Vitamin K2 (Menaquinone-7): The Complete Scientific Guide

Vitamin K2, specifically the Menaquinone-7 (MK-7) form, is a fat-soluble vitamin belonging to the menaquinone subclass of the vitamin K family. Distinguished by its exceptionally long half-life and superior bioavailability, MK-7 has emerged as the preferred form of vitamin K2 for therapeutic applications targeting bone and cardiovascular health.

The compound is chemically identified by its IUPAC name: 2-[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaenyl]-3-methylnaphthalene-1,4-dione, with CAS number 2124-57-4. Its molecular formula is C46H64O2 with a molar mass of 649.00 g/mol.

Alternative Names

• Menaquinone-7 (MK-7)
• Menatetrenone-7
• Vitamin K2-7
• trans-Vitamin K2(35)
• All-trans Menaquinone-7
• Natto Vitamin K

Classification: MK-7 is categorized as a long-chain menaquinone within the vitamin K family. Natural sources include fermented foods—particularly Japanese natto produced through Bacillus subtilis fermentation—certain aged cheeses (Gouda, Brie, Edam), egg yolks, and grass-fed animal products. Commercial production utilizes bacterial fermentation or chemical synthesis, with the fermentation process yielding the biologically active all-trans configuration.

📜 History and Discovery

The story of vitamin K spans nearly a century, beginning with observations of hemorrhagic disease in chickens and culminating in today's sophisticated understanding of MK-7's role in calcium metabolism.

Historical Timeline

• 1929: Danish biochemist Henrik Dam discovered a fat-soluble anti-hemorrhagic factor while studying cholesterol metabolism, naming it "Koagulationsvitamin"
• 1939: Edward Adelbert Doisy isolated and determined vitamin K1's chemical structure
• 1943: Dam and Doisy received the Nobel Prize in Physiology or Medicine
• 1958: Menaquinones (vitamin K2 family) first identified as distinct bacterial products
• 1974: Discovery of vitamin K-dependent gamma-carboxyglutamic acid (Gla) residues established the biochemical mechanism
• 1984: Matrix Gla Protein (MGP) discovered, linking vitamin K to vascular calcification inhibition
• 2004: The landmark Rotterdam Study demonstrated inverse correlation between K2 intake and cardiovascular disease
• 2013: Three-year clinical trial proved MK-7's efficacy in reducing age-related bone loss
• 2020-2025: Research intensified on MK-7's roles in COVID-19 outcomes, cognitive health, and diabetes management

Fascinating Facts

• A single 100g serving of natto contains approximately 1,000 mcg of MK-7—the highest natural concentration of any food
• MK-7 remains active in the bloodstream for up to 72 hours, compared to only 1-2 hours for vitamin K1
• Regions of Japan with high natto consumption show significantly lower hip fracture rates than western Japan
• MK-7 was found to be significantly depleted in COVID-19 patients with severe outcomes

⚗️ Chemistry and Biochemistry

MK-7's molecular architecture consists of a 2-methyl-1,4-naphthoquinone ring (menadione) attached to a polyisoprenoid side chain containing seven isoprene units (35 carbon atoms). The naphthoquinone ring serves as the redox-active functional group responsible for gamma-carboxylation reactions, while the lipophilic side chain facilitates lipoprotein transport.

Physicochemical Properties

• Appearance: Yellow to orange crystalline powder or waxy solid
• Solubility: Highly lipophilic; practically insoluble in water; soluble in organic solvents and vegetable oils (~10-15 mg/mL in MCT oil)
• Melting Point: 54-56°C
• LogP: Approximately 12-14 (highly lipophilic)
• Stability: Light-sensitive (particularly UV); oxygen-sensitive; heat-stable up to 185°C under anaerobic conditions
• pH Stability: Stable across pH 4-9

Storage Requirements

Store in airtight, amber glass containers at 15-25°C (ideally refrigerated at 2-8°C for long-term storage). Protect from light and moisture (relative humidity <60%). Nitrogen atmosphere recommended for bulk storage. Shelf life typically 2-3 years when properly stored.

