PasThe Role Of Vitamin K2 In Reducing The Epidemic Of Osteoporosis
And Heart Disease
*Soroush Niknamian BSc.1, Vahid Hosseini Djenab2 MD, Sora Niknamian3 M.Sc.
1Biology Student at Islamic Azad University, Central Tehran Branch (IAUCTB)
2Shahid Beheshti Medical University
3KN Toosi Department Of Physics
Saina.monthly@gmail.com, vahidjenab46@gmail.com, s.niknamian@gmail.com
Abstract
Naturally occurring forms of vitamin K include phylloquinone (vitamin K1) and a family of molecules called menaquinones (MKs or vitamin K2). Vitamin K2 deficiency may impair the activity of VKDPs and increase the risk of osteoporosis, fractures and heart disease. Phylloquinone is found at high concentrations in green leafy vegetables and certain plant oils, so the deficiency of it is very rare, while most menaquinones are usually found in animal livers and fermented foods. In western style diet the consumption of fermented foods is limited and low, also increasing the use of vegetable oils and the reduction of animal fat, organ meat and increasing the use of antibiotics interferes with vitamin k2 absorption. The blood test for vitamin k2 deficiency is not a regular test worldwide, so this important vitamin is deficient in many people. Heart disease is the leading cause of death in the world and Osteoporosis is increasing dramatically. So increasing the use of fermented foods like natto, increasing animal fat and organ meat in the diet, specially older people, may reduce the risk of heart disease and osteoporosis.
Keywords:
Phylloquinone, heart disease, osteoporosis, fermented foods, organ meat
Introduction
Vitamin K2 or menaquinone has nine related compounds, generally subdivided into the short-chain menaquinones (with MK-4 as the most important member) and the long-chain menaquinones, of which MK-7, MK-8 and MK-9 are nutritionally the most recognized.
Vitamin K2, the main storage form in animals, has several subtypes, which differ in isoprenoid chain length. These vitamin K2 homologues are called menaquinones, and are characterized by the number of isoprenoid residues in their side chains. Menaquinones are abbreviated MK-n, where M stands for menaquinone, the K stands for vitamin K, and the n represents the number of isoprenoid side chain residues. For example, menaquinone-4 (abbreviated MK-4) has four isoprene residues in its side chain. Menaquinone-4 (also known as menatetrenone from its four isoprene residues) is the most common type of vitamin K2 in animal products since MK-4 is normally synthesized from vitamin K1 in certain animal tissues (arterial walls, pancreas, and testes) by replacement of the phytyl tail with an unsaturated geranylgeranyl tail containing four isoprene units, thus yielding menaquinone-4. This homolog of vitamin K2 may have enzyme functions distinct from those of vitamin K1.
Menaquinone-7 is different from MK-4 in that it is not produced by human tissue. MK-7 may be converted from phylloquinone (K1) in the colon by E. coli bacteria.1 However, bacterially derived menaquinones (MK-7) appear to contribute minimally to overall vitamin K status.2,3 MK-4 and MK-7 are both found in the United States in dietary supplements for bone health.
The U.S. Food and Drug Administration (FDA) has not approved any form of vitamin K for the prevention or treatment of osteoporosis; however, MK-4 has been shown to decrease the incidence of fractures up to 87%.4 MK-4 (45 mg daily) has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.5
All K vitamins 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”.6 The number of side chains is indicated in the name of the particular menaquinone (e.g., MK-4 means that four molecular units – called isoprene units – are 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. Traditionally, K vitamins were recognized as the factor required for coagulation, but the functions performed by this vitamin group were revealed to be much more complex. K vitamins play an essential role as cofactor for the enzyme γ-glutamyl carboxylase, which is involved in vitamin K-dependent carboxylation of the gla domain in “Gla proteins” (i.e., in conversion of peptide-bound glutamic acid (Glu) to γ-carboxy glutamic acid (Gla) in these proteins).
Carboxylation of these vitamin K-dependent Gla-proteins, besides being essential for the function of the protein, is also an important vitamin recovery mechanism since it serves as a recycling pathway to recover vitamin K from its epoxide metabolite (KO) for reuse in carboxylation.
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 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 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.7
Vitamin K2 is preferred by the extra-hepatic tissues (bone, cartilage, vasculature) and this may be produced as MK-4 by the animal from K1, or may be of bacterial origin (MK-7, MK-9, and other MK numbers). The latter may be consumed already prepared by bacteria (see below). Discussion is ongoing as to what extent K2 produced by intestinal bacteria contributes to daily vitamin K2 needs. If, however, intestinal bacterial supply was enough to supplement all tissues needing K2, we would not find high fractions of undercarboxylated Gla-proteins in human studies.
