Vitamin K2 is referred to as “the smart vitamin” as it prevents the deposition of calcium in the soft tissues such as coronary arteries. In stead it helps to incorporate calcium into the bones, where it is needed.
Vitamin K is a fat-soluble vitamin that was first identified by Henrik Dam in 1929 for its anti-hemorrhagic activities (1). It was later called vitamin K after the Danish word Koagulation. Vitamin K is an essential nutrient for the normal functioning of our body.
Vitamin K1, Vitamin K2, Vitamin K3
There are three forms of vitamin K:
K2 (menaquinones, MK) with several sub-types; MK4 through MK10. Currently MK4 and MK7 appear to be the most important forms of vitamin K2.
K3 (synthetic menadione).
While Vitamin K1 and K2 occur naturally and are nontoxic, vitamin K3 is man-made and can be toxic. Therefore, vitamin K3 should not be used to treat vitamin K deficiency.
EFFECTS OF VITAMIN K
Vitamin K is an essential cofactor for the conversion of glutamate into gamma-carboxyglutamate. This chemical process is called carboxylation. In this way, vitamin K activates a number of proteins in our body.
Role of Vitamin K in Blood Clotting
Vitamin K1 is primarily involved with the clotting process. It activates a number of proteins called clotting factors (Factors II, VII, IX, X) inside the liver. Therefore, vitamin K deficiency can lead to excessive bleeding which sometime can be fatal. A commonly used blood thinner, Warfarin (Coumadin) acts by interfering with vitamin K. Patients on Warfarin have to be closely monitored in order to prevent excessive thinning of blood.
Can Vitamin K2 Prevent Bone Fractures
In recent years medical science has discovered many other health benefits of Vitamin K in addition to its role in blood clotting.
Vitamin K, especially Vitamin K2 has been found to be important for the health of bones and teeth. it helps to incorporate calcium and phosphorus into the bones via a complex mechanism: There is a special protein in the bone, termed as osteocalcin, which is involved in maintaining the strength of the bone. Normally, osteocalcin undergoes a chemical change, termed gamma-carboxylation for it to be active and carry out its function. Vitamin K2 is essential for gamma-carboxylation of osteocalcin. In this way, vitamin K is intimately involved in keeping our bones strong.
If you are low in vitamin K2, there is a decrease in the gamma-carboxylation of osteocalcin. In other words, there is under-carboxylation of osteocalcin. Think of under-carboxylated osteocalcin (ucOC) as an inactive (abnormal) form of osteocalcin. When you are low in vitamin K2, the blood level of under-carboxylated osteocalcin (ucOC) rises. Therefore, the blood level of under-carboxylated osteocalcin (ucOC) has been considered a sensitive marker of vitamin K2 status in the bone. A high level of under-carboxylated osteocalcin (ucOC) indicates vitamin K2 deficiency and is found to be associated with weak bones and a greater risk of fracture.
Can Vitamin K2 Supplementation Prevent Fractures?
Is there clinical evidence to show that vitamin K2 supplementation can reduce the risk of fracture in individuals suffering from osteoporosis? The answer is yes!
In a study (2) from the Research Institute and Practice for Involutional Diseases, Japan, researchers recruited a total of 241 patients with osteoporosis. Fifty percent of these patients received placebo and fifty percent of patients received vitamin K2. These patients were followed for 2 years. The incidence of clinical fractures during the 2 years of treatment in the placebo group was higher than the vitamin K2-treated group. The blood levels of under-carboxylated osteocalcin (ucOC) at the end of the 2 years in the placebo and the treated group were 3.0 ng/ml and 1.6 ng/ml, respectively. In addition, the serum level of normal osteocalcin showed a significant rise (42% from the basal value) in the treated group at 2 years, compared to 18% for the placebo group. There was no significant change in bone density at the lumbar spine. The researchers concluded that their findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures, although the vitamin K2-treated group did not show any increase in lumbar bone density. Furthermore, vitamin K2 treatment enhances gamma-carboxylation of osteocalcin.
