Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects

Abstract

Vitamin K is required for the carboxylation of Gla-proteins in the liver (coagulation factors) and extra-hepatic tissues, such as bone (osteocalcin, OC), and arterial wall (matrix Gla-protein, MGP). Although the coagulation factors are essentially fully carboxylated under normal conditions, 10-40 % of OC and MGP remains undercarboxylated. We were therefore interested to study the dose -response effects of extra intake of menaquinones on the carboxylation of the extra-hepatic Gla-proteins. A total of forty-two healthy Dutch men and women aged between 18 and 45 years were randomised into seven groups to receive: placebo capsules or menaquinone-7 (MK-7) capsules at a daily dose of 10, 20, 45, 90, 180 or 360 mg. Circulating uncarboxylated OC (ucOC), carboxylated OC (cOC) and desphospho-uncarboxylated MGP were measured by ELISA. The ucOC:cOC ratio was calculated from circulating ucOC and cOC values. Endogenous thrombin potential and peak height were determined by calibrated automated thrombography. To increase the statistical power, we collapsed the treatment groups into three dosage groups: placebo, low-dose supplementation (doses below RDA, Commission Directive 2008/100/EC), and highdose supplementation (doses around RDA, Commission Directive 2008/100/EC). MK-7 supplementation at doses in the order of the RDA (Commission Directive 2008/100/EC) increased the carboxylation of circulating OC and MGP. No adverse effects on thrombin generation were observed. Extra MK-7 intake at nutritional doses around the RDA (Commission Directive 2008/100/EC) improved the carboxylation of the extra-hepatic vitamin K-dependent proteins. Whether this improvement contributes to public health, i.e. increasing the protection against age-related diseases needs further investigation in specifically designed intervention trials.

Bioavailability and Chemical/Functional Aspects of Synthetic MK-7 vs Fermentation-Derived MK-7 in Randomised Controlled Trials

“…Elevated concentrations of ucOC are associated with vitamin K deficiency and an increased risk of hip fractures [5,13,14,35,36]. Supplementation with vitamin K 2 promotes a decrease in ucOC, suggesting that vitamin K 2 contributes to OC carboxylation [9,37]. In the functional study, we observed that synthetic and fermentation-derived MK-7 gave similar steady-state serum concentrations of MK-7, and had similar abilities to reduce the serum ucOC concentration, although the reduction from baseline in the fermentation-derived MK-7 group was not statistically significant.…”

Cardiovascular Calcification and Bone: A Comparison of the Effects of Dietary and Serum Vitamin K and its Dependent Proteins

“…In the few studies of MK7, 360mcg/d reduced ucOC and increased cOC in early postmenopausal women 75 , although a lower dose may also be effective in increasing cOC 9,55 . Nevertheless, reduction of serum ucOC is not always accompanied by improvement in BMD 76 .…”

“…Menaquinone may take 14 different forms, of which MK4 and MK7 are the most studied, with high quantities of MK7 found in the Japanese food natto, made from fermented soy. Both forms of vitamin K can function as enzyme cofactors in the γ-carboxylation of glutamic acid residues to produce the calcium-binding γ-carboxyglutamate (Gla) proteins, which impact blood coagulation, CV calcification and bone formation, with the mechanisms for all three being similar 8,9 .…”

Outcome of a public consultation on the Draft Scientific Opinion of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on Dietary Reference Values for vitamin K

“…Vitamin K2 intake seems to be the most appropriate strategy to prevent chronic vitamin K insufficiency, and a dietary intake of 45 mcg/day has been reported to have significant health benefits in population-based studies. In dose-response experiments, a supplement of 45-90 µg/day induced a significant decrease of circulating dp-ucMGP levels, demonstrating improvement of extrahepatic vitamin K status [48][49][50]. This amount is obtained by the consumption of 70-100 grams of cheese per day.…”