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Why vitamin K2 could be the missing link for bone health strategies.
The bone-health benefits of vitamin D and calcium and are clear. Numerous studies suggest that vitamin D and calcium increase bone mineral density and decrease the risk of fracture in people over age 65. Vitamin D increases calcium absorption. Calcium is the most abundant mineral in bone-making up approximately 33% of bone mineral content-and it is the most abundant mineral in the body. The essentiality of calcium stretches to muscle function, neuron health, blood clotting, and its role as a cofactor for a multitude of enzymes.
However, this may not paint the whole picture for calcium. Some researchers have suggested that high calcium intake may lead to increased heart risk.
Mark Bolland and colleagues conducted a meta-analysis of several placebo-controlled trials of calcium or calcium and vitamin D intake (British Medical Journal, 2011) and concluded that calcium supplements, with or without vitamin D, increased the risk of heart events-especially myocardial infarction. A prospective study involving 388,229 men and women aged 50 to 71 from the National Institutes of Health-AARP Diet and Health Study (JAMA Internal Medicine, 2013) suggested that high intake of calcium was associated with increased risk of cardiovascular disease-related death in men, but not in women. Another analysis, looking at data from the third National Health and Nutrition Examination Survey (NHANES III) (PLoS One, 2013), found that women with serum calcium levels in the top 5% of the study had significantly increased risk of death from ischemic heart disease, whereas no such association was found for men.
Still, other studies, such as one conducted by Elizabeth Samelson and colleagues from Harvard Medical School, indicate no increased risk of arterial calcification with increased calcium intakes (American Journal of Clinical Nutrition, 2012). While it still remains controversial as to why high levels of calcium may be linked to these effects, it certainly raises potential concerns.
What is known about calcium and heart health is that in individuals with atherosclerosis, a form of hardening of the arteries, circulating calcium encourages the formation of arterial plaque. Researchers have also identified an association between osteoporosis and heart disease risk factors, particularly vascular calcification. This is commonly regarded as the “calcification paradox” (Trends in Molecular Medicine, 2009).
Individuals experiencing the calcification paradox appear to have calcium deficiency in their bones and calcium excess in their blood vessels. What can explain this? It seems that, in these individuals, calcium has a difficult time entering bone tissue (where it belongs) and, thus, stays in circulation (where it’s not needed in such amounts). There is a deficit in calcium transport. The missing link–and a possible explanation for why high calcium levels can contribute to heart risk–may be a deficiency of vitamin K, especially vitamin K2.
Vitamin K comes in two naturally occurring forms: K1, is the form made by plants, and K2 is generally derived from microbial sources, animal products, and natural production in the human gut. K2 forms are generally known as menaquinones.
Research suggests that longer-chain forms of vitamin K2 (menaquinones such as MK-7, 8 and 9; the number designations refer to the number of isoprenoid units on the molecule) may be the preferred forms because they have longer half-lives and are active in circulation for greater periods of time. Despite the fact that the majority of vitamin K intake is in the form of K1, the biological half-life of K1 is typically only 1-1.5 hours, whereas the half-life of MK-7, for example, is in the range of several days.
Most vitamin K1 is retained in the liver and used for synthesis of clotting factors. The menaquinones (K2), on the other hand, are incorporated into lipoproteins and set free into circulation (Food and Nutrition Research, 2012). Menaquinones can, thus, perform another function of vitamin K: they can mediate the body’s calcium homeostasis and transport. They do this by interacting with two proteins: osteocalcin and matrix Gla protein.
Osteocalcin and matrix Gla protein are calcium-binding proteins that are present in blood circulation. Research has found that circulating osteocalcin is a measure of bone formation (Nature Reviews Endocrinology, 2013), as this protein takes calcium out of circulation and delivers it to the bone matrix. Osteocalcin is regulated by activated vitamin D.
