Vitamin K — Benefits Deep Dive

Butter from grass-fed cows, a source of vitamin K2 (MK-4)
Butter from grass-fed cows, a source of vitamin K2 (MK-4)

Vitamin K is the cofactor for gamma-carboxylation, the chemical step that activates a family of vitamin K-dependent proteins: the coagulation factors made in the liver, osteocalcin in bone, Matrix Gla Protein (MGP) in the vessel wall, and Gas6 (McCann 2009; Linus Pauling Institute). Each page below takes one area in which vitamin K2 (the menaquinones) has been studied — arterial calcification, bone, the MK-7 and MK-4 forms, and glucose metabolism — and sets out what the cohort studies and trials found, including the neutral, negative and retracted results.

Deep-Dive Articles

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Arterial Calcification Prevention

Matrix Gla Protein (MGP) is a vitamin K-dependent inhibitor of arterial calcification; mice lacking it die of arterial calcification within two months (Luo 1997). Deep dive through the Rotterdam Study (an observational cohort: coronary heart disease mortality RR 0.43 in the top versus bottom third of menaquinone intake), the PROSPECT-EPIC cohort, the Knapen arterial-stiffness trial, dp-ucMGP as a vascular biomarker, the calcium paradox, warfarin-induced calcification in rats, and the VitaK-CAC coronary calcium trial.

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Bone Health & Osteoporosis

Osteocalcin carries three vitamin K-dependent Gla residues that are critical for its structure (Gundberg 2012). The 45 mg/day MK-4 trials (Shiraki 2000 in Japan, Knapen 2007 in the Netherlands), the 4,378-woman Japanese OF study that was negative on its primary vertebral-fracture endpoint (Inoue 2009), the retracted and flagged papers from one Japanese research group, the Knapen 3-year MK-7 bone-density trial, the neutral trials, ucOC as a bone biomarker, the K2 + D3 + calcium question, the natto geographic fracture correlation, and the 2019 meta-analysis that judged the fracture evidence insufficient (Mott 2019).

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MK-7 vs MK-4 — Comparing the K2 Forms

How the two most-studied menaquinones differ. MK-7 has a much longer half-life than vitamin K1 and accumulates in blood with daily intake (Schurgers 2007); at a nutritional dose MK-7 raised serum levels while MK-4 was not detectable in serum (Sato 2012). The bone trials split by form: microgram-dose MK-7 trials in Western populations and 45 mg/day MK-4 trials, mostly Japanese (Shiraki 2000). Also covered: the cis/trans MK-7 isomer question, natto-derived versus synthetic sources, and the doses the trials used.

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Insulin Sensitivity & Metabolic Health

Mouse work from the Karsenty laboratory proposed osteocalcin as a hormone: mice lacking it showed glucose intolerance and insulin resistance (Lee 2007). The human trials are small: Choi 2011 (MK-4, 30 mg three times daily for 4 weeks in 42 healthy young men; insulin sensitivity rose) and Yoshida 2008 (500 mcg/day vitamin K1 for 36 months in older adults; lower insulin resistance in men, no difference in women), alongside Dutch cohort data on dietary K1, K2 and type 2 diabetes (Beulens 2010). In mice the uncarboxylated form of osteocalcin is the active one (Ferron 2010), whereas the Choi authors concluded that in humans the carboxylated form may be the one linked to insulin sensitivity; a 2012 review found the mouse hypothesis not supported by the limited human data (Gundberg 2012).

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Table of Contents

  1. Deep-Dive Articles
  2. Why K2 Is Studied Across So Many Systems
  3. Research Papers: Arterial Calcification
  4. Research Papers: Bone Health
  5. Research Papers: MK-7 vs MK-4 Forms
  6. Research Papers: Insulin Sensitivity & Metabolic
  7. Research Papers: Cross-Cutting (Mechanism, Safety)
  8. External Authoritative Resources
  9. Connections
  10. Featured Videos

Why K2 Is Studied Across So Many Systems

Vitamin K acts through one biochemical reaction — gamma-carboxylation of glutamate residues — and that reaction activates a whole family of vitamin K-dependent proteins; McCann and Ames counted 16 known vitamin K-dependent proteins (McCann 2009). The ones most discussed in the K2 research are:

