

These four tissues are all able to pull vitamin K from the blood. However, the
uptake from the liver is much greater for K1 than for other tissues. Very
important recent findings indicate that vitamin K2, and not K1 inhibits
Warfarin-induced arterial calcification. This research is important for those
on Warfarin, and has implications for the majority of us who are unaware that
we are deficient in this lifesaving nutrient.

Because the liver needs so much vitamin K, this can leave the cartilage and bone
GCGA proteins with inadequate levels. Hence the dietary vitamin K requirement
for bone, and the special requirements for the cardiovascular system and
cartilage may not be met even though normal clotting factor production occurs,
as this occurs in the liver. Therefore, the requirement to keep the vasculature
clear of accumulating calcium and to keep the bones well supplied with calcium
may not be adequately supplied. This is why the recent discoveries on the value
of vitamin K2 and its recent commercial availability can make a great difference
in the lives of millions - probably a majority of the population would benefit.

The FDA's current recommendations for vitamin K dosage is based solely on the liver's requirements alone. It has been identified that a large percentage of the enzymes that do not receive GCGA because of a vitamin K1 or K2 deficiency, become unable to mobilize calcium and place it into the bone where it belongs. This GCGA-deficient enzyme is known as under-carboxylated osteocalcin (ucOC). It was found that this occurs in the majority of the healthy adult population indicating subclinical vitamin deficiency in a large portion of the population. 3,4 Though this is subclinical in terms of obvious symptoms, the first symptoms may be osteoporosis or acute coronary disease... the first symptom may even be death.

The results of a vitamin K intervention study have been examined in which both bone mineral density and vascular elasticity were shown to increase. 5 Other studies have demonstrated consistent findings adding to the conclusion that vitamin K1, and preferably, a good amount of vitamin K2, may be some of the best protection for preventing calcification of the arteries, and for protection against osteoporosis.

Oral anticoagulant medications such as Warfarin or Coumadin, etc., which are the most commonly used anticoagulants, are vitamin K antagonists. Vitamin K may lessen the concentration of the anticoagulants.

Scientific Studies

An excellent history and review of Vitamin K is offered in a number of scientific papers - one being Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age by Braam, Knapen, Geusens, Brouns, Hamulyak, Gerichhausen, and Vermeer, epub 2003. See below for more study results:

In 1984 it was found that patients with osteoporotic fractures had circulating vitamin K levels which were over 70% lower than those in the control group. 6 The data was consistent with other studies show ing that low serum vitamin K is associated with low mineral density, which is a high risk factor for bone fracture. 7-9

In analyzing British and American populations, it was found that they did not meet the RDA levels of 1.5 micrograms per day per kg of body weight (10-12) and that low intake is associated with low bone mineral density which is associated with risk of bone fracture.

In the Nurses Health Study, over 72,000 women between 38 and 63 years of age were followed for 10 years. The risk of fracture in the lower quintile for vitamin K intake almost doubled that in the higher quintile. 13

In the Framingham study of an older group of patients, with an average age of 75 years, the results were more dramatic. 14 Subjects in the highest quartile for vitamin K intake had a significantly lower hip fracture risk. 15

Hence the critical involvement of vitamin K in bone health and its general deficiency in our population is firmly established.

Vitamin K Supplementation Retards Postmenopausal Bone Loss

In the Maastricht osteo study, 188 postmenopausal women between 50 and 60 years
old were treated for 3 years with daily supplements. 16 There was a placebo
group which received only maltodextrin and the second group received minerals,
500 mg/day of calcium, 150 mg/day of magnesium, 10 mg/day of zinc and 320
IU/day of vitamin D3. The third group received these minerals plus the vitamin
D3 and l mg/day of vitamin K1. The group without vitamin K benefited only
transiently. In the group with vitamin K, bone loss at the femoral neck was
retarded by 35%-40% compared to the other mineral vitamin D group. It is stated
that if these effects continued over decades, lifelong supplementation could
postpone fractures by up to 10 years.

Further research of the D-Bavis study using calcium (1000 mg), vitamin D (10 ug)
and vitamin K (200 mcg) per day, supported the previous findings. They also
found a significant increase in bone mineral content and density in the vitamin
K group. 17

The authors concluded that combined supplementation with vitamin K1 and D3 at
dietary relevant levels improved bone mass density at the trabecular bone site
and that the equivalent supplementation in high osteoporotic risk groups may be
beneficial. Extremely high doses 45-90 mg/day of vitamin K2 are successfully
used in the treatment of osteoporosis in Japan. 18-20 These doses of K2 exceed
RDA levels by 1000 fold and no side effects were noted.