In another analytical study (3), researchers from the Institute for Integrated Sports Medicine, Keio University School of Medicine, Japan evaluated the effect of vitamin K Supplementation on the bones of postmenopausal women. They analyzed seven clinical trials. Their findings showed that high dose vitamin K(1) and vitamin K(2) supplementation improved indices of bone strength in the hip bone and reduced the incidence of hip fractures. Vitamin K treatment did not cause a significant increase in bone density. They concluded the beneficial effect of vitamin K1 and vitamin K2 supplementation on the bones of postmenopausal women is mediated by mechanisms other than bone mineral density.
In another analytical study (4) from Hangzhou Xiasha Hospital, China, researchers analyzed the data from nineteen randomized controlled trials. There were a total of 6759 participants. Researchers found that postmenopausal women with osteoporosis, who took vitamin K2, had a significant improvement of bone density at the lumbar spine. In addition, it significantly decreased the incidence of vertebral fractures. The level of undercarboxylated osteocalcin ((ucOC) ) came down and the level of normal osteocalcin increased in women who took vitamin K2.
In conclusion, there is a mounting clinical evidence to show the beneficial effects of vitamin K2 in preventing fractures in postmenopausal women with osteoporosis. However, there is conflicting data on the effect of vitamin K2 on bone mineral density. What is clear is that it exerts its beneficial effect on the bone through osteocalcin, a protein in the bone that seems to play an important role in the process of mineralization of the bone. Calcium and Phosphorus are important ingredient for the mineralization of the bone. That is where vitamin D is crucial. Vitamin D increases absorption of calcium and phosphorus from the intestines. In this way, Vitamin D and Vitamin K2 appear to act in concert in keeping our bones strong.
Effects Of Combination Therapy With Vitamin K2 And Vitamin D On The Bone
Both vitamin K2 and vitamin D exert beneficial effects on the strength of bone. It makes sense to combine vitamin K2 and vitamin D in keeping our bone healthy. An interesting study (5) from Erciyes University, Turkey investigated the role of combination therapy with vitamin K2 and vitamin D on the bones of children with Thalassemia major, who frequently suffer from weakening of the bones. The researchers enrolled twenty children (12 girls, 8 boys; age varied from 3 to 18 ) with thalassemia major. These children received dietary supplement with vitamin K2 (50 mcg of MK7) and vitamin D (5 mcg calcitriol). Their bone mineral density was evaluated at the baseline, sixth, and 12th month of treatment. The researchers found a significant improvement in the bone mineral density at the lumbar spine of these children at the sixth and 12th month of treatment.
Vitamin K2 And Diabetes
Patients with Diabetes are at increased risk of fractures due to weakening of the bones as well as other factors (peripheral neuropathy, obesity, disequilibrium) that makes them more susceptible to falling down. Can vitamin K2 reduce the risk of fractures among diabetics? A good review (6) on this topic comes from Keio University School of Medicine, Japan. According to the authors, clinical studies of Type 2 diabetic patients have shown low osteocalcin concentration to be associated with an increased risk of fractures. And vitamin K2 administration in a Type 2 diabetic rat model has been shown to increase serum osteocalcin as well as bone strength.
Vitamin K2 and the Cardiovascular System
Vitamin K2 also activates (carboxylates) another protein, called Matrix Gla Protein (MGP), which is present in LDL cholesterol in your blood. Activated MGP exerts important beneficial effects on your arteries: It may prevent calcification of the arteries, including coronary arteries and the aorta.
