Vitamin K2 - Benefits for Heart and Bone Health
Vitamin K2: The Forgotten Vitamin
Vitamin K2 is an essential fat-soluble vitamin vital for optimal bone and cardiovascular health. It regulates the transport and distribution of calcium in the body. K2 variant MK-7 surpasses other K2 forms due to its superior bioavailability, longer half-life, and lower dosage requirement. Vitamin K2 has a long history that spans centuries and continents, but it remained ‘the forgotten vitamin’ for a long time. Thanks to several scientific studies on vitamin K2 spanning almost two decades, K2 was reborn with a new vigor. These studies demonstrate the effects of K2 supplementation on bone and cardiovascular health. The efficacy of vitamin K2 was studied in multiple population segments including women and children. Apart from these scientific milestones, perfecting of organic synthesis of all-trans vitamin K2 MK-7 (similar in biological activity and function to fermentation- derived K2) and microencapsulation of K2 MK-7 (which made MK-7 stable in formulation) enabled K2 to enter the mainstream.
Vitamin K2 Puts Calcium Into Balance
Calcium is the key link connecting vitamin K2 to bone and cardiovascular health. Vitamin K2 directs calcium to the bones instead of the arteries. K2’s mechanism of action involves activation (by carboxylation) of two key proteins – osteocalcin and matrix Gla-protein (MGP). Osteocalcin plays a role in the integration of calcium into the bone matrix whereas K2-activated MGP binds free-floating calcium and prevents calcium deposition in arteries. Fermented food products like the soy-based Japanese dish natto, are the major sources of dietary K2.
Studies have established a link between a K2- rich diet and improved bone-mineral density. Western diets, on the other hand, are deficient in vitamin K2. Hence, nutritional supplementation is the only way to overcome dietary K2 deficiencies. K2 MK-7 together with calcium and vitamin D3 is an optimal combination for bone health. Similar formulations for heart health containing K2 and other heart-protecting ingredients can provide a superior health benefit.
Vitamin K1 or phylloquinone accounts for around 90% of the total dietary vitamin K intake. Green leafy vegetables such as green salads, broccoli, kale, and spinach are the major sources of K1. Although the intake of vitamin K in the general population is between 70-250 μg/day, less than 20% of vitamin K1 from dietary sources is absorbed by the body (poor bioavailability). The major function of K1 is to aid blood coagulation by activating blood-clotting proteins.
Vitamin K2 or menaquinones comprise a group of structurally similar molecules which differ in their chain length and biological activity. Their side chains can vary from 4-14 isoprenoid units (designated as MK-n, n being the number of side chains). MK-4 and MK-7 are the most important menaquinones. MK-4 can be obtained from meat, dairy, and eggs whereas MK-7 is mainly found in fermented foods such as cheese, yogurt, and natto (a fermented Japanese soybean product). Vitamin K2 is essential for optimal bone and heart health.
Vitamin K2 MK-7 is superior to MK-4 regarding biological activity and half-life in the body. MK-7 has a halflife of about 72 hours whereas it is only about 1.5 hours for MK-4. Therefore, MK-7 remains biologically active in the body longer and allows for a better bodily distribution and activation of extra-hepatic K2-dependent proteins such as osteocalcin and matrix gla-protein (MGP). These differences arise from the differences in the distribution and breakdown of the two MK forms. MK-4 is mainly transported in the blood via triglyceride- rich lipoproteins whereas low-density lipo - proteins transport MK-7. MK-7 reaches bones and vessel walls easier than MK-4. The daily requirement of MK-7 is much lower compared to MK-4 (around 90-120 μg/day for MK-7 and 45,000 μg three times a day for MK-4).