Low Vitamin K Intake as a Risk Factor for Cardiovascular Disease

256 postmenopausal women were studied by Jie, et. al. in the EPOZ study. They
found an inverse correlation between long term vitamin K intake and
arterosclerotic aorta calcification. 21 Only vitamin K1 (phylloquinone) was
included in the study.

A subsequent study of 4500 participants of the Rotterdam study by Gelejinse, et.
al. reports a much stronger negative correlation between long term, lower than
adequate intake of vitamin K2 (menaquinone) and aortic calcification. The data
was stronger for K2 than for K1. This is consistent with the suggestion of
preferential uptake of K2 by the vessel wall. 22

Vitamin K Supplementation Prevents Age Related Vascular Stiffening

In an animal study in rabbits with high cholesterol, vitamin K2 was shown to
decrease circulating cholesterol concentrations, suppress progression of
vascular plaque, thickening in the vessels, and pulmonary atherosclerosis. 23
In a study of rats on arterial calcification, vitamin K2 completely prevented
calcification, whereas vitamin K1 had little effect. 24 A three year study
involving postmenopausal women (a group which is generally known to be at risk
for vascular illness), the elastic properties of the carotid artery were
recorded using ultrasound. A supplement of 1 mg/day of vitamin K1 completely
abolished age-related arterial stiffening, whereas the placebo group showed a
decrease of 13% of elastic properties of the vasculature during the test
period. 25

Dietary & Supplemental Forms of Vitamin K1 & K2

Most of our dietary vitamin K1 comes from vegetables - about 80%. Vitamin K2 is
obtained mainly from the "good" bacteria produced in the digestive tract and is
also found in certain fermented foods. 26 The absorbability of the vitamin K2
from the GI tract bacteria is uncertain. 27 The absorption of vitamin K1 from
vegetables is about 10%.

"However, both K1 and K2 are well absorbed from supplements as long as they are
taken with some dietary fat to stimulate bile secretion." 28

Recommendations of a European Expert Group

In November 2002, a number of European experts in the fields of vitamin K
research, bone metabolism and cardiovascular disease met to review all the
available scientific data to formulate an opinion on the amount of recommended
dietary vitamin K and the use of vitamin K-containing supplements, for optimal
bone and vascular health. Some of the conclusions from this meeting are
summarized below:

Daily intake of between 200 and 500 mcg/day of vitamin K through food sources
may be required for optimal health.

Accumulating evidence suggests there is a synergistic effect between vitamins K,
D and calcium (and of course, magnesium). Optimal health effects may be obtained
from combined supplementation of vitamins K, D and minerals.

Any risks associated with high consumption of either vitamin K1 or K2 appear
minimal, with intakes up to 1 mg/day of vitamin K1 and 45 mg/day of vitamin K2,
often having been used with no observed side effects.

The only potential problem with high levels of vitamin K supplementation relates
to interference with oral anticoagulant medications such as Warfarin and
Coumadin, which are antagonists of vitamin K. Patients on oral anticoagulant
treatment should not use vitamin K supplements and avoid strong fluctuations in
their daily dietary vitamin K intake. However, in a systematic dose-response
study of patients on oral anticoagulant therapy, it was demonstrated that the
stability of anticoagulation was not significantly affected by vitamin K
supplementation at doses below 150 mcg/day. 30 Patients on anticoagulant
medications should consult with their physician or healthcare practitioner
regarding vitamin K.

Other Benefits of Vitamin K

We have discussed the beneficial effects of vitamin K on bone density,
cardiovascular health, and the Syndrome X diseases, however, there are even
more benefits to vitamin K supplementation.

Anti-Inflammatory

Further research has demonstrated vitamin K's anti-inflammatory action. As the
body ages, levels of the inflammation-promoting cytokine interleukin-6 (IL-6)
increase. Once IL-6 becomes out of ba lance with the other cytokines,
inflammation accelerates. It has been observed that people with arthritis,
Alzheimer's disease, and atherosclerosis have higher levels of IL-6. In a study
done by the National Research Institute in Italy, it was shown that subjects
with the highest levels of IL-6 were almost twice as likely to develop
mobility-related disabilities.

Diabetes

The second highest concentration of vitamin K in the body is in the pancreas,
which plays a major role in blood sugar and insulin regulation. In animal
studies, Japanese researchers found that when they induced vitamin K
deficiency, the test animals developed Type II diabetes. 31

Antioxidant

Research has indicated that vitamin K has antioxidant activity comparable to
vitamin E and CoQ10. 32,33 Animal studies have demonstrated complete hepatic
(liver) protection from induced oxida tive stress using vitamin K, and was
found to be 80% as effective as vitamin E in preventing oxidation.

