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3 reasons to include vitamin K2 in vitamin D supplements

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Vitamins D and K are powerful nutrients in their own right, but their potential effects in combination may be where their real strength is found.

Many people have become familiar with vitamin D’s potential impact on optimal immunity and bone health. However, not everyone is aware of the important role that vitamin K (particularly K2) plays in vitamin D function. Suffice it to say that vitamin K2 helps to unlock the full potential of the “sunshine vitamin.”

Forgotten vitamin, big potential

Vitamin K is an important fat-soluble molecule that comes in two forms—K1 (phylloquinone) and K2 (menaquinone [MK]). It helps to activate and regulate multiple proteins in the body (known as vitamin K-dependent proteins), including those needed for blood clotting, bone metabolism and heart health. For example, prothrombin—a protein directly involved in blood clotting—is vitamin K dependent. Osteocalcin and matrix Gla protein (MGP)—two calcium-binding proteins—also require vitamin K to produce healthy bone tissue. Here, the proteins need to be carboxylated by vitamin K in order to function properly.

Vitamin K2 can be found in small quantities in a variety of food sources, including animal products and fermented foods, like cheese. However, Western diets provide very low amounts of vitamin K2—particularly K2 MK-7, which is the least naturally available form. When circulating concentrations of vitamin K2 are insufficient, a greater proportion of prothrombin, osteocalcin and MGP remain un-carboxylated and therefore inactive; which may increase the risk of cardiovascular disease (CVD), lower bone mass density and osteoporosis.1 This means that supplementation is essential to achieve optimal vitamin K2 status and benefit from its health supporting properties, both alone and in combination with vitamin D3.

The perfect pair

Vitamin D has been in the spotlight in recent years, especially with consumers becoming hyperaware of its possible immune health benefits. Although it is most well-known for its role in immunity and bone health, identification of vitamin D receptors (VDR) in nearly all tissue types throughout the body indicates that the vitamin has diverse and widespread effects on most aspects of human health. Indeed, vitamin D3 initiates several important biological processes in the body by “switching on” genes related to the expression of certain proteins, including osteocalcin and MGP. But as mentioned previously, vitamin K2 is essential for the activation of these proteins, suggesting that it may support the effects of vitamin D.

Several factors suggest that formulating with vitamins D and K2 together may help elicit the full benefits of each vitamin.

1. Vitamins K2, D and immunity

The Covid-19 pandemic has forever transformed consumer attitudes toward health and immunity. Taking a more preventive approach to immune health is top of mind for many. Globally, consumers recognize that optimal nutritional status is important for immunity, especially after periods of infection when the body’s demand for energy, vitamins and minerals increases for recovery. To support their immune health needs, people are therefore increasingly making dietary choices—or choosing nutritional solutions—that bring a range of potential immunity benefits.

Low serum vitamin D levels have been significantly associated with a higher risk of Covid-19 infection.2,3 This has led many consumers to seek and purchase nutritional solutions including this ingredient.

However, in recent years, the scientific community has begun investigating the benefits of vitamin K2 for immune health, both alone and in combination with vitamin D3. This started after a number of studies reported poor vitamin K status in hospitalized adults with Covid-19 infection, leading some research groups to explore the impact of this in patients.4,5 One research group explored the impact of vitamin D and K status on the inflammatory response and clinical outcomes of patients with Covid-19.6 The study found that interleukin (IL)-6 levels were significantly higher in patients with poorer outcomes (indicating a more severe inflammatory response) compared to those with good outcomes. Desphospho-un-carboxylated MGP (dp-ucMGP) levels—a biomarker of vitamin K status—were associated with IL-6 levels. This suggests a correlation between vitamin K deficiency and higher IL-6 levels, and means vitamin K status was linked to the severity of Covid-19 infection. Another study confirmed that lower vitamin K status correlated with worse COVID-19 infection and predicted mortality in patients with the infection.7 Thus, vitamin K supplementation, alone or in combination with vitamin D, may improve the clinical outcomes of Covid-19.

It’s also important to understand the effects of vitamin D and K2 in the regulation of calcium metabolism and the potential negative effects of high vitamin D supplementation if vitamin K2 levels are insufficient. A higher vitamin D status indicates increased absorption of calcium. While this mineral plays an important role in the body, vitamin K2 is necessary for the regulation of calcium—where it prevents it from being deposited in soft tissues, like arteries or lungs, and directs it to where it is really needed … the bones.

Supplementation with high doses of vitamin D3 to support individuals against the impact of Covid-19 could therefore have a negative impact on patients if they are deficient in vitamin K2. One study investigating this theory concluded there is an interplay between vitamins D and K at the time of acute Covid-19 infection, where they work synergistically to help protect against calcification and damage in the lungs.8 Here, vitamin D promotes MGP synthesis, but vitamin K is critical for the activation of MGP. Without this action, accumulation of calcium on elastic fibers may result in higher risk of elastic fiber damage in the lungs. Optimizing vitamin D and K2 status before acute infection may therefore help to regulate overwhelming calcification and inflammation, which may subsequently improve clinical outcomes.