Matrix Gla protein is found in bone, cartilage, and soft tissue such as blood vessels. Investigations in animals have found that matrix Gla protein reduces the calcification of cartilage and soft tissue while playing a significant role in bone development. According to Ellen Cranenburg’s group at the CARIM School for Cardiovascular Diseases in the Netherlands, inactivated or “uncarboxylated” circulating matrix Gla protein serves as a biomarker for arterial calcification (Journal of Vascular Research, 2008).
In order for osteocalcin and matrix Gla protein to support calcium transport, they need to be activated or “carboxylated,” and vitamin K is essential for the carboxylation process. When human dietary intake of vitamin K is less than optimal, this leads to chronic undercarboxylation of both proteins. According to Sarah Booth and Ala Al Rajabi of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, investigations in humans suggest that up to 50% of osteocalcin is uncarboxylated in normal individuals, which is a reflection of insufficient vitamin K intake in the human diet (Vitamins & Hormones, 2008). This can lead to detrimental effects on bone health, as calcium doesn’t reach the bones in adequate amounts, while also leaving large amounts of calcium in circulation for potential deposits in the blood vessels, contributing to vascular stiffness and heart disease.
The landmark research piquing the interest of the vitamin K research community is likely the analysis of data from a population-based study known as the Rotterdam Study. Conducted by Johanna Geleijnse’s group from the Erasmus Medical Center in Rotterdam (the Netherlands), the researchers examined whether dietary intake of vitamin K1 (phylloquinone) and K2 (menaquinone) were related to aortic calcification and coronary heart disease (The Journal of Nutrition, 2004). The analysis revealed significant associations between higher dietary menaquinone intake and reductions in mortality from heart disease, all-cause mortality, and severe aortic calcification. No similar protective effects were evident with the intake of vitamin K1. The researchers concluded that menaquinone intake may be important for a reduced risk of coronary heart disease, likely because of its effect against vascular calcification.
Gerrie-Cor Gast and colleagues, also from the Netherlands, investigated the association between menaquinone intake and coronary heart disease using data from the Prospect-EPIC cohort, consisting of over 16,000 women aged 49 to 70 (Nutrition, Metabolism & Cardiovascular Diseases, 2009). They confirmed protective benefits associated with high intake of menaquinones, and found that longer-chain forms such as MK-7, MK-8, and MK-9 had the most beneficial effects, with each daily increase of 10 mcg providing a 9% risk reduction in mortality.
Since a primary mechanism of vitamin K2 is to carboxylate matrix Gla protein (the protein that serves as a biomarker for vascular calcification) researchers have continued to evaluate plasma levels of dephosphorylated uncarboxylated matrix Gla protein and its association with various patient populations suffering with chronic conditions. Leon Schurgers and colleagues in the Netherlands and France looked at plasma levels of uncarboxylated matrix Gla protein in patients suffering with various stages of chronic kidney diseases (Clinical Journal of the American Society of Nephrology, 2010). Their results showed that levels increased progressively with severity of kidney disease, and were positively associated with the aortic calcification score.
In another investigation Thor Ueland and colleagues from Norway and the Netherlands assessed this same biomarker in patients with aortic stenosis (a form of decreased blood flow to the heart) and found significantly increased circulating levels of this matrix Gla protein compared to healthy controls (Journal of Internal Medicine, 2010). This result suggests that increases in uncarboxylated matrix Gla protein play a role in decreased heart function in this population. Data from these studies, along with what is known about vitamin K2 action on MGP, support the idea that higher menaquinone intake can be protective against heart disease.
Menaquinones activate osteocalcin, which facilitates the delivery of calcium from blood circulation to bone tissue; but, this may not be menaquinone’s only benefit to bone health. Emory University’s Masayoshi Yamaguchi, PhD, and M. Neale Weitzmann, PhD, recently identified a unique dual mechanism whereby menaquinones facilitate both pro-anabolic and anti-catabolic effects on bone cells (International Journal of Molecular Medicine, 2010). They discovered that menaquinones suppress the activation of NF-kB, a signaling molecule that mediates the inflammatory process. By suppressing this molecule, menaquinones can stimulate the production of osteoblasts (cells that build bone tissue) while suppressing the production of osteoclasts (cells that break down bone tissue). This evidence furthers the potential benefits of menaquinone intake on bone health and highlights the multifaceted actions of K2 on the skeletal system.