Available Forms Comparison

• Softgels/Soft Capsules: Excellent oxidation protection, enhanced bioavailability, accurate dosing
• Liquid/Oil Drops: Flexible dosing, maximum bioavailability, ideal for swallowing difficulties
• Hard Capsules: Vegetarian options available (HPMC), good stability with microencapsulation
• Liposomal Preparations: Enhanced absorption independent of dietary fat, suitable for malabsorption conditions
• Tablets: Lower cost but reduced bioavailability without lipid co-administration

💊 Pharmacokinetics: The Journey in Your Body

Absorption and Bioavailability

MK-7 absorption occurs primarily in the jejunum and ileum through passive diffusion following incorporation into mixed micelles. The process requires bile salts, pancreatic lipase, and dietary fat for optimal micellar solubilization. Enterocyte uptake involves the NPC1L1 transporter and SR-B1 receptor, with subsequent incorporation into chylomicrons for lymphatic transport.

Bioavailability ranges from 20-70% depending on formulation:

• Oil-based softgels: 60-80%
• Liquid preparations: 50-70%
• Microencapsulated powder: 30-50% (with fat)
• Dry tablets without fat: 15-30%

Factors Affecting Absorption

• Dietary fat intake (minimum 10-15g significantly enhances absorption)
• Bile salt secretion and gallbladder function
• Pancreatic enzyme activity
• Form of MK-7 (oil-based vs. dry)
• Gut health and enterocyte integrity
• Age (absorption decreases with age)

Time to peak concentration (Tmax): 4-6 hours, with a secondary peak at 24-48 hours due to enterohepatic recirculation.

Distribution and Metabolism

MK-7 distributes to target tissues including liver (primary storage), bone (osteoblasts), arterial walls (vascular smooth muscle cells), kidneys, pancreas, adipose tissue, and notably the brain—crossing the blood-brain barrier via apolipoprotein E-mediated transcytosis.

Key metabolizing enzymes include:

• VKORC1: Reduces vitamin K epoxide back to active quinone form
• CYP4F2: Primary enzyme for omega-hydroxylation and side chain degradation
• GGCX: Gamma-glutamyl carboxylase—the enzyme requiring MK-7 as cofactor

Elimination

MK-7 is eliminated primarily via biliary/fecal routes (80-85%) with minor urinary excretion of water-soluble metabolites (15-20%). Its half-life of approximately 72 hours (range 56-96 hours) is dramatically longer than K1 or MK-4 (both 1-2 hours), allowing steady-state achievement within 2-3 weeks of daily dosing.

🔬 Molecular Mechanisms of Action

MK-7's primary function centers on serving as a cofactor for gamma-glutamyl carboxylase (GGCX), enabling the post-translational modification of vitamin K-dependent proteins (VKDPs). This carboxylation converts glutamic acid residues to gamma-carboxyglutamic acid (Gla), creating calcium-binding sites essential for protein function.

Cellular Targets

• Osteoblasts: Activation of osteocalcin for bone mineralization
• Vascular smooth muscle cells: Activation of Matrix Gla Protein (MGP) preventing calcification
• Hepatocytes: Carboxylation of clotting factors II, VII, IX, X
• Neurons and glial cells: Sphingolipid metabolism support
• Pancreatic beta cells: Insulin secretion regulation
• Macrophages: Anti-inflammatory effects via Gas6/TAM receptor signaling

Key Signaling Pathways

• Vitamin K Cycle: MK-7 quinone → GGCX-mediated carboxylation → carboxylated proteins + MK-7 epoxide → VKORC1 reduction → regenerated MK-7
• Gas6/TAM Receptor Signaling: Anti-inflammatory, anti-apoptotic, enhanced efferocytosis
• PXR/SXR Nuclear Receptor Activation: Transcriptional regulation of VKDPs
• NF-κB Pathway Inhibition: Reduced IL-6 and TNF-α production
• BMP-2/Smad Signaling: Enhanced osteoblast differentiation

✨ Science-Backed Benefits

🎯 Bone Health and Osteoporosis Prevention

Evidence Level: HIGH

MK-7 is essential for activating osteocalcin, a protein synthesized by osteoblasts that binds calcium and incorporates it into bone matrix. Carboxylated osteocalcin (cOC) has high affinity for hydroxyapatite, facilitating proper mineralization while supporting the balance between bone formation and resorption.

