Vitamin K, a fat-soluble vitamin, was first known for its essential role in the functioning of several proteins involved in blood clotting or coagulation (which is important to prevent excessive bleeding after an injury).1 In fact, the “K” in vitamin K is derived from the German word “koagulation.” Now, vitamin K is understood to offer additional benefits, including its role delivering vitamin-K dependent proteins, which are necessary for bone mineralization (e.g., helping to keep calcium in the bone).2
The two naturally occurring forms of vitamin K are K1 and K2. Plants synthesize phylloquinone, which is also known as vitamin K1. Friendly intestinal bacteria synthesize a range of vitamin K2 forms collectively referred to as menaquinones.3 The menaquinone form of vitamin K2 will be designated according to the number of repeating five-carbon units in the side chain of the molecule. For example, if there are seven repeating five-carbon units, the designation will be menaquinone-7, or MK-7. These two forms of vitamin K have different benefits to offer for human health, apparently with K2 offering the greater range of benefits.
Vitamin K Deficiency
Adults at risk of vitamin K deficiency include those taking vitamin K antagonist anticoagulant drugs and individuals with significant liver damage or disease.4 Additionally, individuals with disorders of fat malabsorption may be at increased risk of vitamin K deficiency.5 Symptoms of deficiency include easy bruising and bleeding. This may occur as nosebleeds, bleeding gums, blood in the urine, blood in the stool, tarry black stools or extremely heavy menstrual Bleeding. Vitamin K deficiency in infants may result in life-threatening bleeding within the skull.4
The daily value for vitamin K is 80 mcg. Of course, daily value is a one-size-fitsall measurement or “adults and children 4 or more years of age,” so it lacks accuracy. This is different from the adequate intake (AI) level for vitamin K established by the Food and Nutrition Board of the Institute of Medicine established. The AI for men 19 or more years of age is 120 mcg/day, and 90 mcg/day for women. However, in some of the studies about to be presented, significantly higher doses of 45 mg have been used, which is about 500 times higher than the AI for vitamin K.
Nevertheless, there is no known toxicity associated with high doses of the vitamin K1 or K2 (although the same is not true for synthetic vitamin K3, menadione). Consequently, no tolerable upper level (UL) of intake has been established for vitamin K1 or K2.6
Regardless of dose, vitamin K antagonizes the effects of oral anticoagulants such as warfarin (Coumadin), and should not be used concurrently with this medication.
Osteocalcin and matrix Gla protein (MGP) are vitamin-K dependent proteins that have been isolated in bone. Osteocalcin is a protein synthesized by osteoblasts, and is thought to be related to bone mineralization. MGP has been found in bone, cartilage and soft tissue, including blood vessels. Research suggests MGP prevents the calcification of soft tissue and cartilage, while facilitating normal bone growth and development.7-9
Various clinical trials in women have reported that 45 mg of vitamin K2 daily improved bone mineral density (BMD), significantly reduced bone loss, reduced the risk of fracture and improved measures of bone strength.10-13 Likewise, in a meta-analysis of seven Japanese randomized controlled trials, vitamin K2 supplementation was associated increased BMD and a statistically significant reduction in fracture incidence. Specifically, supplementation lowered risk for vertebral fractures by 60 percent, hip fractures by 77 percent and non-vertebral fractures by 81 percent; all associations were statistically significant.14 The daily dose used in six of the trials was 45 mg, while one of the trials used 15 mg. While these are very high doses of vitamin K2, a more recent study has demonstrated efficacy for bone health at a significantly lower dose.
In a three-year study15, 244 healthy postmenopausal women received a daily dose of 180 mcg of vitamin K2 as MK-7, or a placebo. Compared to placebo, vitamin K2 significantly decreased the age-related decline in bone mineral content and BMD at the lumbar spine and femoral neck. Bone strength was also favorably affected by K2. In addition, K2 significantly decreased the loss in vertebral height.
Calcification of atherosclerotic plaques occurs as the condition progresses (i.e., like cementing in the plaque). This results in decreased elasticity of the blood vessels and increases the risk of clot formation, which is the usual cause of a heart attack or stroke. Vitamin Kdependent proteins have been shown to inhibit vascular calcification, and so are thought to promote cardiovascular health. In a population-based study16, 4,807 subjects were analyzed for their vitamin K intake as well as other risk factors for poor cardiovascular health. The results showed that the relative risk for poor cardiovascular health was significantly reduced, as was severe aortic calcification with vitamin K2 intake (but not with vitamin K1).
In a cross-sectional study17 among 564 post-menopausal women, 62 percent with coronary calcification, higher dietary intake of vitamin K2 (but not vitamin K1) was associated with a reduced risk of coronary calcification. In addition, preliminary clinical evidence18 indicates that 45 mg/day vitamin K2 helped significantly lower cholesterol levels in patients on continuous ambulatory peritoneal dialysis after three months, lending further credence to this nutrient’s role in cardiovascular health.