Alzheimer's

About 25% of the population have a genetic predisposition for developing
Alzheimer's disease - they carry the E4 form of the lipoprotein apoE.
Interestingly, people who carry this gene have been found to have low levels of
vitamin K. Calcification and the development of lesions in blood vessels that
feed the brain tissues are believed to be a component of Alzheimer's
development. Further research may reveal high-dose vitamin K therapy to be
preventive.

Japanese Study on Vitamin K2 & Viral Cirrhosis-Related Liver Cancer

Japanese researchers have recently discovered that vitamin K2 may play a
significant role in prevention of liver cancer caused by viral cirrhosis. In a
2004 study published in the Journal of the American Medical Association, 40
women diagnosed with viral liver cirrhosis were studied, in which 21 were given
45 mg vitamin K2 per day. Vitamin K2 was found to decrease the risk of the
development of liver cancer in female patients with viral cirrhosis, possibly
by delaying the onset of the cancer. 34 For over seven years, the patient's
progress was closely followed. The proportion of patients who developed liver
cancer was significantly smaller in the group of women treated with the vitamin
K2 (2 of 21), compared to the non-treated group (9 of 19). The annual incidence
of liver cancer in the treated group was 1.6%, compared to the non-treated
group, which was 8.8%. The researchers believe that a substance called
geranyl-geraniol (a by-product of vitamin K2), induces cell death in tumor
cells suggesting that it may play an important role in cell growth inhibition.
The researchers wrote, "The study indicates that vitamin K2 decreases the risk
of liver cancer to about 20% compared to the control group." The researchers
also commented that these are only preliminary results and further research
needs to be done through clinical trials.

Vitamin K2 References:

1. Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of
K-vitamins in healthy subjects. Biochim Biophys Acta. 2002 Feb
15;1570(1):27-32.

2. Kelleys Textbook of Internal Medicine, Fourth Edition, 2000, Lippincott,
Williams and Wilkins, Philadelphia, PA.

3. Knapen MH, Jie KS, Hamulyak K, Vermeer C. Vitamin K-induced changes in
markers for osteoblast activity and urinary calcium loss. Calcif Tissue Int.
1993 Aug;53(2):81-5.

4. Booth SL, Sokoll LJ, O'Brien ME, Tucker K, Dawson-Hughes B, Sadowski JA.
Assessment of dietary phylloquinone intake and vitamin K status in
postmenopausal women. Eur J Clin Nutr. 1995 Nov;49(11):832-41.

5. Vermeer C, Braam L, Schurgers L, Brouns F. Agro-Food Industry Hi-Tech 2002,
13:11-15.

6. Hart JP, Catterall A, Dodds RA, Klenerman L, Shearer MJ, Bitensky L, Chayen
J. Lancet ii 283 (1984).

7. Hart JP, Shearer MJ, Klenerman L, Catterall A, Reeve J, Sambrook PN, Dodds
RA, Bitensky L, Chayen J. Electrochemical detection of depressed circulating
levels of vitamin K1 in osteoporosis. J Clin Endocrinol Metab. 1985
Jun;60(6):1268-9.

8. Hodges SJ, Pilkington MJ, Stamp TC, Catterall A, Shearer MJ, Bitensky L,
Chayen J. Depressed levels of circulating menaquinones in patients with
osteoporotic fractures of the spine and femoral neck. Bone. 1991;12(6):387-9.

9. Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD. Circulating levels of
vitamins K1 and K2 decreased in elderly women with hip fracture. J Bone Miner
Res. 1993 Oct;8(10):1241-5.

10. Booth SL, Pennington JA, Sadowski JA. Food sources and dietary intakes of
vitamin K-1 (phylloquinone) in the American diet: data from the FDA Total Diet
Study. J Am Diet Assoc. 1996 Feb;96(2):149-54.

11. Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr. 1998
May;128(5):785-8.

12. Thane CW, Paul AA, Bates CJ, Bolton-Smith C, Prentice A, Shearer MJ. Intake
and sources of phylloquinone (vitamin K1): variation with socio-demographic and
lifestyle factors in a national sample of British elderly people. Br J Nutr.
2002 Jun;87(6):605-13.

13. Feskanich D, Weber P, Willett WC, Rockett H, Booth SL, Colditz GA. Vitamin K
intake and hip fractures in women: a prospective study. Am J Clin Nutr. 1999
Jan;69(1):74-9.

14. Booth SL, Broe KE, Gagnon DR, Tucker KL, Hannan MT, McLean RR, Dawson-Hughes
B, Wilson PW, Cupples LA, Kiel DP. Vitamin K intake and bone mineral density in
women and men. Am J Clin Nutr. 2003 Feb;77(2):512-6.

15. Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, Wilson PW,
Ordovas J, Schaefer EJ, Dawson-Hughes B, Kiel DP. Dietary vitamin K intakes are
associated with hip fracture but not with bone mineral density in elderly men
and women. Am J Clin Nutr. 2000 May;71(5):1201-8.

