Vitamin K2 and Cardiovascular Calcification: Mechanistic Foundations, Conflicting Clinical Evidence, and Unresolved Questions

Cardiovascular calcification is an active, complex process involving osteogenic transformation, inflammation, extracellular vesicle release, and impaired mineral buffering. These changes result from mineral imbalance and reduced levels of calcification inhibitors. Vitamin K supports the γ-carboxylation of matrix Gla protein (MGP) and other mineralization inhibitors, though some calcification defenses do not depend on vitamin K. Vitamin K deficiency and warfarin therapy increase circulating dephosphorylated-uncarboxylated MGP (dp-ucMGP), which is linked to greater vascular calcification. Preclinical studies demonstrate that disruption of the vitamin K-MGP axis promotes calcification. Supplementation with vitamin K1 or K2 can reduce, prevent, or partially reverse mineralization in certain animal models. In contrast, evidence from human studies is less consistent. Observational studies have identified an association between menaquinone (vitamin K2) intake and cardiovascular outcomes, but causality has not been established. Most randomized trials have shown neutral results for aortic-valve and chronic kidney disease-associated calcification, while the VitaK-CAC and DANCODE studies reported slower progression of coronary artery calcium in selected populations with moderate or severe baseline coronary calcification. These discrepancies may be due to differences in calcification phenotypes, disease stage, vitamin K forms, dosing regimens, vitamin D status, renal function, and response to vitamin K antagonists such as warfarin. Coronary intimal, valvular, and arterial medial calcification should be regarded as phenotypically distinct entities. This review evaluates the mechanistic, preclinical, and clinical evidence linking vitamin K2 to cardiovascular calcification and highlights population groups that warrant further clinical investigation. Large, adequately powered, and phenotype-specific clinical trials are needed to determine whether appropriately dosed vitamin K2 is a safe and cost-effective intervention for slowing valvular and vascular calcification.