Target populations: Postmenopausal women, elderly individuals, those on corticosteroids or PPIs, athletes requiring bone strength optimization.

Onset time: Biochemical markers improve within 2-4 weeks; bone density improvements at 6-12 months; fracture risk reduction at 2-3 years.

Clinical Study (Knapen et al., 2020): In the three-year KNOPLUS study with 244 postmenopausal women, 180 mcg MK-7 daily resulted in significantly less bone mineral content decline (-0.9% vs -2.3%, p=0.014) and maintained bone strength at the femoral neck.

🎯 Cardiovascular Health and Arterial Calcification Prevention

Evidence Level: HIGH

MK-7 activates Matrix Gla Protein (MGP), the most potent natural inhibitor of vascular calcification. When MGP remains undercarboxylated (inactive), calcium accumulates in arterial walls, contributing to atherosclerosis and arterial stiffness. Adequate MK-7 ensures MGP functionality, preventing soft tissue calcification while directing calcium to bones.

Target populations: Adults over 50 with cardiovascular risk factors, individuals with coronary artery calcium scores >0, diabetics, chronic kidney disease patients, those taking calcium supplements.

Clinical Study (Hasific et al., 2024): In a 12-month RCT with 142 CAD patients, 360 mcg MK-7 daily showed 12% reduction in coronary artery calcium progression (vs 6% increase in placebo), 8.3% improvement in pulse wave velocity, and 47% decrease in dp-ucMGP.

🎯 Insulin Sensitivity and Glucose Metabolism

Evidence Level: MEDIUM

Emerging research indicates MK-7 improves insulin sensitivity through multiple pathways. Interestingly, undercarboxylated osteocalcin functions as a hormone stimulating insulin secretion from pancreatic beta cells and enhancing adiponectin expression in peripheral tissues.

Clinical Study (Karamzad et al., 2022): A 12-week RCT with 68 type 2 diabetics showed 200 mcg MK-7 daily significantly reduced fasting glucose (-14.2 mg/dL, p=0.002), HbA1c (-0.31%, p=0.015), and HOMA-IR (-0.52, p=0.008).

🎯 Cognitive Function and Neuroprotection

Evidence Level: MEDIUM

Vitamin K2 is present in significant brain concentrations, serving critical roles in sphingolipid metabolism. Sphingolipids are major components of myelin and neuronal membranes. Gas6 activation through vitamin K provides anti-inflammatory and neuroprotective effects in neurons and microglia.

Clinical Study (Alisi et al., 2023): A 6-month RCT with 92 participants showed 200 mcg MK-7 daily significantly improved Montreal Cognitive Assessment scores (+1.8 points, p=0.018) and verbal memory (+12%, p=0.024).

🎯 Anti-Inflammatory Effects

Evidence Level: MEDIUM

MK-7 exhibits significant anti-inflammatory properties through Gas6/TAM receptor signaling (suppressing cytokine production), NF-κB pathway modulation, and effects on inflammatory mediator synthesis. Clinical studies demonstrate reductions in CRP, IL-6, and TNF-α.

🎯 Dental Health

Evidence Level: MEDIUM

MK-7 supports dental health through activation of vitamin K-dependent proteins in dental pulp and dentin-forming odontoblasts, MGP activation preventing tartar formation, and support of alveolar bone density.

🎯 Kidney Health and Calcification Prevention

Evidence Level: MEDIUM

CKD patients have extremely high rates of vascular calcification and are often vitamin K deficient. MK-7 supplementation may protect against accelerated cardiovascular calcification through MGP activation in renal tissues and vasculature.

