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Vitamin K - Future Promise

by Maurice Mckeown, BDS, PhD
(Our New Zealand correspondent)

Many years ago I was doing my doctoral research in a department whose main focus was bone research. One of the issues most perplexing was the tendency of the body, as it aged, to become calcified in all the wrong places. We were also aware that in some parts of the body calcification did not occur when required. Today we have a much better insight into these problems.

The subject of this, less than comprehensive, review is of course vitamin K. There has been substantial and potentially beneficial research on this vitamin in recent years; yet it has not received star billing like vitamin D.

Medical science has produced some impressive (and expensive) procedures to combat cardiovascular disease and osteoporosis. There are even a few drugs from Big Pharma which seem to be of modest value in both treatment and prevention. Yet prevention is so much better than cure and nature is much smarter than Big Pharma scientists.

Vitamin K was discovered by Danish scientist Henrik Dam in 1929. Vitamin K was, and still is, known as the clotting drug - (K for coagulation in both Danish and German) in the minds of most GP's who combat unwanted clotting with vitamin K antagonists as anticoagulants in thrombosis victims. Vitamin K is also prescribed for newborns who may lack proper blood clotting function.

We are now just beginning to understand that vitamin K has many other beneficial roles in the body. Most of this research is focused on vitamin K2, a molecule quite similar to K1 but with a different tail structure. Perhaps it is best to ask a series of questions.

Where do we get K vitamins in our diet?

Vitamin K1 comes from green leafy vegetables and is thus abundant in healthy diets. It is also present in legumes and some vegetable oils. The primary sources of K1 in our diet appear to be spinach, kale, broccoli and brussel sprouts. Vitamin K in spinach may have some absorption limitations. Vitamin K1 is absorbed into the body in the small intestine with the help of bile salts.

Vitamin K2 is a much less common constituent in most diets. The K2 molecule has a long straight tail. The length is designated by the MK number. There doesn't seem to be a detailed understanding of the virtues of the different versions. Note that MK-4 can be made in the human body whereas MK-7 cannot. The quantity in meat and egg products is negligible. Meats contain the short chain menaquinones which appear to equate to vitamin K1 in biochemical relevance. Cheeses contain the longer chain varieties.

There are small amounts in meat, eggs, specific cheeses and other dairy products. The notable exception is the Japanese diet where the fermented soy bean product natto contains large quantities. If you eat it regularly that should suffice. Unfortunately natto is not popular on the Western palate. I have to report that I don't find it unpleasant- just uninteresting! One hundred grams of natto could contain around 1000 mcg of MK-7 plus some MK-6 and 8.

In contrast a serving of chicken might contain eight mcg, one of beef around one mcg and an egg might contain five mcg in its yolk. Hard (fermented) cheese contains small amounts of MK-4 and nearly 70 mcg of MK-8 and 9. Unfermented cheeses contain no K2. It should be noted that fermentation of any food, in itself, is not a guarantee of vitamin K content. The production of vitamin K is the result of the action of specific bacteria. An example of this is the Indonesian fermented soy food tempeh, which does not seem to contain any K2. Recently the use of K vitamins by different bacteria has been studied as a possible method of inhibiting their function.

What is the relationship between K1 and K2 in our bodies?

It has been known for a long time that K1 can be converted to K2 in the body. It has also been known that bacteria in our gut can manufacture K2. Studies in germ free rats have shown that their bodies can convert K1 to MK-4 (one form of K2), thus bacteria are not necessary for this step. Unfortunately this reassuring news has recently been tempered by new information which has demonstrated that the K1 to K2 conversion is limited in our bodies - even in conditions where K1 intake is high. Also there is good reason to suppose that although gut bacteria can and do produce K2, little of the K2 produced gets into the body proper because the bacteria retain much of it for their own uses and absorption into the body is not thought to be favourable to fat soluble elements in the lower gut. Animals that eat their own faeces do seem to have sufficient K2!

What are the main modes of action by K2 in the body?

