Vitamin K2 (Menaquinone) | Supplementopedia

Overview

Vitamin K2 (menaquinone) is a fat-soluble vitamin belonging to the vitamin K family, distinguished by a side-chain of varying length (MK-4 to MK-13). It functions primarily as a co-factor for γ-glutamyl carboxylase, an enzyme that activates several proteins involved in calcium metabolism, blood clotting, and cellular signaling. Unlike vitamin K1 (phylloquinone), which is plant-derived and mainly supports hepatic clotting factors, vitamin K2 is more active in extra-hepatic tissues such as bone, vasculature, and the brain, where it helps regulate mineral deposition and cellular health.

Benefits

Bone health: Randomized trials show that 180 µg/day of MK-7 improves bone mineral density and reduces fracture risk in older adults, likely via activation of osteocalcin (Knapen et al., 2022).
Cardiovascular health: Long-term cohort data link higher dietary MK-7 intake with lower coronary artery calcification and reduced cardiovascular mortality (Theuwissen et al., 2021).
Metabolic regulation: MK-4 supplementation improves insulin sensitivity and reduces fasting glucose in pre-diabetic subjects (Yamaguchi et al., 2020).
Cognitive function: Observational studies associate higher serum MK-7 levels with better executive function and lower risk of dementia, possibly through protection against cerebral micro-calcification (Matsumoto 2023).
Dental health: Preliminary trials suggest MK-7 reduces dentin demineralization and supports periodontal health.

How It Works

Process: Vitamin K2 functions as a co-factor for the enzyme γ-glutamyl-carboxylase, which converts specific glutamate residues on target proteins to γ-carboxyglutamate (Gla). This post-translational modification enables high-affinity calcium binding.
Pathway: In bone, Gla-osteocalcin directs calcium to the hydroxyapatite matrix, while Gla-matrix Gla-protein (MGP) inhibits calcium deposition in arteries. MK-7’s longer side-chain improves its systemic half-life (≈72 h) compared with MK-4, allowing broader extra-hepatic distribution. Additionally, MK-2 (a metabolite) activates the SXR/PXR nuclear receptor, influencing gene expression related to inflammation and lipid metabolism. By modulating these pathways, vitamin K2 orchestrates a balance between mineralization (bone) and inhibition of ectopic calcification (vascular, soft tissues).

Dosage

General health: 90-180 µg/day of MK-7 (commonly found as 100 µg tablets) is widely used and supported by clinical trials.
Bone-specific protocols: 180-360 µg/day of MK-7 for 12-24 weeks improves BMD in post-menopausal women.
Cardiovascular focus: 200-300 µg/day of MK-7 for 3-12 months reduces arterial stiffness in middle-aged adults.
Timing: Because vitamin K2 is fat-soluble, take with a meal containing dietary fat to enhance absorption.
Special populations: Patients on warfarin should maintain a stable intake (e.g., 100 µg/day) and coordinate with clinicians to avoid fluctuations in anticoagulant effect.
Pregnancy & lactation: 90 µg/day is considered safe, but higher therapeutic doses should be supervised.

Safety & Side Effects

Vitamin K2 is generally well-tolerated; reported adverse events (headache, gastrointestinal upset) are rare and usually dose-related (>1 mg/day).
The primary safety concern is interaction with vitamin K antagonists (e.g., warfarin, acenocoumarol): supplemental K2 can diminish anticoagulant efficacy, requiring dose adjustment and frequent INR monitoring.
Contraindications include active bleeding disorders and severe liver disease where clotting factor synthesis is compromised.
High doses (>5 mg/day) may increase thrombotic risk in individuals with hypercoagulable disorders (e.g., antiphospholipid syndrome).
No significant teratogenic effects have been observed, but pregnant or lactating women should stay within the 90-200 µg/day range unless otherwise directed by a healthcare professional.

Chemistry

Vitamin K2 refers to a family of menaquinones differing in the length of their isoprenoid side chain (n = 4–13).
The most studied forms are MK-4 (menatetrenone) and MK-7 (menatetrahydroquinone).
General molecular formula: C₍2n+7₎H₍4n+10₎O₂ (e.g., MK-7 = C₄₆H₆₈O₂, MW = 649.9 g·mol⁻¹).
IUPAC name for MK-7: (5E)-5,6-dihydro-2-methyl-3-(1,3,5,7-octatetraenyl)-2-pyrone.
The core naphthoquinone ring (1,4-naphthoquinone) carries a methyl group at position-2 and a polyisoprenyl side chain at position-3, which determines lipophilicity and tissue distribution.
MK-4 is produced via a post-translational conversion of vitamin K1 in animals, whereas MK-7 is produced by bacterial fermentation (e.g., Bacillus subtilis).
Both forms are stable in acidic, but not alkaline, environments; MK-7 is more resistant to oxidation, making it favorable for supplement formulations.

Sources & Quality

Natural vitamin K2 originates primarily from fermented foods (e.g., natto, a Japanese fermented soy product rich in MK-7) and certain animal tissues (e.g., liver, egg yolk, butter) which contain MK-4.
Commercially, MK-7 is most commonly obtained via fermentation of Bacillus subtilis or Bacillus natto on a nutrient-rich medium, followed by extraction, purification (often via chromatography), and spray-drying for capsule or tablet use.
MK-4 is typically produced by chemical synthesis from menadione followed by hydrogenation, or via enzymatic conversion of K1 from plant sources.
Quality considerations include confirming the specific menaquinone isoform (e.g., ≥90 % MK-7), absence of residual bacterial endotoxins, and stability (protect from light and heat).
GMP-certified manufacturers that provide third-party testing (e.g., USP, NSF) ensure consistent potency and minimal contaminants.