Some individuals are at high risk for the calcification of arteries. These are patients with diabetes, chronic kidney failure, hyperparathyroidism and atherosclerosis. A number of factors place these patients at increased risk of calcification of the arteries. These are stress, high blood pressure, high calcium and high phosphorus in the blood ( high Ca x P product). These factors can initiate a process in which smooth muscle cells in the blood vessels transform into bone-like cells, which then start to deposit bone-crystals (hydroxyapatite) in the cell wall. Hydroxyapatite bone crystals are made up of calcium and phosphorus. MGP can inhibit the formation of hydroxyapatite crystals. In this way, MGP may play a crucial role in preventing calcification in the arterial walls.
As mentioned earlier, vitamin K2 is essential to activate (carboxylase) MGP. The levels of dephosphorylated, un-carboxylated MPG (dp-ucMGP) are used as a marker for vitamin K deficiency in the blood vessels and have been found to correlate with cardiovascular morbidity.
Can Vitamin K2 Prevent Heart Disease?
In an excellent study (7) from Erasmus Medical Center Rotterdam, The Netherlands, the researchers evaluated the effects of dietary intake of Vitamin K1 and Vitamin K2 on coronary heart disease, aortic atherosclerosis and overall mortality in 4807 men and women over the age of 55, who lived in a defined district of Rotterdam in the Netherlands. The study had a mean duration of follow-up of 7.2 years. Intake of vitamin K2, but not vitamin K1, was found to be associated with a decrease in the risk of coronary heart disease, aortic atherosclerosis and overall mortality.
Main dietary sources of vitamin K1 in this study were green leafy vegetables and vegetable oils. For vitamin K2, the dietary sources were meats and eggs (MK4 only), fish, sauerkraut, cheese, and other dairy produce (MK5 through MK10). The authors made an interesting observation that cheese has not been established as a dietary risk factor for cardiovascular disease in epidemiological studies, despite its high levels of saturated fat and salt. They hypothesized that vitamin K2 in cheese could exert a beneficial effect in the cardiovascular system and that the high cheese consumption in France and Mediterranean countries may possibly account for lower prevalence of coronary heart disease.
In another study (8) from University Medical Center Utrecht, The Netherlands, the researchers investigated if there was a link between dietary intake of vitamin K1 and vitamin K2 with calcification of coronary arteries in a cross-sectional study among 564 post-menopausal women. They found that sixty-two percent of the women had coronary calcification. Vitamin K2 intake was associated with decreased coronary calcification. They concluded that high dietary vitamin K2 intake, but probably not vitamin K1, is associated with reduced coronary calcification. Adequate vitamin K2 intakes could therefore be important to prevent cardiovascular disease.
Vitamin K2 And Cancer
Vitamin K2 appears to be an anti-cancer agent, according to several recent scientific studies. In an experimental study (9) from Tokyo Medical University, Japan, researchers showed that vitamin K2 showed anti-cancer properties against leukemia cells in their laboratory. In another experimental study (10) from Tokyo Medical University, Japan, researchers were able to show anti-cancer properties of vitamin K2 in lung cancer cells in their laboratory. In an experimental study (11) from Showa University, Japan, researchers were able to show anti-cancer properties of vitamin K2 against ovarian cancer cells in their laboratory. In an experimental study (12) from Shanghai Jiao Tong University, China, researchers were able to show anti-cancer effects of vitamin K2 in liver cancer cells in their laboratory. In an experimental study (13) from University of Illinois, USA, researchers were able to show anti-cancer effects of vitamin K2 in prostate cancer cells in their laboratory. In another experimental study (14) from Kawasaki Medical School, Japan, researchers showed an inhibitory effect of vitamin K2 on the Multiple myeloma cells. In another experimental study (15) from Thomas Jefferson University, USA. researchers showed that vitamin K1 as well as K2 were able to inhibit the growth of pancreatic cancer cells in their laboratory.
In these studies, vitamin K2 was able to either kill cancer cells or stop their further growth or even change their growth into normal cells. These are exciting new studies, although still experimental and done on cancer cells in the laboratory. In any case, it brings a new hope in dealing with cancer. It does not seem to have any side-effects. It is definitely worth-trying if you are dealing with a cancer.