The best known roles for K2 are in the prevention of arterial wall calcification and in bone integrity. In effect K2 acts as a cop directing traffic at a busy junction. It ensures that calcium ends up in bone and not in the walls of the arterial system. Science is still working on what goes on in bone. The bone protein osteocalcin (discovered in 1975) is activated by a process called gamma-carboxylation. That process is made possible by K2 and indeed K1. If no carboxylation occurs then calcium cannot bind to the protein to initiate the calcification process. Measures of the degree of carboxylation seem to be the best way of assessing the vitamin's status in the body.

It is likely that K2 has a specific binding protein in the nucleus of the osteoblast (a bone making cell). As an added advantage the tail of the K2 molecule, unlike that of the K1 molecule, suppresses the formation of osteoclasts which are bone removing cells. It is also very likely that K2 has other advantageous functions in bone. A known one is its inhibition of a prostaglandin involved in osteoclast formation. It is important to point out that these functions of K2 in bone appear to be independent of the carboxylation process which is involved in the vitamin's site-specific actions mentioned above.

The calcification of arterial tissue (hardening of the arteries) has been viewed as an irreversible process. Additionally the study by the Maastricht research group has demonstrated that arterial calcification is reversible, in rodents at least, with vitamin K. The relative merits of Vitamin K1 and 2 have not yet been fully explored. It seems from this Dutch study that massive doses of K1 may be required to reverse arterial calcification while K2 may provide similar benefits at physiological doses. (1)

What other functions might K2 have in the body?

K2 has been implicated in the optimum functioning of various body systems. This suggests that its deficiency may contribute to various disease states. For example, a recent study suggests it may be able to correct a mitochondrial genetic malfunction in fruit flies, which has been associated with Parkinson's disease.(2) Interestingly Parkinson's patients have a higher risk of bone fractures and they can be treated with large doses of K2 to reduce fracture risk and enhance vitamin D status.(3)

K2 deficiency is also suspected to be involved in the formation of varicose veins. (4)

K2 has been shown to protect the liver from cancerous change in subjects with cirrhosis and it may help prevent advanced prostate cancer.

Administration of K2 (not K1) to lab rats has resulted in increased testosterone levels. (5)

K2 seems to have the ability to inhibit ectopic calcification. For example it has been shown that it can inhibit calcification in the dermis of the skin. (6)

Similar processes may be involved in its anti-arthritic benefits. (7)

K2 may have specific anti-cancer activity in the prostate. The EPIC study, that very large European study on diet and health, has found that longer chain menaquinones are associated with a reduced risk of advanced prostate cancer and shorter chain ones eg. from meat which are mildly protective for non-aggressive forms of the disease. (8)

Low vitamin K levels appear to result in impaired pancreatic function in rats. The pancreas is rich in K thus its deficiency may be a diabetic risk factor in man. (9)

What form of vitamin K is best?

Vitamin K1 has not been shown to have valuable cardio and bone protecting activity. The preferred form of K2 is the MK-7 variety. Supplementation of MK-4 has not resulted in enhanced plasma MK-4 levels, while supplementing with MK-7 on a regular basis results in substantial and prolonged increases in tissue levels and reductions in uncarboxylated osteocalcin. It has also been claimed that the best source of MK-4 in the body is MK-7! The actions of MK-4 appear to be largely confined to the liver.

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How can we use K2 to provide health benefits?

It is reported that all K2 supplementing studies have demonstrated improvements in bone density while studies using K1 have not done so. The mainstream medical drugs, notably the bisphosphonates and hormone replacement therapies have by contrast shown very small benefits. Their limited success is probably due in part to their mode of action, which seems only to address one aspect of the problem - the resorption side of the equation in bone. It should also be pointed out that the question of bone integrity is not just an issue involving the amount of calcium in bone. The other elements in living bone are just as important. Thus improved bone mineral density, seen on bone scans as a result of standard treatments, does not necessarily mean the bone is stronger and more resistant to fracture.

There are two key proteins in bone - osteocalcin and osteopontin, both of which are products of osteoblasts (bone forming cells). They are joined together. When bone is subject to a blow the bond between them deforms. This seems to be a protective mechanism. More severe trauma leads to rupture of the bond. It seems that osteocalcin is the point of fracture, so bone deficient in osteocalcin is more prone to fracture. Osteocalcin can only be incorporated into bone in its carboxylated form, which in turn can only be produced when sufficient vitamin K is present. (10)

In the cardiovascular system K2 has been shown to minimize calcification in arteries. In one animal study it seems to have reversed pre-existing calcification.