Vitamin K2 MK-7 exists in two isomeric forms – cis and trans. The trans isomer is the naturally-occurring and the most bioactive form of MK-7. Alltrans MK-7 is linear in structure due to an extended system of isoprenoid units whereas the cis isomers are non-linear. Hence, the cis MK-7 does not fit well into subcellular structures, leaving K2-dependent enzymes and proteins inactivated. Fermentation-derived vitamin K2 MK-7 is usually a mixture of trans and cis isomers along with other compounds. Trans MK-7 must be purified from this mixture to obtain the bioactive substance. Synthetic K2 MK-7, on the other hand, bypasses these issues as the final product obtained is alltrans K2 MK-7 with no contamination from cis isomers or other compounds
Western diets are currently deficient in vitamin K2 as the daily dietary intake of K2 has reduced over the past hundred years. In the previous century, it was common to eat vitamin K2-rich foods like cured fish and aged cheese. The exact knowledge of K2 MK-7 intake levels in different countries is lacking. Inactive proteins – osteocalcin and matrix Gla-protein (MGP) – are the biomarkers of vitamin K2 deficiency. Osteocalcin incorporates calcium into bone whereas MGP binds excess calcium in the blood to prevent its deposition in arteries. Both proteins are dependent on vitamin K2 as both need to be activated by K2 in a carboxylation process to function properly. The ratios of carboxylated and uncarboxylated osteocalcin and MGP in the blood are, therefore, important biomarkers of vitamin K2 status in the human body. Multiple scientific studies over the past two decades have shown that in western populations, a high percentage of osteocalcin and MGP remain in the inactive (uncarboxylated) form as demonstrated by blood samples from healthy subjects.
Supplementation can overcome the K2 deficiency. K2 supplementation increases the amount of activated osteocalcin and MGP. For example, a study with healthy volunteers demonstrated that before supplementation with vitamin K2, levels of inactive osteocalcin were high, whereas afterward they were low and most of the osteocalcin was activated. To achieve sufficient osteocalcin activation, research indicates that 90-120 μg of vitamin K2 as a daily dose is sufficient. Populations that reach the recommended daily dose, such as Japanese people consuming natto, were shown to have lower rates of bone and heart disease. Other epidemiological studies in Japan also strengthen the notion that MK-7 promotes bone health. Studies have also recognized the beneficial effects of vitamin K2 supplementation in reducing levels of inactive osteocalcin and MGP, and thereby improving bone and cardiovascular health.
Calcium is the building block of bones. Vitamins D3 and K2 regulate calcium utilization in the body. Vitamin D3 promotes intestinal uptake and transport of calcium ensuring sufficient blood calcium levels for normal mineralization of collagen matrix in the skeleton. Vitamin K2 activates osteocalcin, a protein which helps incorporate calcium into the bone matrix. Hence, optimal levels of calcium and vitamins D3 and K2 must be maintained throughout our lives, particularly during childhood and puberty, when most of the bone mass is made, and during the later years when the risk of fracture is more.
Several studies demonstrate the link between vitamin K2 and bone health in adults and children.Children need high levels of vitamin K2 to support their rapid growth. However, studies show that vitamin K2 levels in children and adolescents are low and that the inactive form of osteocalcin (ucOC, undercarboxylated osteocalcin) is more abundant than the active form (cOC, carboxylated osteocalcin) when compared to other age groups. Vitamin K2 MK-7 supplementation elevates activated osteocalcin levels in children.
Osteoporosis, a condition characterized by brittle bones with low mineral density, is rampant among the aging population. Clinical studies involving postmenopausal women revealed that they benefited from a daily low dose of MK-7 for three years with a resulting reduced age-related decline in bone mineral density. Also, women diagnosed with osteopenia improved their bone microstructure with MK-7 supplementation.
Dietary intake of vitamin K is sufficient to cover our body ’s needs to activate blood clotting factors. Contrary to blood clotting factors, studies show that most people do not consume the required amount for sufficient activation of proteins involved in calcium transport (recommended daily intake levels of up to 120 μg vitamin K depending on age and gender). Studies also demonstrate that this deficiency can be compensated by vitamin K2 supplementation to make up dietary shortcomings and thereby increase the activation of K2-dependent proteins required for optimal bone health.
Excess calcium in the body can have detrimental effects on health. It can accumulate in blood vessels and other soft tissues. Hence, proper calcium utilization by the body is not only relevant for bone health but also for cardiovascular health. Vitamin K2 mediates calcium distribution and utilization in the body. K2 activates matrix glaprotein (MGP) by carboxylation to become cMGP which binds free-floating calcium, preventing it from being deposited in arteries. Low blood K2 levels result in higher levels of inactive MGP (dpucMGP, a de-phosphorylated and undercarboxylated form), which is incapable of binding to calcium. This may lead to arterial calcification, a condition resulting from calcium build-up within the vascular smooth muscle cells in tunica media (the middle layer of an artery), reducing the elasticity of the vessel and increasing the risk of cardiovascular events.