Natural Sources Of Vitamin K
Vitamin K naturally exists in 2 forms, namely phylloquinone (K1) and a group called vitamin K2, also called menaquinones or MK , with several sub-types. MK4 and MK7 have been clinically studied the most.
K1 is widely distributed in green and leafy vegetables such as spinach, lettuce, broccoli, kale, watercress and chard.
Vitamin K2 is mostly present in the following foods: grass-fed butter (MK4), eggs (MK4), yogurt (MK7), fermented cheese (MK7), fermented soy, called natto (MK7), kimchi ( MK7) and Sauerkraut (MK7).
Vitamin K2 is also produced by healthy intestinal bacteria, but in small amounts. Unfortunately, broad-spectrum antibiotics kill your healthy intestinal bacteria. In an excellent study (16) from the University of Saskatchewan, Canada, researchers were able to show a significant reduction in the amount of vitamin K2 stored in the liver, after the use of the broad-spectrum antibiotics. Use of probiotics may be able to restore normal intestinal flora and the synthesis of vitamin K2.
A small amount of vitamin K1 (about 10%) is converted to vitamin K2. But you cannot depend on vitamin K1 for all of your dietary needs of vitamin K2, as humans cannot absorb more than about 200 mcg of vitamin K1.
Vitamin K2 Supplements: MK7 Versus MK4
Most people cannot get adequate amounts of Vitamin K2 from their diet. Therefore, they need to take vitamin K2 supplement.
Vitamin K2 in supplements:
Vitamin K2 as MK4 in supplements is synthetic. It is made from the extract of the tobacco plant. To get it from dairy products and eggs would be very expensive.
On the other hand, MK7 in supplements usually comes from natto, which is fermented soy and is part of Japanese cuisine. Natto, however, is highly unpalatable for most non-Japanese. But MK7 from natto in supplement form does not have a bad taste.
Another advantage of MK7 over MK4: MK7 has a long half-life of about 3 days, which means it stays in your body longer as compared to MK4, which has a very short half-life of about one hour. Therefore, you can take a MK7 supplement once a day, but you will have to take a MK4 supplement three to four times a day to maintain a good level of vitamin K2 in your body.
How Much Vitamin K2 Supplement?
The optimal dose of vitamin K2 is not established yet. In clinical studies, researchers have used a wide range for a daily dose.
In Japan, vitamin K2 as Menaquinone4 (MK4) is the standard medical treatment for osteoporosis. They use it as a daily dose of 45 mg. However, in a recent study (17), from the National Institute of Health and Nutrition, Japan, researchers used a low-dose of MK-4 supplementation as 1.5 mg per day for 6-12 months in postmenopausal women, and showed there was an improvement in bone health. In another recent study (18), researchers from Maastricht University, The Netherlands used a low dose of MK7 as 180 microgram per day in postmenopausal women for 3 years. MK7 at this small dose prevented age-related decline in bone mineral density.
Kidney dialysis patients are particularly prone to arterial calcification. In a study (19) from the University Hospital Düsseldorf, Germany, researchers assessed the status of vitamin K2 in their hemodialysis patients by measuring their dephosphorylated-uncarboxylated MGP and uncarboxylated osteocalcin levels. They found their patients were quite low in vitamin K2 as demonstrated by a 4.5-fold higher dephosphorylated-uncarboxylated MGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with controls. Vitamin K2 supplementation was given as 135 microgram per day to one group of patients and 360 microgram per day to another group. They found the response rates in the reduction in dephosphorylated-uncarboxylated MGP levels were 77% and 93% in the groups receiving a daily dose of 135 microgram and 360 microgram of MK7, respectively.
