Vitamin K2 Needs an RDI Separate from Vitamin K1

Vitamin K and its essential role in coagulation (vitamin K [Koagulation]) have been well established and accepted the world over. Many countries have a Recommended Daily Intake (RDI) for vitamin K based on early research, and its necessary role in the activation of vitamin K-dependent coagulation proteins is known. In the past few decades, the role of vitamin K-dependent proteins in processes beyond coagulation has been discovered. Various isoforms of vitamin K have been identified, and vitamin K2 specifically has been highlighted for its long half-life and extrahepatic activity, whereas the dietary form vitamin K1 has a shorter half-life. In this review, we highlight the specific activity of vitamin K2 based upon proposed frameworks necessary for a bioactive substance to be recommended for an RDI. Vitamin K2 meets all these criteria and should be considered for a specific dietary recommendation intake.

[1]  S. Booth,et al.  Vitamin-k , 2021, Reactions Weekly.

[2]  K. Kouda,et al.  Natto Intake is Inversely Associated with Osteoporotic Fracture Risk in Postmenopausal Japanese Women. , 2019, The Journal of nutrition.

[3]  B. Sopko,et al.  LC–MS/MS quantitative analysis of phylloquinone, menaquinone-4 and menaquinone-7 in the human serum of a healthy population , 2019, PeerJ.

[4]  L. Schurgers,et al.  The Bone—Vasculature Axis: Calcium Supplementation and the Role of Vitamin K , 2019, Front. Cardiovasc. Med..

[5]  L. Schurgers,et al.  Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease , 2019, International journal of molecular sciences.

[6]  F. Dehghani,et al.  A potential biotechnological process for the sustainable production of vitamin K1 , 2019, Critical reviews in biotechnology.

[7]  A. Jardine,et al.  Vitamin K status, supplementation and vascular disease: a systematic review and meta-analysis , 2018, Heart.

[8]  R. Marcucio,et al.  Cellular biology of fracture healing , 2018, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[9]  B. Bammens,et al.  Poor Vitamin K Status Is Associated With Low Bone Mineral Density and Increased Fracture Risk in End‐Stage Renal Disease , 2018, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  Shangshu Zhang,et al.  Vitamin K status and cardiovascular events or mortality: A meta-analysis , 2018, European journal of preventive cardiology.

[11]  M. Shearer,et al.  Key Pathways and Regulators of Vitamin K Function and Intermediary Metabolism. , 2018, Annual review of nutrition.

[12]  M. Ferron,et al.  VKORC1L1, An Enzyme Mediating the Effect of Vitamin K in Liver and Extrahepatic Tissues , 2018, Nutrients.

[13]  S. Xanthoulea,et al.  Menaquinone Content of Cheese , 2018, Nutrients.

[14]  L. Schurgers,et al.  Desphospho-Uncarboxylated Matrix-Gla Protein Is Increased Postoperatively in Cardiovascular Risk Patients , 2018, Nutrients.

[15]  You-qing Huang Combined treatment of vitamin K and teriparatide on bone metabolism and biomechanics in rats with osteoporosis , 2017, Experimental and therapeutic medicine.

[16]  R. Marles,et al.  US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K , 2017, Nutrition reviews.

[17]  G. Schwalfenberg,et al.  Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health , 2017, Journal of nutrition and metabolism.

[18]  M. Makki,et al.  High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: risk factors and response to vitamin K2, A pre-post intervention clinical trial , 2017, BMC Nephrology.

[19]  Xueyan Fu,et al.  Multiple Vitamin K Forms Exist in Dairy Foods , 2017, Current developments in nutrition.

[20]  L. Schurgers,et al.  Slower Progress of Aortic Valve Calcification With Vitamin K Supplementation: Results From a Prospective Interventional Proof-of-Concept Study. , 2017, Circulation.

[21]  D. Cundiff,et al.  Cardiovascular Disease Death Before Age 65 in 168 Countries Correlated Statistically with Biometrics, Socioeconomic Status, Tobacco, Gender, Exercise, Macronutrients, and Vitamin K , 2016, Cureus.

