Vitamin K1 & K2 as MK-7 and MK-4: Differences and Applications

by Dr. Gene Bruno, DBM, MS,RH(AHG), The Vitamin Professor | November 1, 2024

Vitamin K, particularly vitamin K2, represents a significant segment of the vitamin market. In fact, the global vitamin K2 market size was estimated at $421.1 million in 2023 and is projected to grow at a CAGR of 10.8 percent from 2024 to 2030.1 Certainly, vitamin K2 as menaquinone-7 (MK-7) has been recognized for its role in bone health and cardiovascular health, and to a lesser extent MK-4 has also been recognized for its role in bone health. However, MK-7 has other benefits beyond bone and cardiovascular health, and vitamin K1 also has meaningful benefits to offer regarding cardiovascular health. This article reviews the differences between and the applications for vitamin K1 and K2 as MK-7 and MK-4. Let’s start with a little background.

Background

Discovered in 1929, vitamin K was originally identified for its role as a blood-clotting (coagulation) cofactor.2 In the 1970s, vitamin K-dependent proteins (VKDPs) were discovered, which led to a more comprehensive understanding of vitamin K’s role with respect to bone and cardiovascular health.3

Additionally, two forms of this fat-soluble vitamin exist: vitamin K1 and K2. Plants synthesize phylloquinone (aka, vitamin K1), and intestinal microbiota and fermentation of some foods synthesize a range of K2 forms collectively referred to as menaquinones (e.g., MK-4 and MK-7).4 The menaquinones have a number designation according to the number of repeating 5-carbon units in its side chain. For example, if there are seven repeating 5-carbon units, the designation will be MK-7.5

The Cardiovascular Benefits of Vitamin K2 as MK-7

In 2016, I wrote an article for Vitamin Retailer6 discussing research which my co-author and I previously published in a scientific journal.7 The research showed that the primary way in which vitamin K acts to promote cardiovascular health is by inhibiting calcification in the arteries, which would otherwise lead to atherosclerosis. Specifically, some of the 17 VKDPs have been identified to date act as calcification inhibitors. These include osteocalcin (OC), also known as bone Gla protein (synthesized by osteoblasts), and matrix Gla protein (MGP, found in cartilage, bone and soft tissue, including blood vessel walls). These proteins are local inhibitors of calcification in the tissues in which they exert their function. Here’s how it works.

Carboxylation is a process in which a carboxylic acid group is reacted with a substance such as a protein—and carboxylation is necessary for the formation of critical VKDPs that have a positive impact on arterial stiffness and bone strength. Since 10 to 40 percent of VKDPs remain undercarboxylated, research was conducting showing that the MK-7 form of vitamin K2 was effective in increasing the carboxylation of VKDPs.8

In the research, we also discussed the population-based Rotterdam study,9 which included 4,807 subjects, and which provided the first evidence for a link between vitamin K and vascular health. The results showed the relative risk of coronary heart disease mortality and calcification of the aorta (an artery in the heart) was reduced in those with high intakes of vitamin K2, compared to those with a lower intake. Another study10 with 564 post-menopausal also showed a decreased risk of coronary calcification with higher intakes of vitamin K2.

Even more meaningful was a three year, double-blind, placebo-controlled trial11 in which 248 postmenopausal women received 180 mcg/day of MK-7 or a placebo for three years to examine the effect on arterial stiffness (i.e., caused by calcification). The results were that supplementation with MK-7 significantly decreased measures of aortic stiffness and improved undercarboxylated VKDPs by 50 percent.

The Bone Health Benefits of Vitamin K2 as MK-7 & MK-4

In another three-year, double-blind, placebo-controlled trial,12 244 healthy postmenopausal women also received 180 mcg/day of MK-7 or a placebo for three years, this time to examine indicators of bone health. The results were that MK-7 decreased age-related decline in bone mineral content and bone mineral density, and favorably affected bone strength and decreased loss in vertebral height. Also, postmenopausal women with osteopenia (bone softening) also demonstrated a preservation of bone structure with 375 mcg/day MK-7.13

It is important to understand that MK-4 also has significant research to support its role in bone health. In fact, it could be argued that it has more research for this purpose than MK-7. It should also be noted that the doses used of MK-4 are higher (although safe) than MK-7. For example, in one randomized, double-blind, placebo-controlled trial,14 1.5 mg/day of MK-4 for 6-12 months in postmenopausal women improved carboxylation of VKDPs and helped maintain bone mineral density. Similar results were seen in another study15 with 600 mcg/MK-4. When 5 mg/day MK-4 was used there was a significant improvement in carboxylation of VKDPs, with no additional benefit compared to 45 m/day MK-4.16

This is particularly meaningful since there are seven randomized controlled trials17-23 demonstrating that 45 mg/day of MK-4 improved carboxylation of VKDPs and bone mineral density and reduced the incidence of fracture in osteoporosis patients. Likewise, there are seven human studies24-30 demonstrating that 45 mg/day of MK-4 improved bone quality in various population types.