In summary, vitamin K is a fat-soluble vitamin. Vitamin K1 is involved in blood clotting, while vitamin K2 has its effects on a wide range of other tissues in the body. In concert with vitamin D, it may prevent osteoporosis, especially in post-menopausal women. It may prevent calcification of arteries and therefore, reduce the risk of cardiovascular disease. It also appears to be a promising anti-cancer agent.
At the Jamila Diabetes And Endocrine Medical Center, I recommend vitamin K2 as MK7 in a dose of 200 microgram per day.
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- Huang ZB1, Wan SL, Lu YJ, Ning L, Liu C, Fan SW. Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials. Osteoporos Int. 2014 Dec 17
- Ozdemir MA1, Yilmaz K, Abdulrezzak U, Muhtaroglu S, Patiroglu T, Karakukcu M, Unal E. The efficacy of vitamin K2 and calcitriol combination on thalassemic osteopathy. J Pediatr Hematol Oncol. 2013 Nov;35(8):623-7.
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- Beulens JW1, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009 Apr;203(2):489-93
- Miyazawa K1, Yaguchi M, Funato K, Gotoh A, Kawanishi Y, Nishizawa Y, Yuo A, Ohyashiki K. Apoptosis/differentiation-inducing effects of vitamin K2 on HL-60 cells: dichotomous nature of vitamin K2 in leukemia cells. Leukemia. 2001 Jul;15(7):1111-7.
- Yokoyama T1, Miyazawa K, Yoshida T, Ohyashiki K. Combination of vitamin K2 plus imatinib mesylate enhances induction of apoptosis in small cell lung cancer cell lines. Int J Oncol. 2005 Jan;26(1):33-40.
- Sibayama-Imazu T1, Fujisawa Y, Masuda Y, Aiuchi T, Nakajo S, Itabe H, Nakaya K. Induction of apoptosis in PA-1 ovarian cancer cells by vitamin K2 is associated with an increase in the level of TR3/Nur77 and its accumulation in mitochondria and nuclei. J Cancer Res Clin Oncol. 2008 Jul;134(7):803-12.
- Yao Y1, Li L, Zhang H, Jia R, Liu B, Zhao X, Zhang L, Qian G, Fan X, Ge S. Enhanced therapeutic efficacy of vitamin K2 by silencing BCL-2 expression in SMMC-7721 hepatocellular carcinoma cells. Oncol Lett. 2012 Jul;4(1):163-167.
- Samykutty A1, Shetty AV, Dakshinamoorthy G, Kalyanasundaram R, Zheng G, Chen A, Bosland MC, Kajdacsy-Balla A, Gnanasekar M. Vitamin k2, a naturally occurring menaquinone, exerts therapeutic effects on both hormone-dependent and hormone-independent prostate cancer cells. Evid Based Complement Alternat Med. 2013;2013:287358.
- Tsujioka T1, Miura Y, Otsuki T, Nishimura Y, Hyodoh F, Wada H, Sugihara T. The mechanisms of vitamin K2-induced apoptosis of myeloma cells. Haematologica. 2006 May;91(5):613-9.
- Showalter SL1, Wang Z, Costantino CL, Witkiewicz AK, Yeo CJ, Brody JR, Carr BI. Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway. J Gastroenterol Hepatol. 2010 Apr;25(4):738-44.
- Conly J1, Stein K. Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med. 1994 Dec;17(6):531-9.
- Koitaya N, Sekiguchi M, Tousen Y, Nishide Y, Morita A, Yamauchi J, Gando Y, Miyachi M, Aoki M, Komatsu M, Watanabe F, Morishita K, Ishim Y. Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. J Bone Miner Metab. 2013 May 24.
- Knapen MH, Drummen NE, Smit E, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013 Mar 23
- Westenfeld R1, Krueger T, Schlieper G, Cranenburg EC, Magdeleyns EJ, Heidenreich S, Holzmann S, Vermeer C, Jahnen-Dechent W, Ketteler M, Floege J, Schurgers LJ. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis. 2012 Feb;59(2):186-95.
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