At least two studies have raised concerns that supplementation with calcium and usually vitamin D may increase the risk of cardiovascular disease in women taking the combination to try to prevent osteoporosis.(11) It has also been proposed that the addition of vitamin K2 might eliminate this risk. (Cees Vermeer - Letter to the British Medical Journal, 1 Feb 2008)

Vitamin K may have other benefits beyond bone and the cardiovascular system. Mentioned above is possible protection against prostate cancer. It has also been shown to protect the liver from cancerous change in subjects with cirrhosis and it may help prevent advanced prostate cancer. Thus we must infer some form of general anti-neoplastic role. (12) (13)

Should everyone take K2?

Cees Vermeer has observed that in their K2 investigations they found no one who had optimum carboxylation levels. This suggests that we would all benefit from MK-7 supplementation. It does not of course answer the question of what might constitute an acceptable level of carboxylation. Vermeer suggests that daily intake of around 180 mcg may be necessary for an ideal degree of carboxylation to be achieved.

In the Western diet both vitamin K1 and K2 are lacking. In the case of K1 (phyloquinone), we get most from a few leafy vegetables and spices. It seems highly unlikely that regular dietary sources can provide quantities which would lead to optimum carboxylation of osteocalcin in bone. A study in which young healthy adults were given large amounts of supplemental phyloquinone confirmed that quantities far in excess of dietary intake were required for carboxylation to approach 100%.(14)

There are of course many unanswered questions. How high a carboxylation level is required to protect bone integrity? What are the K1 absorption capabilities of older healthy people; not to mention those with compromised health? (It seems that absorption of K2 is not a problem) How are we to address the problem of those taking vitamin K antagonists for blood clotting problems?

Studies in western countries have all shown that food sources provide little K2. The only solution seems to be supplementation or perhaps we all could develop a taste for natto where available! Read vitamin K2 supplement labels carefully. They will say vitamin K2 - but there are different types. If the label only says Menaquinone it is almost certainly MK-4. If it says "from Natto" it is MK-7. The relative merits of the different menaquinones do not seem to have been fully explored. The numbers refer to the length of the tail of the molecules concerned. It is clear from the work of the Maastricht research group that MK-7 has a much longer half-life in the body than MK-4 due to differences in the way it is metabolized.

It is clear that K2 provides protection against arterial calcification and also enhances bone health. Dutch research suggests that women who have diets with higher levels of K2 (not K1) have less arterial calcification.(15) It has also been shown that the higher menaquinones may provide substantial protection from cardiovascular disease in older women. Natto and fermented cheeses and some other dairy products, provide longer chain menaquinones. (16)

The prevalence of osteoporosis and indeed cardiovascular disease suggests that many older people should take a K2 supplement. Japanese research has demonstrated that high levels of K2 are required in the plasma of older women (above 70 years) to achieve adequate levels of carboxylation implying that carboxylation efficiency is age-related. (17)

Those who have been taking antibiotics, which indiscriminately kill their intestinal bacteria, are known to have dramatically lower levels of vitamin K2 in their gut. The possible effect on bodily K2 levels is unclear. (18)

Very large doses of vitamin k have been used to treat osteoporosis in Japan for many years and do not appear to have resulted in serious side effects. Mega doses of vitamin K have not resulted in increased clotting risk.

The bones of the young

Vitamin K intake in children is low probably because foods like broccoli, spinach and kale are not popular. Unfortunately their vitamin K needs are higher than adults because osteocalcin levels in growing bone are 8-10 times greater than adult levels. It has been shown that improving vitamin K status results in stronger denser bone in children. (19) Could we speculate that denser bone in youth might alleviate bone loss in old age?

