by Dr. John Neustadt

NBI has become a global leader in vitamin K research and product development. Since 2006 I’ve studied the biochemistry and health effects of MK4 and shared my research at medical conferences and universities. The US FDA granted four Orphan Drug Designations after reviewing research I submitted on the MK4^Ⓡ form of vitamin K and agreeing that it has great health potential.

Twenty years ago research on vitamin D was emerging and people were starting to understand the benefits of this nutrient. Vitamin D is a fat-soluble vitamin with dozens of effects in the body. These include boosting the immune system, promoting healthy bones and teeth, supporting brain and nervous system health and supporting lung function and cardiovascular health. Vitamin D also influences the expression of genes involved in cancer development.

Like Vitamin D, vitamin K is a fat-soluble, powerfully versatile nutrient that’s crucial for health. Although initially thought to only have a role in promoting healthy blood clotting (coagulation), MK4 has many other important activities, including healthy effects on bone metabolism, nerves, the brain and blood vessels. MK4 also effects cellular processes involved in killing cancer cells.

Why MK4?

Unlike vitamin D where there’s only one fully activated form in the body, called vitamin D3, there are many types of active vitamin K. The two categories of vitamin K molecules are vitamin K1 and vitamin K2. There are different types of vitamin K2. The most common forms of vitamin K2 found in dietary supplements are MK4 and MK7.

Plants synthesize vitamin K1 and animals can create the MK4 form of vitamin K2 by converting vitamin K1 to MK4. In foods MK4 is found in dairy and meats but at levels much smaller than those studied and shown to be helpful in human clinical trials. While there are different forms of vitamin K2, only MK4 has been shown in clinical trials to maintain strong bones, promote healthy bone density and bone matrix.

In contrast to MK4, MK7 isn’t produced by the body. Instead, it’s synthesized by bacteria. These two forms of vitamin K2 are chemically different. To our body’s biochemistry, details are crucial. If a molecule differs by just one atom it can have different effects, and the differences in the structure of MK4 and MK7 explain the different health benefits.

MK4 has been shown to reduce fractures in people with osteoporosis. MK7 has never been shown to reduce fractures in any clinical trials. While both MK4 and MK7 may improve bone density, bone density is not the most important thing with osteoporosis. Breaking a bone is. Bone density only predicts 44% of women who will break a bone and only 21% of men.  And only MK4 has been shown to reduce fractures in clinical trials. 

MK4 is also the only form of vitamin K shown to have anticancer properties. These were demonstrated in controlled clinical trials, case reports and laboratory studies. There’s more about this further down in the blog.

MK4 provides wide-ranging health benefits, including:

1. Bone. Promotes healthy platelet, white and red blood cell production in people with leukemias. Grows stronger bones and shown in clinical trials to reduce fractures more than 80%. Stopped and reversed bone loss from medications (eg, prednisone) in multiple clinical trials. Administered to lung transplant patients in one clinical trial and prevented bone loss.
2. Brain. May improve brain health by promoting healthy nerve production.
3. Breast. MK4 appears in the breast milk of lactating women.
4. Liver. Reduced by 80% development of liver cancer a clinical trial of people with Hepatitis C. Decreased recurrence of liver cancer and regression of liver cancer in published studies. Caused normalization of liver cancer blood markers.
5. Blood. Promotes healthy platelets, white and red blood cells. Used for healthy blood clotting.

MK4 has been found concentrated in other organs such as the kidneys, lungs, pancreas, spleen and testes; however, MK4’s role in those tissues has still not been defined.

MK4 and Bone Health

MK4 in the dose of 45 mg/day has been shown in human clinical trials to grow stronger bones and reduce fractures more than 80%.

MK4 has been approved as a treatment for osteoporosis and the pain of osteoporosis in Japan since 1995. In the United States MK4 is not considered a medicine and is available only as a dietary supplement.

MK4 accumulates in tissues throughout the body, where it has its beneficial effects. It accumulates in the spleen, liver, kidneys, brain, testes, breasts, pancreas, lung and other tissues. Like other nutrients, MK4 is involved in many biochemical pathways. It helps promote healthy platelet and blood production, decreases markers of inflammation, and promotes connective tissue (collagen) production, making it helpful in tissues throughout the entire body.

