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The Emerging Role of Vitamin K2

Manouchehr Saljoughian, PharmD, PhD
Department of Pharmacy,
Alta Bates Summit Medical Center,
Berkeley, California



1/20/2012
US Pharm. 2012;37(1):HS-12-HS-14.  

Vitamin K refers to a group of fat-soluble vitamins with similar chemical structures that are needed for blood coagulation. Research over the last few decades has shown a new and emerging role for this vitamin in treating osteoporosis and cardiovascular diseases. Other new and exciting applications for this vitamin have been found in treating Alzheimer’s disease, skin aging, and a variety of cancers. This vitamin was discovered in the 1920s and was called “K” for koagulation due to its role in blood coagulation.1 Unfortunately, many people are not aware of the health benefits of vitamin K. The K vitamins have been underrated and misunderstood until very recently by both the scientific community and the general public.

Although the effect of magnesium and vitamin D3 on calcium metabolism was previously known, the importance of vitamin K in regulating the healthy function of calcium has only recently been recognized.2 Vitamin K has now been found to have a role in putting calcium in the right places in the body, such as in the bones and blood, and preventing pathologic calcification of the vessels and soft tissues.2

There are three different types of vitamin K: K1, which is found in plants; K2, which is made by bacteria or fermentation; and K3, which is synthetic and, because of the generation of free radicals, is considered toxic. All members of the vitamin K group share a methylated naphthoquinone ring structure and vary in the aliphatic side chain attached at the 3-position. Although these vitamins share a major physiological role, each has other distinct physiological properties. Interestingly, the body is able to convert vitamin K1 to the more active K2.2

Unlike other fat-soluble vitamins (A, D, and E), the body does not store vitamin K. It is recycled by the body but not in significant amounts, and therefore deficiencies are common.3 This is probably due to inadequate dietary intake, lack of cofactors, prescription drugs, and environmental stressors that place high demands on the body’s vitamin K reserves.

Vitamin K Vitamers

Vitamin K1 Phytonadione: This vitamin is the natural form of vitamin K, which is found in plants and provides the primary source of vitamin K to humans through dietary consumption. Vitamin K1 is a yellow, viscous oil and is soluble in vegetable oils. Vitamin K1 is also called phylloquinone since it is an indirect product of photosynthesis in plant leaves, where it occurs in chloroplasts and participates in the overall photosynthetic process. Interestingly, vitamin K1 is sensitive to sunlight (destroyed after 1 hour). It is unaffected by diluted acids but is destroyed by basic solution and transformed by reducing agents. The absorption of vitamin K1 from servings of green vegetables ranging from 200 to 400 g without added fat is only between 5% and 10%.3 The oral recommended dietary allowance ranges from 90 to 120 mcg/day. The oral bone preservation dose is 10 mg/day.

Although the oral route is the safest way to use this vitamin, subcutaneous use is the preferred parenteral route. The intramuscular (IM) route should be avoided due to the risk of hematoma formation, and the IV route should be reserved for emergency use only. The American College of Chest Physicians recommends the IV route in patients with serious or life-threatening bleeding secondary to the use of vitamin K antagonists such as warfarin.

Vitamin K2 (Menaquinone): By far the most important form of vitamin K is K2. Vitamin K2 has several isoforms or analogues called MK-4 to MK-10. Mammals can synthesize K2 MK-4 from K1 to some degree, so dietary K1 and other forms of vitamin K may contribute to K2 MK-4 status. K2 MK-4 is the most active isoform. This vitamin provides major protection from osteoporosis and pathologic calcification. Calcification of the arteries and soft tissues is a major known consequence of aging. Vitamin K2 is found in animals and bacteria, including beneficial probiotic bacteria from the gastrointestinal (GI) tract. Antibiotics interfere with normal growth of healthy bacteria and impact vitamin K2 production.4

It is generally believed that humans require preformed K2 in the diet to obtain optimal health. This is also supported by feeding experiments. The absorption of vitamin K2 from natto, a fermented soy food, is nearly complete.

