All About Vitamin K2
Vitamin K2 is a newly discovered essential vitamin that is building a significant body of clinical evidence demonstrating its crucial significance in the fight against the most common and devastating diseases of our time: osteoporosis and cardiovascular disease. These conditions contribute to difficulties in the functioning of society and are the most common cause of death worldwide, and both can be linked to a deficiency in vitamin K2. Part of the K family of vitamins, vitamin K2 is a fat-soluble vitamin that helps the body efficiently utilize calcium. By activating different K-dependent proteins, it directs calcium toward bones and away from the arteries.
The Vitamin K family consists of a group of fat-soluble vitamins that are divided into vitamin K1 – one molecule (phylloquinone) – and vitamin K2 – a group of molecules (menaquinones). Menaquinones is the group name for a family of related compounds, generally subdivided into short-chain menaquinones (with MK-4 as the most nutritionally important) and the long-chain menquinones, of which MK-7, MK-8, and MK-9 are the most nutritionally recognized.
Vitamins K1 and K2 are similar in structure: they share a “quinone” ring, but differ in the length and degree of saturation of the carbon tail and the number of side chains.1 The number of side chains (isoprene units) is indicated in the name of the particular menaquinone. For example, MK-7 denotes 7 isoprene units attached to the carbon tail; and this influences the transport to different target tissues.
The mechanism of action of vitamin K2 is similar to vitamin K1. K vitamins play an essential role as cofactor for the enzyme γ-glutamyl carboxylase, which is involved in carboxylation of the vitamin K-dependent proteins – specifically, the conversion of peptide-bound glutamic acid (Glu) to γ-carboxy glutamic acid (Gla).
Carboxylation Reaction – ‘Vitamin K Cycle’
Carboxylation of vitamin K-dependent proteins (called Gla-proteins) serves as a recycling pathway to recover vitamin K from its epoxide metabolite (KO) for reuse in carboxylation. Several human Gla-containing proteins synthesized in several different types of tissues have been discovered:
- Coagulation factors (II, VII, IX, X), as well as anticoagulation proteins (C, S, Z). These Gla-proteins are synthesized in the liver and play an important role in blood homeostasis.
- Osteocalcin. This non-collagenous protein is secreted by osteoblasts and plays an essential role in the formation of mineral in bone.
- Matrix gla protein (MGP). This calcification inhibitory protein is found in numerous body tissues, but its role is most pronounced in cartilage and in arterial vessel walls.
- Growth arrest-specific protein 6 (GAS6). GAS6 is secreted by leucocytes and endothelial cells in response to injury and helps in cell survival, proliferation, migration, and adhesion.
- Proline-rich Gla-proteins (PRGP), trans-membrane Gla-proteins (TMG), Gla-rich protein (GRP) and periostin. The precise functions are still unexplored.
Vitamin K2’s isoprenoid units (ex. MK-7) are geranylgeranyl derivatives that influence bone function via another mechanism than as a cofactor for enzymatic carboxylation. The mechanism for the anti-osteoclastogenic properties of vitamin K been suggested that the geranylgeranyl-like side chain on vitamin K2 may induce apoptosis of osteoclasts in vitro2 or may act by down-regulating protein kinase C.3 MK-7 affects the function of the osteoblasts by inducing the expression of osteoblast-specific genes [ex: osteocalcin, osteoprotegerin, receptor activator of NF-kB (RANK) and RANK ligand (RANKL)]. 4 Interestingly, in contrast to what was observed for vitamin K2, the scientists failed to identify any anti-NF-κB activity associated with vitamin K1.
Vitamin K2 is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Mitochondrial dysfunction can be reversed by vitamin K2, which serves as a mitochondrial electron carrier, helping to maintain normal ATP production.