[22]  M. Mona,et al.  Bioavailability and Chemical/Functional Aspects of Synthetic MK-7 vs Fermentation-Derived MK-7 in Randomised Controlled Trials. , 2016, International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition.

[23]  Prasenjit Manna,et al.  Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: A review. , 2016, Nutrition.

[24]  Min Seuk Kim,et al.  The inhibitory effect of vitamin K on RANKL-induced osteoclast differentiation and bone resorption. , 2015, Food & function.

[25]  S. Booth,et al.  Gamma-Carboxylation and Fragmentation of Osteocalcin in Human Serum Defined by Mass Spectrometry* , 2015, Molecular & Cellular Proteomics.

[26]  L. Ning,et al.  Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials , 2015, Osteoporosis International.

[27]  C. Vermeer,et al.  Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women , 2015, Thrombosis and Haemostasis.

[28]  K. Maresz Proper Calcium Use: Vitamin K2 as a Promoter of Bone and Cardiovascular Health. , 2015, Integrative medicine.

[29]  M. Aoki,et al.  Low-dose menaquinone-4 improves γ-carboxylation of osteocalcin in young males: a non-placebo-controlled dose–response study , 2014, Nutrition Journal.

[30]  C. Reutelingsperger,et al.  The realm of vitamin K dependent proteins: shifting from coagulation toward calcification. , 2014, Molecular nutrition & food research.

[31]  C. Vermeer,et al.  Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study. , 2014, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[32]  J. Lupton,et al.  Exploring the benefits and challenges of establishing a DRI-like process for bioactives , 2014, European Journal of Nutrition.

[33]  J. Reichrath,et al.  Vitamin K: an old vitamin in a new perspective , 2014, Dermato-endocrinology.

[34]  S. Booth,et al.  The role of menaquinones (vitamin K₂) in human health. , 2013, The British journal of nutrition.

[35]  M. Shearer,et al.  Effect of low‐dose supplements of menaquinone‐7 (vitamin K2) on the stability of oral anticoagulant treatment: dose–response relationship in healthy volunteers , 2013, Journal of thrombosis and haemostasis : JTH.

[36]  C. Vermeer,et al.  Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women , 2013, Osteoporosis International.

[37]  P. Boyaval,et al.  Quantitative measurement of vitamin K2 (menaquinones) in various fermented dairy products using a reliable high-performance liquid chromatography method. , 2013, Journal of dairy science.

[38]  L. Schurgers,et al.  Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women , 2012, Nutrition Journal.

[39]  S. Giannini,et al.  Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  A. D'Angelo,et al.  Consequences of vitamin K2 deficiency in hemodialysis patients. , 2012, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[41]  Y. Manios,et al.  Changes in Parameters of Bone Metabolism in Postmenopausal Women Following a 12-Month Intervention Period Using Dairy Products Enriched with Calcium, Vitamin D, and Phylloquinone (Vitamin K1) or Menaquinone-7 (Vitamin K2): The Postmenopausal Health Study II , 2012, Calcified Tissue International.

[42]  M. Shearer,et al.  Vitamin K nutrition, metabolism, and requirements: current concepts and future research. , 2012, Advances in nutrition.

[43]  L. Schurgers,et al.  Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. , 2012, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[44]  P. Pasqualetti,et al.  PIVKA-II plasma levels as markers of subclinical vitamin K deficiency in term infants , 2012, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[45]  G. Eide,et al.  Intake of vitamin K1 and K2 and risk of hip fractures: The Hordaland Health Study. , 2011, Bone.

[46]  T. Preston,et al.  Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7 , 2011, Toxicology mechanisms and methods.

[47]  R. Estruch,et al.  Dietary vitamin K intake is associated with bone quantitative ultrasound measurements but not with bone peripheral biochemical markers in elderly men and women. , 2011, Bone.

[48]  M. Delong,et al.  High prevalence of hypovitaminosis D status in patients with early Parkinson disease. , 2011, Archives of neurology.

[49]  O. Franco,et al.  Is vitamin K consumption associated with cardio-metabolic disorders? A systematic review. , 2010, Maturitas.

[50]  D. van der A,et al.  Dietary Phylloquinone and Menaquinones Intakes and Risk of Type 2 Diabetes , 2010, Diabetes Care.