2. Heart health benefits

The role of vitamin K2 in cardiovascular health has mostly been studied in isolation.9 However, evidence also hints at a synergistic effect of vitamin K2 combined with vitamin D for heart health.10-13 Animal and human studies suggest that optimal concentrations of both vitamin D and K2 are beneficial for cardiovascular health because they help to reduce the amount of “free” calcium in the bloodstream. Indeed, one review highlighted that vitamin D and calcium supplementation, alongside vitamin K2 deficiency, can induce long-term cardiovascular disease—highlighting an important potential interplay between vitamin D and K2.9 Another study found that rats exposed to high doses of vitamin D without the addition of sufficient vitamin K2 exhibited higher levels of arterial calcification, significantly increasing mortality rate.14 This suggests vitamin D alone is not able to prevent harmful levels of arterial calcification. Similar to the effects of vitamin D on calcification in the lungs (discussed above), this is the result of MGP not being activated by vitamin K2, leading to a build-up of calcium in the arteries. Whereas when K2 is supplemented, MGP is carboxylated, effectively binding to calcium in the vascular system and decreasing the risk of vascular mineralization.10

3. Stronger bones

The bone matrix contains cells called osteoclasts and osteoblasts that are responsible for breaking down and building up bone in an ongoing remodeling process. Osteoblasts secrete osteocalcin into the blood which, when activated by vitamin K2, binds to calcium and transports it from the blood and into the bones.

Because vitamin D3 only promotes the expression of osteocalcin in its inactive or un-carboxylated form, this means the body is unable to effectively regulate the integration of calcium into the bones without vitamin K2. An adequate intake of vitamin K2 ensures the effective carboxylation of osteocalcin, in turn helping the body to bind calcium to bones while keeping levels in the bloodstream at the right quantity to avoid vascular calcification. If adequate vitamin K2 intake is not achieved, this can lead to diminished bone mass, higher fracture risk and the calcification of arteries and other soft tissues—similar to the effects of the natural aging process.15

Research has shown that vitamin K2 enhances vitamin D3-mediated osteocalcin production and accumulation, and the effects of vitamin D3 and K2 on bone mass density are better when used in combination.16 This illustrates that the perfect pair help to increase bone strength and density together, suggesting that supplementation with both vitamins could help to reduce the risk of fractures and bone loss in older adults and support the development of strong bone health in children.

Next-gen vitamin K2

Among all of the K vitamins, vitamin K2 MK-7 exhibits the best bioavailability and longest half-life, with a half-life of 72 hours compared to two hours observed with K1. Due to its quick uptake and long half-life, K2 MK-7 reaches bones and vessel walls more easily, resulting in more effective activation of proteins, like osteocalcin. With this in mind, K2 MK-7 is often considered the most effective form of vitamin K, widely used in dietary supplement developments.

Yet some supplements containing cis MK-7 are still available on the market, despite it being considered biologically inactive and therefore potentially ineffective. Due to the shape of the molecule, cis MK-7 cannot bind to the sites of enzymes, meaning the vitamin K-dependent proteins remain inactivated. On the other hand, all-trans MK-7 is bioactive, therefore it is important for supplements to include the highest possible percentage of this form of vitamin to achieve the desired health benefits.

Lena Leder, Ph.D., is the science and content manager at Kappa Bioscience AS. She obtained her doctorate in nutrition from the University of Oslo in Norway and is a board member of the Norwegian Nutrition Society. Passionate about nutrition, health and R&D, Leder has broad experience from academia and the food industry with a special focus on healthy dietary patterns and fat quality in the diet, inflammation and other cardiovascular risk factors in dietary intervention studies.

References

1 Lanham-New SA. “Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment.” Proc Nutr Soc. 2008;67:163-176.

2 Oristrell J et al. “Vitamin D supplementation and COVID-19 risk: a population-based, cohort study.” J Endocrinol Invest. 2022;45:167-179.

3 Teshome A et al. “The Impact of Vitamin D Level on COVID-19 Infection: Systematic Review and Meta-Analysis.” Front Public Health. 2021;9:624559.

4 Anastasi E et al. “Vitamin K deficiency and COVID-19.” Scand J Clin Lab Invest. 2020;80:525-527.

5 Dofferhoff ASM et al. “Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19.” Clin Infect Dis. 2020;73:e4039-e4046.

6 Visser MPJ et al. “Effects of vitamin D and K on interleukin-6 in COVID-19.” Front Nutr. 2022.

7 Linneberg A et al. “The Association of Low Vitamin K Status with Mortality in a Cohort of 138 Hospitalized Patients with COVID-19.” Nutrients. 2021;13:1985.

8 Desai AP et al. “Vitamin K & D deficiencies are independently associated with COVID-19 disease severity.” Open Forum Infect Dis. 2021;8:ofab408.

9 Ballegooijen AJ van and Beulens JW. “The role of vitamin K status in cardiovascular health: evidence from observational and clinical studies.” Curr Nutr Rep. 2017;6:1-9.

10 Fu X et al. “9-cis retinoic acid reduces 1alpha,25-dihydroxycholecalciferol-induced renal calcification by altering vitamin K-dependent gamma-carboxylation of matrix gamma-carboxyglutamic acid protein in A/J male mice.” J Nutr. 2008;138:2337-2341.

11 Miyake N et al. “1,25-Dihydroxyvitamin D3 promotes vitamin K2 metabolism in human osteoblasts.” Osteoporos Int. 2001;12:680-687.

12 Arbour NC et al. “Transcriptional control of the osteocalcin gene by 1,25-dihydroxyvitamin D-2 and its 24-epimer in rat osteosarcoma cells.” Biochim Biophys Acta. 1995;1263:147-153.

13 Seyama Y et al. “Effect of vitamin K2 on experimental calcinosis induced by vitamin D2 in rat soft tissue.” Int J Vitam Nutr Res. 1996;66:36-38.

14 Price PA et al. “Warfarin-Induced Artery Calcification is Accelerated by Growth and Vitamin D.” Arterioscler Thromb and Vasc Biol. 2000;20:317-327.

15 Shearer MJ. “The Roles of Vitamins D and K in Bone Health and Osteoporosis Prevention.” Proc Nutr Soc. 1997;56:915-937.

16 Kuang X et al. “The Combination Effect of Vitamin K and Vitamin D on Human Bone Quality: A Meta-Analysis of Randomized Controlled Trials.” Food Funct. 2020;11:3280-3297.

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