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Vitamin K2: Putting Calcium Where It Belongs

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.

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