MK4 has been shown to decrease fractures and has 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 more than 80% independent of the number of falls sustained. MK4 also has been cited as a potential strategy for drug-induced bone loss, such as osteoporosis caused by prednisone. In clinical trials, MK4 (45 mg daily) prevented bone loss and/or fractures caused by:

• corticosteroids (eg, prednisone, dexamethasone, prednisolone)
• anorexia nervosa
• cirrhosis of the liver
• postmenopausal osteoporosis
• disuse from stroke
• primary biliary cirrhosis
• leuprolide treatment (for prostate cancer)

Fractures are a serious problem resulting in handicapped children. A case report was published of an institutionalized, bedridden 8-year-old girl with Arnold-Chiari deformity with low bone mineral density (BMD) whose BMD increased with MK4 treatment. MK4 also inhibited phenytoin-induced bone loss in rats; prevented and increased bone formation in rat that had a nerve removed, which created paralysis osteoporosis), an animal model for immobilization osteoporosis; prevented and increased bone formation in rats that had their testes removed, which is an animal model for osteoporosis caused by testosterone deficiency; and improved healing time and bone quality in experimentally induced bone fractures in rats alone and in the presence of prednisone. 

MK4 and Cancer Cells

The same dose of MK4 (45 mg/day) shown to grow stronger bones has also been demonstrated in published clinical trials, case reports and basic laboratory research to kill cancer cells, support healthy blood production in people with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and promote health in people with liver cancer and promyelocytic leukemia.

MDS and AML are diseases of deficient blood production. A blast cell is an immature white blood cell produced in bone marrow. There are different subtypes of AML, which are distinguished from other related blood disorders by the presence of more than 20% blast cells in the bone marrow. MDS is differentiated by AML by having a lower percentage of blast cells. The underlying development of AML and MDS consists of bone marrow cells getting stuck in the earliest stages of development.

This inability for the bone marrow to produce healthy blood cells results in two disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia (low platelets), and neutropenia (low neutrophils). Second, the natural life cycle of the cells is interrupted. Cell typically die and are regenerated at regular intervals. But with cancer, including AML, this process of programmed cell death (apoptosis) doesn’t happen. Instead of cells dying and being recycled by the body, these cells accumulate in the bone marrow, blood, and, frequently, the spleen and liver.

As a supportive nutrient, MK4 is the only form of vitamin K shown to help. Fourteen clinical trials and case reports evaluated the ability of MK4 to promote healthy cells in nearly 600 people with cancer. Additionally, laboratory research has studied MK4’s effects on isolated cancer cells. Conclusions of this research showing the potential benefits of this nutrient for people with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) liver cancer (hepatocellular carcinoma) and acute promyelocytic leukemia have been published in more than 15 medical journals. 

MK4 and Healthy Collagen

MK4 promotes healthy collagen production, the most abundant protein in the body. Collagen is the scaffolding that gives shape and strength to cells and organs. Collagen is a category of connective tissue that includes 29 different types of collagen that differ in size, structure, and function.

Collagen is required for every cell in the body to grow, divide and carry out their important functions. It is so abundant that it accounts for 30% of all proteins. Collagen is found in bones, tendons, ligaments, skin and nerves. Collagen is vital for skin elasticity and helps create and maintain firmness and suppleness. Without healthy collagen, skin sags.

Collagen creates the shape of the lungs and exists throughout our cardiovascular system in blood vessels and the heart, as well as in the kidneys, nerves, pancreas, liver, testes, breasts, brain and eyes. In cancer, it’s the destruction of collagen by cancer cells that allows the cancer to spread throughout the body. This process is called metastasis.

Liver cancer studies show that MK4 reduces chemicals called matrix metalloproteinases (MPP) that cause connective tissue breakdown and are involved in the spread of cancer.

