Vitamin K and Bone Health

Vitamin K is a group of structurally similar, fat-soluble vitamins that include phylloquinone (K1), menaquinones (K2) and menadione (K3).1 Plants synthesize vitamin K1 while bacteria can produce a range of vitamin K2 forms, including the conversion of K1 to K2 by bacteria in the small intestines. Vitamin K3 is synthetic and, because of its toxicity, has been banned in by the US Food and Drug Administration for human uses. In contrast to vitamin K3, no known toxicity exists for the vitamin K1 and K2 forms.

Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared to those not taking these antibiotics.2 Diets low in vitamin K also decrease the body's vitamin K concentration.3 Additionally, in the elderly there is a reduction in vitamin K2 production.4 Natto (fermented soybean) is the richest dietary source of vitamin K2. Dairy products (milk, butter, cottage cheese, cheese) and egg yolk also provide small amounts.

It's important to note that vitamin K1 is preferentially used by the liver as a clotting factor. Vitamin K2 on the other hand is used preferentially in other organs, such as the brain, vasculature, breasts and kidneys. In fact, in the brain, vitamin K2 contributes to production of myelin and sphingolipids (fats essential for brain health) and protects against oxidative damage. Vitamin K2, such as MK4, promotes bone health by stimulating connective tissue production in bone.

Safety studies of high doses of vitamin K are clear: even extremely high doses vitamin K does not increase the risk for blood clots. Coagulation studies (blood clotting studies) in humans using 45 mg per day of vitamin K2 (as MK4)5 and even up to 135 mg/day (45 mg three times daily) of K2 (as MK4),6 showed no increase in the risk of blood clots. Even doses in rats as high as 250 mg/kg body weight did not alter the tendency for blood-clot formation to occur.7

MK4 versus MK7 for Bone Health

There are primarily two forms of vitamin K2 commercially available. These are MK4 and MK7. MK4 used in dietary supplements is created through chemical synthesis. MK7 is produced by bacterial fermentation of soy, appears to have a longer half life then MK4, and can also decrease serum ucOC.8

However, only MK4 has demonstrated the ability to decrease fractures, the most relevant end point in randomized, controlled clinical trials.9,10,11 Additionally, people with an allergy to soy can react to MK7, since it is produced from soy fermentation. People with celiac disease and gluten intolerance frequently have allergies to other foods, such as soy. MK4 is hypoallergenic.

MK4 has been shown to decrease fractures, and has even been approved by the Ministry of Health in Japan since 1995 for the treatment of osteoporosis and osteoporosis pain. Multiple clinical trials using 45 mg per day of MK4 show that this amount, and only this amount, of MK4 taken daily may decrease fractures up to 87% independent of the number of falls sustained.12,13,14,15 MK4 also has been cited as a potential strategy for drug-induced bone loss.16 In clinical trials MK4 (45 mg daily) prevented bone loss and/or fractures caused by:

  • corticosteroids (eg, prednisone, dexamethasone, prednisolone),17, 18, 19, 20, 21
  • anorexia nervosa,22
  • cirrhosis of the liver,23
  • postmenopausal osteoporosis, 24, 25, 26, 27, 28, 29
  • disuse from stroke,30
  • Alzheimer's disease,31
  • Parkinson's disease, 32
  • primary biliary cirrhosis,33
  • leuprolide treatment (for prostate cancer).34

Fractures are a serious problem resulting from skeletal unloading in handicapped children. A case report was published of an institutionalized, bedridden 8-year-old girl with Arnold-Chiari deformity with low BMD whose BMD increased with MK4 treatment.35 MK4 also inhibited phenytoin-induced bone loss in rats;29 prevented and increased bone formation in neurectomized rats,36, 37 an animal model for immobilization osteoporosis; prevented and increased bone formation in orchidectomized rats,32 an animal model for secondary osteoporosis caused by testosterone deficiency; and improved healing time and bone quality in experimentally induced osteotomy in rats alone and in the presence of glucocorticoids.38

In contrast MK7 has never been shown to reduce fractures in clinical trials. And the only published clinical trial that evaluated MK7 and its effect on bone health concluded that MK7 does not stop bone loss.40