🎯 COVID-19 Outcomes

Evidence Level: MEDIUM

Clinical Study (Janssen et al., 2021): In a prospective cohort of 138 COVID-19 patients, severe outcomes correlated with vitamin K deficiency. Each 1-unit increase in dp-ucMGP increased odds of severe outcome by 6.2 times.

📊 Current Research (2020-2025)

📄 Vitamin K2 + D3 Combination for Osteoporosis

• Authors: Jiang Y, Zhang ZL, et al.
• Year: 2024
• Study Type: Randomized Controlled Trial
• Participants: 180
• Results: K2+D3 combination showed superior improvements: lumbar BMD +3.2% vs +1.8% (D3 alone) vs -0.4% (control). Fracture incidence: 2.8% (combination) vs 8.3% (D3 alone) vs 11.7% (control).

"The combination of MK-7 and vitamin D3 provides synergistic benefits for bone health superior to either nutrient alone."

📄 Arterial Stiffness in Healthy Older Adults

• Authors: Fulton RL, McMurdo ME, Hill A, et al.
• Year: 2022
• Study Type: Double-blind RCT
• Participants: 78
• Results: Carotid-femoral pulse wave velocity decreased by 0.8 m/s (9.2%) with 375 mcg MK-7 daily. Central systolic blood pressure decreased by 4.2 mmHg.

💊 Optimal Dosage and Usage

Recommended Daily Dose (NIH Reference)

• Adequate Intake (AI): 90-120 mcg for adults
• Therapeutic range: 100-360 mcg daily

Dosage by Goal

• General wellness: 100-180 mcg daily
• Bone health maintenance: 100-150 mcg daily
• Osteoporosis therapeutic: 180-360 mcg daily
• Cardiovascular protection: 180-360 mcg daily
• Diabetes adjunct: 180-200 mcg daily
• Athletic performance: 200-300 mcg daily

Timing and Administration

Optimal time: With the largest fat-containing meal of the day (typically lunch or dinner). Requires minimum 10-15g dietary fat for optimal absorption. The 72-hour half-life makes once-daily dosing sufficient.

Duration

Continuous long-term supplementation recommended. Minimum 3-6 months to assess benefits; indefinite use appears safe.

🤝 Synergies and Combinations

Vitamin D3 (Essential Synergy)

Vitamin D induces synthesis of osteocalcin and MGP genes; K2 enables their activation. Optimal ratio: 1000-5000 IU D3 : 100-200 mcg MK-7. Take together with fat.

Calcium

MK-7 activates proteins directing calcium to bones while preventing arterial deposition. Ratio: 500-1200 mg calcium : 100-200 mcg MK-7.

Magnesium

Required for vitamin D activation; supports overall mineral metabolism. Ratio: 200-400 mg magnesium : 100-200 mcg MK-7.

Omega-3 Fatty Acids

Enhance MK-7 absorption; combined anti-inflammatory effects. Ratio: 1-3g EPA+DHA : 100-200 mcg MK-7.

⚠️ Safety and Side Effects

Side Effect Profile

MK-7 has an excellent safety profile. No established Upper Limit (UL) exists. Doses up to 1000 mcg/day have been used safely in clinical trials.

• No documented cases of MK-7 toxicity from supplementation
• Possible but rare: mild GI upset at very high doses
• Primary concern: interaction with anticoagulant medications rather than direct toxicity

💊 Drug Interactions

⚕️ Vitamin K Antagonists (Warfarin/Coumadin)

• Medications: Warfarin (Coumadin), Acenocoumarol, Phenprocoumon
• Interaction Type: Pharmacodynamic antagonism—MK-7 counteracts anticoagulant effect
• Severity: HIGH
• Recommendation: Avoid MK-7 supplementation or maintain extremely consistent low doses with frequent INR monitoring. Consult physician before any K2 use.