The preeminent role that collagen plays in bone health, fracture healing and fracture prevention has been well documented. Bone matrix is a dynamic, two-part system in which the mineral part provides the stiffness and the collagen-fibers part provides flexibility and the for bone ability to absorb energy from a fall and not break. Therefore, destruction of bone collagen can increase fracture risk. In studies of people with osteoporosis, a loss of bone collagen has been associated with increase fracture risk.

The important role of collagen is demonstrated in rare diseases where collagen production is damaged. There are more than 200 disorders that affect connective tissue. Some of these are inherited at birth (genetic) and some are acquired during someone’s lifetime. Examples of genetic connective tissue disorders include Ehlers-Danlos syndrome, Marfan syndrome and osteogenesis imperfecta. Those that can be acquired include osteoarthritis, systemic lupus erythematosus (SLE) and emphysema.

The importance of maintaining and promoting collagen health cannot be overemphasized. MK4 supports healthy collagen.

MK4 has many more health benefits beyond collagen. It grows stronger bones, kills cancer cells, promotes healthy nerves, decreases inflammatory markers and has been shown to remove calcium from arterial walls.

MK4 and Brain Health

In the brain, MK4 is involved in maintaining and promoting healthy nerves as part of the pathway for the production of sphingolipids. Sphingolipids for the lining around nerve cells that allow for healthy nerve impulses.  The brain and spinal cord form the central nervous system. Nerves going to and from the spinal cord to muscles, bone, skin and internal organs make up the peripheral nervous system. Nerves provide a common pathway for electrochemical communication to and from tissues throughout the body. Each nerve is covered externally by a dense sheath of connective tissue (collagen), the epineurium. Surrounding nerves are “myelin sheaths.” MK4 promotes collagen production and in the brain, MK4 accumulates in the midbrain, pons medulla, cerebellum, olfactory bulb, thalamus, hippocampus and striatum meaning that MK4 may have powerful beneficial effects on brain and nerve function.

Here’s what each of those brain regions do and why their health is so important:

1. Midbrain. The midbrain or mesencephalon is associated with vision, hearing, motor control, sleep/wake, arousal (alertness), and temperature regulation.
2. Pons medulla. The pons medulla is the lower half of the brainstem. It is frequently referred to as simply the medulla. It contains the cardiac, respiratory, vomiting and vasomotor centers and deals with involuntary functions such as breathing, heart rate and blood pressure.
3. Cerebellum. The cerebellum plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established. The cerebellum does not initiate movement, but it contributes to coordination, precision, and accurate timing.
4. Olfactory bulb. The olfactory bulb is involved in the perception of smell.
5. Thalamus. The thalamus relays sensory and motor signals to the cerebral cortex along with the regulation of consciousness, sleep, and alertness.
6. Hippocampus. The hippocampus plays important roles in short- and long-term memory and spatial navigation.

MK4 and Inflammation

Inflammation plays a role in the initiation and progression of many diseases, including cardiovascular disease, cancer, diabetes, obesity and depression. MK4 reduces the expression of nuclear factor kappa beta (NF-κB), a major marker of inflammation.

MK4 and Cardiovascular Health

MK4 affects proteins involved in the process of arterial calcifications, also called hardening of the arteries, which can cause heart attacks. In one study of the effect of MK4 on this process, the researchers concluded, that their findings suggest that MK4 acts as an anti-calcification component in the vessel wall. And in another study MK4 (but not vitamin K1) was shown to prevent calcium buildup in arteries.

Is MK4 Safe?

More than 7,000 people have taken 45 mg daily (and higher doses) of MK4 for up to eight years in clinical trials without any serious side effects.

Because vitamin K is used to promote healthy blood clotting, and MK4 is a form of vitamin K, sometimes people ask if MK4 (45 mg/day) increases the risk for dangerous blood clots. The answer is a resounding no. Both animal and clinical studies support the conclusion that MK4 has no dangerous effects on blood clotting. To read more on this, read my blog, When Your Doctor’s Good Intention is Bad Advice.

It’s important to know, however, that the anticoagulant effect of the drug warfarin, which functions by interfering with the clotting effect of vitamin K, can be disrupted with as little as 1 mg of vitamin K. The only documented reason people should absolutely not take MK4 is if they take the warfarin, which is also called coumadin.