Vitamin K2 is the name for the menaquinones, a family of fat-soluble vitamin K compounds that differ by the length of their side chain. Two forms dominate supplements and research: menaquinone-4 (MK-4) and menaquinone-7 (MK-7). They behave very differently in the body, and the evidence for one should not be assumed to apply to the other.
Vitamin K2 is mostly sold as an over-the-counter supplement (Schurgers et al., Blood 2007). In Japan, however, high-dose MK-4 (as the drug menatetrenone, 45 mg/day) has been an approved osteoporosis treatment since 1995. The single most important safety fact is that vitamin K2 directly opposes warfarin and other vitamin K antagonists: in a controlled study, as little as 10 µg/day of MK-7 lowered the INR in some anticoagulated volunteers.
This page summarizes what clinical trials, meta-analyses and regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Class | Fat-soluble vitamin; menaquinones (MK-4 through MK-13) |
| Main supplemental forms | MK-4 (menatetrenone) and MK-7 (often natto-derived) |
| Route | Oral |
| Studied doses | MK-7: 180–720 µg/day in trials; MK-4: 45 mg/day (Japanese osteoporosis dose) |
| Half-life | MK-7 ≈ 3 days (≈ 72 h); vitamin K1 about 1–2 h (review data) |
| Key mechanism | Cofactor for γ-carboxylation of clotting factors, osteocalcin and matrix Gla protein |
| Regulatory status | Sold as an over-the-counter supplement; menatetrenone (MK-4) approved as an osteoporosis drug in Japan in 1995 |
| Key interaction | Reduces the effect of warfarin and other vitamin K antagonists |
What it is
All forms of vitamin K share the same ring structure (2-methyl-1,4-naphthoquinone, also called menadione) and differ in the side chain attached to it (Dupuy et al., Food Sci Nutr 2025). Vitamin K1 (phylloquinone) comes from green plants. The menaquinones carry a side chain of repeating isoprenoid units, and the number after “MK” counts those units.
| Form | Side chain | Main origin | Typical sources |
|---|---|---|---|
| Vitamin K1 (phylloquinone) | Phytyl chain | Made by plants and algae | Leafy greens, plant oils |
| MK-4 | 4 isoprenoid units | Made in animal tissues from vitamin K1; also synthetic (menatetrenone) | Meat, eggs, dairy; drug in Japan |
| MK-7 | 7 isoprenoid units | Made by bacteria | Natto (fermented soybeans), fermented foods |
Natto is by far the richest food source of vitamin K2, with about 900 µg of MK-7 per 100 g. Its bacterium, Bacillus subtilis var. natto, produces the MK-7 (Mladěnka et al., Nutr Rev 2022).
All forms of vitamin K serve the same basic function. Vitamin K is a cofactor for an enzyme that adds carboxyl groups to glutamate residues on specific proteins (γ-carboxylation), which lets those proteins bind calcium. The best-known vitamin K-dependent proteins are:
- the clotting factors II, VII, IX and X, plus the anticoagulant proteins C and S, made in the liver (Jantoven label);
- osteocalcin, a bone protein;
- matrix Gla protein (MGP), an inhibitor of calcium deposits in the vessel wall (Vlasschaert et al., Nutrients 2020).
The interest in K2 for bones and arteries comes from the idea that these “extrahepatic” (outside the liver) proteins are often incompletely carboxylated even when clotting is normal (Mladěnka et al., Nutr Rev 2022). Trials measure this with blood markers such as undercarboxylated osteocalcin (ucOC) and dephospho-uncarboxylated MGP (dp-ucMGP).
Pharmacokinetics: why MK-4 and MK-7 are not interchangeable
The two forms differ most in how long they stay in the blood.
| Measure | MK-7 | MK-4 | Vitamin K1 |
|---|---|---|---|
| Elimination half-life | ≈ 3 days | Not measurable at nutritional doses (see below) | ≈ 1–2 h |
| Single 420 µg dose in healthy women | Peak at 6 h; detectable up to 48 h | Not detectable in serum at any time point | Not tested |
| 7 days of 60 µg/day | Serum MK-7 rose in all subjects | Serum MK-4 did not rise | Not tested |
| Prolonged daily intake vs K1 | Accumulates to 7–8× higher levels | Not tested | Serum level only slightly above placebo |
Sources: half-lives from Mladěnka et al., Nutr Rev 2022; single-dose and 7-day data from Sato et al., Nutr J 2012; accumulation data from Schurgers et al., Blood 2007.