Additional Benefits for MK-7

In addition to its cardiovascular and bone health benefits, MK-7 has also demonstrated benefits for muscle cramps, polycystic ovary syndrome, rheumatoid arthritis and glucose/insulin modulation.

• Muscle cramps: A randomized, placebo-controlled clinical trial31 found that 360 mcg/day MK-7 reduced the frequency, duration and severity of muscle cramps in 39 hemodialysis patients.

• Polycystic ovary syndrome (PCOS): A randomized, double-blind, placebo-controlled clinical trial32 found that 90 mcg/day MK-7 significantly decreased serum fasting insulin, insulin resistance, serum triglyceride, dihydrotestosterone levels, free androgen index, waist circumference and body fat mass, as well as significantly increasing skeletal muscle and sex hormone binding globulin in PCOS patients. It also improved depression status.33

• Rheumatoid arthritis (RA): A randomized, cross-sectional, clinical study34 found that 100 mcg/day MK-7 added to normal therapeutic regimen decreased erythrocyte sedimentation rate (which are increased in RA), disease activity score assessing 28 joints, C-reactive protein (CRP, an inflammation marker), and matrix metalloproteinase (a tissue damage marker) in rheumatoid arthritis patients.

• Glucose/insulin modulation: A double-blinded, placebo-controlled, randomized trial35 found that 360 mcg/day MK-7 lowered fasting plasma glucose, glycated hemoglobin in patients with type-2 diabetes.

Cardiovascular Benefits for Vitamin K1

As stated at the beginning of this article, vitamin K1 also has meaningful benefits to offer regarding cardiovascular health—specifically with regard to arterial calcification:

• Hypertension medication users: A study36 of 296 participants with extreme coronary artery calcium (CAC) progression and 561 randomly selected participants without extreme CAC progression found that hypertension medication users with low serum vitamin K1 were more likely to have extreme CAC progression than were medication users without extreme CAC progression.

• Preexisting coronary artery calcification: A double-blind trial of 388 healthy men and postmenopausal women with preexisting coronary artery calcification found that those receiving a multivitamin with 500 mcg/day vitamin K1 had 6 percent less progression of CAC than did those who received the multivitamin alone.37

• Aortic and coronary artery calcification: A double-blind, randomized, placebo-controlled trial38 found that 10 mg/day vitamin K1 study helped prevent the development of newly calcifying lesions within the aorta and the coronary arteries in diabetic patients.

• Lower risk of cardiovascular complications: A population study39 found that middle-aged subjects with no history of atherosclerotic cardiovascular disease who had the highest intake of dietary vitamin K1 intake (162–800 mcg) had a 21 percent lower risk of CVD-related hospitalization and complications over 17-22 years when compared to those with the lowest intake (73–101 mcg).

Available Forms of Vitamin K & Complementary/Synergistic Considerations

Vitamin K2 as MK-7 is available in synthetic form, as well as in both natto (soy) and chickpea-derived forms for those who prefer a soy-free option (e.g., K2Go by Nutraland USA). Vitamin K2 as MK-4 is only available in synthetic form. Vitamin K1 is available in synthetic form and as a natural alfalfa-derived form (from Nutraland USA).

Consider that there are complementary advantages to concurrent use of the various forms of vitamin K. For example, if the goal is to support cardiovascular health, a combination of vitamin K1 and vitamin K2 as MK-7 has advantages. If the goal is to support bone health, then a combination of vitamin K2 as both MK-7 and MK-4 is a good choice.

In addition, there is a synergistic relationship between vitamin K and vitamin D. In a study40 conducted with chronic kidney disease patients, artery thickness of the carotid intima-media was significantly lower in those receiving vitamin K2 as MK-7 and vitamin D3 compared to D3 alone. A two-year randomized study41 found that the combined administration of vitamin D3 and vitamin K2 (as MK-4), was effective in increasing the bone mineral density in postmenopausal women with osteoporosis. Another study42 in women with estrogen deficiency found that MK-4 combined with vitamin D3 partially prevented bone loss caused by estrogen deficiency.

