MK-4 (menatetrenone)

MK-4 isn't a sensible supplement for bone or longevity. If you want vitamin K2, MK-7 at 90–180 µg a day is the sensible default. On warfarin or another vitamin-K-antagonist anticoagulant, any vitamin K needs your prescriber first.

What it is

Vitamin K2 is a family of molecules called menaquinones, and MK-4 (menaquinone-4, or menatetrenone) is one of them. Like the other forms, it switches on proteins that need vitamin K to bind calcium, such as osteocalcin in bone. Ordinary food supplies a little: egg yolk, butter and dark poultry meat carry MK-4, but in amounts far below what nutritional studies suggest is needed to shift those proteins. The full story of vitamin K, and of MK-7, the form most supplements use, is on Vitamin K2.

Why the form matters

MK-4 leaves the blood fast. Like vitamin K1, it is cleared within about an hour or two, while MK-7 stays for several days.^[1] At food-level doses it is also poorly absorbed, so nutritional doses of MK-4 don't raise blood levels at all, and a small daily MK-7 dose keeps the vitamin K-dependent proteins switched on in a way that nutritional MK-4 cannot.^[2]

So MK-4 is used at drug doses: the Japanese osteoporosis protocol gives about 45 mg a day, in several doses, roughly 250 times more than a supplement capsule.

The fracture trials, and why they don't bear the weight

The meta-analysis that reported large fracture reductions pooled seven Japanese menaquinone trials, including trials from a Japanese research group whose work has since faced serious integrity concerns; many of that group's menatetrenone papers have been retracted. The meta-analysis now carries a formal correction warning about its conclusions, and its own senior author published a caution to readers.^{[3] [4] [5]} A second, unrelated Japanese osteoporosis trial that included a vitamin K2 arm has since had its integrity questioned too.^[6]

The one large trial free of those concerns enrolled 4,378 women with osteoporosis and gave half of them 45 mg a day on top of calcium, for three years, against calcium alone; it was open-label, though the results were assessed blind. It missed its primary endpoint in both groups it studied, and there were more adverse events on the drug.^[7]

What the pooled evidence shows now

A pooled analysis of menatetrenone trials found a small gain in spine density but no significant drop in spinal fractures.^[8]

The most careful re-analysis, by the same York team that issued the caution and with every trial from the suspect group removed, found no reliable effect of vitamin K on bone density or spinal fractures in post-menopausal or osteoporotic women. It found possibly fewer clinical fractures of any kind (2.2% vs 3.1% of participants), but that result lost statistical significance when only the best-quality trials were counted, meaning no effect at all could no longer be ruled out, so any benefit is unproven. Most of the fracture trials behind it used 45 mg a day of MK-4, not supplement-dose MK-7, and a 2020 correction that removed one more questioned trial left these results essentially unchanged.^{[9] [10]}

The brain: a lead, not a reason

MK-4 is the main form of vitamin K in brain tissue, and post-mortem research links higher brain MK-4 to less Alzheimer pathology. That is observational, and any benefit for thinking or memory in living people is unproven.^[11]

What to do

1. For a vitamin K2 supplement, choose MK-7 at 90–180 µg a day. Food-level MK-4 doesn't raise blood levels.
2. Treat 45 mg MK-4 as a prescription osteoporosis drug, not a supplement. Its fracture evidence is unproven once the questioned trials are set aside, and the large trial saw more adverse events on the drug.
3. On warfarin or another vitamin-K-antagonist anticoagulant, don't start any vitamin K without your prescriber. The reasons are on Vitamin K2.
4. For bone, train first. Heavy resistance training and impact loading do far more for bone than any vitamin; see Bone density.

Further reading

• Sato T et al. Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Nutr J 2012.^[12]
• Mott A et al. Effect of vitamin K on bone mineral density and fractures in adults: an updated systematic review and meta-analysis of randomised controlled trials. Osteoporos Int 2019.^[13]
• Inoue T et al. Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab 2009.^[14]
• Torgerson DJ. Caution to Readers About Systematic Review on Vitamin K and Prevention of Fractures That Included Problematic Trials. JAMA Intern Med 2018.^[15]
• Vermeer C. Vitamin K: the effect on health beyond coagulation — an overview. Food Nutr Res 2012.^[16]