The Role of Vitamin K2 in Bone and Cardiovascular Health
Tal Friedman, ND
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Keywords

Bone mineral density
Calcification
Cardiovascular disease
Menaquinone
Osteoporosis
Vitamin K
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Abstract

Vitamin K is an essential nutrient present in plants, animals, and fermented products that plays an important role in a number of biological systems. Recent evidence suggests that vitamin K has potential health benefits far beyond its role in activating coagulation factors. It appears that vitamin K2 (menaquinones) play an important role in optimal bone and cardiovascular health. The central role of vitamin K is the synthesis of γ-carboxyglutamate, which occurs during the vitamin K cycle. The vitamin K cycle allows important proteins, namely osteocalcin and matrix Gla protein, to become activated. These vitamin K‐dependent proteins are of particular importance to bone and cardiovascular health. It has been noted that activated matrix GLA protein may inhibit the formation of vascular calcifications, while activated osteocalcin is implicated in proper bone mineralization and overall calcium homeostasis. Evidence has also shown that a significant number of otherwise healthy persons may be consuming inadequate amounts of menaquinones and are at greater risk for bone and cardiovascular illness. Although more research is needed to elucidate appropriate therapeutic dosage ranges, it would seem that ensuring adequate intake of menaquinone may be of great importance for bone and cardiovascular disease prevention.

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References

Ferland G. The discovery of vitamin K and its clinical applications. Ann Nutr Metab. 2012; 61:213–8.
Shearer MJ, Bach A, Kohlmeier M. Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. J Nutr. 1996; 126(4 Suppl):1181S–6S.
Schurgers LJ, Vermeer C. Determination of phylloquinone and menaquinones in food: effect of food matrix on circulating vitamin K concentrations. Haemostasis. 2000; 30:298–307.
Trumbo P, Yates AA, Schlicker S, Poos M. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc. 2001; 101:294–301.
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; 96:149–54.
Thijssen HH, Drittij-Reijnders MJ. Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4. Br J Nutr. 1994; 72:415–25.
Tie JK, Jin DY, Straight DL, Stafford DW. Functional study of the vitamin K cycle in mammalian cells. Blood. 2011; 117:2967–74.
Rishavy MA, Hallgren KW, Wilson LA, et al. The vitamin K oxidoreductase is a multimer that efficiently reduces vitamin K epoxide to hydroquinone to allow vitamin K-dependent protein carboxylation. J Biol Chem. 2013; 288:31556–66.
Esmon CT, Suttie JW, Jackson CM. The functional significance of vitamin K action: difference in phospholipid binding between normal and abnormal prothrombin. J Biol Chem. 1975; 250:4095–9.
El Asmar MS, Naoum JJ, Arbid EJ. Vitamin K dependent proteins and the role of vitamin K2 in the modulation of vascular calcification: a review. Oman Med J. 2014; 29:172–7.
Hauschka PV, Lian JB, Cole DE, Gundberg CM. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev. 1989; 69:990–1047.
Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr. 2012; 3:166–73.
Neve A, Corrado A, Cantatore FP. Osteocalcin: skeletal and extra-skeletal effects. J Cell Physiol. 2013; 228:1149–53.
Booth SL, Martini L, Peterson JW, et al. Dietary phylloquinone depletion and repletion in older women. J Nutr. 2003; 133:2565–9.
van Dam-Mieras MC, Hemker HC. Half-life time and control frequency of vitamin K-dependent coagulation factors: theoretical considerations on the place of factor VII in the control of oral anticoagulation therapy. Haemostasis. 1983; 13:201–8.
Nemerson Y. Regulation of the initiation of coagulation by factor VII. Haemostasis. 1983; 13:150–5.
Nakano T, Ishimoto Y, Kishino J, et al. Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J Biol Chem. 1997; 272:29411–4.
Prieto AL, Weber JL, Tracy S, et al. Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system. Brain Res. 1999; 816:646–61.
Hamilton DW. Functional role of periostin in development and wound repair: implications for connective tissue disease. J Cell Commun Signal. 2008; 2:9–17.
Shiraishi H, Masuoka M, Ohta S, et al. Periostin contributes to the pathogenesis of atopic dermatitis by inducing TSLP production from keratinocytes. Allergol Int. 2012; 61:563–72.
Masuoka M, Shiraishi H, Ohta S, et al. Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest. 2012; 122:2590–600.
Romanos GE, Asnani KP, Hingorani D, Deshmukh VL. PERIOSTIN: role in formation and maintenance of dental tissues. J Cell Physiol. 2014; 229:1–5.
Hoang QQ, Sicheri F, Howard AJ, Yang DSC. Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature. 2003; 425:977–80.
Taira H, Fujikawa Y, Kudo O, et al. Menatetrenone (vitamin K2) acts directly on circulating human osteoclast precursors. Calcif Tissue Int. 2003; 73:78–85.
Price PA, Otsuka AA, Poser JW, et al. Characterization of a gamma-carboxyglutamic acid-containing protein from bone. Proc Natl Acad Sci USA. 1976; 73:1447–51.
