Vitamin K is the common name for a family of compounds with similar γ-carboxylation activity. Three mixtures of vitamin K are known: Phylloquinone, or vitamin K1, which is mainly found in green plants, menaquinone or vitamin K2, which is a bacterial by-product and is therefore primarily found in fermented or food of animal origin. Finally, menadione, or vitamin K3, which occurs when the side chain of isoprene has a length of 0, which is a synthetic compound found only in supplements.
For decades, the coagulation process has been considered as the only vitamin K function, but many vitamin K-dependent proteins have been discovered, at least 14 different proteins so far. Four proteins (factors VII, IX, X and prothrombin) and three anticoagulant proteins (protein C, protein S and protein G), mainly synthesized in the liver, two bone and extracellular matrix proteins (osteocalcin and Gla protein) Gas6, as well as four membrane proteins with functions not yet defined (PRGP1, PRGP2, TMG3 and TMG4).
In addition to blood and bone, vitamin K-dependent proteins are present in dentin, renal stones, atherosclerotic plaque, semen, nervous tissue and urine. Protein Gla residues function as calcium ligands and are vital for the biological activity of proteins.
While γ-carboxylation of glutamic acid residues in vitamin K-dependent proteins occurs in part with K1 and K2, some K2-specific γ-carboxylations have been reported. Menaquinone has recently been shown to be a steroid receptor ligand (SXR) and therefore functions as an inducer of mRNA synthesis for osteoblast biomolecules such as alkaline phosphatase, osteoprotegerin, osteopontin and Gla protein.
First indications of a connection between vitamin K and bone health
In the mid-1970s, the first report was presented on severe bone malformations in children born to mothers who received vitamin K antagonists during the first trimester. Shortly after that, it was reported that patients who had had an acute hip fracture or suffered from chronic spinal fracture had lower plasma phylloquinone levels compared to healthy controls, as confirmed by other studies later.
These findings have led to more research on this issue, and since then many studies have shown that vitamin K is vital for optimum bone health. Both epidemiological and intervention studies have investigated the relationship between vitamin K and bone health.
The Framingham Heart Study and the Nursing Health Study, two major epidemiological studies, showed that vitamin K intake, assessed with a food frequency questionnaire, is associated with the risk of hip fracture and bone mineral density (BMD). In the Nursing Health Study, which included 72,327 women aged 38-63 years, an intake <109 mg/day of vitamin K was associated with a 30% higher risk of hip fractures than with higher doses of vitamin K.
Similar results were recorded in the study Framingham Heart with 888 senior men and women. They also showed that there was no correlation between vitamin K intake and BMD in senior men and women, but significantly lower bone density was found in the neck in a group of women with low vitamin K intake (70 mg/day) compared to those with the highest uptake (309 mg/day).
Studies with dietary intervention and an impact assessment on risk indicators have also been performed and biomarkers for bone formation and bone resorption were used as the endpoints. In two such studies, 1 mg of phylloquinone was given for 2 weeks in healthy pre- and postmenopausal volunteers with bone formation and reabsorption markers not affected by phylloquinone therapy except for hydroxyproline and calcium and gamma-carboxylation of osteocalcin which increased in both studies.
In contrast, another study of 10 mg of phylloquinone for 30 days showed an increase in bone formation markers and a reduction in bone resorption markers in eight female long-distance runners.
Studies have shown that there are differences in the effect of vitamins K1 and K2. Long-term studies are required to see if vitamin K1 has an impact on the risk of fracture. In addition to the distinct possibility that vitamins K1 and K2 differ in their activity in bone metabolism and therefore differ in relation to the prevention of osteoporosis and bone fractures, and other factors may be essential to explain the different effects found in various studies, for example, absorption, metabolism and excretion, dietary intake and source as well as selection of biomarkers.
Absorption and dietary intake of vitamin K
Phylloquinone is absorbed in the uterus and the ileum in a process that is dependent on the simultaneous presence of dietary fat as well as a regular flow of bile and pancreatic juice. Free phylloquinone is absorbed almost 100%, while the phylloquinone from food is less well incorporated. Bacterial menaquinones can be synthesised from the intestinal microflora as evidenced by the presence of bacteria-derived menaquinone in the liver, particularly MK-10 and MK-11.
The availability of phylloquinone in the bones is affected by apolipoprotein E (apo E) acting as a ligand for cellular uptake by lipoproteins. The Apo E genotype has been associated with a risk of osteoporotic fracture, low BMD and lipoprotein-mediated transfer of phylloquinone to bones.
Phylloquinone occurs in large quantities in green leafy vegetables and vegetable oils and kinds of margarine, while menaquinones are mainly found in the liver, certain cheeses and soy products that have been fermented. In addition to dietary sources of vitamin K, human gut flora also contributes to vitamin K levels with the contribution of intestinal flora can be very consistent with research.
The intake of vitamins K1 and K2 varies among the different populations, with vitamin K2 intake being high in some parts of Asia where the consumption of fermented soy products is high while phylloquinone is the primary source of vitamin K intake in most Western countries. In general, it has been observed that vitamin K intake increases with age probably due to higher consumption of green vegetables in older age groups.
Bügel, S. (2008) Vitamin K and bone health in adult humans. Vitam. Horm. 78:393-416
: Complete D3, K2 & Co factors