It has been suggested that vitamin K2 may play an important role in maintaining healthy levels of bone mineral density (BMD). However, data on the subject is inconclusive – some clinical trials show no improvement of BMD after vitamin K supplementation. First indications came from patients with femoral neck fractures, who demonstrated extremely low levels of circulating vitamin K. The strong association between vitamin K2 deficiency and impaired bone health was later proved by both laboratory and clinical studies. It has been found that vitamin K deficiency results in a decreased level of active osteocalcin, which in turn increases the risk for fragile bones.5,6 Research also showed that vitamin K2 – but not K1– combined with calcium and vitamin D can decrease bone turnover.7 Moreover, a significant study clearly demonstrated that vitamin K2 is essential for maintaining bone strength in postmenopausal women, and also improved bone mineral content and femoral neck width.8
More evidence supporting the unique function of vitamin K2 came from Japan. Japanese studies published in 2006 and 2008 link Japan’s greater levels of BMD to its widespread consumption of natto, a traditional breakfast dish made of fermented soybeans. Increased intake of MK-7 from natto seems to result in higher levels of activated osteocalcin and a significant reduction in fracture risk.9,10 One study showed an inverse correlation between the amount of natto consumed, in different regions of Japan, and the number of hip fractures. In regions of the country where natto is not part of the daily diet, hip fractures are more common.11
A recent double-blind, randomized clinical trial shows that when 180 mcg MK-7 is taken daily for three years, it improves bone mineral density and bone strength.12 In this study of 244 healthy post-menopausal women, the MK-7 group showed significantly decreased circulating uncarboxylated osteocalcin (ucOC), a well-established biomarker for bone and vitamin K status. After 3 years, both bone mineral content (BMC) and bone mineral density (BMD), as well as bone strength (BS) were statistically significantly better for the MK-7 group compared to the placebo group.
Patients suffering from osteoporosis were shown to have extensive calcium plaques, which impaired blood flow in the arteries. This simultaneous excess of calcium in one part of the body (arteries), and lack in another (bones) – which may occur even in spite of calcium supplementation – is known as the “Calcium Paradox.” The underlying cause is vitamin K2 deficiency, which leads to significant impairment in the function of MGP, the most potent inhibitor of vascular calcification known. However, research showed that vascular calcification might not only be prevented, but even reversed by increasing the daily intake of vitamin K2.13
The strongly protective effect of K2 – but not vitamin K1 – on cardiovascular health was confirmed by several studies, including the famed Rotterdam Study of 4,800 subjects.14 Results of more than 10 years of follow-up were verified by researchers who also demonstrated that among K vitamins, the long-chain types of K2 (MK-7 through MK-9) are the most important for efficiently preventing excessive calcium accumulation in the arteries.15
A recently finished clinical trial for menaquinone-7 showed substantial benefits in preventing age-related stiffening of arteries resulting in increase of the cf-PWV (carotid-femoral pulse wave velocity) in the placebo group, but not in the menaquinone-7 group. Most remarkably, menaquinone-7 not only prevented stiffening, it also resulted in an unprecedented statistically significant improvement of vascular elasticity both measured with ultrasound techniques and PWV.16
Chronic Kidney Disease
Vascular calcification, whether in the context of chronic kidney disease (CKD) or not, is a predictor of cardiovascular morbidity and mortality associated with extensive vascular calcification. In the past years, the development of vascular calcification was discovered to be actively regulated and as being influenced by both promoters and inhibitors of calcification.
MGP is a central calcification inhibitor produced by vascular smooth muscle cells and needs post-translational modification by vitamin K-dependent gamma-carboxylation to be fully active. Circulating non-phosphorylated non-carboxylated MGP, formed as a result of vitamin K deficiency in CKD, is associated with enhanced cardiovascular disease and with decreased overall survival.
Hemodialysis patients experience severe vascular calcifications, and most of them have a functional vitamin K deficiency. One study, which showed that inactive MGP levels can be decreased markedly by daily vitamin K2 supplementation, provided for the first time evidence for a functional vitamin K deficiency in hemodialysis patients, and that the deficiency could be treated effectively by vitamin K2 supplementation.17
Peripheral arterial disease (PAD) is a major vascular complication and the leading cause of amputation in people with diabetes. Diabetes accelerates atherosclerosis and increases the incidence of vascular calcification (VC), which is an independent predictor of cardiovascular and overall mortalities in patients with type 2 diabetes.
A recent study demonstrated that high inactive MGP levels were associated with increased cardiovascular risk (PAD and heart failure) in patients with type 2 diabetes. Given that VC in general and peripheral calcification in particular are major problems in patients with diabetes, modulation of vitamin K status might be an interesting therapeutic option.18
Human studies on the impact of vitamin K deficiency in brain function are limited. Yet a recent study found that patients with early-stage Alzheimer’s disease consumed less vitamin K than did cognitively intact control subjects.19 In 2001, Allison hypothesized that vitamin K deficiency could contribute to the pathogenesis of Alzheimer’s disease, based on the potential actions of vitamin K in the brain and through a link to the apolipoprotein E genotype. The apolipoprotein E_4 allele, an established risk factor for Alzheimer’s disease, is also associated with lower plasma vitamin K levels.20
Vitamin K has long been known to be essential for the synthesis of sphingholipid, which possess important cell-signaling functions, and are present in high concentrations in brain cell membranes. Also,vitamin K-dependent proteins are now known to play key roles in the central and peripheral nervous systems. Notably, protein Gas6 has been shown to be actively involved in cell survival, chemotaxis, mitogenesis, and cell growth of neurons and glial cells.
