Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health.
Vitamin K is well known for its role in the synthesis of a number of blood coagulation factors. During recent years vitamin K-dependent proteins were discovered to be of vital importance for bone and vascular health. Recommendations for dietary vitamin K intake have been made on the basis of the hepatic requirements for the synthesis of blood coagulation factors. Accumulating evidence suggests that the requirements for other functions than blood coagulation may be higher. This paper is the result of a closed workshop (Paris, November 2002) in which a number of European vitamin K experts reviewed the available data and formulated their standpoint with respect to recommended dietary vitamin K intake and the use of vitamin K-containing supplements.
Accumulating evidence suggests that in many aspects arterial calcification mimics bone formation, which prompts interest in the effects of vitamin K on the vasculature. Previous population-based studies reported a significant reduction in aortic calcification with high vitamin K1  and vitamin K2 intake , and a significant inverse correlation was found between vitamin K2 intake, and the incidence of both ischaemic heart disease and cardiovascular mortality . Based on these findings the effect of treatment on arterial characteristics was monitored in the Maastricht osteostudy. These unpublished findings clearly demonstrated that supplementation with vitamin K1 can protect against vascular hardening and loss of arterial elasticity. High dose MK-4 also seems to have cholesterol lowering properties as shown in studies in rabbits  and humans .
Extremely high doses (45–90mg/day) of MK-4 have been used for the treatment of postmenopausal osteoporosis in Japan for several years [66, 67]. After the positive outcomes of the first clinical trials, the treatment is now used on a large scale; thus far, no adverse side-effects have been reported. A number of independent groups have claimed that this medication results in complete prevention of further bone loss in postmenopausal women, and in some women even a significant gain in BMD [68, 69]. The treatment was also reported to be successful in other groups at risk for bone loss such as haemodialysis patients and those treated with corticosteroids.
In considering the potential efficacy of pharmacological doses of MK-4 it should be noted that there is evidence for a secondary function of this analogue over and above its role in glutamate carboxylation. The available evidence (mainly from cell culture experiments) suggests that MK-4 (but not K1) may also be associated with production of interleukin-6, regulate the synthesis of PGE2 , or inhibit the mevalonate pathway in a comparable way to bisphosphonates , but at present only preliminary data exist.
Any risks associated with relatively high consumption of either K1 or K2 appear minimal, with intakes up to 1 mg/d K1 and 45 mg/d MK-4 often having been used without observed adverse events. Two possible exceptions exist. Firstly a potential problem relates to interference with oral anticoagulants. However, a systematic dose-response study among subjects on oral anticoagulant treatment demonstrated that the stability of anticoagulation was not significantly affected by vitamin K supplements at doses below 100 μg/day . Secondly, preliminary studies have suggested that high vitamin K1 supplementation (i. e. above 1 mg/day) can contribute to periodontal disease via a bacterial mechanism on gingival tissue (S. Hodges, unpublished data).