Ducy P, Desbois C, Boyce B, et al. Increased bone formation in osteocalcin-deficient mice. Nature. 1996; 382:448–52.
Ingram RT, Park YK, Clarke BL, Fitzpatrick LA. Age- and gender-related changes in the distribution of osteocalcin in the extracellular matrix of normal male and female bone: possible involvement of osteocalcin in bone remodeling. J Clin Invest. 1994; 93:989–97.
Boskey AL, Gadaleta S, Gundberg C, et al. Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the function of osteocalcin. Bone. 1998; 23:187–96.
Binkley NC, Krueger DC, Engelke JA, et al. Vitamin K supplementation reduces serum concentrations of under-gamma-carboxylated osteocalcin in healthy young and elderly adults. Am J Clin Nutr. 2000; 72:1523–8.
Binkley NC, Krueger DC, Kawahara TN, et al. A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation. Am J Clin Nutr. 2002; 76:1055–60.
Sato T, Schurgers LJ, Uenishi K. Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Nutr J. 2012; 11:93.
Koshihara Y, Hoshi K, Okawara R, et al. Vitamin K stimulates osteoblastogenesis and inhibits osteoclastogenesis in human bone marrow cell culture. J Endocrinol. 2003; 176:339–48.
Koshihara Y, Hoshi K. Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro. J Bone Miner Res. 1997; 12:431–8.
Koshihara Y, Hoshi K, Ishibashi H, Shiraki M. Vitamin K2 promotes 1α,25(OH)2 vitamin D3-induced mineralization in human periosteal osteoblasts. Calcif Tissue Int. 1996; 59:466–73.
Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008; 100:530–47.
Akedo Y, Hosoi T, Inoue S, et al. Vitamin K2 modulates proliferation and function of osteoblastic cells in vitro. Biochem Biophys Res Commun. 1992; 187:814–20.
Akiyama Y, Hara K, Tajima T, et al. Effect of vitamin K2 (menatetrenone) on osteoclast-like cell formation in mouse bone marrow cultures. Eur J Pharmacol. 1994; 263:181–5.
Hara K, Akiyama Y, Nakamura T, et al. The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain. Bone. 1995; 16:179–84.
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.
Gast GCM, de Roos NM, Sluijs I, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009; 19:504–10.
Booth SL, Broe KE, Gagnon DR, et al. Vitamin K intake and bone mineral density in women and men. Am J Clin Nutr. 2003; 77:512–6.
Feskanich D, Weber P, Willett WC, et al. Vitamin K intake and hip fractures in women: a prospective study. Am J Clin Nutr. 1999; 69:74–9.
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.
Ushiroyama T, Ikeda A, Ueki M. Effect of continuous combined therapy with vitamin K2 and vitamin D3 on bone mineral density and coagulofibrinolysis function in postmenopausal women. Maturitas. 2002; 41:211–21.
Iwamoto J, Takeda T, Ichimura S. Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J Orthop Sci. 2000; 5:546–51.
Iwamoto J, Takeda T, Ichimura S. Combined treatment with vitamin K2 and bisphosphonate in postmenopausal women with osteoporosis. Yonsei Med J. 2003; 44:751–6.
Dawson-Hughes B. Bone loss accompanying medical therapies. N Engl J Med. 2001; 345:989–91.
Somekawa Y, Chigughi M, Harada M, Ishibashi T. Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide. J Clin Endocrinol Metab. 1999; 84:2700–4.
Koitaya N, Sekiguchi M, Tousen Y, et al. Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. J Bone Miner Metab. 2014; 32:142–50.
Rehman Q, Lane NE. Effect of glucocorticoids on bone density. Med Pediatr Oncol. 2003; 41:212–6.
Yonemura K, Kimura M, Miyaji T, Hishida A. Short-term effect of vitamin K administration on prednisolone-induced loss of bone mineral density in patients with chronic glomerulonephritis. Calcif Tissue Int. 2000; 66:123–8.
Inoue T, Sugiyama T, Matsubara T, et al. Inverse correlation between the changes of lumbar bone mineral density and serum undercarboxylated osteocalcin after vitamin K2 (menatetrenone) treatment in children treated with glucocorticoid and alfacalcidol. Endocr J. 2001; 48:11–8.
Forli L, Bollerslev J, Simonsen S, et al. Dietary vitamin K2 supplement improves bone status after lung and heart transplantation. Transplantation. 2010; 89:458–64.
Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005; 25:932–43.
Doherty TM, Asotra K, Fitzpatrick LA, et al. Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci USA. 2003; 100:11201–6.
Detrano RC, Doherty TM, Davies MJ, Stary HC. Predicting coronary events with coronary calcium: pathophysiologic and clinical problems. Curr Probl Cardiol. 2000; 25:374–402.
Jeziorska M, McCollum C, Wooley DE. Observations on bone formation and remodelling in advanced atherosclerotic lesions of human carotid arteries. Virchows Arch. 1998; 433:559–65.