[51]  S. Booth,et al.  Vitamins K and D status in stages 3-5 chronic kidney disease. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[52]  M. Shearer,et al.  The external quality assurance of phylloquinone (vitamin K(1)) analysis in human serum. , 2009, Biomedical chromatography : BMC.

[53]  B. Ames,et al.  Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? , 2009, The American journal of clinical nutrition.

[54]  J. Witteman,et al.  A high menaquinone intake reduces the incidence of coronary heart disease. , 2009, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[55]  Xueyan Fu,et al.  Measurement of deuterium-labeled phylloquinone in plasma by high-performance liquid chromatography/mass spectrometry. , 2009, Analytical chemistry.

[56]  J. Iwamoto,et al.  High-dose vitamin K supplementation reduces fracture incidence in postmenopausal women: a review of the literature. , 2009, Nutrition research.

[57]  T. Trikalinos,et al.  Opportunities and challenges in conducting systematic reviews to support the development of nutrient reference values: vitamin A as an example. , 2009, The American journal of clinical nutrition.

[58]  D. Moher,et al.  Issues related to the conduct of systematic reviews: a focus on the nutrition field. , 2008, The American journal of clinical nutrition.

[59]  George Tomlinson,et al.  Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial , 2008, PLoS medicine.

[60]  M. Shearer,et al.  Metabolism and cell biology of vitamin K , 2008, Thrombosis and Haemostasis.

[61]  K. Nakagawa,et al.  Conversion of Phylloquinone (Vitamin K1) into Menaquinone-4 (Vitamin K2) in Mice , 2008, Journal of Biological Chemistry.

[62]  S. Sasaki,et al.  Vitamin K content of foods and dietary vitamin K intake in Japanese young women. , 2007, Journal of nutritional science and vitaminology.

[63]  R. Watanabe,et al.  Quantitative measurement of tetrahydromenaquinone-9 in cheese fermented by propionibacteria. , 2007, Journal of dairy science.

[64]  L. Schurgers,et al.  Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. , 2007, Blood.

[65]  Lisa M. Miller,et al.  Subclinical vitamin K deficiency in hemodialysis patients. , 2007, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[66]  H. Takimoto,et al.  Vitamin K and the prevention of fractures. , 2007, Archives of internal medicine.

[67]  S. Lanham-New,et al.  Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. , 2006, Archives of internal medicine.

[68]  M. Iki,et al.  Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. , 2006, The Journal of nutrition.

[69]  S. Booth,et al.  Vitamin k contents of meat, dairy, and fast food in the u.s. Diet. , 2006, Journal of agricultural and food chemistry.

[70]  N. Tsugawa,et al.  Determination of plasma Vitamin K by high-performance liquid chromatography with fluorescence detection using Vitamin K analogs as internal standards. , 2005, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[71]  N. Tsugawa,et al.  Method for the determination of vitamin K homologues in human plasma using high-performance liquid chromatography-tandem mass spectrometry. , 2005, Analytical chemistry.

[72]  M. Shearer,et al.  Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. , 2004, Blood.

[73]  Douglas L. T. Rohde,et al.  Modelling the recent common ancestry of all living humans , 2004, Nature.

[74]  S. Booth,et al.  Vitamin K content of nuts and fruits in the US diet. , 2003, Journal of the American Dietetic Association.

[75]  S. Booth,et al.  Dietary phylloquinone depletion and repletion in older women. , 2003, The Journal of nutrition.

[76]  A. Shenkin Dietary reference values for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium and zinc , 2003 .

[77]  Toshiro Sato,et al.  Difference in the metabolism of vitamin K between liver and bone in vitamin K-deficient rats , 2002, British Journal of Nutrition.

[78]  L. Schurgers,et al.  Differential lipoprotein transport pathways of K-vitamins in healthy subjects. , 2002, Biochimica et biophysica acta.

[79]  S. Myou,et al.  Vitamin K Administration to Elderly Patients with Osteoporosis Induces No Hemostatic Activation, Even in Those with Suspected Vitamin K Deficiency , 2001, Osteoporosis International.

