Vitamin K2 and the Next Frontier

Multiple human studies have shown vitamin K2 positively impacts bone mineral content and bone mass, which have a direct correlation on bone strength. However, newer research is looking at the elucidation of molecular mechanisms of vascular smooth muscle cell-derived vitamin K-dependent proteins (VKDP) by which vascular calcification is initiated and propagated.

Uncarboxylated vitamin K-dependent calcium-regulatory proteins directly relate to development of calcifications. Vitamin K is a key regulator of vascular calcification via activation of vitamin K-dependent proteins such as matrix Gla protein (MGP).¹ Knowledge about vitamin K status may propel therapeutic strategies to prevent and treat vascular calcification with high vitamin K supplementation. Over recent years, vitamin K2 has been shown to inhibit and regress preformed vascular calcifications in preclinical models,² as well as inhibit vascular calcification and age-related stiffening in the healthy elderly populations.³

Importantly, these findings will help to illuminate the importance of vitamin K2 and provide new insights in prognostic and preventive measures. To date, no drugs have been successful in reducing or inhibiting vascular calcification; thus, vitamin K2 would even have pharmaceutical potential.

Understanding Vascular Calcification and Its Impact

Arterial calcification plays such a profound role in cardiovascular health that it can be used as a measure to predict biological aging. In a cohort of 10,377 asymptomatic individuals followed for five years for all-cause mortality, measures of coronary artery calcium were used to estimate the number of life years lost.⁴ Results showed a direct relationship between coronary artery calcium and observed age (p<0.0001). The team found a calcium score <10 resulted in a reduction in observed age by 10 years in subjects older than 70 years, while a calcium score >400 added up to 30 years of age to younger patients.

The population-based Rotterdam study provided the first evidence for a link between vitamin K status and vascular health.⁵ The study included 4,807 subjects who were analyzed for their vitamin K intake as well as its relationship to aortic calcification and coronary heart disease (CHD). The results showed the relative risk of CHD mortality was reduced in the mid- and upper-tertiles of dietary menaquinone, compared to the lower tertile, and was inversely related to all-cause mortality and severe aortic calcification. Interestingly, phylloquinone intake was not related to any of the outcomes.

In similar research, the association between intake of phylloquinone and menaquinone with coronary calcification was examined in a cross-sectional study among 564 post-menopausal women.⁶ Results revealed 62 percent (n=360) of the women had coronary calcification. Menaquinone intake was associated with decreased relative risk of coronary calcification (p=0.03). As with the Rotterdam cohort, this study showed high dietary menaquinone intake, but not phylloquinone, was associated with reduced coronary calcification.

Vascular calcification has emerged as an independent risk factor for cardiovascular morbidity and mortality, but especially in the aging population and in patients with chronic kidney disease and diabetes. For instance, chronic kidney disease patients on hemodialysis tend to have a functional vitamin K deficiency and experience severe calcification, which results in increased circulating dephospho-uncarboxylated MGP (dp-ucMGP). Based on the knowledge of vitamin K2’s mechanism, researchers hypothesized that these patients could benefit from vitamin K2 therapy.

To that end, 53 hemodialysis patients were randomized and given 45 mcg, 135 mcg or 360 mcg of vitamin K2 as MK-7 (as MenaQ7®) daily for six weeks to see if the supplementation improved the bioactivity of vitamin K-dependent proteins as assessed by circulating dephospho-uncarboxylated MGP (dp-ucMGP), undercarboxylated osteocalcin (ucOC) and noncarboxylated prothrombin (ucFII; PIVKA-II).⁷

The results showed vitamin K2 supplementation induced a dose- and time-dependent decrease in circulating dp-uc MGP, ucOC and PIVKA-II levels. The best efficacy was achieved with the highest dose of vitamin K2 (360 mcg/d), where response rate in the reduction in dp-uc MGP levels was 93 percent. In short, the study showed evidence of a functional vitamin K deficiency in hemodialysis patients, which can be treated effectively with vitamin K2 (MK-7) supplementation.

These findings have led to several clinical trials, such as the VitavasK (NCT01742273), VitaK-CAC (NCT01002157), VITAKAN- DOP (NCT01232647), SAFEK (NCT01533441) and OVWAK VII (NCT00990158), all of which are underway. The results of these trials will provide further insights into the therapeutic potential of vitamin K in treating both bone disorders and vascular diseases.