In the Blood study, both K1 and MK-7 were well absorbed, with peak levels about 4 hours after intake. MK-7 also produced more complete carboxylation of osteocalcin (Schurgers et al., Blood 2007). The practical consequence is that microgram doses of MK-7 raise blood levels, while MK-4 is used at milligram doses (45 mg/day in Japan), roughly 150–180 times higher than the recommended daily vitamin K intake (Iwamoto, Nutrients 2014).
Because vitamin K is fat-soluble, it is absorbed from the gut in micelles formed with bile acids (Mladěnka et al., Nutr Rev 2022).
No single intake standard exists for vitamin K2 on its own. The European Food Safety Authority sets an adequate intake of 1 µg/kg/day for total vitamin K (Mladěnka et al., Nutr Rev 2022). The Japanese osteoporosis guideline lists 250–300 µg/day of vitamin K as the intake to aim for (Orimo et al., Arch Osteoporos 2012).
Approved medical use: MK-4 for osteoporosis in Japan
Menatetrenone is a synthetic vitamin K2 chemically identical to MK-4. Japan’s Ministry of Health, Labour and Welfare approved it as an osteoporosis drug, so in Japan it is a prescription medicine rather than a supplement (Iwamoto, Nutrients 2014). The Japanese 2011 osteoporosis guideline lists it as approved in 1995 at 45 mg/day orally (Orimo et al., Arch Osteoporos 2012).
A Japanese dose-finding study tested 15, 45, 90 and 135 mg/day and found 45 mg/day to be the minimum effective dose for bone mass measures (Iwamoto, Nutrients 2014). The guideline graded the evidence for menatetrenone as follows (Orimo et al., Arch Osteoporos 2012):
| Outcome | Guideline grade for menatetrenone | For comparison: alendronate |
|---|---|---|
| Bone mineral density | B | A |
| Vertebral fractures | B | A |
| Non-vertebral fractures | B | A |
| Hip fractures | C | A |
Because the supporting trials were small, menatetrenone is used as a second-line osteoporosis drug in Japan (Iwamoto, Nutrients 2014). In US prescribing information, the form named for reversing warfarin is vitamin K1, not K2 (Jantoven label).
What the research shows
Bone: MK-4 (45 mg/day) trials
The key trials are Japanese, open-label and of mixed quality.
| Trial | Design and n | Dose and duration | Main result |
|---|---|---|---|
| Shiraki et al., JBMR 2000 | Open-label RCT, 241 patients with osteoporosis | 45 mg/day vs no treatment, 24 months | Clinical fractures 10.9% vs 30.3% (p = 0.0273); lumbar BMD −0.5% vs −3.3% |
| Inoue et al., OF study, J Bone Miner Metab 2009 | Open-label RCT with blinded evaluation, 4,378 postmenopausal women | 45 mg/day plus calcium vs calcium alone, 36 months | No significant difference in new vertebral fractures (primary endpoint) |
| Binkley et al., JBMR 2009 | Double-blind RCT, 381 healthy postmenopausal North American women | MK-4 45 mg/day or K1 1 mg/day vs placebo, 12 months; all received calcium and vitamin D3 | Lower ucOC, but no change in BMD, bone turnover markers or hip geometry |
The OF study is by far the largest MK-4 trial. Its full analysis was negative. A benefit appeared only in subgroups with advanced disease, such as women with at least five vertebral fractures at baseline, and adverse events were more frequent with menatetrenone (Inoue et al., 2009). The Shiraki fracture rates are taken from Iwamoto’s summary table (Iwamoto, Nutrients 2014).