  1. Osteocalcin (bone). Three vitamin K-dependent Gla residues are critical for osteocalcin's structure, which appears to regulate the maturation of bone mineral; the percentage of circulating osteocalcin that is not carboxylated is used as a biomarker of vitamin K status (Gundberg 2012). The trials are covered on the bone-health page.
  2. Matrix Gla Protein (vascular wall). MGP's calcium-binding activity is regulated by vitamin K-dependent carboxylation of up to five glutamate residues and by phosphorylation of serine residues (Linus Pauling Institute). MGP is a potent inhibitor of arterial calcification (Schurgers 2008), and mice lacking it die of arterial calcification (Luo 1997). Its inactive form, dp-ucMGP, rose with chronic kidney disease stage and was associated with the severity of aortic calcification (Schurgers 2010). The research is covered on the arterial-calcification page.
  3. Osteocalcin (endocrine, in mice). In mouse and cell studies osteocalcin stimulated insulin expression in beta cells and adiponectin in fat cells (Lee 2007), and the uncarboxylated form was described as the active hormone (Ferron 2010). A 2012 review found that this hypothesis is not supported by the limited human data (Gundberg 2012). The human trials are covered on the insulin-sensitivity page.
  4. Gas6. A vitamin K-dependent ligand of the TAM receptors (Tyro3, Axl, Mer); Gas6 has been involved in phagocytosis, cell adhesion, cell proliferation and protection against apoptosis (Linus Pauling Institute). Gas6 and the TAM receptors are abundantly expressed in the nervous system, where TAM signaling has been studied in myelination, mainly in mouse models (Shafit-Zagardo 2018).
  5. Coagulation factors II, VII, IX and X (liver). These make up the core of the coagulation cascade and are synthesized in the liver (Linus Pauling Institute). In mouse knockouts the coagulation proteins were essential while osteocalcin, MGP and Gas6 were not; the "triage" model proposes that the preferential delivery of dietary vitamin K1 to the liver preserves coagulation when vitamin K is limited, while the less critical proteins outside the liver may be shortchanged (McCann 2009).

The two K2 forms behave differently. MK-7 has a very long half-life compared with vitamin K1 and accumulated to 7- to 8-fold higher serum levels during prolonged intake (Schurgers 2007); after a single nutritional dose, MK-7 was detected in serum for up to 48 hours, while MK-4 was not detectable (Sato 2012). Most Western trials used microgram doses of MK-7; pharmacological doses of MK-4 (menatetrenone) are used in Japan in the treatment of osteoporosis (Linus Pauling Institute), and the Japanese trials used 45 mg/day (Shiraki 2000). See MK-7 vs MK-4 for the trial-by-trial comparison.

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Research Papers: Arterial Calcification

  1. Rotterdam Study (Geleijnse 2004, J Nutrition) — observational cohort of 4,807 adults; coronary heart disease mortality RR 0.43 (0.24–0.77), top versus bottom tertile of menaquinone intake; phylloquinone not related to any outcome. — doi:10.1093/jn/134.11.3100
  2. MGP knockout mice (Luo 1997, Nature) — spontaneous arterial rupture. — doi:10.1038/386078a0
  3. Knapen arterial stiffness trial (2015, Thromb Haemost) — doi:10.1160/TH14-08-0675
  4. PROSPECT-EPIC cohort (Beulens 2009, Atherosclerosis) — Search PubMed
  5. Warfarin-induced calcification regression in rats (Schurgers 2007, Blood) — doi:10.1182/blood-2006-07-035345
  6. Aortic valve calcification slowing (Brandenburg 2017, Circulation) — doi:10.1161/CIRCULATIONAHA.116.027011
  7. K2 in hemodialysis patients (Caluwe 2014, NDT) — doi:10.1093/ndt/gft464
  8. VitaK-CAC trial protocol (Vossen 2015, Nutrients) — doi:10.3390/nu7115443
  9. Vitamin K status & CV systematic review (Lees 2019, Heart) — doi:10.1136/heartjnl-2018-313955
  10. dp-ucMGP in CKD (Schurgers 2010, CJASN) — doi:10.2215/CJN.07081009

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Research Papers: Bone Health