In a Japanese research study, 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. The researchers believe that a substance called geranyl-geraniol (a byproduct of vitamin K2) induces cell death in tumor cells, suggesting that it may play an important role in cell-growth inhibition. The study indicated that vitamin K2 decreased the risk of liver cancer to about 20% compared to the control group.5

Vitamin K supplementation delays postmenopausal bone loss. High doses of Vitamin K2 (45-90 mg/day) in combination with vitamin D3 (320 IU/day) and calcium (500 mg/day) in postmenopausal women between 50 and 60 years reduced bone loss at the femoral neck by 35% to 40% compared to a control group. This happened in a period of 3 years. It is stated that if these effects continued over decades, lifelong supplementation could postpone fractures by up to 10 years.6

The combined supplementation of vitamin K2 and D3 and calcium at dietary relevant levels also improved bone mass density at the trabecular bone and indicated that the equivalent supplementation in patients with osteoporosis may be beneficial.6 The oral osteoporosis treatment dose is 45 mg of vitamin K2 daily.6

Although vitamin D3 has been known as the bone vitamin because it puts the osteocalcin gene into action and acts swiftly on bones, the slower acting vitamin K2 has been recognized as being just as important for bone maintenance. The human skeleton is fully replaced every 8 to 10 years with good, dense bones, and these two vitamins have a big role in the process.

Mylodysplastic syndromes (MDS) is a disorder related to leukemia, but unlike leukemia, MDS cells can be induced to develop into mature normal cells, and that is where vitamin K shows its role. Vitamin K treatment of bone marrow cells from patients with MDS strongly induces apoptosis of the diseased cells. Vitamin K2 also induces MDS cells to differentiate into healthy white blood cells, even when full-blown leukemia has developed. The combination of vitamin K2 and vitamin D3 achieved good differentiation in a laboratory study of leukemic cells, suggesting that it might be effective therapy for both MDS and leukemia. The oral dose for MDS is 45 to 90 mg of vitamin K2 analogue MK-4 daily.7

Vitamin K3 (Menadione): Vitamin K3 (2-methyl-1,4-naphthoquinone) is a structural precursor of vitamins K1 and K2, which are essential for blood clotting. Menadione is a synthetic chemical compound sometimes used as a nutritional supplement because of its vitamin K activity. Despite the fact that it can serve as a precursor to various types of vitamin K, menadione is generally not used as a nutritional supplement in economically developed countries. Menadione for human use at pharmaceutical strength is available in some countries with large lower income populations. Large doses of menadione have been reported to cause adverse outcomes including hemolytic anemia due to deficiency of the G6PD enzyme, neonatal brain or liver damage, or neonatal death in some rare cases. In the United States, menadione supplements are banned by the FDA because of their potential toxicity.8

Conversion of Vitamin K1 to K2

The ability to convert vitamin K1 to K2 varies widely between species and breeds of animals. Vitamins K1 and K2 chemically share a common ring-structured nucleus but possess different types of side chains. The first step in the conversion of K1 to K2 appears to be the cleavage of its side chain in either the liver or the GI tract, yielding vitamin K3 or menadione; much of this metabolite is detoxified by the liver and excreted in the urine, while the remaining portion can be used to synthesize K2 in tissues.

Humans require dietary preformed vitamin K2 for optimal health, due to its superiority over K1. Vitamin K2 is at least three times more effective than vitamin K1 at activating proteins related to skeletal metabolism. While intake of vitamin K2 is inversely associated with heart disease in humans, intake of vitamin K1 is not. This nutritional superiority makes it clear why it is important to use food rich in vitamin K2 like the organs and fats of grass-fed animals and the deeply colored orange butter from animals grazing on rich pastures.9

Mode of Action

Vitamin K is necessary for normal clotting of blood in humans. Specifically, vitamin K is required for the liver to make several factors that are necessary for blood to properly clot. Vitamin K2 works by acting as a cofactor in the carboxylation of glutamic acid via an enzyme (gamma glutamyl carboxylate) to form a modified form of glutamic acid called gamma carboxyglutamic acid (GCGA) in a variety of critical plasma proteins. Without this step, the regulation of calcium concentration will be affected in various tissues.10

There are a number of different forms of GCGA proteins: osteocalcin is the most abundant GCGA protein and is synthesized in bones; the blood-clotting factors are synthesized in liver; and the matrix proteins are synthesized in the cartilage and in the vessel walls of arteries. Without vitamin K, these proteins are inactive for their intended functions.