Scientific and clinical studies investigating the effect of vitamin K2 MK-7 on cardiovascular health demonstrate a significant reduction in arterial stiffness and slower progression of calcification. High blood levels of nonactivated MGP (dp-ucMGP) correlates with low vitamin K status and vascular calcification. Higher levels of nonactivated MGP have been observed in people aged 65 and older, people at specific risk for vascular calcification, including those with rheumatoid arthritis, aortic valve disease, aortic stenosis, heart failure, chronic kidney disease (CKD), and patients taking vitamin K antagonists. Furthermore, there is an inverse relationship between non-activated MGP and cardiovascular patient survival. In a study of 577 older individuals, non-activated MGP was associated with increased risk of cardiovascular disease, independent of other risk factors and vitamin D status. This effect was attributed to low vitamin K status.
Vitamin K2 supplementation can mitigate these effects by reducing non-activated MGP levels in healthy adults. In a double-blinded, randomized, placebo-controlled clinical trial, arterial stiffness was investigated in 244 healthy postmenopausal women over a period of three years, supplemented with either 180 μg of MK-7 or a placebo. Among the participants with an elevated arterial stiffness at baseline, the stiffness index was significantly improved compared to the placebo group. A beneficial effect of MGP activation was also seen among the participants taking MK-7 which experienced a 50% decrease in circulating dp-ucMGP compared to the placebo group. Vitamin K2 doses from 90 μg and higher improve the carboxylation (thereby activation) of MGP in healthy adults.
Pregnancy is a time when the body ’s demand for calcium is very high. Pregnant women not only undergo substantial skeletal remodeling in preparation for giving birth but also need to account for the fetus’s high demand for calcium for skeletal formation. In extreme cases, this can result in pregnancy-associated osteoporosis, a condition characterized by severe pain in expectant mothers caused by vertebral fractures. As vitamins K2 and D3 are the vital ingredients that regulate calcium distribution and utilization in the body, K2 supplementation can improve bone health during pregnancy and reduce the risk of bone-related pain. Apart from mothers’ health, K2 supplementation may also ensure bone health of infants, even after birth. Skeletal development before birth may set the tone for future bone health.
Studies involving expectant mothers demonstrate the benefits of vitamin K2 supplementation during pregnancy. Vitamin K2 is poorly transported from a mother to unborn child. This can be remedied through K2 supplementation. In a Japanese study, women given 20 mg of vitamin K2 about a week before they gave birth had more K2 in their blood compared to the control group (women who were not given K2). Notably, K2 levels were also elevated in umbilical cord blood, indicating the increased transfer of K2 to the child. As a result, none of the children born to K2-treated mothers showed signs of vitamin K deficiency at birth, compared to 90% of the children whose mothers were not given vitamin K. Interestingly, levels of vitamin K2 in breast milk on the fifth day after birth were significantly higher in women who were given K2 before they gave birth.
The levels of vitamin K in breast milk are typically very low at less than 1 ng/ml. A study showed that infants fed only breast milk during the first six months of life had inadequate vitamin K intake (less than 1 μg/kg/day). The mothers of the infants were getting enough vitamin K (more than 1 μg/kg/day), so the problem seems to be an inadequate transfer of vitamin K from the mother ’s body to her milk. Infants fed a typical supplemented formula were getting approximately 100 times more vitamin K than the breastfed infants, and their circulating vitamin K levels were approximately 20 times higher. Similarly, lactating mothers can also increase the levels of vitamin K2 in their breast milk by taking K2. A study showed increased levels of vitamin K in the breast milk of new mothers who took 5 mg/day of vitamin K1. Additionally, vitamin K levels were also elevated in the blood of their breastfed children. However, it remains unclear whether K2 delivery via breast milk is adequate, so additional supplementation for infants might be required.