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Examining Vitamin K

by Brian Tanzer | June 1, 2011

The 1943 Nobel Prize in Physiology or Medicine was awarded to Danish biochemist Henrich Dam and Edward Doisy of St. Louis University for their characterization of vitamin K, so named because a lack of this vitamin causes a defect in blood koagulation. The letter K used to designate the vitamin is derived from the German word Koagulations vitamin.

Vitamin K is a fat-soluble vitamin. It is unique in that it can be produced in the body, but not specifically by body tissue; it is synthesized by gastrointestinal (GI) bacteria. The past 10 years has seen a significant increase in research and overall interest in this often-considered long forgotten and little-known vitamin. Early work on vitamin K focused mostly on its role in the blood-clotting process. More recent studies have focused on the vitamin’s role in cardiovascular and bone health.

Before reviewing some of this data, one must understand the different forms of vitamin K and how form and structure determine function and benefit/risk for disease.

Vitamin K1 vs. K2

Vitamin K1 (phylloquinone) is the form of vitamin K that is isolated from green plants (e.g. spinach and kale). The bacterially synthesized forms of the vitamin originally were called vitamin K2 and are now more appropriately designated as menaquinones. A wide range of menaquinones are synthesized by bacteria, but it is the long-chain menaquinones (MK-6-MK-10) that are the most common. Vitamin K2 can be synthesized by bacteria in the GI tract and is also found in fermented foods such as cheese, and Japanese natto (fermented soy).

In food supplements the three major forms of vitamin K are: MK-4 made via organic synthesis, K1 (also synthesized) and MK-7 (naturally derived via natto). Once absorbed, both K1 and K2 are incorporated into triglycerides with K1 being rapidly cleared by the liver and MK-7 being redistributed to the peripheral tissue via LDL.1 Due to the differences in chemical structure, the longer half-life (three days vs. one to two hours) and demonstrated sixfold Higher cofactor activity make a significant contribution to the greater overall biological activity of K2.2,3 It is vitamin K2 that is most utilized by peripheral tissues including bone, cartilage and soft tissue.

Cardiovascular Health Role of Calcium

Vitamin K2 seems to play a significant role in maintaining the proper balance of calcium within bone and arterial tissue.Studies demonstrate a relationship between cardiovascular disease (CVD) and osteoporosis; the common factor being calcium. Recognized by some as the “calcium paradox,” whereas a calcium deficiency may lead to a loss of bone density and eventual osteoporosis, an excess of calcium in the blood may increase the risk for atherosclerosis.

Role of Vitamin K

The landmark “Rotterdam Study” provided important data to support the role of vitamin K2 in cardiovascular health4— 4,800 healthy elderly subjects with the highest one-third of vitamin K2 intake had a 57 percent reduced risk of dying from CVD compared with those with the lowest intake. In addition, a 52 percent reduced risk of less vascular calcification and a reduced risk of death from
CVD. Vitamin K1 provided no significant cardiovascular protection!

In a recent meta-analysis of 15 randomized trials conducted over the last 20 years, researchers suggested that calcium supplements increase the risk of heart attack by About 30 percent.5 A critical factor to consider is the lack of any studies that included vitamin K intake as part of the meta-analysis. Why is this important?Vitamin K2 is essential for the carboxylation (activation) of matrix-Gla protein (MGP), which is one of the most potent inhibitors of vascular calcification and arterial plaque stabilization; its importance demonstrated by the fact that there seems to be no effective alternative mechanism for inhibition of vascular calcification.6 Early work in this area showed that when the MGP gene was deleted in mice, all died within six to eight weeks after birth as a result of severe calcification of the “elastic” components of the arteries causing them to rupture.7 In humans, a mutation in the MGP gene results in Keutel syndrome, an unusual disorder characterized by calcification of the aorta and coronary arteries.8 Both cardiovascular calcification and MGP activity are directly related to vitamin K2 intake.6,7

Research is currently underway to determine if and how vitamin K2 can be used to reduce the incidence and or progression of CVD. In addition, we must consider whether individuals with CVD should be maintained on a seemingly endless prescription for anticoagulation drugs (vitamin K antagonists) such as warfarin/Coumadin® when studies show an increased vascular calcification in patients on warfarin9, more severe aortic valve calcification in dialysis patients on long-term warfarin treatment10 and short-term, low-dose Marcoumar treatment.11 This class of drugs has also been shown to negatively impact bone health.