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 natto8 made of fermented soybeans and Bacillus subtilis, which provides an unusually rich source of K2 as long-chain MK-7: its consumption in Northern Japan has been linked to significant improvement in K vitamin’s status and bone health in many studies. The intense smell and strong taste, however, make this soyfood a less attractive source of K2 for Westerners’ tastes. Supplement food companies sell nattō extract, standardized for K2 content, in capsules. It is not known whether B. subtilis will produce K2 with other legumes (chickpeas, beans, lentils).
Food sources of vitamin K2 include fermented or aged cheeses, eggs, meats such as chicken and beef and their fat, livers, and organs, and in fermented vegetables, especially natto, as well as sauerkraut and kefir.9
Vitamin K2 (menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products.10 Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans (natto), and in most fermented cheeses.11 In natto, none of the vitamin K is from menaquinone-4, and in cheese only 2–7% is.12
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.13 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.14 Furthermore, OAC is often linked to an undesired soft-tissue calcification in both children and adults.15,16 This process has been shown to be dependent upon the action of K vitamins. Vitamin K deficiency results in undercarboxylation of MGP. Vascular calcification was shown to appear in warfarin-treated experimental animals within two weeks.17 Also in humans on OAC treatment, two-fold more arterial calcification was found as compared to patients not receiving vitamin K antagonists.18,19 Among consequences of anticoagulant treatment: increased aortic wall stiffness, coronary insufficiency, ischemia, and even heart failure. Arterial calcification might also contribute to systolic hypertension and ventricular hypertrophy.20,21 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 warfarin (Coumadin) treatment, or treatment with other vitamin K antagonist drugs, are therefore advised not to consume diets rich in K vitamins. However, the latest research proposed to combine vitamins K with OAC to stabilize the INR (International normalized ratio, a laboratory test measure of blood coagulation).
Materials And Methods
In the Rotterdam study, those who had the highest intake of Vitamin K2 were 52% less likely to develop calcification of the arteries, and had a 57% lower risk of dying from heart disease, over a 7-10 year period26.
Another study of 16,057 women found that participants with the highest intake of vitamin K2 had a much lower risk of heart disease. For every 10 micrograms of K2 they consumed per day, the risk of heart disease was reduced by 9%27.
For the record, vitamin K1 had no influence in either of those studies. However, keep in mind that the studies above are so-called observational studies, which can not prove cause and effect. Unfortunately, the few controlled trials that have been done used the K1 form, which seems to be ineffective28.
There is a highly plausible biological mechanism for its effectiveness, and strong correlations found in observational studies. The importance of this can not be overstated. cardiovascular disease is the world’s most common cause of death. It killed 14 million people in the year 2012 alone29.
There is quite a bit of evidence from controlled trials that K2 has major benefits for bone health. A 3-year trial in 244 postmenopausal women found that those taking vitamin K2 supplements had much slower decreases in age-related bone mineral density32.
Lengthy studies on Japanese women have shown similar benefits, although they did use very high doses. Out of 13 trials, only one failed to show significant improvement.
Seven of those trials also reported fractures and found that vitamin K2 reduced spinal fractures by 60%, hip fractures by 77% and all non-spinal fractures by 81%33.
In line with these findings, the Japanese officially recommend vitamin K supplementation for the prevention and treatment of osteoporosis 34.
Results
Calcium build-up in the arteries around the heart is a huge risk factor for heart disease22,23,24.
For this reason, anything that can reduce this accumulation of calcium may help prevent heart disease.
This is where vitamin K2 is believed to help, by helping to prevent calcium from being deposited in the arteries25.
Osteoporosis is a common problem in Western countries. It is especially common among elderly women and strongly raises the risk of fractures. Vitamin K2 plays a central role in calcium metabolism, the main mineral found in bones. Vitamin K2 activates the calcium-binding activity of two proteins called Matrix gla protein and osteocalcin, which help to build and maintain bones30,31.