These four organs (bones, liver, cartilage, and arterial walls) are able to pull vitamin K from the blood. However, the liver will uptake more vitamin K than the other organs to make clotting factors and leave cartilage and bones with inadequate levels of GCGA proteins. To keep the vasculature clear of accumulating calcium and the bones well supplied with calcium, supplemental vitamin K is necessary. It has been identified that enzymes without the GCGA component are unable to mobilize calcium and place it into the bone where it belongs. The subclinical vitamin K deficiency in a large portion of the population will lead to symptoms of osteoporosis and acute coronary disease.10

The FDA’s current recommendations for vitamin K dosage are based solely on the liver’s requirement alone. The requirements of vitamin K range from 5 mcg for infants up to 120 mcg for adult males and 90 mcg for adult females per day. Several research projects have demonstrated that vitamin K1, and especially vitamin K2, may provide some of the best protection against calcification of the arteries and osteoporosis.

A unique mechanism of vitamin K’s activity is so-called oncosis, a form of stress-activated ischemic cell death to which tumor cells are particularly susceptible. Because of their high growth rate, tumor cells consume large amounts of glucose. They then quickly outgrow their blood supplies and, due to this high metabolism, use up oxygen rapidly, leaving them especially vulnerable to oxidative stress. Vitamin K2 targets tumor cells for destruction by stimulating oxidative stress, without toxicity to healthy tissues.11

Antagonists

Warfarin is a blood-thinning drug that functions by inhibiting vitamin K–dependent clotting factors. Warfarin is prescribed for people with various heart conditions such as atrial fibrillation, artificial heart valves, clotting disorders (hypercoagulability), or placement of indwelling catheters/ports. Usually, blood tests must be done regularly to evaluate the extent of blood thinning, using a test for prothrombin time (PT) or international normalized ratio (INR). Vitamin K can decrease the blood-thinning effects of warfarin and will therefore lower the PT or INR value. This may increase the risk of clotting.12

People taking warfarin are usually warned to avoid foods with high vitamin K1 content (such as green leafy vegetables) and to avoid vitamin K1 supplements. Conversely, vitamin K1 is used to treat overdoses or excess anticoagulant effects of warfarin and to reverse the effects of warfarin prior to surgery or other procedures. Because the effects of warfarin on anticoagulation are usually delayed by several days, the PT/INR may not increase immediately at the time of overdose. If a patient’s blood becomes too thin, the person should be placed under strict medical supervision and may use oral or injected vitamin K1 to help reverse the effects of warfarin. The anticoagulation reversal dose is one dose of 2.5 mg of vitamin K1 followed by immediate reevaluation.13

REFERENCES

1. Shepherd AJ. An overview of osteoporosis. Altern Ther Health Med. 2004;10:26-33.
2. Bugel S. Vitamin K and bone health in adult humans. Vitam Horm. 2008;78:393-416.
3. Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008;100(4):530-547.
4. Beulens JW, Bots ML, Atsma F, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009;203:489-493.
5. Kakizaki S, Sohara N, Sato K, et al. Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection. J Gastroenterol Hepatol. 2007;22(4):518-522.
6. Bolton-Smith C, McMurdo ME, Paterson CR, et al. Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. J Bone Miner Res. 2007;22(4):509-519.
7. Abe Y, Muta K, Hirase N, et al. Vitamin K2 therapy for mylodysplastic syndrome. Rinsho Ketsueki [in Japanese]. 2002;43(2):117-121.
8. Shukla S, Wu CP, Nandigama K, et al. The naphthoquinones, vitamin K3 and its structural analog plumbagin, are substrates of the multidrug resistance-linked ABC drug transporter ABCG2. Mol Cancer Ther. 2007;6(12, pt 1):3279-3286.
9. Okano T, Shimomura Y, Yamane M, et al. Conversion of phylloquinone into menaquinone-4 in mice, J Biol Chem. 2008;283:11270-11279.
10. Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamin in healthy subjects. Biochem Biophys Acta. 2002;1570(1):27-32.
11. Verrax J, Taper H, Buc Calderon P.  Targeting cancer cells by an oxidant-based therapy. Curr Mol Pharmacol. 2008;1(1):80-92.
12. Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr. 1998;128(5):785-788.
13. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:160S-198S.

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