Vitamin K2 for women: are there any particularities

Vitamin K2 (menaquinones) is actively marketed to women as a means "for bones and blood vessels", especially in combination with vitamin D3. Some of these claims rest on real clinical studies conducted specifically in postmenopausal women, and some on extrapolation from laboratory data. Our editorial team examines what is known for certain and where the evidence base is still thin.

What vitamin K2 is and how it differs from K1

Under the name "vitamin K" a group of fat-soluble compounds with the same naphthoquinone core is grouped together. Vitamin K1 (phylloquinone) comes mainly from green leafy vegetables. Vitamin K2 is a family of menaquinones, designated MK-4, MK-7, MK-9 and so on depending on the length of the side chain.

The biochemical function of all forms is common: they are a cofactor of the enzyme gamma-glutamyl carboxylase. This enzyme "activates" calcium-binding proteins — clotting factors in the liver, osteocalcin in the bones and matrix Gla protein (MGP) in the vessel wall. Without carboxylation these proteins cannot perform their role.

The difference between the forms lies in pharmacokinetics. A study by Schurgers and co-authors (2007) showed that MK-7 has a considerably longer half-life than K1 and therefore provides a more stable blood concentration and more effective carboxylation of extrahepatic proteins. MK-4, on the contrary, is eliminated quickly, so in clinical studies it was used in high doses.

The hypothesis underlying K2’s popularity is that the liver "takes" vitamin K first of all for the clotting factors, while the bones and blood vessels receive the remainder. That is why, on an ordinary diet, the proportion of undercarboxylated osteocalcin and MGP may remain noticeable. This hypothesis is biochemically sound, but the question of how much correcting these markers changes clinical outcomes is still open.

Norms for women and dietary sources

The US Institute of Medicine set an adequate intake for vitamin K: 90 µg per day for adult women and 120 µg for men. This norm applies to vitamin K in general and is based mainly on data about K1. There is no separate norm specifically for K2, either in the US or in the EU. EFSA proposes 70 µg per day for adults without a division by sex.

During pregnancy and lactation the IOM norm for women does not change — 90 µg per day. For the infant the situation is different: vitamin K crosses the placenta poorly and is present in breast milk in small amounts, so newborns are routinely given vitamin K1 to prevent hemorrhagic disease. This is a medical procedure not connected with the mother taking K2.

In a typical European diet, K2 comes mainly from cheeses and animal products. Women who limit dairy, for example on a vegan diet, get less of it, although some MK-4 is formed in the tissues from K1.

So, there is no "female" norm specifically for K2. The particularities concern not the requirement but the state of bone tissue after menopause — it is precisely in this group that the key studies were conducted.

Menopause and bone tissue

After menopause, the decline in estrogens accelerates the loss of bone mass, and women become the main risk group for osteoporosis. That is why most randomized studies of vitamin K in relation to bones have been conducted specifically in postmenopausal women.

The most frequently cited is a three-year study by Knapen and co-authors (2013) involving 244 healthy postmenopausal women. Taking 180 µg of MK-7 per day reduced the proportion of undercarboxylated osteocalcin and slowed the age-related decline in bone mineral density in the lumbar spine and femoral neck, and also reduced the loss of vertebral height. This study did not evaluate fractures as an endpoint.

At the same time, other works did not confirm the results. In a study by Emaus and co-authors (2010) in women in early menopause, MK-7 over a year had no effect on bone-mass loss. In the Canadian ECKO study (Cheung et al., 2008), vitamin K1 in women with osteopenia did not change mineral density, although there were fewer fractures in the vitamin group — a result that needs confirmation.

In Japan, menatetrenone (MK-4) in pharmacological doses is registered as a medicine for treating osteoporosis. A meta-analysis by Cockayne and co-authors (2006) found a reduction in fracture risk with vitamin K intake, but the authors emphasized that most of the included studies were small Japanese works with MK-4, and called for large independent trials.

• K2 biochemically improves the carboxylation of osteocalcin — this is proven.
• The effect on bone density in postmenopausal women is contradictory: there are positive and neutral studies.
• The effect on fractures for MK-7 at low doses is not proven.
• K2 does not replace medicines for treating osteoporosis, calcium and vitamin D when indicated.

Blood vessels, pregnancy and other questions

The second popular promise is protection of the blood vessels from calcification. In the observational Rotterdam study (Geleijnse et al., 2004), a higher intake of menaquinones from food was associated with lower mortality from coronary heart disease and less calcification of the aorta. For K1 no such association was observed.

There are fewer randomized data. In the same three-year study by Knapen and co-authors, a separate analysis (2015) showed an improvement in measures of arterial stiffness in postmenopausal women who took MK-7, especially in those whose stiffness was elevated at baseline. However, the effect on heart attacks or strokes in women was not studied.

As for pregnancy: vitamin K2 as a separate supplement for pregnant women has no evidence-based indications, and data on the safety of high doses during this period are limited. An ordinary diet covers the requirement, and any supplements during pregnancy should be agreed with an obstetrician-gynecologist.

For women who train, no separate ergogenic effects of K2 have been described. For female athletes with amenorrhea and low energy availability, the priority for the bones is restoring energy balance and menstrual function, not individual vitamins.

Safety and interactions

No tolerable upper intake level has been set for vitamin K: no toxicity has been described with intake from food or supplements in healthy people. In studies of MK-7 at doses typical for supplements, no significant side effects were observed, and clotting parameters in healthy people remained normal.

The main limitation is interaction with anticoagulants — vitamin K antagonists, primarily warfarin. Such drugs act precisely by blocking the vitamin K cycle, so any change in its intake, especially in the form of MK-7 with a long half-life, can reduce the effectiveness of therapy and increase the risk of thrombosis. Women taking warfarin may start taking K2 only with a doctor’s permission.

Direct oral anticoagulants (apixaban, rivaroxaban and so on) are not affected by vitamin K the way warfarin is, but taking any supplements during anticoagulant therapy should still be discussed with a doctor.

Since K2 is fat-soluble, it is better absorbed with food containing fats. The popular combination with vitamin D3 is biologically logical, but there is still insufficient convincing evidence of an advantage of the combination over separate intake in terms of clinical outcomes.

Editorial conclusions

There is no separate vitamin K2 norm for women; the general adequate intake of vitamin K for women according to the IOM is 90 µg per day.

The most data on K2 have been obtained in postmenopausal women: MK-7 improves biochemical bone markers and, according to individual studies, slows the loss of bone density and reduces arterial stiffness. However, the results are inconsistent, and the effect on fractures and cardiovascular events is not proven.

K2 is safe for most healthy women but is incompatible with self-directed use while on warfarin.

Our editorial team also recommends reading the articles "Calcium for women: are there any particularities", "Vitamin K2 after 40" and "Calcium after 40".

References

1. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2001.
2. Knapen MH, Drummen NE, Smit E, et al. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013;24(9):2499–2507.
3. Knapen MH, Braam LA, Drummen NE, et al. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: a double-blind randomised clinical trial. Thromb Haemost. 2015;113(5):1135–1144.
4. Emaus N, Gjesdal CG, Almås B, et al. Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial. Osteoporos Int. 2010;21(10):1731–1740.
5. Cheung AM, Tile L, Lee Y, et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med. 2008;5(10):e196.
6. Cockayne S, Adamson J, Lanham-New S, et al. Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166(12):1256–1261.
7. Schurgers LJ, Teunissen KJ, 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.
8. 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.