Menaquinone 4

• Bone health
• Cardiovascular health
• Calcium regulation
• Tissue-specific vitamin K activity

• Neurological health
• Reproductive health
• Reduced inflammation
• Dental health
• Skin health
• Mitochondrial function

Menaquinone-4 (MK-4) is a short-chain form of vitamin K2 with unique biological activities that distinguish it from other vitamin K forms. Like all vitamin K compounds, MK-4 serves as a cofactor for the enzyme gamma-glutamyl carboxylase, which activates vitamin K-dependent proteins through carboxylation. This post-translational modification enables these proteins to bind calcium ions, which is essential for their biological functions. In bone metabolism, MK-4 activates osteocalcin, allowing it to bind calcium and incorporate it into the bone matrix, thereby promoting bone mineralization and strength.

Similarly, MK-4 activates Matrix Gla Protein (MGP), which prevents calcium deposition in soft tissues and arterial walls, protecting against vascular calcification. What distinguishes MK-4 from other menaquinones is its tissue-specific distribution and unique non-carboxylation-related functions. MK-4 is the predominant form of vitamin K in the brain, pancreas, salivary glands, and reproductive organs, suggesting specialized roles in these tissues. Unlike longer-chain menaquinones, MK-4 can be synthesized in various tissues from vitamin K1 (phylloquinone) through a conversion process involving the enzyme UBIAD1.

This tissue-specific conversion allows for localized production of MK-4 where needed, independent of dietary intake. MK-4 uniquely functions as a ligand for the Steroid and Xenobiotic Receptor (SXR)/Pregnane X Receptor (PXR), a nuclear receptor that regulates the expression of genes involved in bone metabolism, cellular growth, and detoxification processes. Through SXR activation, MK-4 upregulates genes that enhance bone formation and suppress bone resorption, providing a mechanism for its bone-protective effects that is independent of its role in protein carboxylation. In the brain, MK-4 appears to support sphingolipid synthesis, which is crucial for myelin formation and neuronal signaling.

It also exhibits anti-inflammatory properties by inhibiting the production of pro-inflammatory cytokines and may protect against oxidative stress through mechanisms that are still being elucidated. MK-4 has been shown to induce apoptosis in various cancer cell lines, suggesting potential anti-cancer properties. This effect appears to be specific to MK-4 and not shared by other vitamin K forms, highlighting its unique pharmacological profile. The short side chain of MK-4 (four isoprenoid units) gives it different pharmacokinetic properties compared to longer-chain menaquinones like MK-7.

MK-4 has a shorter half-life in circulation (approximately 1-2 hours) but may accumulate more effectively in certain tissues due to its lipophilicity and tissue-specific uptake mechanisms.

The optimal dosage of Menaquinone-4 (MK-4) varies significantly depending on the intended use. For general health maintenance, lower doses of 50-150 μg daily may be sufficient. However, for therapeutic effects, particularly for bone health, much higher doses of 15-45 mg (15,000-45,000 μg) daily have been used in clinical studies. This large discrepancy between nutritional and therapeutic doses is unique to MK-4 among vitamin K forms.

Menaquinone-4 (MK-4) has moderate bioavailability compared to longer-chain menaquinones, with approximately 20-40% absorption when taken with a fat-containing meal. As a fat-soluble vitamin, MK-4 requires dietary fat for optimal absorption in the small intestine. Its short side chain makes it less lipophilic than longer-chain menaquinones like MK-7, which affects its solubility and incorporation into mixed micelles during digestion.

Take with a meal containing healthy fats to enhance absorption, Oil-based or emulsified formulations improve bioavailability, Microencapsulation technology can protect MK-4 from degradation in the stomach, Liposomal delivery systems may enhance cellular uptake, Combining with medium-chain triglycerides (MCT) oil can improve absorption, Dividing higher therapeutic doses (e.g., 45 mg daily) into three equal doses taken with meals throughout the day, Consuming with sources of vitamin D may enhance overall effectiveness due to synergistic effects

MK-4 has a relatively short half-life in circulation (approximately 1-2 hours) compared to longer-chain menaquinones like MK-7 (72 hours). This short half-life necessitates more frequent dosing for therapeutic applications. For general health maintenance at lower doses (50-150 μg), once-daily administration with a fat-containing meal is typically sufficient. However, for therapeutic doses used for bone health (45 mg daily), clinical studies have divided this into three equal doses of 15 mg taken with meals throughout the day to maintain more consistent blood levels.

Morning administration with breakfast is common for single daily doses, but there is no strong evidence that time of day significantly affects absorption when taken with food. For individuals taking medications that may interact with vitamin K (such as warfarin), consistent timing and dosing are essential to maintain stable anticoagulation. Despite its short serum half-life, MK-4 may accumulate in tissues over time, particularly in organs that preferentially take up and store this form of vitamin K2, such as the brain, pancreas, and reproductive organs.

• Rare and generally mild gastrointestinal discomfort
• Allergic reactions (extremely rare)
• Potential interference with anticoagulant medications (warfarin/Coumadin)
• Mild skin rash (rare)
• Transient elevation of liver enzymes (rare, at high doses)

• Individuals on vitamin K antagonist anticoagulant therapy (e.g., warfarin) without medical supervision
• Known hypersensitivity to menaquinone-4 or any component of the formulation
• Caution advised during pregnancy and lactation due to limited safety data at pharmacological doses
• Severe liver disease (due to potential impact on vitamin K metabolism)

• Vitamin K antagonist anticoagulants (warfarin/Coumadin) – MK-4 can reduce the effectiveness of these medications
• Antibiotics – May reduce vitamin K production by gut bacteria, potentially enhancing MK-4 effects
• Bile acid sequestrants (cholestyramine, colestipol) – May reduce absorption of fat-soluble vitamins including MK-4
• Orlistat and other lipase inhibitors – May reduce absorption of fat-soluble vitamins including MK-4
• Statins – Theoretical interaction as both may affect bone metabolism, though clinical significance is unclear
• No significant interactions with other common medications have been reported

No official upper limit has been established for MK-4. Remarkably, even at pharmacological doses of 45 mg daily (300 times higher than typical nutritional doses), MK-4 has demonstrated an excellent safety profile in clinical trials. In Japan, where MK-4 is approved as a medication for osteoporosis at a dose of 45 mg daily, long-term safety data has not revealed significant adverse effects. Unlike many fat-soluble vitamins that can accumulate to toxic levels, vitamin K does not appear to cause hypervitaminosis even at high doses.

This is likely because vitamin K is rapidly metabolized and excreted, and the body has effective mechanisms to recycle and regulate vitamin K. However, individuals with certain medical conditions or those taking medications that interact with vitamin K should consult healthcare providers before taking high-dose MK-4 supplements.

In the United States, Menaquinone-4 (MK-4) is regulated as a dietary supplement ingredient under the Dietary Supplement Health and Education Act (DSHEA) of 1994. It is not approved as a drug for the prevention or treatment of any disease, despite its pharmaceutical status in Japan. The FDA allows qualified health claims related to vitamin K and bone health, though not specifically for MK-4. Manufacturers must ensure product safety and cannot make disease treatment claims.

Unlike in Japan, where high-dose MK-4 (45 mg daily) is prescribed for osteoporosis, such therapeutic applications are not officially recognized by the FDA.

Japan: MK-4 holds a unique regulatory status in Japan, where it is approved as a prescription medication (menatetrenone) for the treatment of osteoporosis at a dose of 45 mg daily. It has been used clinically since 1995 and is covered by the Japanese national health insurance system for this indication. This represents one of the few cases worldwide where a vitamin form is recognized and regulated as a pharmaceutical agent at doses far exceeding nutritional requirements.

Eu: The European Food Safety Authority (EFSA) has approved MK-4 as a safe ingredient in food supplements. In 2009, EFSA established an Adequate Intake (AI) for vitamin K of 70 μg/day for adults, though this does not distinguish between K1 and K2 forms. The European Commission has authorized certain health claims related to vitamin K’s contribution to normal blood clotting and maintenance of normal bones, which apply to MK-4 as a form of vitamin K. However, unlike Japan, the EU does not recognize MK-4 as a medication for osteoporosis.

Canada: Health Canada has approved MK-4 as a Natural Health Product (NHP) ingredient. It is included in the Natural Health Products Ingredients Database with approved claims for bone health and blood coagulation. The recommended daily allowance is similar to European standards. High-dose applications similar to the Japanese pharmaceutical use are not approved.

Australia: The Therapeutic Goods Administration (TGA) regulates MK-4 as a complementary medicine ingredient. It is listed in the Australian Register of Therapeutic Goods (ARTG) and can be used in listed medicines with appropriate evidence levels for claims. As in most Western countries, Australia does not recognize the high-dose therapeutic applications approved in Japan.

China: The National Medical Products Administration (NMPA) regulates MK-4 as a health food ingredient. New regulations implemented in recent years have increased scrutiny of health claims and quality standards for supplements containing MK-4. Limited approval exists for therapeutic applications.

Medium for nutritional doses, high for therapeutic doses

For standard nutritional MK-4 supplements (100-150 μg daily dose), the typical cost ranges from $0.20 to $1.00 per day, depending on brand and formulation. For therapeutic doses (45 mg daily) used for bone health, costs increase significantly to $2.00-$5.00 per day for pharmaceutical-grade products. In Japan, where MK-4 is prescribed as a medication (menatetrenone), costs may be partially covered by health insurance.

The cost-efficiency of MK-4 varies dramatically depending on the intended use and dosage. For general nutritional purposes at lower doses (50-150 μg daily), MK-4 represents reasonable value comparable to other vitamin supplements. However, for therapeutic applications requiring pharmacological doses (45 mg daily, or 300 times higher than nutritional doses), the cost-efficiency equation changes substantially. At therapeutic doses, several factors affect the value proposition: First, the high dosage requirement (45 mg daily) makes MK-4 significantly more expensive than many other bone health supplements.

Second, the need for multiple daily doses due to MK-4’s short half-life (typically three 15 mg doses) adds to the complexity and potential compliance issues. Third, the clinical evidence for bone health benefits at these doses is substantial, particularly from Japanese studies, potentially justifying the higher cost for individuals with osteoporosis or at high risk. Fourth, compared to prescription osteoporosis medications like bisphosphonates, even high-dose MK-4 may be cost-competitive and may have a more favorable side effect profile for long-term use. For maximum cost efficiency with therapeutic doses, consumers should consider: pharmaceutical-grade MK-4 (menatetrenone) similar to what’s used in clinical studies; products with verified potency through third-party testing; formulations that enhance absorption to potentially allow for lower effective doses; and combination products that include synergistic nutrients like vitamin D3 and calcium for comprehensive bone support.

For general health maintenance, lower-dose MK-4 or mixed vitamin K2 supplements (containing both MK-4 and MK-7) may offer better value than high-dose MK-4 alone.

Properly formulated and packaged MK-4 supplements typically have a shelf life of 2-3 years from the date of manufacture. However, this can vary based on formulation, packaging, and storage conditions. Microencapsulated or stabilized formulations may have extended shelf life.

Store in a cool, dry place away from direct sunlight and heat sources. Optimal temperature range is 59-77°F (15-25°C). Refrigeration is not necessary but may extend potency in hot climates. Keep container tightly closed to protect from moisture and oxygen exposure. For oil-based or liquid formulations, refrigeration after opening may help maintain freshness. Avoid storing in bathrooms or other humid environments.

Exposure to ultraviolet light and direct sunlight – MK-4 is photosensitive and can degrade when exposed to UV radiation, High temperatures – Heat accelerates oxidation and isomerization processes that reduce potency, Oxygen exposure – Oxidation is a primary degradation pathway for MK-4, Humidity – Can accelerate degradation, especially in powder formulations, pH extremes – MK-4 is most stable at neutral to slightly acidic pH, Presence of oxidizing agents or certain minerals in formulations, Improper packaging – Permeable packaging materials can allow oxygen and moisture penetration, Extended storage beyond expiration date – Gradual loss of potency occurs over time even under ideal conditions, Freeze-thaw cycles – Can affect stability, particularly in liquid formulations

Synthesis Methods

Natural Sources

Quality Considerations

Menaquinone-4 (MK-4) has a unique historical trajectory that differs from other forms of vitamin K. While vitamin K itself was discovered by Henrik Dam in 1929 (for which he received the Nobel Prize in 1943), the specific identification and understanding of MK-4 came much later. Traditional diets rich in animal foods, particularly organ meats and animal fats, naturally provided MK-4, though its nutritional significance was not recognized until the late 20th century. The modern history of MK-4 as a therapeutic agent began in Japan in the 1990s.

Japanese researchers identified MK-4’s potential benefits for bone health and conducted extensive clinical trials using pharmacological doses (45 mg daily). This research led to the approval of MK-4 (under the name menatetrenone) as a prescription medication for osteoporosis in Japan in 1995. This represents a unique case where a vitamin form was approved as a pharmaceutical at doses hundreds of times higher than typical nutritional requirements. The Japanese approval of MK-4 for osteoporosis treatment sparked international interest in its therapeutic potential.

However, regulatory approaches have varied significantly between countries. While Japan embraced MK-4 as a prescription medication, most Western countries have classified it as a dietary supplement, subject to less rigorous regulation. A key discovery in MK-4 research was the identification of its unique tissue-specific distribution and the body’s ability to convert other forms of vitamin K to MK-4 in certain tissues. This conversion, mediated by the enzyme UBIAD1, explained the presence of MK-4 in tissues even when dietary intake was primarily from vitamin K1 (phylloquinone) in plants.

This finding, elucidated in the early 2000s, highlighted MK-4’s special biological significance beyond being merely one form of vitamin K. Another significant historical development was the discovery that MK-4 functions as a ligand for the Steroid and Xenobiotic Receptor (SXR)/Pregnane X Receptor (PXR), providing a mechanism for its effects on bone metabolism independent of protein carboxylation. This finding, published in 2003, expanded understanding of MK-4’s biological roles beyond the classical vitamin K functions. In recent years, research interest in MK-4 has expanded beyond bone health to include potential benefits for cardiovascular health, neurological function, and cancer prevention.

However, clinical evidence remains strongest for its applications in bone health, reflecting its historical development as an osteoporosis treatment in Japan.

Cockayne S, Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ. Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166(12):1256-1261., Huang ZB, Wan SL, Lu YJ, Ning L, Liu C, Fan SW. Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials. Osteoporos Int. 2015;26(3):1175-1186., Fang Y, Hu C, Tao X, Wan Y, Tao F. Effect of vitamin K on bone mineral density: a meta-analysis of randomized controlled trials. J Bone Miner Metab. 2012;30(1):60-68.

MK-4 supplementation for cognitive function in older adults – Investigating potential neuroprotective effects, Combination therapy of MK-4 with vitamin D for osteoporosis prevention, MK-4 effects on glucose metabolism and insulin sensitivity, Comparative effectiveness of different vitamin K2 forms (MK-4 vs MK-7) for bone health markers