The mitochondria in the cell supply energy needed for their operation by transporting electrons. This activity is disrupted in Parkinsons’ patients resulting in no energy production, causing brain cells to die and lose neural communication, which leads to lack of movement (akinesia), tremors, and muscle stiffness.
Parkinson’s patients have several genetic defects, including PINK 1 and Parkin mutations, that lead to reduced mitochondrial activity. In one study, researchers gave vitamin K2 to fruit flies with a genetic defect in PINK1 or Parkin. As a result, mitochondrial energy production and electron transport were restored. Human studies are needed in this area.
Chronic inflammation is considered an underlying pathology of many diseases that remain poorly understood and treated. Cardiovascular disease (CVD) is not only considered as a disorder of lipid accumulation, but also as a disease characterized by low-grade inflammation of the endothelial cells and an inappropriate healing response of the vascular lining.
Researchers evaluated and confirmed the potential for high-purity natural vitamin K2 to inhibit gene expression and production of pro-inflammatory markers by human monocyte-derived macrophages (hMDMs) from two sources (hMDMs and THP-1) in vitro, but human study is still required in this area.
Laboratory experiments, population-based studies, and clinical trials tightly link better vitamin K status to strong, healthy bones. The beneficial role of vitamin K in children was confirmed by one study that revealed a positive association between vitamin K status and bone mineral content.21 Findings from previous studies indicated also that additional vitamin K intake may improve bone geometry and positively influence the gain in bone mass. In a study of 223 healthy girls (aged 11-12 years), researchers found a positive relation between vitamin K status and bone mineral density.22
Children have much higher bone metabolism than adults, so they need K vitamins in significantly larger quantities. Results from numerous studies suggest a pronounced vitamin K deficiency in bone. In the majority of examined children, a high amount of undercarboxylated osteocalcin was observed, indicating a poor K vitamin status.23 A similar observation was made showing the interdependence between vitamin K status and bone turnover.24 This research suggests the requirement for K vitamins may be higher than the current recommendation, which was set in accordance only with coagulation needs.
A 2014 study confirmed previous findings showing that healthy children and adults above 40 years were classified as groups with prominent vitamin K deficiency and thus appropriate groups for vitamin K supplementation.25
Vitamin K is absorbed along with dietary fat from the small intestine and transported by chylomicrons in the circulation. Most of vitamin K1 is carried by triacylglycerol-rich lipoproteins (TRL) and rapidly cleared by the liver; only a small amount is released into the circulation and carried by LDL and HDL. MK-4 is carried by the same lipoproteins (TRL, LDL, and HDL) and cleared fast as well. The long-chain menaquinones (MK-7, MK-8, MK-9) are absorbed in the same way as vitamin K1 and MK-4, but are efficiently redistributed by the liver in predominantly LDL (VLDL). Since LDL has a long half-life in the circulation, these long-chain menaquinones can circulate for extended times resulting in higher bioavailability for extra-hepatic tissues as compared to vitamin K1 and MK-4. Accumulation of vitamin K in extra-hepatic tissues has direct relevance to vitamin K functions not related to hemostasis.26
In 2012, Canadian health writer Kate Rhéaume-Bleue suggested the Recommended Daily Allowance (RDA) for K vitamins (range of 80-120 mcg) might be too low.27 Earlier suggestions in the scientific literature, which note that the RDA is based on hepatic (i.e., related to the liver) requirements only, date back as far as 1998.28,29 This hypothesis is supported by the fact that the majority of the Western population exhibits a substantial fraction of undercarboxylated extra-hepatic proteins. Thus, complete activation of coagulation factors is satisfied, but there doesn’t seem to be enough vitamin K2 for the carboxylation of osteocalcin in bone and MGP in the vascular system.30,31
The highest concentrations of vitamin K1 are found in green leafy vegetables, as well as non-leafy green vegetables, several vegetable oils, fruits, grains and dairy. Apart from animal livers, the richest dietary source of long-chain menaquinones are fermented foods (from bacteria, not molds or yeasts) typically represented by cheeses (MK-8, MK-9) in Western diets and natto (MK-7) in Japan.
Natural K2 is also found in bacterial fermented foods, like mature cheeses and curd. The MK-4 form of K2 is often found in relatively small quantities in meat and eggs. The richest source of natural K2 is the traditional Japanese dish natto32 made of fermented soybeans, which provides an unusually rich source of MK-7: to intense smell and strong taste, however, make this soy food a less attractive source of natural K2 for Western tastes.