Conclusion

Three commercially viable forms of vitamin K include K1, K2 as MK-7 and K2 as MK-4. Each form has its own distinct advantages. Research has demonstrated the cardiovascular benefits of K1 and K2 as MK-7, while other research has demonstrated the benefits of MK-7 and MK-4 for bone health. Additionally, research has demonstrated that MK-7 also has benefits for muscle cramps, polycystic ovary syndrome, rheumatoid arthritis and glucose/insulin modulation. These various forms of vitamin K may be used together and/or in combination with vitamin D3 to maximize complementary/synergistic effects.

References

1 Vitamin K2 Market Size & Trends. Grand View Research. Retrieved July 23, 2024, from www.grandviewresearch.com/industry-analysis/vitamin-k2-market-report#:~:text=Vitamin%20K2%20Market%20Size%20%26%20Trends,10.8%25%20from%202024%20to%202030.

2 Food and Nutrition Board, Institute of Medicine: Vitamin K, Chapter 5, in Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academy Press, Washington, District of Columbia, USA (2001).

3 Ferland, G. “The discovery of vitamin K and its clinical applications,” Ann. Nutr. Metab., 61(3), 213-218 (2012).

4 Shearer, M.J. “Vitamin K”, Lancet, 345(8944), 229-234 (1995).

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6 Bruno G. New Research on Vitamin K2. Vitamin Retailer. May 2016: 38-39.

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8 Bruno G. New Research on Vitamin K2. Vitamin Retailer. May 2016: 38-39.

9 Geleijnse, J.M., Vermeer, C., Grobbee, D.E., et al. “Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study,” J. Nutr., 134, 3100-3105 (2004).

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11 Knapen MH, Braam LA, Drummen NE, Bekers O, Hoeks AP, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Thromb Haemost. 2015;113(5):1135-1144.

12 Knapen MH, Drummen NE, Smit E, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013;24(9):2499-2507.

13 Rønn SH, Harsløf T, Pedersen SB, Langdahl BL. Vitamin K2 (menaquinone-7) prevents age-related deterioration of trabecular bone microarchitecture at the tibia in postmenopausal women. Eur J Endocrinol. 2016 Dec;175(6):541-549.

14 Koitaya N, Sekiguchi M, Tousen Y, Nishide Y, Morita A, Yamauchi J, Gando Y, Miyachi M, Aoki M, Komatsu M, Watanabe F, Morishita K, Ishimi Y. Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. J Bone Miner Metab. 2014 Mar;32(2):142-50.

15 Nakamura E, Aoki M, Watanabe F, Kamimura A. Low-dose menaquinone-4 improves γ-carboxylation of osteocalcin in young males: a non-placebo-controlled dose-response study. Nutr J. 2014 Aug 27;13:85.

16 Giri TK, Newton D, Chaudhary O, Deych E, Napoli N, Villareal R, Diemer K, Milligan PE, Gage FB. Maximal dose-response of vitamin-K2 (menaquinone-4) on undercarboxylated osteocalcin in women with osteoporosis. Int J Vitam Nutr Res. 2020 Jan;90(1-2):42-48.

17 Iwamoto J. Vitamin K2 Therapy for Postmenopausal Osteoporosis. Nutrients. 2014; 6(5):1971-1980.

18 Su S, He N, Men P, Song C, Zhai S. The efficacy and safety of menatetrenone in the management of osteoporosis: a systematic review and meta-analysis of randomized controlled trials. Osteoporos Int. 2019 Jun;30(6):1175-1186.

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20 Purwosunu Y, Muharram, Rachman IA, Reksoprodjo S, Sekizawa A. Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia. J Obstet Gynaecol Res. 2006 Apr;32(2):230-4.

21 Miki T, Nakatsuka K, Naka H, Kitatani K, Saito S, Masaki H, Tomiyoshi Y, Morii H, Nishizawa Y. Vitamin K(2) (menaquinone 4) reduces serum undercarboxylated osteocalcin level as early as 2 weeks in elderly women with established osteoporosis. J Bone Miner Metab. 2003;21(3):161-5.

22 Shiraki M, Shiraki Y, Aoki C, Miura M. Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res. 2000 Mar;15(3):515-21.

