Abstract
The role and importance of vitamin K as a cofactor in the ã-carboxylation of coagulation-proteins factor II, VII, IX and X is well-known. But, during the last 30 years, a number of observations have indicated a role for the vitamin also in other areas, for example in bone physiology. The first clue to this connection, was the description of the Fetal Warfarin Syndrome, where children are born with nasal hypoplasia, stippled epiphyses and distal extremity hypoplasia, due to the administration of warfarin, a vitamin K-antagonist, to their mothers during the first trimester.
The discovery of vitamin K-dependent bone proteins, osteocalcin being the most studied, has led to experimental studies where it has been shown that osteocalcin has affinity for hydroxyapatite, and is a negative regulator of bone production. Carboxylation of osteocalcin seems to be essential for the protein’s biological activity, and undercarboxylated osteocalcin has reduced affinity for hydroxyapatite. Increased serum noncarboxylated osteocalcin is associated with low serum vitamin K and warfarin-treatment. Clinical studies, which have examined the role of osteocalcin in osteoporosis, have shown conflicting results. Some indicate that undercarboxylated osteocalcin is an independent determinant of bone density, and may predict risk for hip fractures, while other studies don’t show this association. Increased intake or supplementation of vitamin K show a retardation in postmenopausal bone loss, and is associated with decreased risk of hip fracture. Supplementation using pharmacological doses of vitamin K2 is established as treatment of osteoporosis in Japan.
In addition to this, vitamin K might influence bone health independent of it’s role in ã-carboxylation. Vitamin K inhibits the production of interleukin-6 and prostaglandins in cell cultures, these cytokines being potent inducers of bone resorption. An important finding is that vitamin K2 might regulate the transcription of bone-specific genes via the Steroid and xenobiotic receptor (SXR).
Warfarin inhibits the ã-carboxylation of osteocalcin and other vitamin K-dependent proteins, and serious adverse effects of warfarin on bone metabolism have been demonstrated in animal models. Clinical studies on whether warfarin affects bone quality have so far shown conflicting results, some indicate that increased fracture rate and reduced bone density are associated with oral anticoagulation, others not. Warfarin is mostly used by elderly who are at risk of getting osteoporosis and osteoporotic fractures, which causes high incidence of morbidity and mortality. The effects of warfarin on bone are controversial, and future longitudinal studies must provide additional evidence if any conclusion on this topic are to be drawn.
This literature study discusses these topics more extensively, with focus on vitamin K, vitamin K-dependent bone proteins, and their relations to osteoporosis and warfarin-treatment.