  1. Knapen MK-7 3-year BMD trial (2013, Osteoporos Int) — Search PubMed
  2. Shiraki menatetrenone 45 mg fracture trial (2000, JBMR) — Search PubMed
  3. Knapen hip geometry trial (2007, Osteoporos Int) — Search PubMed
  4. Cockayne systematic review & meta-analysis (2006, Arch Intern Med) — Search PubMed — Expression of concern (JAMA Intern Med 2018: PubMed PMID: 29582046)
  5. Kaneki natto geographic fracture correlation (2001, Nutrition) — Search PubMed
  6. Feskanich Nurses' Health Study hip fracture (1999, AJCN) — Search PubMed
  7. Cheung ECKO trial, 5 mg/day K1: no effect on bone density; fewer clinical fractures as a secondary outcome the study was not powered for (2008, PLoS Med) — doi:10.1371/journal.pmed.0050196
  8. Huang meta-analysis postmenopausal K2 (2015, Osteoporos Int) — Search PubMed
  9. SXR/PXR receptor mechanism (Tabb 2003, JBC) — doi:10.1074/jbc.M303136200
  10. Inoue T et al. (2009). Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab 27(1):66–75 — PubMed PMID: 19082528
  11. Mott A et al. (2019). Effect of vitamin K on bone mineral density and fractures in adults: an updated systematic review and meta-analysis of randomised controlled trials. Osteoporos Int 30(8):1543–1559 — PubMed PMID: 31076817 — correction 2020: PubMed PMID: 32965511
  12. Gundberg CM, Lian JB, Booth SL (2012). Vitamin K-dependent carboxylation of osteocalcin: friend or foe? Adv Nutr 3(2):149–157 — PubMed PMID: 22516722

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Research Papers: MK-7 vs MK-4 Forms

  1. Sato comparative bioavailability MK-4 vs MK-7 (2012, Nutr J) — Search PubMed
  2. Inaba low-dose MK-7 osteocalcin carboxylation (2015, JNSV) — doi:10.3177/jnsv.61.471
  3. Yamaguchi & Weitzmann, vitamin K2 and NF-κB in bone cells (2011, Int J Mol Med) — Search PubMed
  4. Iwamoto J, Sato Y (2013). Menatetrenone for the treatment of osteoporosis. Expert Opin Pharmacother 14(4):449–458 — PubMed PMID: 23346882 — Retracted (retraction notice: PubMed PMID: 31437064)
  5. Schurgers LJ et al. (2007). Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood 109(8):3279–3283 — PubMed PMID: 17158229
  6. Schurgers MK-7 hepatic vs extrahepatic uptake — PubMed: Schurgers MK-7 hepatic/extrahepatic
  7. Nakagawa K et al. (2010). Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature 468(7320):117–121 — PubMed PMID: 20953171
  8. Cis vs trans MK-7 isomer bioactivity — PubMed: cis/trans MK-7 isomers

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Research Papers: Insulin Sensitivity & Metabolic

  1. Lee NK et al (Karsenty) — Endocrine regulation of energy metabolism by the skeleton (2007, Cell) — doi:10.1016/j.cell.2007.05.047
  2. Choi MK-4 (menatetrenone) insulin sensitivity trial (2011, Diabetes Care) — doi:10.2337/dc11-0551
  3. Yoshida vitamin K supplementation insulin resistance (2008, Diabetes Care) — doi:10.2337/dc08-1204
  4. Beulens K1 / K2 and type 2 diabetes risk (2010, Diabetes Care) — doi:10.2337/dc09-2302
  5. Ferron insulin signaling in osteoblasts and osteocalcin activation, mouse study (2010, Cell) — doi:10.1016/j.cell.2010.06.003
  6. Manna vitamin K and metabolic syndrome review — PubMed: Manna K and MetS review
  7. Sakamoto vitamin K2 glucose tolerance — PubMed: Sakamoto K2 glucose

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Research Papers: Cross-Cutting (Mechanism, Safety)

  1. Gamma-glutamyl carboxylase mechanism — PubMed: gamma-glutamyl carboxylase mechanism
  2. VKORC1 polymorphisms and warfarin sensitivity — PubMed: VKORC1 polymorphism warfarin
  3. McCann JC, Ames BN (2009). Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr 90(4):889–907 — PubMed PMID: 19692494
  4. Vitamin K2 long-term safety profile — PubMed: K2 long-term safety
  5. Gas6 / TAM receptor signaling — PubMed: Gas6 TAM signaling
  6. Shafit-Zagardo B, Gruber RC, DuBois JC (2018). The role of TAM family receptors and ligands in the nervous system: from development to pathobiology. Pharmacol Ther 188:97–117 — PubMed PMID: 29514053
  7. Schurgers LJ, Cranenburg EC, Vermeer C (2008). Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost 100(4):593–603 — PubMed PMID: 18841280
  8. Theuwissen vitamin K status in healthy volunteers (2014) — doi:10.1039/c3fo60464k
  9. Hartley Cochrane review primary CV prevention (2015) — doi:10.1002/14651858.CD011148.pub2

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External Authoritative Resources

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Connections

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