The synthetic (and less effective) short-chain vitamin K1 is commonly used in food supplements. In case of vitamin K2, the most popular forms are MK-4 and MK-7.
There are two kinds of vitamin K deficiency: acute and chronic. Widely recognized, acute deficiency is characterized by unusual bleeding from gums, nose, or the gastrointestinal tract. Consequences can be severe, including internal clogging, strokes, lung damage, and death caused by immoderate blood loss. Vitamin K deficiency may also occur with the use anticoagulant drugs (i.e., warfarin or other coumarins), prolonged use of antibiotics, gallbladder disease, and Crohn’s disease.
Chronic vitamin K deficiency is less obvious than acute deficiency. It is actually more dangerous because there are no alarming symptoms and the results – impairments in bone, cardiovascular health, and other disease of aging – might be severe.
It had been long believed that vitamin K deficiency is rare. Requirements could be easily met via diet and microbial biosynthesis by bacteria living in the gut. However, recent scientific data show that that mean dietary intake of vitamin K is currently significantly lower than it was 50 years ago, while the daily consumption of vitamin K has gradually decreased since 1950.33
This shortage can be partly explained by alterations in food composition and different preparation practices. Food used to be made in the presence of various bacteria species (synthesizing vitamin K2). Now, sterile conditions introduced by international standards of food manufacturing stop microorganisms, including beneficial flora, from multiplying and penetrating the human body.
The presently used Recommended Dietary Intake for vitamin K might be too low. The need for complete activation of coagulation factors is satisfied, but it’s not enough to fulfill all of vitamin K’s benefits.
The most suitable measurement techniques to determine vitamin K levels is to determine the amount of the circulating undercarboxylated form of the vitamin K-dependent proteins in the blood (e.g., the level of carboxylated osteocalcin or MGP). Food frequency questionnaires only give rough estimates, and HPLC to look at circulating vitamin K levels correspond primarily to the daily intake of K-containing foods.
Recent studies found a clear association between long-term anticoagulant treatment (OAC) and reduced bone quality due to reduction of active osteocalcin. OAC might lead to an increased incidence of fractures, reduced bone mineral density/bone mineral content, osteopenia, and increased serum levels of undercarboxylated osteocalcin.34 Bone mineral density was significantly lower in stroke patients with long-term warfarin treatment compared to untreated patients, and osteopenia was probably an effect of warfarin interference with vitamin K recycling.35 Furthermore, OAC is often linked to soft-tissue calcification in both children and adults.36,37 This process has been shown to be dependent upon the action of K vitamins.
Vascular calcification was shown to appear in warfarin-treated animals within 2 weeks.38 Also in humans on OAC treatment, 2-fold more arterial calcification was found as compared to patients not receiving vitamin K antagonists.39,40 Among consequences of OAC: increased aortic wall stiffness, coronary insufficiency, ischemia, and even heart failure. Arterial calcification might also contribute to systolic hypertension and ventricular hypertrophy.41,42 Coumarins, by interfering with vitamin K metabolism, might also lead to an excessive calcification of cartilage and tracheobronchial arteries.
Anticoagulant therapy is usually instituted to avoid life-threatening diseases and a high vitamin K intake interferes with the anticoagulant effect. Patients on coumarin treatment are advised not to consume diets rich in K vitamins. However, the latest research proposed to combine K vitamins with OAC to stabilize the INR.
There is no known toxicity associated with high doses of menaquinones (vitamin K2). Individuals taking anticoagulant medications, such as warfarin (coumarins) should consult their doctor before taking vitamin K2. Unlike the other fat-soluble vitamins, vitamin K is not stored in any significant quantity in the liver; therefore toxic level is not a described problem. All data available at this time demonstrate that vitamin K has no adverse effects in healthy subjects. Animal models involving rats, if generalizable to humans, show that MK-7 is well-tolerated.43
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4 Int J Mol Med. 2005 Feb;15(2):231-6. Menaquinone-7 regulates the expressions of osteocalcin, OPG, RANKL and RANK in osteoblastic MC3T3E1 cells.
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6 Knapen MH, Nieuwenhuijzen Kruseman AC, Wouters RS, Vermeer C. Correlation of serum osteocalcin fractions with bone mineral density in women during the first 10 years after menopause. Calcif Tissue Int. 1998;63(5):375-9.
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Vitak BV, a research company considered experts in all aspects of vitamin K and vitamin K-dependent proteins.