Is Vitamin D3 + K2 (Vitamin D3 + Vitamin K2) safer than Vitamin D3 alone in terms of reducing the risk of calcification of aortic valves and arteries?

Vitamin D3 + K2 vs. Vitamin D3 Alone for Vascular and Valvular Calcification Risk

Vitamin D3 combined with K2 is safer than vitamin D3 alone for reducing the risk of aortic valve and arterial calcification, as vitamin K2 helps direct calcium to bones rather than blood vessels. 1

Mechanism of Vascular Calcification with Vitamin D3

Vitamin D3 supplementation alone presents several cardiovascular risks:

• High-dose vitamin D supplements can induce severe aortic calcification across multiple species 1
• Vitamin D-hormones stimulate smooth muscle cell proliferation and induce expression of fibroblast growth factor-23 (FGF-23), linked to adverse cardiovascular events 1
• Vitamin D accumulates in atherosclerotic plaque and may accelerate both atherosclerosis and cardiovascular calcification 1
• Cardiovascular calcification occurs through many of the same processes as bone mineralization, including induction of osteogenic factors by vitamin D-hormones 1

Role of Vitamin K2 in Preventing Calcification

Vitamin K2 serves as a protective factor against vascular calcification through several mechanisms:

• K2 is a cofactor for the carboxylation of Matrix Gla Protein (MGP), one of the most potent inhibitors of vascular calcification 2
• K2 supplementation significantly reduces dephosphorylated-undercarboxylated MGP (dp-ucMGP) levels, which is a marker of vitamin K deficiency 3, 2
• The VitaVasK trial demonstrated that vitamin K1 supplementation resulted in 56% less progression of thoracic aorta calcification compared to standard care 1

Clinical Evidence for Combined Supplementation

Recent clinical trials provide important insights:

• In patients with CAC scores ≥400 AU, vitamin K2 (720 μg/day) plus vitamin D (25 μg/day) supplementation showed lower coronary artery calcification progression compared to placebo (Δ288 vs Δ380 AU, P = 0.047) 4
• Safety events were fewer in participants receiving K2+D3 supplementation compared to placebo (1.9% vs 6.7%, P = 0.048) 4
• While some studies show mixed results in general populations, the benefit appears most pronounced in those with already established severe calcification 3, 4

Practical Recommendations

For patients concerned about vascular calcification risk:

1. Assess baseline risk:

   • Consider measuring baseline coronary artery calcium score in high-risk individuals
   • Evaluate vitamin D status with 25(OH)D levels

2. Supplementation strategy:

   • For patients taking vitamin D3 supplements, add vitamin K2 (preferably MK-7 form)
   • Typical effective doses in studies: 720 μg/day of vitamin K2 with 25 μg/day (1000 IU) of vitamin D3 3, 4
   • Avoid high-dose vitamin D3 supplementation without K2, especially in patients with risk factors for vascular disease

3. Monitoring:

   • The safe upper limit for vitamin D3 is considered 4,000 IU daily 1, 5
   • Monitor calcium levels if on higher doses of vitamin D3
   • Consider dp-ucMGP levels as a functional marker of vitamin K status when available

Cautions and Contraindications

• Vitamin K supplementation is contraindicated in patients on vitamin K antagonists like warfarin 6
• Patients with coagulation disorders should avoid vitamin K2 supplementation 6
• The risk of vitamin D toxicity increases at 25(OH)D3 plasma concentrations >150 ng/ml (>375 nmol/L) 1

Special Considerations

• Patients with chronic kidney disease are at particularly high risk for vascular calcification and may benefit most from combined supplementation 1
• Patients with existing coronary artery calcification scores ≥400 AU appear to derive greater benefit from K2+D3 supplementation 4
• Non-calcium-based phosphate binders may be preferable in patients with evidence of vascular calcification 1

By ensuring adequate vitamin K2 status alongside vitamin D3 supplementation, calcium is more likely to be directed to bones rather than deposited in blood vessels and heart valves, potentially reducing cardiovascular risk.