What to Combine Vitamin K2 With

Vitamin K2 has gone from an obscure nutrient to a staple of "bone and heart" supplement formulas, usually sold alongside vitamin D3. But what does it actually work with, and are there combinations to avoid? The editorial team explains the biology behind the popular pairings and what the evidence does and does not support.

Vitamin K2 in brief

Vitamin K is not a single compound but a family. Vitamin K1 (phylloquinone) comes mainly from green leafy vegetables and is primarily used by the liver to produce blood-clotting factors. Vitamin K2 (menaquinones) is found in fermented foods, cheese, egg yolks and some meats, and is also produced in small amounts by gut bacteria.

The two forms of K2 most often found in supplements are MK-4 and MK-7. MK-7, traditionally derived from natto (fermented soybeans), has a much longer half-life in the blood, measured in days rather than hours, which allows once-daily dosing in the microgram range. MK-4 is cleared quickly and is typically used in much larger, milligram doses in Japanese clinical practice.

The key function of vitamin K in all its forms is to activate proteins through a process called carboxylation. Among these are osteocalcin, which helps bind calcium into bone, and matrix Gla protein (MGP), which helps prevent calcium from being deposited in blood vessel walls.

The UK does not set a formal RNI for vitamin K, but guidance suggests about 1 microgram per kilogram of body weight per day is adequate for adults. EFSA set an adequate intake of 70 micrograms per day for adults, without distinguishing between K1 and K2.

Vitamin K2 and vitamin D3

The most popular pairing is with vitamin D3, and there is a sound biological rationale. Vitamin D increases the production of vitamin K-dependent proteins such as osteocalcin and MGP. Vitamin K2 then activates them. In other words, vitamin D raises the number of "workers", and vitamin K gives them their tools.

This has led to the idea that taking vitamin D without enough vitamin K could leave more inactive proteins and, in theory, favour calcium being deposited in the wrong places. This is a plausible hypothesis, but in people taking ordinary vitamin D doses with a normal diet, it has not been demonstrated as a clinical problem.

For a UK resident, the more important point is that most adults are advised to consider 10 micrograms (400 IU) of vitamin D daily during autumn and winter, and many sports physicians recommend more for athletes with confirmed low levels. Adding K2 to this is reasonable, particularly for those who eat few fermented foods, but it is not mandatory.

Combination products typically provide 25–100 micrograms of D3 (1,000–4,000 IU) with 50–200 micrograms of MK-7. Before choosing a high vitamin D dose, it is worth having a blood test, since the right amount depends on your baseline.

Calcium, magnesium and fat

Calcium is the mineral that vitamin K-dependent proteins ultimately handle, so pairing K2 with an adequate calcium intake makes sense. Dietary calcium from dairy, fortified plant drinks, tinned fish with bones and green vegetables is preferred over high-dose supplements, which in some analyses have been linked to cardiovascular concerns.

Magnesium is less often discussed but plays a supporting role: it is required for the activation of vitamin D in the liver and kidneys. A diet low in magnesium can blunt the response to vitamin D, which indirectly affects the K2–D3 partnership. Wholegrains, nuts, seeds and legumes cover most needs.

Vitamin K2 is fat-soluble. Taking it with a meal that contains some fat, such as breakfast with eggs, yoghurt or nuts, improves absorption considerably compared with taking it with just water on an empty stomach. Many supplements are supplied in oil-filled softgels for the same reason.

Combinations that need caution

The single most important caution concerns vitamin K antagonist anticoagulants, mainly warfarin in the UK. Warfarin works by blocking the recycling of vitamin K. Changes in vitamin K intake, whether from diet or supplements, can alter the INR and therefore the risk of clots or bleeding.

MK-7 is particularly potent in this respect: research has shown that even relatively low doses can measurably affect anticoagulation in people on vitamin K antagonists. Anyone taking warfarin should not start, stop or change a vitamin K supplement without speaking to their anticoagulation clinic first.

The newer direct oral anticoagulants, such as apixaban and rivaroxaban, do not act through vitamin K, so K2 does not interfere with them in the same way. Even so, anyone on anticoagulants should tell the prescriber about every supplement they take.

• Warfarin: do not take K2 without agreement from the anticoagulation clinic.
• Orlistat and bile acid sequestrants: may reduce absorption of fat-soluble vitamins including K.
• Long-term broad-spectrum antibiotics: may lower gut bacterial vitamin K production.
• Very high-dose vitamin E: may interfere with vitamin K activity.

Some people take vitamin A, D, E and K together in one "ADEK" product. That is convenient, but it makes it easier to overshoot vitamin A and D. Checking the total daily amount across all products is worthwhile.

What the research shows for bones and arteries

Most robust human data on K2 relate to bone. In a three-year Dutch trial in healthy postmenopausal women, 180 micrograms of MK-7 daily helped reduce age-related loss of bone mineral density and bone strength compared with placebo. Japanese studies with high-dose MK-4 have also shown effects on fracture risk, although results across trials are inconsistent.

Evidence on the cardiovascular system is mostly observational. The Rotterdam Study found that higher dietary intake of menaquinones was associated with lower aortic calcification and coronary heart disease mortality. Randomised trials testing whether supplements slow arterial calcification have so far produced mixed results.

For athletes, there is very little direct research. The theoretical interest lies in bone health for those at risk of low energy availability, such as endurance runners, and in general vascular health, but K2 should not be seen as a substitute for adequate energy intake and resistance training, which remain the strongest supports for bone.

Vitamin K2 has no known toxicity at supplement doses in healthy people, and no tolerable upper limit has been set by EFSA. The main risks are interactions, not overdose.

Conclusions of the editorial team

Vitamin K2 combines sensibly with vitamin D3, an adequate calcium intake mainly from food, magnesium-rich foods and a meal containing fat for absorption.

The strongest evidence concerns bone density in older women; cardiovascular benefits are plausible but not confirmed by trials. Direct evidence in athletes is scarce.

The one combination to avoid without medical supervision is K2 with warfarin. For everyone else, MK-7 at typical supplement doses is a low-risk addition if the diet lacks fermented foods.

The editorial team also recommends our pieces on vitamin D levels in athletes, on calcium needs for runners and on magnesium forms and their absorption.

References

1. Knapen MHJ, Drummen NE, Smit E, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013;24(9):2499–2507.
2. Schurgers LJ, Teunissen KJF, Hamulyák K, et al. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007;109(8):3279–3283.
3. Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134(11):3100–3105.
4. van Ballegooijen AJ, Pilz S, Tomaschitz A, Grübler MR, Verheyen N. The synergistic interplay between vitamins D and K for bone and cardiovascular health: a narrative review. Int J Endocrinol. 2017;2017:7454376.
5. EFSA Panel on Dietetic Products, Nutrition and Allergies. Dietary reference values for vitamin K. EFSA J. 2017;15(5):4780.
6. Scientific Advisory Committee on Nutrition. Vitamin D and Health. London: Public Health England; 2016.