Bone: what the meta-analyses show
A 2006 meta-analysis pooled seven trials with fracture data. All were Japanese and used MK-4 (Cockayne et al., Arch Intern Med 2006):
| Outcome | Odds ratio (95% CI) |
|---|---|
| Vertebral fractures | 0.40 (0.25–0.65) |
| Hip fractures | 0.23 (0.12–0.47) |
| All non-vertebral fractures | 0.19 (0.11–0.35) |
These numbers should not be taken at face value. In 2018 the journal attached a correction titled “Caution of Conclusions of a Meta-analysis Including Problematic Trials”, and the senior author warned readers that the review had included problematic trials (Torgerson, JAMA Intern Med 2018).
The same York group published an updated review of 36 trials in 2019 (Mott et al., Osteoporos Int 2019). For postmenopausal or osteoporotic patients it concluded:
- there is no evidence that vitamin K affects bone mineral density or vertebral fractures;
- vitamin K may reduce clinical fractures, but the evidence is insufficient to confirm this;
- effects shrank and lost significance when trials at high risk of bias were removed.
In 2020 the authors issued a further correction adjusting all estimates that included another Japanese trial (the Yamaguchi Osteoporosis Prevention Study), after its integrity was questioned (Mott et al., Osteoporos Int 2020).
Bone: MK-7 trials
The main MK-7 bone trial gave 244 healthy postmenopausal Dutch women 180 µg/day of MK-7 or placebo for 3 years (Knapen et al., Osteoporos Int 2013). MK-7 improved vitamin K status and reduced the age-related decline in bone mineral content and density at the lumbar spine and femoral neck, but not at the total hip. Fractures were not a primary outcome, and no MK-7 trial has shown a reduction in fractures.
Vascular calcification and arterial stiffness
MK-7 consistently lowers dp-ucMGP, the inactive form of the calcification inhibitor MGP. Whether this translates into less calcification is the open question. Trials so far are mixed:
| Trial | Population and n | Intervention and duration | Primary result |
|---|---|---|---|
| Knapen et al., Thromb Haemost 2015 | 244 healthy postmenopausal women | MK-7 180 µg/day vs placebo, 3 years | Carotid-femoral pulse wave velocity (arterial stiffness) improved; dp-ucMGP fell 50% vs placebo |
| Zwakenberg et al., AJCN 2019 | 68 people with type 2 diabetes and CVD | MK-7 360 µg/day vs placebo, 6 months | No benefit; active calcification on PET tended to increase (p = 0.06); no effect on CT calcification |
| Witham et al., K4Kidneys, JASN 2020 | 159 adults with CKD stage 3b–4 | Vitamin K2 400 µg/day vs placebo, 12 months | No difference in pulse wave velocity, BP or other vascular measures |
| De Vriese et al., Valkyrie, JASN 2020 | 132 hemodialysis patients with atrial fibrillation | Warfarin-class drug vs rivaroxaban vs rivaroxaban plus vitamin K2 2,000 µg three times weekly, 18 months | No significant difference in coronary, aortic or valve calcification |
| Diederichsen et al., AVADEC, Circulation 2022 | 365 men (mean age 71) with aortic valve calcification | MK-7 720 µg plus vitamin D 25 µg/day vs placebo, 24 months | No effect on valve calcification: difference 17 AU (95% CI −86 to 53; p = 0.64) |
| Vossen et al., VitaK-CAC, JAMA Cardiol 2026 | 167 analyzed patients with symptomatic coronary disease (CAC 50–400 AU) | MK-7 360 µg/day vs placebo, 2 years | Slower rise in coronary calcium score (p = 0.02); clinical meaning not established |
In AVADEC, dp-ucMGP fell with MK-7 plus vitamin D (−212 vs +45 pmol/L; p under 0.001), yet valve, aortic and coronary calcification did not progress more slowly (Diederichsen et al., 2022). The vitamin D side of that combination is covered on the Vitamin D3 page.
VitaK-CAC is the first sizeable positive calcification trial. In the placebo group, the median calcium score rose from 145 to 214 AU over 2 years, versus 135 to 184 AU with MK-7. The authors note that the clinical significance for plaque stability remains to be determined (Vossen et al., 2026).