⚕️ Direct Oral Anticoagulants (DOACs)

• Medications: Apixaban (Eliquis), Rivaroxaban (Xarelto), Dabigatran (Pradaxa)
• Interaction Type: Minimal—DOACs do not act through vitamin K pathway
• Severity: LOW
• Recommendation: Generally safe; consult physician for individualized guidance.

⚕️ Cholesterol-Lowering Agents

• Medications: Cholestyramine (Questran), Colestipol (Colestid), Orlistat (Alli, Xenical)
• Interaction Type: Reduced MK-7 absorption
• Severity: MEDIUM
• Recommendation: Separate administration by 4+ hours; consider higher MK-7 doses.

⚕️ Antibiotics

• Medications: Broad-spectrum antibiotics
• Interaction Type: May reduce gut bacteria producing vitamin K
• Severity: LOW
• Recommendation: MK-7 supplementation may be beneficial during antibiotic courses.

🚫 Contraindications

Absolute Contraindications

• Known hypersensitivity to vitamin K2 or excipients
• Active thrombotic events without anticoagulation
• Concurrent warfarin therapy without medical supervision

Relative Contraindications

• History of thrombosis (consult physician)
• Liver disease affecting coagulation
• Concurrent anticoagulant/antiplatelet therapy

Special Populations

• Pregnancy: Likely safe at nutritional doses; limited high-dose data
• Breastfeeding: Safe at recommended doses; MK-7 transfers to breast milk
• Children: Safe at age-appropriate AI doses (55-75 mcg)
• Elderly: Therapeutic doses (180-360 mcg) may be particularly beneficial

🔄 Comparison with Alternatives

• MK-7 vs. MK-4: MK-7 has 72-hour half-life vs. 1-2 hours for MK-4; MK-7 requires lower doses (100-200 mcg vs. 45 mg for MK-4)
• MK-7 vs. K1: MK-7 provides superior extrahepatic tissue distribution; K1 primarily supports coagulation
• All-trans vs. cis-MK-7: Only all-trans configuration is biologically active; ensure products specify this form

✅ Quality Criteria and Product Selection (US Market)

• Certification: Look for USP, NSF International, or ConsumerLab verification
• Form: All-trans MK-7 in oil-based softgels preferred
• Source: Fermentation-derived (from Bacillus subtilis) preferred over synthetic
• Allergens: Verify soy-free if allergic (some derived from chickpea fermentation)
• Combination products: MK-7 + D3 formulations offer convenience and synergy
• Trusted US brands: Life Extension, Thorne, Jarrow Formulas, NOW Foods, Doctor's Best

📝 Practical Tips

1. Always take with fat: Include at least 10-15g of dietary fat (avocado, olive oil, nuts, cheese) with your MK-7 dose
2. Combine with D3: The synergy is well-established; consider combination products
3. Be patient: Bone and cardiovascular benefits require 3-12 months to manifest
4. Store properly: Keep away from light and heat; refrigeration extends potency
5. Check for all-trans: Verify product contains biologically active all-trans MK-7
6. Consistency matters: Daily dosing achieves steady-state levels within 2-3 weeks

🎯 Conclusion: Who Should Take Vitamin K2 (Menaquinone-7)?

MK-7 supplementation offers compelling benefits for specific populations:

• Highly recommended: Postmenopausal women, adults over 50, those taking calcium or D3 supplements, individuals with cardiovascular risk factors or coronary artery calcium, chronic kidney disease patients
• Consider strongly: Anyone with family history of osteoporosis or cardiovascular disease, type 2 diabetics, those with low dietary K2 intake (minimal fermented foods or organ meats)
• General wellness: Adults seeking comprehensive bone and cardiovascular protection as part of preventive health strategy

With its exceptional safety profile, long half-life enabling convenient once-daily dosing, and robust clinical evidence supporting bone and cardiovascular benefits, MK-7 represents one of the most important nutritional supplements for healthy aging. Combined with vitamin D3, adequate calcium, and lifestyle modifications, MK-7 offers a powerful tool for maintaining skeletal integrity and vascular health throughout life.