Tota-Maharaj R, Blaha MJ, McEvoy JW, et al. Coronary artery calcium for the prediction of mortality in young adults <45 years old and elderly adults >75 years old. Eur Heart J. 2012; 33:2955–62.
Kramer CK, Zinman B, Gross JL, et al. Coronary artery calcium score prediction of all cause mortality and cardiovascular events in people with type 2 diabetes: systematic review and meta-analysis. Br Med J. 2013; 346:f1654.
Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008; 358:1336–45.
Cranenburg ECM, Koos R, Schurgers LJ, et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost. 2010; 104:811–22.
Dalmeijer GW, van der Schouw YT, Magdeleyns E, et al. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 2012; 225:397–402.
Levy RJ, Zenker JA, Lian JB. Vitamin K-dependent calcium binding proteins in aortic valve calcification. J Clin Invest. 1980; 65:563–6.
Schurgers LJ, Cranenburg ECM, Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost. 2008; 100:593–603.
Luo G, Ducy P, McKee MD, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997; 386:78–81.
Schurgers LJ, Teunissen KJ, Knapen MH, et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol. 2005; 25:1629–33.
Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest. 1994; 93:2393–402.
Dhore CR, Cleutjens JP, Lutgens E, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001; 21:1998–2003.
Mayer O Jr, Seidlerová J, Bruthans J, et al. Desphospho-uncarboxylated matrix Gla-protein is associated with mortality risk in patients with chronic stable vascular disease. Atherosclerosis. 2014; 235:162–8.
Schurgers LJ, Teunissen KJ, Hamulyák K, et al. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007; 109:3279–83.
Weijs B, Blaauw Y, Rennenberg RJ, et al. Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. Eur Heart J. 2011; 32:2555–62.
Rennenberg RJMW, van Varik BJ, Schurgers LJ, et al. Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans. Blood. 2010; 115:5121–3.
Beulens JWJ, Bots ML, Atsma F, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009; 203:489–93.
Villines TC, Hatzigeorgiou C, Feuerstein IM, et al. Vitamin K1 intake and coronary calcification. Coron Artery Dis. 2005; 16:199–203.
Shea MK, O’Donnell CJ, Hoffmann U, et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. 2009; 89:1799–807.
Cheung CL, Sahni S, Cheung BMY, et al. Vitamin K intake and mortality in people with chronic kidney disease from NHANES III. Clin Nutr. 2015; 34:235–40.
Caluwé R, Vandecasteele S, Van Vlem B, et al. Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study. Nephrol Dial Transplant. 2014; 29:1385–90.
Knapen MHJ, Braam LA, Drummen NE, et al. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: a double-blind randomised clinical trial. Thromb Haemost. 2015; 113:1135–44.
Masterjohn C. Vitamin D toxicity redefined: vitamin K and the molecular mechanism. Med Hypotheses. 2007; 68:1026–34.
Kirfel J, Kelter M, Cancela LM, et al. Identification of a novel negative retinoic acid responsive element in the promoter of the human matrix Gla protein gene. Proc Natl Acad Sci USA. 1997; 94:2227–32.
Schurgers LJ, Barreto DV, Barreto FC, et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin J Am Soc Nephrol. 2010; 5:568–75.
Oliva A, Della Ragione F, Fratta M, et al. Effect of retinoic acid on osteocalcin gene expression in human osteoblasts. Biochem Biophys Res Commun. 1993; 191:908–14.
Miyake N, Hoshi K, Sano Y, et al. 1,25-Dihydroxyvitamin D3 promotes vitamin K2 metabolism in human osteoblasts. Osteoporos Int. 2001; 12:680–7.
Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol. 2000; 20:317–27.
Bresson JL, Flynn A, Heinonen M, et al. Vitamin K2 added for nutritional purposes in foods for particular nutritional uses, food supplements and foods intended for the general population and vitamin K2 as a source of vitamin K added for nutritional purposes to foodstuffs, in the context of Regulation (EC) 258/97. Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies (Question No EFSA-Q-2005-179 and EFSA-Q-2007-079). Adopted on 2 October 2008. EFSA J. 2008; 822:1–31.
Kawashima H, Nakajima Y, Matubara Y, et al. Effects of vitamin K2 (menatetrenone) on atherosclerosis and blood coagulation in hypercholesterolemic rabbits. Jpn J Pharmacol. 1997; 75:135–43.
Ronden JE, Groenen-van Dooren MM, Hornstra G, Vermeer C. Modulation of arterial thrombosis tendency in rats by vitamin K and its side chains. Atherosclerosis. 1997; 132:61–7.
Theuwissen E, Cranenburg EC, Knapen MH, et al. Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects. Br J Nutr. 2012; 108:1652–7.
Westenfeld R, Krueger T, Schlieper G, et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis. 2012; 59:186–95.
Bushra R, Aslam N, Khan AY. Food-drug interactions. Oman Med J. 2011; 26:77–83.
Theuwissen E, Magdeleyns EG, Braam LA, et al. Vitamin K status in healthy volunteers. Food Funct. 2014; 5:229–34.
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