In the 1970s, the vitamin K–dependent mechanism of posttranslationally γ-carboxylating specific Glu residues to form Gla residues in certain bloodclotting factors was fully elucidated.
The reduced form of vitamin K (the hydroquinone or quinol form) is a required cofactor for this carboxylation reaction.
The discovery of this unique calcium-binding amino acid, Gla, begged the question as to whether there are additional Gla-containing proteins in other tissues that contain significant amounts of calcium. Bone was an obvious target of investigation, and in 1975 Hauschka et al88 identified a Gla-containing protein in bone.
Further research isolated, characterized, sequenced, and determined the 3-dimensional structure of this protein, which was named OC. Relative to bone, there are 3 known VKD proteins: OC, matrix Gla protein, and protein S.
The vitamin K metabolic cycle is functional in osteoblasts, as well as in the liver.
In addition to the liver's requirement for vitamin K to synthesize functional coagulation proteins, the discovery of OC made evident that extrahepatic tissues (ie, bone) require vitamin K for local production of tissue-specific VKD proteins (ie, OC and matrix Gla protein). Bone may preferentially use different forms of vitamin K than the liver.
Epidemiological studies and clinical trials consistently indicate that vitamin K has a positive effect on bone mineral density and decreases fracture risk. Typical dietary intakes of vitamin K are below the levels associated with better BMD and reduced fracture risk; thus issues of increasing dietary intakes, supplementation, and/or fortification arise. To effectively address these issues, large-scale, intervention trials of vitamin K are needed. The effects of coumarin-based anticoagulants on bone health are more ambiguous, with retrospective studies suggesting that long-term therapy adversely affects vertebral BMD and fracture risk. Anticoagulants that do not affect vitamin K metabolism are now available and make clinical trials feasible to answer the question of whether coumarins adversely affect bone. The research suggests that at a minimum, clinicians should carefully assess anticoagulated patients for osteoporosis risk, monitor BMD, and refer them to dietitians for dietary and supplement advice on bone health. Further research is needed to make more efficacious decisions about vitamin K intake, anticoagulant therapy, and bone health.