A systematic review of nine controlled trials concluded that vitamin K “does not consistently prevent” progression of calcification, atherosclerosis or arterial stiffness, though it may help people who already have calcification (Vlasschaert et al., Nutrients 2020). No trial has yet shown fewer heart attacks, strokes or deaths with vitamin K2.
Side effects and risks
Warfarin and other vitamin K antagonists
This is the most important risk. Warfarin works by inhibiting the vitamin K-dependent synthesis of clotting factors, so extra vitamin K reduces its effect. The warfarin label lists “increased vitamin K intake” as a cause of a decreased INR response, and advises more frequent INR checks when starting or stopping botanicals (Jantoven label). INR (international normalized ratio) is the blood test used to keep warfarin in its target range.
MK-7 is especially potent here because of its long half-life. In a dose-response study, 18 healthy volunteers were anticoagulated with acenocoumarol (a warfarin-like drug), and 15 reached a target INR of 2.0. They then received increasing MK-7 doses (Theuwissen et al., J Thromb Haemost 2013):
| MK-7 dose | Effect on anticoagulation |
|---|---|
| 10 µg/day | Clinically relevant INR drop in at least 40% of subjects |
| 20 µg/day | Clinically relevant INR drop in at least 60% of subjects |
| 45 µg/day | Group mean INR fell by ≈ 40% |
The authors concluded that MK-7 supplements should be avoided in patients on vitamin K antagonists. An earlier study had already warned that 50 µg/day or more of MK-7 may interfere with oral anticoagulants in a clinically relevant way (Schurgers et al., Blood 2007). The 2013 authors described 45 µg as the usual retail dose at the time, and the trials above used 180–720 µg/day. In Japan, warfarin use is a contraindication to menatetrenone (Iwamoto, Nutrients 2014).
Clotting in people not on anticoagulants
There has been concern that high vitamin K intake could cause excessive clotting. A review found this has not been observed, possibly because the sites available for γ-carboxylation are limited (Mladěnka et al., Nutr Rev 2022). In AVADEC, cardiovascular events were equal (10 vs 10) on MK-7 plus vitamin D and placebo (Diederichsen et al., 2022).
General tolerability
Natural vitamin K1 and K2 have very low toxicity, with almost no reported cases of systemic toxicity (Mladěnka et al., Nutr Rev 2022). Reported side effects of K2 are mostly minor stomach complaints and skin rashes that resolve on stopping. Possible side effects of menatetrenone are mainly gastrointestinal, such as stomach discomfort and diarrhea (Iwamoto, Nutrients 2014). In the large OF study, adverse events were more frequent with menatetrenone plus calcium than with calcium alone (Inoue et al., 2009).
Vitamin K3 (menadione), a synthetic form with no side chain, is different: in high doses it can cause hemolytic anemia, particularly in newborns (Mladěnka et al., Nutr Rev 2022). It should not be confused with K2.
Who should be cautious
- People taking warfarin, acenocoumarol or other vitamin K antagonists.
- People whose anticoagulation depends on a stable vitamin K intake, since starting or stopping a supplement changes it.
- Anyone expecting K2 to treat osteoporosis on its own: its drug approval is Japanese, and a North American trial of MK-4 45 mg/day found no bone density benefit (Binkley et al., 2009).
Key takeaways
- MK-4 and MK-7 are different. MK-7 has a half-life of about 3 days and raises blood levels at microgram doses; MK-4 at nutritional doses is barely detectable in serum.
- Warfarin is the main risk. As little as 10–20 µg/day of MK-7 lowered the INR in many anticoagulated volunteers; trial authors advise avoiding MK-7 with vitamin K antagonists.
- MK-4 is an approved drug in Japan. Menatetrenone 45 mg/day has been approved there for osteoporosis since 1995, as a second-line option.
- Fracture evidence is weaker than it looks. Early meta-analyses included problematic trials; the 2019 update found no effect on bone density or vertebral fractures and insufficient evidence for other fractures.
- Vascular results are mixed. MK-7 reliably lowers inactive MGP, but most calcification trials were negative; one 2026 trial found slower coronary calcium progression, with no proven clinical benefit yet.
Sources
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