These benefits are emphasized when looking at the results of human intervention trials on vitamin K2. In a recently published three-year trial, Martinus Knapen and colleagues from Maastricht University in the Netherlands assessed the benefits of supplementation with menaquinone MK-7 on maintenance of bone mineral density and bone strength in healthy postmenopausal women (Osteoporosis International, 2013). Women received MK-7 (180 mcg/day) or a daily placebo for three years. The researchers found that MK-7 supplementation significantly decreased the age-related decline in bone mineral content and bone mineral density assessed at the lumbar spine and neck of the femur, while also increasing bone strength. Furthermore, MK-7 supplementation was significantly associated with less loss of vertebral height in the mid-back region. These findings suggest that MK-7 significantly impacts bone density and strength in postmenopausal women.
The menaquinone MK-4 (a shorter-chain form of vitamin K2 with four isoprenoid units on the molecule’s side chain, as opposed to MK-7 , which has seven isoprenoid units) has been previously studied for its ability to support bone health in high doses, generally 45 mg per day. In Japan, this is used as an approved treatment for osteoporosis. A recent study by Noriko Koitaya and colleagues from the National Institute of Health and Nutrition in Tokyo set out to explore whether a much lower dose of MK-4 (1.5 mg/day) would have similar benefits for bone health (Journal of Bone and Mineral Metabolism, 2013). The study included post-menopausal women aged 50 to 65. They were divided into a placebo and treatment arm and treated for 12 months. Serum uncarboxylated osteocalcin concentrations were assessed at baseline and found to be elevated in both groups. At both 6 and 12 months, the serum uncarboxylated osteocalcin concentrations were significantly lower in the MK-4 group compared to placebo. After 12 months, the placebo group showed a significant loss of bone mineral density in the forearm compared to the six-month assessment; however, the group supplementing with MK-4 showed no significant decrease in bone mineral density, suggesting that even a low dose of long-term MK-4 is beneficial.
A common perception is that excessive intake of menaquinones (and vitamin K, in general) may excessively interfere with the clotting process. While it’s true that vitamin K is an essential nutrient for production of clotting factors, it doesn’t seem that excessive vitamin K causes the clotting system to become overactive. Once the clotting factors are fully carboxylated with vitamin K, the excess vitamin K is then available for other functions throughout the body; thus, no increased risk of clot formation is expected. Cees Vermeer of Maastricht University states that thousands of patients taking high-dose vitamin K2 for several years have been closely monitored in his institute, using highly sensitive techniques designed to assess increased risk of thrombus formation. No such clotting tendencies were found (Food and Nutrition Research, 2012). The obvious exception is in those patients on blood thinners, since the common anticoagulants thin the blood by functioning as vitamin K-antagonists. Apart from individuals on these medications, menaquinone intake and supplementation is unlikely to be of concern.
Calcium and vitamin D are both essential for optimal health. Calcium is the most abundant mineral in the body and vitamin D’s myriad benefits continue to be uncovered. Vitamin D serves to increase calcium absorption from the intestines. Once calcium is in circulation, vitamin K is needed to transport it from the bloodstream and blood vessels and into bone tissue, where most of it belongs. Activated vitamin D regulates the production of osteocalcin in osteoblasts, while the menaquinones are responsible for activating osteocalcin to perform its calcium-transport function. Without vitamin K, the calcium train stops, causing an excess of calcium in circulation and a deficiency in the bones. The menaquinones are the engines that make the calcium train go. Given the high prevalence of subclinical vitamin K2 deficiency and the low dietary prevalence of this vitamin, supplementing with additional K2 completes the cycle, allowing calcium and vitamin D to do their duty. Vitamin K2 may just be the master key that unlocks the “calcification paradox.”