Ageing issues

We know that the body's ability to convert K1 to K2 falls dramatically as we age. We also know that it is likely that increasing age causes an increased requirement for K2 in order to maintain an appropriate level of carboxylation of osteocalcin. (20) Elderly women have been shown to have less carboxylated osteocalcin, but the reasons are unclear and may not be related to vitamin K deficiency. (21)

It would seem prudent to add a K2 supplement, in the form of MK-7, to our diets. Fifty to one hundred mcg daily seems appropriate as a starting point. This may be particularly relevant for those suffering cardiovascular or osteoporosis problems. The mainstream approach to bone loss and restoration is to prescribe calcium supplements (with the possible addition of vitamin D and magnesium), or to use hormone replacement therapy. The value of these strategies seems limited. Controversy exists about whether extra calcium supplementation is a safe procedure. It has been suggested by the Maastricht research group that any adverse effects on the cardiovascular system might be mitigated by concurrent supplementation with MK-7 as mentioned above.

I would like to briefly address the issue of vitamin K antagonists designed to inhibit blood clotting. Warfarin-based products have proved very valuable in controlling unwanted clotting. Yet it has to be admitted that they do have a tendency to encourage arterial calcification in the long term. Some newer substitutes may be better in some respects, but can have disastrous consequences as their effects cannot be immediately reversed. This can result in hemorrhaging patients requiring massive blood transfusions. Vitamin K researchers are well aware of these issues. The Maastricht group has done a study where they have measured coagulation components in the blood of normal subjects taking varying amounts of vitamin K2. They have concluded that daily consumption of no more than 45 mcg of K2 is unlikely to affect coagulation markers and may indeed provide greater stability to vitamin K intake and thus warfarin dosage. Does this mean that warfarin users can take small doses of K2 while continuing with their medication; thus protecting their arteries and valves? Alas we do not know and your doctor may not want to find out. There may be alternative anti-coagulation systems in the pipeline. The rutinosides could be one of them. (22)

In conclusion

We are far from a full understanding of the role of K vitamins in our bodies. There is good reason to suppose that they play an important, perhaps vital role, in maintaining optimum health. They appear to have very low toxicity. It seems to me that we cannot await future studies to further elaborate their benefits. I suggest we should ensure that we have enough vitamin K2 by supplementing with MK-7.

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REFERENCES

  1. Schurgers et al. Blood 2006 Nov 30 (Epub ahead of print)
  2. Vos M. et al. Vitamin K2 Is a Mitochondrial Electron Carrier That Rescues Pink1 Deficiency. Science, 2012; DOI: 10.1126/science.1218632
  3. Sato Y Bone 2002 31: 114-118
  4. Cario-toumaniantz C. et al. J Vasc Res 20077 44:444-459
  5. Asagi Ito Lipids in Health and Disease 2011 10:158
  6. Gheduzzi D. et al. Laboratory investigation 2007 87:998-1008
  7. Okamoto H IUBMB life Vol 60:6:355-361
  8. Nimptsch K et al. AJCN 2008 87:4; 985-992
  9. Sakamoto N. et al. Int J Vit Nutr Res (1999) 69:27-31
  10. Poundarik A.A. et al. Dilatational band formation in bone. PNAS 2012; 109 (47): 19178 DOI: 10.1073/pnas.1201513109
  11. Bolland MJ et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ. 2008;336(7638):262-6.
  12. Habu D, Shiomi S, Tamori A, et al. Role of vitamin K2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver. JAMA 2004;292:358-61.
  13. Nimptsch K. et al. Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg), AJCN April 2008, Volume 87, Number 4, Pages 985-992
  14. Binkley N.C. et al. AJCN 2002 76: 1055-60
  15. Beulens J.W. et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis, April 2009, pp. 489-93
  16. Gast GCM et al., A high menaquinone intake reduces the incidence of coronary heart disease, Nutr Metab Cardivasc Dis, September 2009, pp. 504-10
  17. Tsugawa AJCN 2006 83:380-6
  18. Kimura S. et al J Nutr Sci Vitaminol (Tokyo) 1992 Spec No: 425-8
  19. Van Summeren MJ et al. K vitamins status is associated with childhood bone mineral content. Br J Nutr. 2008;1-7.
  20. Tsugawa AJCN 2006 83:380-6
  21. Plantalech L. et al. (1991) J Bone Miner Res 6:1211-16
  22. Dar and Tabassum, International Current Pharmaceutical Journal 2012, 1(12): 431-435

This article was first published in the March 2013 issue (#243) of International Health News

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