[80]  V. Piironen,et al.  Determination of phylloquinone and menaquinones in animal products with fluorescence detection after postcolumn reduction with metallic zinc. , 2000, Journal of agricultural and food chemistry.

[81]  L. Schurgers,et al.  Determination of Phylloquinone and Menaquinones in Food , 2000, Pathophysiology of Haemostasis and Thrombosis.

[82]  M. Shiraki,et al.  Vitamin K2 (Menatetrenone) Effectively Prevents Fractures and Sustains Lumbar Bone Mineral Density in Osteoporosis , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[83]  A. Hofman,et al.  Nutritional Intake of Vitamins K1 (Phylloquinone) and K2 (Menaquinone) in The Netherlands , 1999 .

[84]  R. Mahley,et al.  Uptake of chylomicrons by the liver, but not by the bone marrow, is modulated by lipoprotein lipase activity. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[85]  M. Shearer,et al.  Bone health of adult hemodialysis patients is related to vitamin K status. , 1997, Kidney international.

[86]  S. Booth,et al.  Relationships between dietary intakes and fasting plasma concentrations of fat-soluble vitamins in humans. , 1997, The Journal of nutrition.

[87]  T. Sassa,et al.  Effect of dietary fat content on oral bioavailability of menatetrenone in humans. , 1996, Journal of pharmaceutical sciences.

[88]  C. Vermeer,et al.  Effect of food composition on vitamin K absorption in human volunteers , 1996, British Journal of Nutrition.

[89]  M. Shearer,et al.  Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. , 1996, The Journal of nutrition.

[90]  I. Morita,et al.  The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain. , 1995, Bone.

[91]  H. Thijssen,et al.  Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4 , 1994, British Journal of Nutrition.

[92]  P. Delmas,et al.  Detection and measurement of vitamins K1 and K2 in human cortical and trabecular bone , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[93]  M. Shearer Vitamin K metabolism and nutriture. , 1992, Blood reviews.

[94]  C. Vermeer,et al.  Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase. , 1990, Biochimica et biophysica acta.

[95]  D. Hollander,et al.  Vitamin K2 colonic and ileal in vivo absorption: bile, fatty acids, and pH effects on transport. , 1977, The American journal of physiology.

[96]  S. Baba,et al.  Whole-body autoradiographic study of vitamin K distribution in rat. , 1973, Chemical & pharmaceutical bulletin.

[97]  H. Dam,et al.  The occurrence and chemical nature of vitamin K. , 1936, The Biochemical journal.

[98]  Toshiro Sato,et al.  Low-Dose Daily Intake of Vitamin K(2) (Menaquinone-7) Improves Osteocalcin γ-Carboxylation: A Double-Blind, Randomized Controlled Trials. , 2015, Journal of nutritional science and vitaminology.

[99]  R. Marchelli,et al.  Vitamin K2 added for nutritional purposes in foods for particular nutritional uses, food supplements and foods intended for the general population , 2008 .

[100]  K. Berkner Vitamin K-dependent carboxylation. , 2008, Vitamins and hormones.

[101]  S. Booth,et al.  Vitamin K Contents of Grains, Cereals, Fast‐Food Breakfasts, and Baked Goods , 2006 .

[102]  D. Woollard,et al.  Vitamin K in milk and infant formulas: determination and distribution of phylloquinone and menaquinone-4. , 1997, The Analyst.

[103]  Y. Suzuki,et al.  Measurement of K vitamins in animal tissues by high-performance liquid chromatography with fluorimetric detection. , 1989, Journal of chromatography.

[104]  R. Bell Metabolism of vitamin K and prothrombin synthesis: anticoagulants and the vitamin K--epoxide cycle. , 1978, Federation proceedings.

[105]  M. Shearer,et al.  Studies on the absorption and metabolism of phylloquinone (vitamin K1) in man. , 1974, Vitamins and hormones.

[106]  Robert M. Russell,et al.  Dietary Reference Intakes for Vitamin A , Vitamin K , Arsenic , Boron , Chromium , Copper , Iodine , Iron , Manganese , Molybdenum , Nickel , Silver , Vanadium , and Zinc , 2022 .