Bone Health

Besides calcium and vitamin D, vitamin K is essential for healthy bone structure.Similar to the activation of MGP in blood vessel walls, vitamin K is required for the carboxylation of bone-Gla or osteocalcin in the bone matrix. This protein is synthesized by osteoblasts (boneforming cells) and helps regulate the formation of bone tissue by helping calcium bind to the bone matrix.Undercarboxylated osteocalcin (uc OC) is a sensitive marker of vitamin K status whose circulating levels have been shown to increase in patients with osteoporosis, and correlate with risk of hip fracture.12,13

The first randomized controlled trial using vitamin K2 (as MK-7) demonstrated the effects of a median intake (45mcg/day) in healthy children.14 The Study showed that supplementation for eight weeks improves vitamin K status as indicated by reduced levels of ucOC and increased MK-7. In addition, blood coagulation parameters (prothrombin and thrombin potential) were also measured and found to remain constant over time in both the phylloquinone and menaquinine-7 group, demonstrating the safety of the dosage used with respect to blood coagulation.

Vitamin K2 as MK-4 has also been shown to support bone health in postmenopausal women without osteoporosis, but, at much higher/divided doses (15mg three times/day), likely due to its relatively short half-life (one to two hours).
In this study, 45mg/day of K2 as MK-4 for three years helped maintain bone mineral content and femoral neck width resulting in maintenance in calculated bone strength compared to placebo.15

Consumption of natto, fermented soybeans rich in MK-7, is associated with a higher bone density. This was found in both a population study and a smaller study of premenopausal women with a defective vitamin D receptor gene that made them more susceptible to bone loss.16,17

A meta-analysis of studies in the elderly population indicate that the positive effects of vitamin K supplementation on both bone mass and bone strength are related mostly to the vitamin’s ability to increase osteocalcin carboxylation (activation).18 The negative effects of anticoagulant drugs not only impact cardiovascular health, but bone health as well.Long-term use of anticoagulants is associated with an increased risk of osteoporotic fractures and, abnormalities in measures of bone calcification.19-21

The Future of Vitamin K

The synergistic effects of vitamins D and K and calcium have been demonstrated in numerous studies. Since these nutrients complement each other, taking one without the other can lead to potential health problems as recently demonstrated.5 With all the attention vitamin D has received, and rightfully so, supplementation of vitamin D has increased dramatically. The issue with that is when one has adequate calcium and vitamin D, but is deficient in vitamin K, the result may be an increase in vascular calcification and a decrease in bone mineral content. Clinical studies are ongoing to determine with greater accuracy and predictability the mechanisms whereby vitamin K exerts its biological effects, and how it interacts with And affects the activity of other nutrients.There is a significant amount of data to support vitamin K2 supplementation in healthy people. For those with preexisting cardiovascular and or bone disorders, the literature is also plentiful, but consultation with a health care provider should be considered before taking action.

References:

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

2 Schurgers L, Vermeer C. Determination of phylloquinone and menaquinones in food: effect of food matrix on circulating vitamin K concentrations.Haemostasis 2000;30:298-307.

3 Buitenhuis H, Soute B, Vermeer C. Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase. Biochim Biophys Acta 1990;1034:170-175.

4 Witteman et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study. J Nutr 2004;134:3100-3105.

5 Bolland MJ, Avenell A, Reid IA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. Br Med J 2010;341:c3691.

6 Schurgers L, Cranenburg E, Vermeer C. Matrix Gla-protein: The calcification inhibitor in need of Vitamin K. Thromb Haemost 2008;100:593-603.

7 Schurgers L et al. Regression of warfarininduced medial elastocalcinosis by high intake of vitamin K in rats. Blood 2007;109:2823-2831.

8 Weng L et al. Tracheobronchial stenosis in Keutel syndrome. Eur Respir J 2001;17:566-569.

9 Koos R et al. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol 2005;96:747-749.

10 Hopman W et al. Warfarin and aortic valve calcification in hemodialysis patients. J Nephrol 2007;20:417-422.

11 Janzen J et al. Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood 2004;104:3231-3232.

12 Delmas P et al. Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res 1994;9:1591-1595.

13 Vergnaud P et al. Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS study. J Clin Endocrinol Metab 1997;82:719-724.

14 Vermeer C et al. The effect of menaquinone-7 (vitamin K2) supplementation on osteocalcin carboxylation in healthy prepubertal children. Br J Nutr 2009;102:1171-1178.

15 Schurgers L, Vermeer C, Knapen M. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women.Osteoporos Int 2007;18:963-972.

16 Ikeda Y et al. Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. J Nutr 2006;136:1323-1328.

17 Katsuyama H et al. Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women. J Nutr Sci Vitaminol (Tokyo) 2002;48:207-215.

18 Cockayne S et al. Vitamin K and the prevention of fractures: systemic review and meta-analysis of randomized controlled trials. Arch Intern Med 2006;166:1256-1261.

19 Gage B et al. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 2006;166:241-246.

20 Booth S, Mayer J. Warfarin use and fracture risk. Nutr Rev 2000 Jan;58:20-22.

21 Philip W et al. Decreased axial and peripheral bone density in patients taking long-term warfarin.QJM 1995;88:635-640.

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