Another vitamin K-dependent protein, Gas6, was identified in 1993. Gas6 appears to be a cellular growth regulation factor with cell-signaling activities, although its mechanism of action is not known. Nevertheless, it is important for various cellular functions including cell adhesion, cell proliferation and protection against apoptosis (i.e. programmed cell death).19 Gas6 also seems to play important roles in both the developing and aging nervous system.20,21 In addition, Gas6 is involved in regulating platelet signaling and vascular homeostasis.22 It has been found throughout the nervous system, as well in the heart, lungs, stomach, kidneys and cartilage. A potential clinical application for this cellgrowth regulating effect was suggested in in-vitro research where vitamin K2 was shown to suppress the recurrence of abnormal liver cell growth.23,24 Furthermore, in a cohort study, dietary vitamin K2 intake was found to reduce the incident of abnormal prostate cell growth in men by 63 percent.25
Vitamin K & D Synergism
Data show that vitamin K2 enhances vitamin D3 gene induction of osteocalcin (OC), a pro-osteoblastic, noncollagenous protein found in bone matrix.26 Human clinical research has demonstrated that the combination of vitamin D and K2 is more effective in supporting BMD than either nutrient alone. Likewise, research has shown that vitamin D and K both down-regulate proinflammatory cytokines, thereby promoting a healthy inflammatory balance.
Furthermore, vitamins K and D also overlap metabolically at the cellular level in cyclic oxidation and reduction, protecting living cells against oxidative attack.27 Consequently, there is value in jointly supplementing with these two vitamins.
1 Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999.
2 Shearer MJ. The roles of vitamins D and K in bone health and osteoporosis prevention. Proc Nutr Soc. 1997;56(3):915-937.
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5 Ferland G. Vitamin K. In: Bowman BA, Russell RM, eds. Present Knowledge in Nutrition. 9th ed. Volume 1. Washington, D.C.: ILSI Press; 2006:220-230.
6 Food and Nutrition Board, Institute of Medicine. Vitamin K. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, D.C.: National Academy Press; 2001:162-196.
7 Shearer MJ. The roles of vitamins D and K in bone health and osteoporosis prevention. Proc Nutr Soc. 1997;56(3):915-937.
8 Booth SL. Skeletal functions of vitamin K-dependent proteins: not just for clotting anymore. Nutr Rev. 1997;55(7):282-284.
9 Suttie JW. Vitamin K. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006:412-425.
10 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;15:515-21.
11 Iwamoto I, Kosha S, Noguchi S, et al. A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy. Maturitas. 1999;31:161-4.
12 Yonemura K, Kimura M, Miyaji T, Hishida A. Shortterm effect of vitamin K administration on prednisoloneinduced loss of bone mineral density in patients with chronic glomerulonephritis. Calcif Tissue Int. 2000;66:123-8.
13 Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007;18(7):963-972.
14 Cockayne S, Adamson J, Lanham-New S, et al. Vitamin K and the prevention of fractures. Systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166:1256-61.
15 Knapen MH, Drummen NE, Smit E, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013 Sep;24(9):2499-507.
16 Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study. J Nutr. 2004;134:3100-5.
17 Beulens JW, Bots ML, Atsma F, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2008;203(2):489-93.
18 Nagasawa Y, Fujii M, Kajimoto Y, et al. Vitamin K2 and serum cholesterol in patients on continuous ambulatory peritoneal dialysis. Lancet. 1998;351:724.
19 Ferland G. Vitamin K. In: Bowman BA, Russell RM, eds. Present Knowledge in Nutrition. 9th ed. Volume 1. Washington, D.C.: ILSI Press; 2006:220-230.
20 Ferland G. The vitamin K-dependent proteins: an update. Nutr Rev. 1998;56(8):223-230.
21 Tsaioun KI. Vitamin K-dependent proteins in the developing and aging nervous system. Nutr Rev. 1999;57(8):231-240.
22 Maree AO, Jneid H, Palacios IF, Rosenfield K, MacRae CA, Fitzgerald DJ. Growth arrest specific gene (GAS) 6 modulates platelet thrombus formation and vascular wall homeostasis and represents an attractive drug target. Curr Pharm Des. 2007;13(26):2656-2661.
23 Mizuta T, Ozaki I. Hepatocellular carcinoma and vitamin K. Vitam Horm. 2008;78:435-42.
24 Tamori A, Habu D, Shiomi S, et al. Potential role of vitamin K(2) as a chemopreventive agent against hepatocellular carcinoma. Hepatol Res. 2007 Sep;37 Suppl 2:S303-7.
25 Nimptsch K, Rohrmann S, Linseisen J. Dietary Intake of Vitamin K and Risk of Prostate Cancer in the Heidelberg Cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Am J Clin Nutr. 2008;87(4):985-992.
26 Gigante A, Brugè F, Cecconi S, Manzotti S, Littarru GP, Tiano L. Vitamin MK-7 enhances vitamin D3-induced osteogenesis in hMSCs: modulation of key effectors in mineralization and vascularization. J Tissue Eng Regen Med. 2012 Oct 29. Doi: 10.1002/term.1627.
27 Kidd PM. Vitamins D and K as pleiotropic nutrients: clinical importance to the skeletal and cardiovascular systems and preliminary evidence for synergy. Altern Med Rev. 2010 Sep;15(3):199-222.
Gene Bruno, MS, MHS, the dean of academics for Huntington College of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications.