Vitamin K2

• Bone health
• Cardiovascular health
• Calcium regulation
• Arterial flexibility

• Dental health
• Insulin sensitivity
• Mitochondrial function
• Brain health
• Skin health
• Cancer risk reduction

Vitamin K2 exerts its diverse biological effects primarily through its role as a cofactor for the enzyme gamma-glutamyl carboxylase, which catalyzes the post-translational carboxylation of specific glutamic acid (Glu) residues to form gamma-carboxyglutamic acid (Gla) in vitamin K-dependent proteins. This carboxylation process is essential for the activation of these proteins, enabling them to bind calcium ions and fulfill their respective functions. While vitamin K1 (phylloquinone) primarily supports blood coagulation through the activation of clotting factors, vitamin K2 (menaquinones) appears to have a broader range of actions, particularly in extrahepatic (non-liver) tissues. The most well-established mechanism of vitamin K2 involves its activation of osteocalcin, a protein produced by osteoblasts (bone-forming cells).

When carboxylated by vitamin K2, osteocalcin gains the ability to bind calcium and incorporate it into the bone matrix, promoting proper bone mineralization and structure. Inadequate vitamin K2 results in undercarboxylated osteocalcin, which cannot effectively bind calcium, potentially leading to reduced bone mineral density and increased fracture risk. Equally important is vitamin K2’s role in activating Matrix Gla Protein (MGP), a potent inhibitor of tissue calcification. When properly carboxylated, MGP prevents calcium from depositing in soft tissues such as arteries and cartilage.

Without sufficient vitamin K2, undercarboxylated MGP cannot function effectively, potentially allowing inappropriate calcium deposition in arterial walls. This mechanism explains vitamin K2’s paradoxical ability to simultaneously promote calcium incorporation into bone while preventing its deposition in arteries—essentially directing calcium to where it belongs (bones) and away from where it doesn’t (blood vessels). Beyond these classical roles, vitamin K2 activates several other Gla proteins with diverse functions. Growth Arrest-Specific Protein 6 (Gas6) is involved in cell growth regulation, survival, and inflammation.

Gla-rich protein (GRP) appears to inhibit calcification in multiple tissues. Periostin, another vitamin K-dependent protein, contributes to bone and dental health. Vitamin K2 also demonstrates regulatory effects on gene expression that extend beyond its role as a cofactor for gamma-glutamyl carboxylase. Research indicates that vitamin K2, particularly the MK-4 form, can influence the expression of genes involved in bone metabolism, inflammation, and oxidative stress.

It appears to upregulate genes associated with bone formation while downregulating those involved in bone resorption, providing an additional mechanism for its bone-protective effects. In the realm of energy metabolism, vitamin K2 influences mitochondrial function through several pathways. It serves as an electron carrier in the electron transport chain, potentially enhancing ATP production. Additionally, vitamin K2 appears to improve mitochondrial bioenergetics by reducing oxidative stress and supporting membrane integrity.

These effects may contribute to improved cellular energy production and reduced oxidative damage. Vitamin K2 also demonstrates anti-inflammatory properties through multiple mechanisms. It inhibits nuclear factor-kappa B (NF-κB) signaling, a key pathway in inflammatory responses, thereby reducing the production of pro-inflammatory cytokines. This anti-inflammatory action may contribute to vitamin K2’s protective effects in various tissues, including the cardiovascular system and bones.

In the brain, emerging research suggests that vitamin K2 may support neuronal health through its antioxidant properties and by activating specific proteins involved in sphingolipid metabolism. Sphingolipids are important components of cell membranes, particularly abundant in brain tissue, and play roles in cell signaling and survival. The different forms of vitamin K2 (MK-4, MK-7, etc.) appear to have somewhat distinct pharmacokinetics and possibly different tissue distributions, which may influence their biological effects. MK-4 has a shorter half-life but may have unique effects on gene expression, while MK-7 remains in circulation longer, potentially providing more sustained activation of vitamin K-dependent proteins.

Through these diverse and complementary mechanisms—activation of vitamin K-dependent proteins, regulation of gene expression, support of mitochondrial function, and modulation of inflammatory pathways—vitamin K2 influences numerous physiological processes, explaining its wide range of observed health benefits across multiple body systems.

The Adequate Intake (AI) established by the Food and Nutrition Board for vitamin K (combining K1 and K2) is 120 mcg/day for adult men and 90 mcg/day for adult women. However, this recommendation primarily focuses on the amount needed for proper blood clotting and does not specifically address the potentially higher requirements for optimal bone and cardiovascular health. For vitamin K2 specifically, no official Recommended Dietary Allowance (RDA) has been established. Based on clinical research, effective doses for health benefits beyond basic coagulation typically range from 45-320 mcg/day for MK-7 and 1,500-45,000 mcg/day for MK-4.

The optimal dose varies significantly depending on the specific form of vitamin K2, the health goal, individual factors such as age and health status, and dietary intake. MK-7 (menaquinone-7) has a longer half-life and better bioavailability than MK-4, allowing for lower doses and once-daily administration. Clinical studies showing benefits for bone and cardiovascular health have typically used 100-200 mcg/day of MK-7. MK-4 (menaquinone-4) has a shorter half-life, requiring higher doses or multiple daily administrations.

In Japan, 45 mg/day (45,000 mcg) of MK-4 is an approved treatment for osteoporosis, though lower doses may provide benefits for general health maintenance. For general health maintenance in healthy adults with no specific deficiency concerns, 100-200 mcg/day of MK-7 or 1,000-2,000 mcg/day of MK-4 is often recommended. The dietary intake of vitamin K2 in Western populations is estimated to be quite low, typically 10-20 mcg/day, which may be insufficient for optimal activation of vitamin K-dependent proteins in extrahepatic tissues.

Vitamin K2 demonstrates variable bioavailability, with absorption rates typically ranging from 10-80% depending on the specific form (MK-4, MK-7, etc.), formulation, dietary context, and individual physiological differences. As a fat-soluble vitamin, K2 requires dietary fat for optimal absorption. The absorption process begins in the small intestine, where vitamin K2 is incorporated into mixed micelles formed by bile salts and dietary lipids. These micelles facilitate K2’s transport across the intestinal mucosa, where it is taken up by enterocytes.

Within enterocytes, vitamin K2 is incorporated into chylomicrons and released into the lymphatic system, eventually entering the bloodstream. The form of vitamin K2 significantly impacts its bioavailability and pharmacokinetics. MK-7 (menaquinone-7) has substantially better bioavailability than MK-4 (menaquinone-4), with studies showing that MK-7 remains in circulation much longer. MK-7 has a half-life of approximately 3 days, compared to only a few hours for MK-4.

This extended half-life allows MK-7 to reach and activate vitamin K-dependent proteins in extrahepatic tissues more effectively with once-daily dosing. The molecular structure of different menaquinones affects their lipophilicity and distribution. Longer-chain menaquinones like MK-7 are more lipophilic than shorter-chain forms like MK-4, which influences their absorption, transport, and tissue distribution patterns. The trans isomer of vitamin K2 is significantly more bioactive than the cis isomer, with research indicating that the trans form is the naturally occurring and biologically active configuration.

Some supplement formulations may contain a mixture of isomers, potentially reducing their biological activity. Individual factors affecting vitamin K2 absorption include age, genetic variations in vitamin K metabolism, gut health, and nutritional status. Conditions that impair fat absorption, such as certain gastrointestinal disorders, pancreatic insufficiency, or cholestatic liver disease, can significantly reduce vitamin K2 bioavailability. Once absorbed, vitamin K2 is primarily transported by lipoproteins in the bloodstream, with different menaquinones showing varying distribution patterns among lipoprotein fractions.

MK-4 appears to be preferentially taken up by tissues with high metabolic activity, while longer-chain menaquinones may have different tissue distribution patterns. Vitamin K2 demonstrates tissue-specific accumulation, with particular affinity for bone, liver, and arterial tissues, which aligns with its biological roles in these areas. The presence of vitamin K2 in these tissues allows for the activation of vitamin K-dependent proteins that regulate calcium metabolism and utilization.

Consuming with a meal containing healthy fats (olive oil, avocado, nuts) significantly enhances absorption, Oil-based or emulsified supplement formulations improve bioavailability compared to powder forms, Choosing MK-7 form over MK-4 for better bioavailability and longer half-life, Ensuring adequate bile production and flow (crucial for fat-soluble vitamin absorption), Trans isomer formulations provide better bioactivity than cis isomers or mixed isomer products, Medium-chain triglycerides (MCT oil) may enhance absorption compared to long-chain triglycerides, Liposomal delivery systems can increase bioavailability by protecting vitamin K2 and facilitating cellular uptake, Formulations with added phospholipids (lecithin) can enhance micelle formation and absorption, Maintaining healthy gut function and microbiome, as intestinal inflammation or dysbiosis may impair absorption, Addressing any underlying fat malabsorption issues (e.g., with digestive enzymes if pancreatic insufficiency is present)

For optimal absorption of vitamin K2 supplements, timing relative to meals is more important than time of day. Taking vitamin K2 with a meal containing some fat significantly enhances absorption, as the presence of dietary fat stimulates bile release and promotes the formation of mixed micelles necessary for vitamin K2 uptake. A meal containing at least 3-5 grams of fat is generally sufficient to enhance vitamin K2 absorption. For MK-7 (menaquinone-7), with its long half-life of approximately 3 days, the specific timing of supplementation is less critical.

Once-daily dosing at any time of day (with a meal containing fat) is sufficient to maintain stable blood levels. For MK-4 (menaquinone-4), with its much shorter half-life of a few hours, more frequent dosing or higher single doses may be necessary to maintain adequate tissue levels throughout the day. Some practitioners recommend dividing MK-4 supplementation into 2-3 doses throughout the day, each taken with meals. For those taking multiple supplements, vitamin K2 can generally be taken alongside most other supplements without significant interaction concerns.

It is often beneficially paired with vitamin D3 and calcium, as these nutrients work synergistically for bone health, with vitamin K2 helping to direct calcium to bones rather than soft tissues. When using vitamin K2 specifically for bone health, consistency in daily supplementation is more important than specific timing, as its effects on bone metabolism develop over months rather than hours or days. Studies showing benefits for bone mineral density typically involve daily supplementation for 6-36 months. For cardiovascular health applications, similar principles apply—consistent daily supplementation over extended periods appears necessary for significant effects on arterial calcification and stiffness.

For individuals taking medications that may interfere with fat absorption (such as certain cholesterol-lowering drugs or fat blockers), separating vitamin K2 supplementation from these medications by at least 2 hours may help maintain optimal absorption. For those on anticoagulant therapy, particularly vitamin K antagonists like warfarin, it’s important to maintain consistent vitamin K intake rather than making sudden large changes. The timing of vitamin K2 supplementation should be consistent from day to day to help maintain stable anticoagulation. For those with digestive disorders affecting fat absorption (such as pancreatic insufficiency or gallbladder disease), taking vitamin K2 with a digestive enzyme supplement containing lipase may help improve absorption.

• Generally recognized as very safe with minimal reported side effects at recommended doses
• Mild gastrointestinal discomfort (rare)
• Allergic reactions (extremely rare)
• Skin rash (very rare)
• Mild anxiety or nervousness (very rare, primarily with very high doses)
• Note: Most clinical trials report side effect profiles similar to placebo

• Individuals on vitamin K antagonist anticoagulants (e.g., warfarin) should consult healthcare providers before supplementation
• Known hypersensitivity to vitamin K2 or supplement ingredients
• Caution advised in individuals with severe liver disease (may affect vitamin K metabolism)
• Note: These contraindications are primarily precautionary, as vitamin K2 has demonstrated an excellent safety profile across diverse populations

• Vitamin K antagonist anticoagulants (e.g., warfarin): Vitamin K2 may reduce the effectiveness of these medications; consistent intake rather than sudden changes is recommended
• Antibiotics (broad-spectrum): May reduce vitamin K production by gut bacteria, potentially enhancing the effect of supplemental K2
• Bile acid sequestrants (e.g., cholestyramine): May reduce vitamin K2 absorption
• Orlistat and other lipase inhibitors: May reduce vitamin K2 absorption due to decreased fat absorption
• Note: Despite these potential interactions, vitamin K2 generally has fewer significant drug interactions than many other supplements

No official Tolerable Upper Intake Level (UL) has been established for vitamin K2, as no toxicity has been observed even at high doses. This is in contrast to fat-soluble vitamins A and D, which can accumulate to toxic levels. The absence of a defined UL reflects vitamin K2’s excellent safety profile. In clinical studies, doses up to 45 mg (45,000 mcg) of MK-4 per day have been used for osteoporosis treatment in Japan without significant adverse effects.

For MK-7, doses up to 360 mcg daily have been used in research settings with good safety profiles. The body appears to have mechanisms to regulate vitamin K status, including limited intestinal absorption at higher doses and the recycling of vitamin K through the vitamin K cycle, which may help prevent toxicity. For most healthy adults, vitamin K2 supplementation within the typical range of 100-360 mcg/day of MK-7 or 1,000-45,000 mcg/day of MK-4 is unlikely to cause any adverse effects, even with long-term use. The primary safety consideration for vitamin K supplementation involves individuals on vitamin K antagonist anticoagulants like warfarin.

For these individuals, it’s important to maintain consistent vitamin K intake rather than making sudden large changes, as this could affect anticoagulation stability. Many healthcare providers now recommend maintaining consistent vitamin K intake rather than restricting it entirely. For individuals not on anticoagulant therapy, vitamin K2 supplementation appears to have an excellent safety profile with minimal risk of adverse effects, even at doses substantially higher than typical dietary intake. As with any supplement, it’s prudent to use the lowest effective dose for the intended purpose, particularly for long-term use.

Those with specific health conditions, on medications, or with known sensitivities should consult healthcare providers before using vitamin K2 supplements, though adverse interactions are rare.

In the United States, vitamin K2 is regulated as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under this classification, vitamin K2 can be sold without prescription and without requiring FDA approval for safety and efficacy before marketing, unlike pharmaceutical drugs. As a dietary supplement ingredient, manufacturers are responsible for ensuring their products are safe before marketing, though they are not required to provide evidence of safety to the FDA. The FDA can take action against unsafe vitamin K2 products after they reach the market.

The FDA has established a Reference Daily Intake (RDI) for vitamin K of 120 mcg for adults, but this does not distinguish between vitamin K1 and K2. This value is primarily based on the amount needed for proper blood clotting rather than the potentially higher requirements for optimal bone and cardiovascular health. Manufacturers are prohibited from making specific disease claims (such as claiming vitamin K2 treats or prevents osteoporosis or heart disease) but can make structure/function claims (such as ‘supports bone health’ or ‘promotes healthy calcium utilization’). All vitamin K2 supplements must include a disclaimer stating that the product has not been evaluated by the FDA and is not intended to diagnose, treat, cure, or prevent any disease.

The FDA does not regulate the quality or purity of vitamin K2 supplements, which has led to variability in product content. Independent testing has found significant discrepancies between labeled and actual vitamin K2 content in some supplements. Unlike in Japan, where high-dose menaquinone-4 (MK-4) is approved as a prescription drug for osteoporosis treatment, vitamin K2 does not have approved drug status for any indication in the United States.

Eu: In the European Union, vitamin K2 is regulated under the Food Supplements Directive (2002/46/EC) and can be used in food supplements. The European Food Safety Authority (EFSA) has established an Adequate Intake (AI) for vitamin K of 70 mcg/day for adults, without distinguishing between K1 and K2. EFSA has evaluated several health claims for vitamin K, approving claims related to normal blood clotting, maintenance of normal bones, and maintenance of normal blood vessels. These approved claims apply to vitamin K generally, including both K1 and K2 forms. For specific vitamin K2 forms, manufacturers must ensure they meet the definition of vitamin K as established in the regulations. Novel food approval may be required for certain forms or production methods of vitamin K2 that do not have a history of significant consumption in the EU before May 1997.

Canada: In Canada, vitamin K2 is listed in the Natural Health Products Ingredients Database (NHPID) as a medicinal ingredient for use in natural health products. Health Canada has approved specific health claims for vitamin K2 related to bone health and cardiovascular health. Products containing vitamin K2 must have a Natural Product Number (NPN) issued by Health Canada, indicating they have been assessed for safety, efficacy, and quality. Dosage recommendations and specific indications are more standardized than in the U.S. market. Health Canada distinguishes between different forms of vitamin K2 (MK-4, MK-7, etc.) in its regulatory framework, recognizing their different pharmacokinetics and potentially different effects.

Japan: In Japan, menaquinone-4 (MK-4) at a dose of 45 mg/day is approved as a prescription drug for the treatment of osteoporosis, under the name Menatetrenone. This represents a much higher dose than typically used in dietary supplements and reflects Japan’s longer history of clinical research on vitamin K2 for bone health. For lower doses, vitamin K2 is available as a dietary supplement and is also recognized under the Foods for Specified Health Uses (FOSHU) system for bone health claims. Japan has been at the forefront of vitamin K2 research and clinical applications, particularly for bone health, reflecting the traditional consumption of natto (a rich source of MK-7) in Japanese cuisine.

Australia: In Australia, vitamin K2 is listed by the Therapeutic Goods Administration (TGA) as an acceptable ingredient for use in listed complementary medicines. Products containing vitamin K2 can make certain low-level claims related to bone health and cardiovascular function, provided they comply with the evidence requirements of the TGA. As with other jurisdictions, disease prevention or treatment claims are generally not permitted without higher-level registration as a registered medicine, which requires more substantial evidence.

Global Outlook: Globally, vitamin K2 is increasingly recognized as distinct from vitamin K1 in terms of its physiological roles and potential health benefits. Regulatory frameworks are gradually evolving to reflect this distinction, though many still regulate vitamin K as a single category. The trend appears to be moving toward greater acceptance of vitamin K2’s specific roles in bone and cardiovascular health, with some jurisdictions now allowing more specific health claims based on the growing body of scientific evidence. As research continues to expand into vitamin K2’s benefits for various health conditions, regulatory frameworks may evolve to address these emerging applications.

Moderate

$0.10-$0.50 per day for basic MK-7 supplements (100-200 mcg); $0.30-$1.00 per day for premium formulations with higher doses or additional nutrients; $0.05-$0.20 per day for MK-4 supplements (1,000-2,000 mcg); $0.05-$0.30 per day for vitamin K2 from food sources (based on natto, cheese, or egg consumption)

Vitamin K2 offers good value compared to many other supplements, providing evidence-based benefits at a moderate cost. The value proposition varies significantly depending on the form (MK-4 vs. MK-7) and quality of the supplement. MK-7 supplements typically cost $0.10-$0.50 per day for effective doses (100-200 mcg), making them moderately priced compared to other supplements.

This translates to approximately $3-15 per month at standard dosing. While not the least expensive supplement, this cost is reasonable considering the substantial research supporting vitamin K2’s benefits for bone and cardiovascular health. MK-4 supplements are generally less expensive per dose, typically costing $0.05-$0.20 per day for 1,000-2,000 mcg. However, due to MK-4’s shorter half-life, higher doses or more frequent administration may be necessary for optimal effects, potentially offsetting the lower per-unit cost.

When comparing vitamin K2 to pharmaceutical interventions for related conditions, the cost difference is dramatic. While vitamin K2 is not a treatment for established disease, its preventive benefits come at a fraction of the cost of medications for conditions like osteoporosis or cardiovascular disease, which can cost hundreds of dollars per month. For those seeking to support bone or heart health proactively, vitamin K2 represents a cost-effective approach. For specialized formulations, the value calculation becomes more nuanced.

Premium products containing vitamin K2 with synergistic nutrients like vitamin D3, calcium, and magnesium may offer better value than basic products despite the higher price, as these combinations address multiple aspects of bone and cardiovascular health. Similarly, formulations with enhanced bioavailability or stability may justify their premium pricing for some users. When comparing vitamin K2 products, significant quality variations exist in the market. Independent testing has found substantial discrepancies between labeled and actual vitamin K2 content in some supplements.

Products verified by third-party testing organizations may cost slightly more but provide greater assurance of accurate dosing and purity, potentially offering better value despite the higher price. For those able to consistently consume vitamin K2-rich foods, dietary sources may offer the best value at approximately $0.05-$0.30 per day (based on regular consumption of natto, certain cheeses, or egg yolks). However, many people find it challenging to consume sufficient quantities of these foods regularly, particularly natto, which has a strong flavor and aroma that many Western consumers find unpalatable. The cost-effectiveness of vitamin K2 extends beyond direct purchase price when considering potential healthcare savings.

Maintaining bone and cardiovascular health may reduce healthcare utilization, potentially including fewer doctor visits, reduced medication use, and lower risk of fractures or cardiovascular events, which can be extremely costly both financially and in terms of quality of life. For specific applications like bone health, vitamin K2’s daily cost ($0.10-$0.50) is minimal compared to the potential long-term benefits of maintaining bone density and reducing fracture risk, particularly when combined with other bone-supporting nutrients and lifestyle factors.

Vitamin K2 stability varies significantly based on the specific form (MK-4, MK-7, etc.), formulation, storage conditions, and protective measures implemented by manufacturers. Under optimal storage conditions, vitamin K2 in oil-based softgel formulations typically maintains acceptable potency for 18-24 months from the date of manufacture. This is reflected in the expiration dates assigned by manufacturers, though these are often conservative estimates. The primary degradation pathway for vitamin K2 is oxidation, which is accelerated by exposure to light, heat, and oxygen.

As a quinone compound with an unsaturated side chain, vitamin K2 is susceptible to oxidative degradation, which can lead to loss of biological activity. MK-7 (menaquinone-7) appears to have somewhat better inherent stability than MK-4 (menaquinone-4) due to its longer side chain, which may provide some steric protection against oxidation. However, both forms require proper formulation and storage to maintain potency. The stability of vitamin K2 in different supplement forms varies considerably.

Oil-based softgels typically provide the best protection against oxidation by limiting oxygen exposure. Tablets and powders generally have shorter shelf lives due to their increased surface area and greater exposure to environmental factors. In food sources, vitamin K2 stability is affected by processing, cooking, and storage methods. Fermented foods like natto and cheese generally maintain their vitamin K2 content well during normal storage, though extended exposure to light and heat should be avoided.

Some manufacturers add antioxidants like vitamin E, rosemary extract, or ascorbyl palmitate to vitamin K2 formulations to enhance stability by preventing oxidative degradation. These additions can significantly extend shelf life, particularly in more vulnerable formulations like powders. Microencapsulation technology is increasingly used to protect vitamin K2 from environmental factors and extend shelf life. This technology involves encapsulating vitamin K2 particles in a protective matrix, often made of modified starch, protein, or other materials that create a barrier against oxygen, light, and moisture.

Store vitamin K2 supplements in a cool, dry place away from direct light, preferably at temperatures between 15-25°C (59-77°F). Keep containers tightly closed to prevent moisture absorption and minimize oxygen exposure, as both can accelerate degradation of vitamin K2. Avoid storing in bathrooms or other high-humidity areas where temperature and humidity fluctuate. Light protection is particularly important for vitamin K2 stability.

Store in the original opaque container or packaging that blocks light exposure. If transferring to another container, ensure it is opaque and airtight. Refrigeration is generally not necessary for most vitamin K2 supplements but may help extend shelf life, particularly in hot and humid climates. However, avoid freezing liquid vitamin K2 supplements, as this can affect the formulation integrity.

Check product-specific recommendations, as formulations vary in their sensitivity to environmental factors. Some products include oxygen absorbers or desiccants in the packaging to protect against oxidation and moisture – these should be left in place but not consumed. For vitamin K2-rich foods, proper storage can help maintain vitamin K2 content. Fermented foods like natto should be refrigerated according to package directions.

Cheeses should be stored according to their specific requirements, typically refrigerated and properly wrapped to prevent drying. When cooking with vitamin K2-rich animal products, gentle cooking methods are preferable to high-heat methods, which may degrade some of the vitamin K2 content. For opened liquid vitamin K2 supplements, refrigeration may help maintain potency, and they should be used within the timeframe recommended by the manufacturer (typically 1-3 months after opening). If a vitamin K2 supplement changes color significantly, develops an unusual odor, or shows physical changes, it may have degraded and should be replaced.

Oxidation (primary degradation pathway due to vitamin K2’s quinone structure and unsaturated side chain), Light exposure (particularly UV light, which can break down the quinone ring structure), Heat (accelerates oxidation reactions; significant degradation occurs above 40°C/104°F), Oxygen exposure (direct contributor to oxidative degradation), Moisture (can promote hydrolysis and other degradation reactions), pH extremes (vitamin K2 is most stable at neutral to slightly acidic pH), Metal ions (particularly iron and copper, which can catalyze oxidation reactions), Interactions with other ingredients in combination formulations, Isomerization (conversion of active trans isomers to less active cis forms), Freeze-thaw cycles (for liquid formulations)

Synthesis Methods

Natural Sources

Quality Considerations

The history of vitamin K2 as a recognized nutritional compound is relatively recent compared to many other vitamins, though humans have consumed K2-rich foods throughout history. The vitamin K family was first discovered in the 1930s, but the specific recognition and understanding of vitamin K2 as distinct from vitamin K1 has primarily developed over the past few decades. The discovery of vitamin K began in the 1930s when Danish scientist Henrik Dam was studying cholesterol metabolism in chickens. He observed that chicks fed a diet extracted with non-polar solvents developed hemorrhages and their blood took longer to clot.

This condition could not be remedied by adding purified cholesterol back to the diet, leading Dam to conclude that another fat-soluble compound had been removed during the extraction process. He named this compound ‘Koagulationsvitamin’ or vitamin K (from the German word ‘Koagulation’). For this discovery, Dam shared the 1943 Nobel Prize in Physiology or Medicine with Edward Doisy, who later determined vitamin K’s chemical structure. Initially, vitamin K was primarily associated with blood coagulation, and little distinction was made between different forms.

The term ‘vitamin K2’ specifically refers to menaquinones, a group of compounds characterized by a 2-methyl-1,4-naphthoquinone ring structure with a variable-length side chain of isoprenoid units. While vitamin K1 (phylloquinone) is found primarily in green leafy vegetables, vitamin K2 forms are produced by bacteria and found in fermented foods and animal products. Traditional food practices in various cultures have inadvertently incorporated significant sources of vitamin K2, though without knowledge of the specific compound. Natto, a traditional Japanese food made from fermented soybeans, is exceptionally rich in vitamin K2 (specifically MK-7) and has been consumed in Japan for over 1,000 years.

Similarly, traditional cheese-making practices in European cultures produced foods rich in longer-chain menaquinones (MK-8, MK-9). The scientific distinction between vitamin K1 and K2 began to emerge more clearly in the 1970s, but it wasn’t until the 1990s and early 2000s that research began to reveal vitamin K2’s unique roles beyond blood coagulation, particularly in bone and cardiovascular health. A pivotal moment in vitamin K2 research came in the late 1990s and early 2000s with the publication of the Rotterdam Study and other epidemiological research that found associations between vitamin K2 intake (but not K1) and reduced risk of cardiovascular disease and improved bone health. These findings suggested that vitamin K2 had distinct physiological roles separate from K1’s well-established function in blood clotting.

In Japan, high-dose menaquinone-4 (MK-4) has been approved as a treatment for osteoporosis since 1995, under the name Menatetrenone. This represents one of the earliest clinical applications of vitamin K2 as a therapeutic agent rather than simply a nutritional supplement. The understanding of vitamin K2’s mechanisms of action has evolved significantly in recent decades. The discovery of Gla-proteins (gamma-carboxyglutamic acid-containing proteins) that require vitamin K for activation has been crucial to understanding how vitamin K2 influences calcium metabolism in various tissues.

Key proteins include osteocalcin (involved in bone mineralization) and Matrix Gla Protein (MGP, which prevents arterial calcification). The commercial availability of vitamin K2 supplements, particularly MK-7 derived from natto, began to increase in the early 2000s as research on its health benefits expanded. Initially marketed primarily for bone health, vitamin K2 supplements have increasingly been promoted for cardiovascular health as well. In recent years, research on vitamin K2 has expanded to explore potential benefits for other health conditions, including diabetes, certain cancers, and neurological health.

The distinction between different menaquinones (MK-4, MK-7, etc.) has become more important in both research and supplementation strategies, as these forms have different pharmacokinetics and potentially different tissue affinities. Today, vitamin K2 is recognized as an important nutrient with roles distinct from vitamin K1, though both share the basic function of serving as cofactors for the gamma-glutamyl carboxylase enzyme. The historical progression from its discovery as part of the vitamin K complex to the current understanding of its specific roles in calcium regulation and beyond represents a fascinating example of how nutritional science evolves over time.

Vitamin K2 supplementation for prevention of cardiovascular events in patients with coronary artery disease, Effects of vitamin K2 on bone mineral density and fracture risk in postmenopausal women with osteopenia, Combination of vitamin K2 with vitamin D3 for enhanced bone and cardiovascular protection, Vitamin K2 supplementation for improving glucose metabolism in prediabetic individuals, Long-term effects of vitamin K2 on progression of coronary artery calcification (5-year follow-up), Vitamin K2 for prevention of vascular calcification in hemodialysis patients, Effects of vitamin K2 on cognitive function in older adults, Vitamin K2 supplementation for improving physical performance in frail elderly, Comparison of different vitamin K2 forms (MK-4 vs. MK-7) for bone and cardiovascular health, Vitamin K2’s effects on dental health and prevention of dental caries