What role does vitamin K play in maintaining bone health?

How Vitamin K Supports Bone Health

Vitamin K maintains bone health primarily by serving as an essential cofactor for the carboxylation of bone proteins, particularly osteocalcin and matrix Gla-protein (MGP), which are critical for calcium incorporation into bone and may reduce fracture risk in postmenopausal and osteoporotic patients. 1, 2

Primary Mechanisms of Action

Protein Carboxylation for Calcium Metabolism

• Vitamin K acts as a coenzyme for glutamate carboxylase, which converts glutamate residues to gamma-carboxyglutamate (Gla) in bone-related proteins 3
• This gamma-carboxylation is essential for these proteins to attract calcium ions and incorporate them into hydroxyapatite crystals, the mineral component of bone 3
• When vitamin K is insufficient, osteocalcin remains undercarboxylated (ucOC), which is associated with lower bone mineral density and increased fracture risk 4, 3

Key Bone Proteins Affected

• Osteocalcin: The most abundant non-collagenous protein in bone; when properly carboxylated, it appears to contribute directly to bone quality and strength 2
• Matrix Gla-protein (MGP): When carboxylated, this protein appears to chelate and import calcium from blood to bone, reducing osteoporosis risk 2

Additional Mechanisms Beyond Carboxylation

• Menaquinone-4 (vitamin K2) acts as a ligand for the nuclear steroid and xenobiotic receptor (SXR), directly affecting bone metabolism through gene transcription 2
• Vitamin K regulates genetic transcription of osteoblastic markers and modulates bone resorption 4
• Evidence suggests vitamin K positively affects overall calcium balance, a key mineral in bone metabolism 1

Clinical Evidence for Bone Health Benefits

Fracture Risk Reduction

• Meta-analysis of postmenopausal and osteoporotic patients showed vitamin K supplementation reduced the odds of any clinical fracture (OR 0.72,95% CI 0.55 to 0.95) 5
• When restricted to low risk of bias trials, the odds ratio was 0.76 (95% CI 0.58 to 1.01), suggesting a trend toward benefit though not reaching statistical significance 5
• No significant difference was found for vertebral fractures specifically (OR 0.96,95% CI 0.83 to 1.11) 5

Bone Mineral Density Effects

• At the lumbar spine, vitamin K supplementation showed higher percentage change from baseline at 2 years (MD 1.63%, 95% CI 0.10 to 3.16) 5
• At 6 months, improvements were seen in the hip (MD 0.42%, 95% CI 0.01 to 0.83) and femur (MD 0.29%, 95% CI 0.17 to 0.42) 5
• However, removing high risk of bias trials tended to result in smaller, non-significant differences, indicating the evidence quality is limited 5

Vitamin K Deficiency and Bone Health

Markers of Inadequate Status

• Low serum vitamin K1 concentrations are associated with higher fracture risk and lower bone mineral density 4
• Elevated levels of undercarboxylated osteocalcin (ucOC) serve as a functional marker of vitamin K insufficiency and correlate with increased fracture risk 4, 3
• Low dietary intake of both K1 (phylloquinone) and K2 (menaquinones) is associated with compromised bone health 4

Risk Factors for Deficiency

• Vitamin K deposits in the body are scarce and dependent upon dietary supplementation and intestinal absorption 4
• Vitamin K antagonist oral anticoagulants (like warfarin) induce vitamin K deficiency and are associated with increased fracture risk, particularly in men with prolonged use (≥1 year) 6

Synergistic Relationship with Vitamin D

Combined Benefits

• Vitamin K and vitamin D work synergistically on bone density, with an adequate vitamin K supply on top of optimal vitamin D status appearing to add benefit for maintaining bone health 1, 2
• Vitamin D is essential for calcium absorption and bone metabolism, while vitamin K ensures proper utilization of that calcium in bone tissue 2
• Human intervention studies demonstrate that vitamins K and D together can improve bone mineral density more effectively than either alone 1

Clinical Implications

• Emerging evidence suggests vitamin K1 at lower doses may benefit bone health, particularly when coadministered with vitamin D 1
• The combination addresses both calcium availability (vitamin D) and calcium incorporation into bone (vitamin K) 2

Dietary Considerations and Requirements

Current Recommendations

• The Institute of Medicine increased dietary reference intakes to 90 μg/day for females and 120 μg/day for males, approximately 50% higher than previous recommendations 1
• These recommendations are based on saturation of the coagulation system; requirements for optimal bone health may be higher 3
• In most countries, typical dietary intake is sufficient for coagulation but may be inadequate for optimal bone health 3

Important Clinical Caveats

Evidence Quality Limitations

• The available evidence includes low-quality studies reaching disparate conclusions, making it impossible to extract solid conclusions, especially concerning vitamin K supplement use 4
• High-quality studies designed to evaluate fracture as a primary endpoint are needed 4
• Most intervention studies employed vitamin K2 at rather high doses, which has been criticized as a limitation 1

Warfarin Paradox

• While warfarin increases fracture risk through vitamin K antagonism, the relationship between dietary vitamin K intake and bone health in warfarin users remains complex 3
• Low dietary vitamin K intake paired with warfarin may contribute to increased fracture risk 6
• Non-vitamin K antagonist oral anticoagulants (NOACs) like rivaroxaban and apixaban show reduced fracture risk compared to warfarin, though evidence is mixed for dabigatran 6