Discussion
In 1997, researchers from the University of Texas and the University of Montreal developed mice that lacked the gene that codes for MGP. These mice appeared normal for the first two weeks of their lives, after which they developed faster heart beats, stopped growing and died within two months with the rupture of their heavily calcified aortas. The disorganization of their cartilage cells not only produced short stature, but also produced osteopenia and spontaneous fractures.35
The bones of mice that lack the osteocalcin gene mineralize just as well as those of mice that do not lack the gene, but the mineral deposits are organized differently. This could mean that osteocalcin is important to the functional quality of bone and the ability to regulate its shape.36 Isolated human osteoblasts, the cells that lay down the calcified matrix of bone, secrete osteocalcin in response to vitamins A and D.37 The protein-rich matrix surrounding these cells will only accumulate this osteocalcin, however, if it is activated by vitamin K2. Calcification of the extracellular matrix occurs in parallel with the accumulation of osteocalcin, but it is not clear whether this protein plays a direct role in laying down the calcium salts or if its accumulation simply reflects the higher amount of vitamin K2 that is available to activate other proteins involved more directly in mineralization such as MGP.36
When there is an insufficient amount of vitamin K to keep up with the production of vitamin K-dependent proteins, many of these proteins are secreted into the blood in an inactive form. Circulating cells then take up these useless proteins and destroy them.37 By drawing a person’s blood and testing the percentages of circulating osteocalcin that are active and inactive, we can determine whether that person’s bone cells have enough vitamin K to meet their needs. People with the highest percentages of inactive osteocalcin are at a more than five-fold increased risk of hip fracture,38 confirming the value of the test.
By using this test, we can also show that vitamin K2 is the preferred K vitamin of the bones. It takes one milligram per day of a highly absorbable pharmacological preparation of vitamin K1 to maximally activate osteocalcin in human subjects;39 it appears, however, that humans are not capable of absorbing much more than one fifth this amount from whole foods.40 By contrast, large amounts of vitamin K2 are readily absorbed from foods.41 Even when using highly absorbable forms of these vitamins, vitamin K2 is much more effective. Researchers from the University of Maastricht in the Netherlands showed that over the course of 40 days, vitamin K2 was three times more effective than vitamin K1 at raising the percentage of activated osteocalcin. Moreover, the effect of vitamin K1 reached a plateau after just three days, whereas the effect of vitamin K2 increased throughout the entire study. Had it lasted longer, the study may have shown an even greater superiority of vitamin K2.42
We can therefore regard the percentage of inactive osteocalcin primarily as a marker for vitamin K2 status. In the healthy adult population, one hundred percent of the vitamin K-dependent blood coagulants produced by the liver are in their active form. By contrast, in this same population between ten and thirty percent of circulating osteocalcin is in its inactive form. Researchers rarely encounter individuals whose osteocalcin is fully activated.43 This suggests that vitamin K2 deficiency is universal, and that variation in K2 status within the population simply reflects varying degrees of deficiency.
Vitamin K1 supplements produce modest decreases in bone loss in the elderly. A number of Japanese trials, on the other hand, have shown that vitamin K2 completely reverses bone loss and in some cases even increases bone mass in populations with osteoporosis.43 The pooled results of seven Japanese trials show that vitamin K2 supplementation produces a 60 percent reduction in vertebral fractures and an 80 percent reduction in hip and other non-vertebral fractures.44 These studies used extremely high amounts of vitamin K2 and did not observe any adverse effects over the course of several years. Since they used such high doses of K2, however, and no studies have tested lower doses, they do not constitute definitive proof that the vitamin activity rather than some drug-like action unique to the high dose produced such dramatic results. The balance of the evidence, however, suggests that vitamin K2 is essential to skeletal health and that it is a key substance that modern diets do not adequately provide.
Acknowledgement
We thank Sora Niknamian M.Sc. for helping us collecting some data and reviewing this article.
Conclusion
Humans can partly convert vitamin K1 to K2 in the body. This is useful because the amount of vitamin K1 in a typical diet is ten times that of vitamin K2. However, current evidence indicates that the conversion process is inefficient, because we benefit much more from eating vitamin K2 directly.
Vitamin K2 is also produced by gut bacteria in the large intestine, and there is some evidence that broad-spectrum antibiotics can contribute to K2 deficiency.45,46 Unfortunately, the average intake of this important nutrient is incredibly low in the modern diet.
Vitamin K2 is mainly found in certain animal foods and fermented foods, which most people don’t eat much of.
Rich animal sources include high-fat dairy products from grass-fed cows, liver and other organs, as well as egg yolks.47 Vitamin K is fat-soluble, which means low-fat and lean animal products don’t contain much of it.
Animal foods contain the MK-4 subtype, while fermented foods like sauerkraut, natto and miso contain more of the longer subtypes, MK-5 to MK-14.48 If those foods are inaccessible to you, then supplementation is a valid alternative. The benefits of supplementing K2 may be enhanced even further when combined with a vitamin D supplement, because the two vitamins have synergistic effects.49
Although this needs to be studied a lot further, the current research on Vitamin K2 and health is extremely promising. It could have life-saving implications for a lot of people and may reduce the epidemic of heart disease and osteoporosis in the world population.
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