‘Very pleased to find a lower dose supports bone health’: Kyowa study shows new efficacious levels for vitamin K2

By Stephen Daniells

- Last updated on GMT

‘Very pleased to find a lower dose supports bone health’: Kyowa study shows new efficacious levels for vitamin K2

Related tags Bone health Kyowa hakko Vitamin k Osteoporosis

The potential bone health benefits of vitamin K2 menaquinone-4 may be achievable at a daily dose of 600 micrograms, according to a new study from Kyowa Hakko with implications for formulations and health.

Results of the graded dose study, published in the Nutrition Journal​, indicated that the 600 microgram per day dose was associated with a significant lowering of levels of circulating inactive osteocalcin (ucOC). Osteocalcin (cOC) is a vitamin K-dependent protein and is essential for the body to utilize calcium in bone tissue. Without adequate vitamin K, the osteocalcin remains inactive, and thus not effective.

The ratio of ucOC to activated osteocalcin – a sensitive marker of bone’s vitamin K status – also decreased significantly with intakes of at least 600 micrograms per day, they noted.

“Therefore, menaquinone-4 supplementation at 600 micrograms per day after a week’s initial intake at 300 micrograms per day improved vitamin K status in terms of bone health, especially on the basis of serum ucOC level as a marker of vitamin K deficiency and the [ratio of ucOC to activated osteocalcin] as a sensitive marker of gamma-carboxylation of osteocalcin,” ​wrote the researchers.


Ayako Kamimura, PhD, manager, Healthcare Products Development Center for Kyowa Hakko Bio and corresponding author for the study, told NutraIngredients-USA that until now, the lowest efficacious dose of menaquinone-4 for bone metabolism was 1.5 mg/day (which is a dose considered too high to achieve from natural food intakes).

“However, our recent research has discovered that supplementation with MK-4 at 600 micrograms per day or more is likely to be important in terms of vitamin K requirements for bone health.

“We wanted to elucidate the minimum menaquinone-4 dose and we are very pleased with obtaining a lower dose to support bone health.”

K forms

There are two main forms of vitamin K: phylloquinone, also known as phytonadione, (vitamin K1) which is found in green leafy vegetables such as lettuce, broccoli and spinach, and makes up about 90% of the vitamin K in a typical Western diet; and menaquinones (vitamins K2), which make up about 10% of Western vitamin K consumption and can be synthesized in the gut by microflora.

Menaquinones (MK-n: with the n determined by the number of prenyl side chains) can also be found in the diet; MK-4 can be found in animal meat, MK-7, MK-8, and MK-9 are found in fermented food products like cheese, and natto is a rich source of MK-7.

Study details

The Kyowa Hakko scientists recruited 15 health men with an average age of 25to participate in their non-placebo-controlled dose-examination study. The men received daily menaquinone-4 doses of 0, 300, 600, 900, and 1500 micrograms for one week each in increasing order over five weeks. Results showed that activated osteocalcin levels were significantly increased at the 900 micrograms per day or more doses, while significant decreases in inactivated osteocalcin levels and the ratio of inactivated to activated osteocalcin were observed starting at 600 micrograms per day.

“In conclusion, in this graded-dose study, we showed that supplementation with MK-4 at 600 micrograms/day or more is likely to be important in terms of vitamin K requirements for bone health,”​ they wrote. “These relatively low MK-4 dosages (below 1500 micrograms/day) may improve bone formation and reduce bone fracture risk.”

Source: Nutrition Journal
2014, 13​:85, doi:10.1186/1475-2891-13-85
“Low-dose menaquinone-4 improves gamma-carboxylation of osteocalcin in young males: a non-placebo-controlled dose–response study”
Authors: E. Nakamura, M. Aoki, F. Watanabe, A. Kamimura

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