23 Iwamoto J, Takeda T, Ichimura S. Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J Orthop Sci. 2000;5(6):546-51.

24 Je SH, Joo NS, Choi BH, Kim KM, Kim BT, Park SB, Cho DY, Kim KN, Lee DJ. Vitamin K supplement along with vitamin D and calcium reduced serum concentration of undercarboxylated osteocalcin while increasing bone mineral density in Korean postmenopausal women over 60-years-old. J Korean Med Sci. 2011 Aug;26(8):1093-8.

25 Ochiai M, Nakashima A, Takasugi N, Kiribayashi K, Kawai T, Usui K, Shigemoto K, Hamaguchi N, Kohno N, Yorioka N. Vitamin K2 alters bone metabolism markers in hemodialysis patients with a low serum parathyroid hormone level. Nephron Clin Pract. 2011;117(1):c15-9.

26 Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007 Jul;18(7):963-72.

27 Bunyaratavej N, Penkitti P, Kittimanon N, Boonsangsom P, Bonjongsat A, Yunoi S. Efficacy and safety of Menatetrenone-4 postmenopausal Thai women. J Med Assoc Thai. 2001 Oct;84 Suppl 2:S553-9.

28 Plaza SM, Lamson DW. Vitamin K2 in bone metabolism and osteoporosis. A/tern Med Rev 2005;10:24-35.

29 Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int 2007;18:963-972.

30 Somekawa Y, Chigughi M, Harada M, Ishibashi T. Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide. J Clin Endocrinol Metab. 1999 Aug;84(8):2700-4.

31 Xu D, Yang A, Ren R, Shan Z, Li YM, Tan J. Vitamin K2 as a potential therapeutic candidate for the prevention of muscle cramps in hemodialysis patients: A prospective multicenter, randomized, controlled, crossover pilot trial. Nutrition. 2022 May;97:111608.

32 Tarkesh F, Namavar Jahromi B, Hejazi N, Tabatabaee H. Beneficial health effects of Menaquinone-7 on body composition, glycemic indices, lipid profile, and endocrine markers in polycystic ovary syndrome patients. Food Sci Nutr. 2020 Sep 4;8(10):5612-5621.

33 Tarkesh F, Namavar Jahromi B, Hejazi N, Hoseini G. Effect of vitamin K2 administration on depression status in patients with polycystic ovary syndrome: a randomized clinical trial. BMC Womens Health. 2022 Jul 26;22(1):315.

34 Abdel-Rahman MS, Alkady EA, Ahmed S. Menaquinone-7 as a novel pharmacological therapy in the treatment of rheumatoid arthritis: A clinical study. Eur J Pharmacol. 2015 Aug 15;761:273-8.

35 Rahimi Sakak F, Moslehi N, Niroomand M, Mirmiran P. Glycemic control improvement in individuals with type 2 diabetes with vitamin K2 supplementation: a randomized controlled trial. Eur J Nutr. 2021 Aug;60(5):2495-2506.

36 Shea MK, Booth SL, Miller ME, Burke GL, Chen H, Cushman M, Tracy RP, Kritchevsky SB. Association between circulating vitamin K1 and coronary calcium progression in community-dwelling adults: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr. 2013 Jul;98(1):197-208.

37 Shea MK, O’Donnell CJ, Hoffmann U, et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr 2009;89:1799-807.

38 Bellinge JW, Francis RJ, Lee SC, Bondonno NP, Sim M, Lewis JR, Watts GF, Schultz CJ. The effect of vitamin K1 on arterial calcification activity in subjects with diabetes mellitus: a post hoc analysis of a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2022 Jan 11;115(1):45-52.

39 Bellinge JW, Dalgaard F, Murray K, et al. Vitamin K intake and atherosclerotic cardiovascular disease in the Danish Diet Cancer and Health Study. J Am Heart Assoc. 2021;10(16):e020551.

40 Kurnatowska I., Grzelak P., Masajtis-Zagajewska A., et al. Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3-5. Polskie Archiwum Medycyny Wewnętrznej. 2015;125:631–640.

41 Iwamoto J, Takeda T, Ichimura S. Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J Orthop Sci. 2000;5(6):546-51.

42 Somekawa Y, Chigughi M, Harada M, Ishibashi T. Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide. J Clin Endocrinol Metab. 1999 Aug;84(8):2700-4.

Gene Bruno, MS, MHS, Professor Emeritus of Nutra-ceutical Science, is writer, educator and a nutraceutical scientist with more than 45 years of experience educating natural product retailers and health care professionals and formulating natural products for dozens of dietary supplement companies. He has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. Bruno also hosts “The Vitamin Professor Podcast” brought to you by VRM Media. He can be reached at [email protected].