Vitamin K and vascular calcifications
Coronary artery calcium (CAC) has been shown to have increasing prevalence as kidney function declines.3 Indeed, CAC prevalence has been reported in 13% of ‘healthy’ patients without renal disease,21 40% of patients with chronic kidney disease patients not on dialysis,21 57% of patients starting dialysis22 and 83% of patients on long-term dialysis.23 Diets lacking vitamin K can precipitate the development of vitamin K deficiency in as little as 7 days.24 Additionally, subclinical vitamin K deficiency is not uncommon, especially in patients receiving warfarin.25 Cross-sectional and cohort data have shown a lower risk of coronary heart disease (CHD), CHD mortality, all-cause mortality and severe aortic calcifications with higher vitamin K2 (menaquinone) intake5 ,26 (box 1). This was not shown with vitamin K1 intake (phylloquinone, the major dietary source of vitamin K.26 ,27 Thus, dietary vitamin K1 intake, without vitamin K2, may not be sufficient to suppress arterial calcifications and/or reduce risk for subsequent cardiovascular events and death. The menaquinone form of vitamin K (ie, vitamin K2) has been presumed to be more effective than vitamin K1 at preventing and reversing arterial calcifications. It has been proposed that a substantial amount of apparently healthy patients are subclinically vitamin K deficient based on undercarboxylated osteocalcin and MGP,25 presumably increasing the risk of vascular calcifications, cancer and osteoporosis.
Box 1The health benefits of vitamin K (box 1)
Bone health
May help to prevent fractures due to osteopenia and osteoporosis18–20
Trial evidence
Vitamin K1 (5 mg daily) given to 440 postmenopausal women with osteopenia for 2 years in a randomised, placebo-controlled, double-blind trial caused a greater than 50% reduction in clinical fractures (9 vs 20, p=0.04) versus placebo.
A recent meta-analysis has shown that vitamin K2 (45 mg/day) significantly reduces hip (77% reduction), vertebral (60% reduction) and all non-vertebral fractures (81% reduction).20
Cancer (especially liver cancer)
May help to prevent liver cancer and death in patients with liver cirrhosis and hepatocellular carcinoma (HCC)54–61
Trial evidence
Five randomised controlled trials tested vitamin K2 (45 or 90 mg/day) in patients with HCC. Vitamin K2 significantly improved 1-year overall survival, (RR=1.03, 95% CI 1.00 to 1.05, p=0.03)74
Vascular calcifications
May help to prevent vascular calcifications (especially in patients on warfarin)5 ,26 ,75
Trial evidence
Significantly delayed the development of coronary artery calcium in a 3-year, double-blind, randomised controlled trial of 452 patients.
In a 3-year, double-blind, placebo-controlled trial, vitamin K1 (along with vitamin D) significantly delayed the deterioration of arterial elasticity37 in 181 postmenopausal women. This was not found with vitamin D alone.
Coronary heart disease (CHD)
May reduce the risk of CHD, CHD mortality and all-cause mortality5 ,26 ,76
Insulin sensitivity
May help improve insulin sensitivity40
Warfarin international normalised ratio (INR)
May help to stabilise INR in patients on warfarin41
Low vitamin K status (indicated by undercarboxylated MGP) is associated with increased vascular calcifications, and these levels can be improved by effective vitamin K supplementation28–32 It was long believed that vitamin K was only involved in forming coagulation factors (ie, maintaining haemostasis). However, other vitamin-K dependent proteins (containing γ-carboxyglutamate or Gla) are dependent on vitamin-K carboxylation for functionality.33 Vitamin K acts as a cofactor in the conversion of glutamate into Gla. Gla-containing proteins (MGP and osteocalcin) regulate many anticalcification and bone-forming processes in the body, which are dependent on vitamin K in order to be produced. Low levels of vitamin K impair activation of osteocalcin and decrease the activity of osteoblasts (cells important for building bone).33 ,34 Thus, vitamin K is vital to the functionality of proteins such as osteocalcin (important for building bone), (MGP, the most potent arterial calcification inhibitor known) and the growth-arrest sequence-6 protein (Gas6, involved in cell growth regulation35
Vitamin K has been shown to significantly delay the development of CAC in a 3-year, double-blind, randomised controlled trial of 452 patients (229 patients on vitamin K1 and 223 patients in the control group).36 All patients were assigned to a multivitamin (containing 1.6 mg thiamine, 1.8 mg riboflavin, 2.1 mg vitamin B-6, 3 µg vitamin B12, 75 mg vitamin C, 12 mg vitamin E, 6 mg pantothenic acid, 20 mg niacin, 160 µg folate and 30 µg of biotin) as well as calcium (600 mg calcium carbonate) and vitamin D (cholecalciferol 400 IU). In the intention-to-treat (ITT) analysis, CAC progression at baseline and at year 3 was measured in 388 participants, which indicated no difference in the progression of CAC. However, a secondary analysis of 295 participants who were compliant with their supplements (predefined as >85% adherence over 3 years) showed a significantly decreased progression of CAC in the vitamin K1 group (500 µg) compared to the control group (p=0.03). Moreover, in adherent participants with a CAC >10 at baseline (ie, patients with pre-existing arterial calcification), patients assigned to vitamin K1 had a 6% less progression in CAC than those in the control group (p=0.04), whereas there was no benefit of vitamin K1 in patients without baseline CAC. Despite the fact that serum MGP increased in the vitamin K1 group, whereas MGP was decreased in the control group (treatment effect: p<0.03 in ITT and secondary analyses), neither baseline nor change in MGP predicted the change in CAC, suggesting that the benefit of vitamin K on CAC progression is not related to increases in serum MGP. However, since the assay for serum MGP did not differentiate between carboxylated versus undercarboxylated forms of MGP (and it is assumed that only the carboxylated form of MGP is functional as a calcification inhibitor), interpretation of serum MGP is severely problematic. Baseline osteoprotegerin (OPG) concentrations were positively predictive of change in CAC (p=0.004 in ITT adjusted for treatment), corroborating previous evidence suggesting that patients with higher calcification scores have higher baseline serum OPG concentrations. This study also indicated that there was no influence of vitamin K1 on circulating OPG, interleukin 6 and C reactive protein and controlling for the 3-year change in cytokines did not alter the significance of treatment effect on change in CAC. Thus, the effect of vitamin K on CAC might be independent of changes in serum cytokine levels (but not necessarily ruling out vitamin K's benefit on the blunting of the effects of these cytokines). Despite the fact that vitamin K1 has a beneficial effect on CAC in older men and women, larger studies powered for clinical end points (stroke, myocardial infarction and death) are needed to assess the risks and benefits of vitamin K therapy.
Vitamin K administration has been shown to significantly delay the progression of CAC and, in addition, it has also been shown to significantly delay the deterioration of arterial elasticity.37 In another 3-year, double-blind, placebo-controlled trial, vitamin D and vitamin K were investigated. The trial included 181 postmenopausal women who were given (1) a placebo, (2) a supplement containing minerals and vitamin D, or (3) the same supplement with the addition of vitamin K1. The vitamin K1 group had a significant increase in the distensibility coefficient (8.8%, p<0.05), compliance coefficient (8.6%, p<0.05), elasticity (13.2%, p<0.01) and a decrease in pulse pressure (−6.3%; p<0.05). There was no significant difference between the vitamin D and mineral group without vitamin K and the placebo group. In summary, vitamin K1 along with vitamin D has beneficial effects on arterial elasticity.