Another noteworthy study, on the cusp of publication, examined the effects of high-dose vitamin K2 as MK-7 supplementation on CKD-induced cardiovascular calcification.⁸ This three-month interventional study demonstrated that high-dose MK-7 supplementation (100 mcg/g diet) inhibits calcification in a murine model. The effect of MK-7 is—at least in part—mediated via MGP and subsequent inhibition of ectopic calcification.

Interestingly, MK-7 supplementation normalized CKD-induced increased serum phosphate concentrations. More importantly, MK-7 supplementation inhibited both vascular and myocardial calcification in CKD animals on a high phosphate diet, and demonstrated a protective effect of MK-7 supplementation on early stages of cardiovascular calcification.

Our results support previous data from our group, showing vitamin K2 and not vitamin K1 supplementation inhibits vitamin K antagonist-induced VC in rats.⁹ Further, because vitamin K2 has no reported side effects, it seems a promising therapeutic agent.¹⁰

A Remarkable Difference in Healthy Populations

In a recent study published this year in Thrombosis and Haemostasis, 244 post-menopausal women (ages 55 to 65) took 180 mcg of MenaQ7® or a placebo daily for three years.¹¹ Researchers used ultrasound and pulse wave velocity (PWV) to measure cardiovascular health. In the end, carotid artery distensibility (i.e., elasticity or the ability for a blood vessel to stretch or dilate) was significantly improved over a three-year period in those taking vitamin K2 compared with the placebo group. Also, PWV was significantly decreased in the MenaQ7® group, but not the placebo group, demonstrating an increase in the elasticity and reduction.

At the study’s conclusion, the Stiffness Index ß in the vitamin K2 group with initial high arterial stiffness had decreased significantly compared with the slight increase in the placebo group (specifically: 0.67 ± 2.78 versus +0.15 ± 2.51, respectively, p=0.018). These results confirmed K2 not only inhibited age-related stiffening of the artery walls, but also made a statistically significant improvement in vascular elasticity.

There is a growing body of knowledge that not only affects diseased populations, such as coronary patients and dialysis patients, but also healthy populations seeking effective preventive measures to attain long, happy, healthy lives. Vitamin K2 can truly benefits the population as a whole—young and old, men and women.

Leon Schurgers, Ph.D., works as associate professor and senior scientist at the department of biochemistry, the Cardiovascular Research Institute CARIM of University of Maastricht. Schurgers' research line involves the elucidation of molecular mechanisms of vascular smooth muscle cell derived vitamin K-dependent proteins (VKDP) by which vascular calcification is initiated and propagated.

Looking for more information on Vitamin K2?

Leon Schurgers, Ph.D., will speak on “Vitamin K2: Key Vitamin in Controlling Vascular Calcification" as part of the Vitamin K2 Workshop at SupplySide West. The three-hour workshop will take place on Friday, Oct. 9, at Mandalay Bay in Las Vegas. Visit http://west.supplysideshow.com/workshops.aspx for the complete agenda and to get registered.

References

1. Schurgers LJ, Uitto J, Reutelingsperger CP. “Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization." TMM. Apr 2013;19(4):217–226.

2. Schurgers LJ et al. “Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats." Blood. 2007 Apr 1;109(7):2823-31.

3. Knapen MHJ et al. “Menaquinone-7 Supplementation Improves Arterial Stiffness In Healthy Postmenopausal Women: Double-Blind Randomised Clinical Trial." Thrombosis Haemostasis. 2015;19(5):113.

4. Shaw LJ, Raggi P, Berman DS, Callister TQ. “Coronary artery calcium as a measure of biologic age." Atherosclerosis. 2006;188(1):112-119.

5. Geleijnse JM et al. “Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study." J Nutr. 2004;134:3100-3105.

6. Beulens JW et al. “High dietary menaquinone intake is associated with reduced coronary calcification." Atherosclerosis. 2009;203(2):489-493.

7. Westenfeld R et al. “Effect of Vitamin K2 Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial." Am J Kidney Dis. 2012;59(2):186–195.

8. Scheiber D et al. “High-dose menaquinone-7 supplementation reduces cardiovascular calcification in a murine model of extraosseous calcification." Nutrients. 2015, 7, 1-x manuscripts; doi:10.3390/nu70x000x

9. Spronk H et al. “Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats." J Vasc Res. 2003;40:531-537.

10. Brandenburg, VM et al. “Prevention of vasculopathy by vitamin k supplementation: Can we turn fiction into fact?" Atherosclerosis. 2015;240:10-16.

11. Knapen MHJ et al. Op cit.