16. Braam LAJLM, Knapen MHJ, Geusens P, Brouns F, Hamulyak K, Gerichhausen MJW,
Vermeer C. Vitamin K1 supplementation retards bone loss in postmenopausal women
between 50 and 60 years of age. Calcif. Tissue Int. 72, epub (2003).

17. Bolton-Smith C, Mole PA, McMurdo MET, Paterson CR, Shearer MJ. Ann. Nutr.
Metab. 45 Suppl. 1 246 (2001).

18. Orimo H, Shiraki M, Tomita A, Morii H, Fujita T, Ohata M. J. Bone Miner.
Metab. 16:106-112, 1998.

19. Shiraki M, Shiraki Y, Aoki C, Miura M. Vitamin K2 (menatetrenone)
effectively prevents fractures and sustains lumbar bone mineral density in
osteoporosis. J Bone Miner Res. 2000 Mar;15(3):515-21.

20. Iwamoto J, Takeda T, Ichimura S. Effect of menatetrenone on bone mineral
density and incidence of vertebral fractures in postmenopausal women with
osteoporosis: a comparison with the effect of etidronate. J Orthop Sci.
2001;6(6):487-92.

21. Jie KS, Bots ML, Vermeer C, Witteman JC, Grobbee DE. Vitamin K intake and
osteocalcin levels in women with and without aortic atherosclerosis: a
population-based study. Atherosclerosis. 1995 Jul;116(1):117-23.

22. Geleijnse JM, Vermeer C, Schurgers LJ, Grobbee DE, Pols HAP, Witteman JCM.
Thromb. Haemostas. (Suppl July) P473, 2001.

23. Kawashima H, Nakajima Y, Matubara Y, Nakanowatari J, Fukuta T, Mizuno S,
Takahashi S, Tajima T, Nakamura T. Effects of vitamin K2 (menatetrenone) on
atherosclerosis and blood coagulation in hypercholesterolemic rabbits. Jpn J
Pharmacol. 1997 Oct;75(2):135-43.

24. Spronk HM, Soute BA, Schurgers LJ, Thijssen HH, De Mey JG, Vermeer C.
Tissue-specific utilization of menaquinone-4 results in the prevention of
arterial calcification in warfarin-treated rats. J Vasc Res. 2003
Nov-Dec;40(6):531-7. Epub 2003 Dec 3.

25. Braam LAJLM. Thesis, Maastricht ISBN 90-5681-145-2, 2002.

26. Schurgers LJ, Vermeer C. Determination of phylloquinone and menaquinones in
food. Effect of food matrix on circulating vitamin K concentrations.
Haemostasis. 2000 Nov-Dec;30(6):298-307.

27. Ronden JE, Drittij-Reijnders MJ, Vermeer C, Thijssen HH. Intestinal flora is
not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat.
Biochim Biophys Acta. 1998 Jan 8;1379(1):69-75.

28. Vermeer C, Braam L, Knapen M and Schurgers L; Vitamin K supplementation: a
simple way to improve vascular health. Agr Food Industry hi Tech Nov 2003.

29. Vermeer C, Shearer MJ, Zittermann A, Bolton-Smith C, Szulc P, Hodges S,
Walter P, Rambeck W, Stocklin E, Weber P. Beyond deficiency: potential benefits
of increased intakes of vitamin K for bone and vascular health. Eur J Nutr. 2004
Dec;43(6):325-35. Epub 2004 Feb 5.

30. Schurgers LJ. Thesis, Maastricht ISBN 90-5681-138-X, 2002.

31. Sakamoto N, Wakabayashi I, Sakamoto K. Low vitamin K intake effects on
glucose tolerance in rats. Int J Vitam Nutr Res. 1999 Jan;69(1):27-31.

32. Mukai K, Itoh S, Morimoto H. Stopped-flow kinetic study of vitamin E
regeneration reaction with biological hydroquinones (reduced forms of
ubiquinone, vitamin K, and tocopherolquinone) in solution. J Biol Chem. 1992
Nov 5;267(31):22277-81.

33. Mukai K, Morimoto H, Kikuchi S, Nagaoka S. Kinetic study of
free-radical-scavenging action of biological hydroquinones (reduced forms of
ubiquinone, vitamin K and tocopherol quinone) in solution. Biochim Biophys
Acta. 1993 Jul 11;1157(3):313-7.

34. Habu D, Shiomi S, Tamori A, Takeda T, Tanaka T, Kubo S, Nishiguchi S. Role
of vitamin K2 in the development of hepatocellular carcinoma in women with
viral cirrhosis of the liver. JAMA, 2004 Jul 21;292(3):358-61.