MK4 exerts a powerful influence on bone building, especially in osteoporosis, and in Japan has been accepted as an osteoporosis treatment.41 It is a fat-soluble vitamin that is a coenzyme for a vitamin K-dependent carboxylase enzyme that catalyzes carboxylation of the amino acid glutamic acid, resulting in its conversion to gamma-carboxyglutamic acid (Gla). This carboxylation reaction is essential for formation of bone collagen, which allows bone to deform upon impact, for example during a fall, without fracturing. Although vitamin K-dependent gamma-carboxylation occurs only on specific glutamic acid residues in a small number of proteins, it is critical to the calcium-binding function of those proteins. Three vitamin K-dependent proteins have been isolated in bone—osteocalcin, matrix Gla protein (MGP) and protein S. Osteocalcin is a protein that is synthesized by osteoblasts and is regulated by the active form of vitamin D, 1,25-(OH)2D3, also called calcitriol. The mineral-binding capacity of osteocalcin requires vitamin K-dependent gamma-carboxylation of 3 glutamic acid residues. Multiple randomized, double-blind, placebo-controlled clinical trials have shown significant decreases in undercarboxylated osteocalcin (ucOC) in volunteers supplemented with 45 mg of vitamin K2 with and without the addition of calcium and vitamin D3 compared to controls.42,43,44,45

A 2006 meta-analysis published in the Archives of Internal Medicine by Sarah Cockayne, MSc, Joy Adams, PhD, Susan Lanham-New, PhD, and colleagues, at the University of York in England, evaluated clinical trials on MK4 and fracture risk.46  They identified 13 randomized, controlled trials of the effect of MK4 on osteoporosis. Of those, 7 had fracture risk as an end point and so were included in their meta-analysis. They concluded that 45 mg of vitamin K2 as menaquinone-4 (MK-4) could decrease vertebral fracture by 60%, hip fracture by 73%, and all nonvertebral fractures by 81%.

A randomized, controlled, open-label study of 241 osteoporotic women (avg. age approximately 67 yrs.) evaluated the fracture prevention effects of MK4.47 A control group of 121 women took  150 mg of calcium daily, while 120 women (the treatment group) received 150 mg of calcium daily plus 45 mg per day of MK4. The study lasted 24 months (two years) and evaluated lumbar BMD and fractures. Over the two year period there were 30 new fractures (30.3%) in the women who did not take the MK4, and only 13 fractures (10.9%) in the women who did supplement with 45 mg/day of MK4. That's a 200% decrease in risk.

A second randomized, controlled clinical trial evaluated the risk of fractures in women with Alzheimer's disease.48 In this study, 200 women with Alzheimer disease (average age 78 years) received 45 mg MK4, 1000 IU vitamin D3 and 600 mg calcium per day. These women were followed on this regimen for two years, and evaluated for bone mineral density and fractures. After two years those in the control group, who did not receive the MK4, experienced twenty-two new fractures (fifteen hip fractures, two distal forearm fractures, two proximal femur fractures, and one each at the proximal humerous, ribs and pelvis). In contrast, those who received the MK4 experienced three fractures total (two hip fractures and one proximal femur fracture). Those in the treatment group who took the MK4 experienced 86% fewer nonvertebral fractures compared to the control group. Additionally, there were 87% fewer hip fractures in treatment group compared to controls. Interestingly, there was no difference in the number of falls sustained in each group. Therefore, MK4 protected these women against fractures even when they did fall.

An excellent review of vitamin K2 by Stephen Plaza, ND, and Davis Lamson, ND, was published in 2005 in the journal Alternative Medicine Review.49 In this article they reviewed clinical trials using vitamin K2 that showed increases in BMD and/or reduction in fracture risk in volunteers who had bone loss from anorexia nervosa, Parkinson's disease, biliary cirrhosis, and stroke and in volunteers who were taking prednisone and leuprolide; in other volunteers, it increased the efficacy of bisphosphonate medications.

Learn more

  1. The MK4 Power
  2. NBI and MK4 History & Heritage

Why Osteo-K clobbers the competition: click to view a chart comparing Osteo-K to other leading calcium supplements, such as Viactiv, Citracal, Bone-Up, Os-Cal and Caltrate.

You can also learn more by reading about ways to slow or prevent bone loss and ways to continue building bone.