ProsStay and Vitamin K2

Q. Dear Dr. Dean,

In view of the importance of the 100:1 ratio of Vitamin C:Vitamin K3 to the efficacy of ProsStay, can you please tell me if the efficacy would be reduced by additional vitamin K2 supplementation (for improved calcium metabolism)?

In other words, if I was taking a separate K2 supplement, at staggered intervals from ProsStay, could that disrupt the 100:1 efficacy ratio of ProsStay?

Does K2 convert in the body to K3?

Ken McRae

A. Dear Mr. McRae,

Figure 1. Structures of Vitamin K1, K2 (MK4 and MK7), and K3.
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That’s a good question. For others who may not be familiar with Vitamin K and its physiological role, here’s a brief overview.

Vitamin K was discovered in 1929 in Denmark, and received its name from the German word for coagulation—koagulation. It has traditionally been considered to be the “coagulation vitamin,” as it is an integral part of the coagulation cascade in the blood that prevents us from bleeding to death from minor cuts and scratches. It also helps to form intravascular emboli and thromboses that cause heart attacks and strokes.

Research over the past 35 years demonstrates that Vitamin K consists of a number of forms that have multiple effects in the body. The three principle forms of Vitamin K used as supplements include the best-known Vitamin K1 (phylloquinone); Vitamin K2 (menaquinone—actually, a series of “long-chain” menaquinones, the most popular of which are MK-4 and MK-7); and Vitamin K3 (menadione) (Fig. 1).

Figure 2. Sources of Vitamin K.
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Vitamin K1 is formed by plants (green leafy vegetables), and is the principle dietary source of Vitamin K. The MK-4 form of Vitamin K2 is formed in the body in small amounts by conversion of K1; the principle source of MK-7 is from natto, a fermented soy product popular in Japan; Vitamin K3 (menadione)—the “backbone” of vitamin K—was formerly believed to be synthetic, but has recently been found to be a catabolic intermediate in the conversion of K1 into K2 (MK-4).1 (Fig. 2)

Figure 3. Mean percentage of serum undercarboxylated osteocalcin (ucOC) in subjects after phylloquinone doses of 250, 500, 1000, and 2000 μg/d. Both the 1000- and 2000-μg/d doses reduced ucOC more than did the 500-μg/d dose.2
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The recommended dietary intake (RDI) of Vit K1 is about 65–80 mcg—but therapeutic doses range from 500–2,000 mcg (although doses as high as 40 mg per day have been used without signs of toxicity). Osteocalcin is a protein involved in bone metabolism, and appears to be maximally activated at a dietary intake of 1,000–2000 mcg/day (Fig 3).2

MK4 is the most popular menaquanone supplement, and is used in Japan in doses of 45 mg per day for osteoporosis (although benefits begin at doses as low as 1,500 mcg/day.3,4 MK4 raises blood levels of K2, but does not appear to affect blood levels of K1.5

Figure 4. Circulating vitamin K concentrations following a single oral dose of 1 mg each of vitamin K1 and MK7. Points are means from 15 subjects; Note the excellent absorption and prolonged elevation of levels of MK7. indicates K1; and , MK7.
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MK-7 is another form of K2 that can be obtained in the diet (from natto). Effective doses are reported to be 90–360 mcg/day. MK-7 doesn’t seem to have the anti-osteoporotic properties of MK-4. Like MK-4, MK-7 doesn’t convert to K1.6 An advantage of MK-7 over other forms of Vit K is its very long half-life, resulting in much more stable serum levels and accumulation of MK7 to higher levels (7–8 times fold) during prolonged intake.7 (Fig. 4)

As mentioned previously, Vit K3 was formerly believed to be a synthetic form of Vit K, but has recently been confirmed to be an intermediary product in the conversion of K1 into K2 (MK-4).8 Vitamin K1’s anti-cancer properties were first investigated in 1947,9 but all forms of Vit K have been shown to have anti-cancer properties to a greater or lesser degree.10 Nevertheless, Vit K3 (Menadione) is considered to be the most potent cancer fighter11–17—just as Vit K2 (MK4) is considered to be the most effective form for enhancing bone mineral density (BMD) and reducing arterial and cardiac calcification. (Fig. 5)

Figure 5. Vitamin K protects against calcium deposition in the arteries.
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Which brings us to your questions—Does K2 convert in the body to K3, and would K3’s anti-cancer efficacy be reduced by additional vitamin K2 supplementation to improve calcium metabolism?

I don’t think the research has been done to provide a definitive answer. But here’s an educated guess: Remember, Vitamin K1 converts to K2 (MK4 and MK7) and K3. But neither K2 (MK4 nor MK7) nor K3 convert to K1. I have not found any literature to support whether taking additional K2 (as MK4)—which is the most effective form of K2 to enhance calcium metabolism—would impair the cancer-fighting effects of K3. I believe the combination would be synergistic.

Doses of Vitamin K1 as high as 40 mg per day have been reported to be beneficial against cancer, with no toxicity reported in any of the participants.18 45 mg per day of MK4 are reportedly beneficial against cancer (although less effective than K3), but more effective than K3 against osteoporosis. I think you would do well to take high doses of all of these non-toxic forms of vitamin K.

I hope this slightly “unmuddies” the water.

Ward Dean, MD

References

1. Hirota Y, Tsugawa N, Nakagawa K, et al. Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats. J Biol Chem. 2013 Nov 15;288(46):33071–80.
2. Binkley NC, Krueger DC, Kawahara TN, et al. A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation. Am J Clin Nutr. 2002 Nov;76(5):1055–60.
3. 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.
4. Koitaya N, Sekiguchi M, Tousen Y, et al. 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. doi: 10.1007/s00774-013-0472-7. Epub 2013 May 24.
5. Ozuru R, Sugimoto T, Yamaguchi T, Chihara K. Time-dependent effects of vitamin K2 (menatetrenone) on bone metabolism in postmenopausal women. Endocr J. 2002 Jun;49(3):363–70.
6. Theuwissen E, Cranenburg EC, Knapen MH, et al. Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects. Br J Nutr. 2012 Nov 14;108(9):1652–7. doi: 10.1017/S0007114511007185. Epub 2012 Jan 31.
7. Schurgers LJ, Teunissen KJ, Hamulyak K, Knapen MH, Vik H, Vermeer C. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007 Apr 15;109(8):3279–83.
8. Thijssen HH, Vervoort LM, Schurgers LJ, Shearer MJ. Menadione is a metabolite of oral vitamin K. Br J Nutr. 2006 Feb;95(2):260–6.
9. Mitchell JS, Simon-Reuss I. Combination of some effects of x-radiation and a synthetic vitamin K substitute. Nature. 1947; 160:98–99.
10. Wu FY, Liao WC, Chanag HM. Comparison of antitumor activity of vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB) cell viability assays. Life Sci. 1993; 52(22):1797–804.
11. Noto V, Taper HS, Jiang YH, et al. Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. I. Synergism of combined vitamin C and K3 action. Cancer. 1989 Mar 1;63(5):901–6.
12. De Loecker W, Janssens J, Bonte J, Taper HS. Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. II. Synergism with combined chemotherapy action. Anticancer Res. 1993 Jan-Feb;13(1):103–6.
13. Zhang W, Negoro T, Satoh K, et al. Synergistic cytotoxic action of vitamin C and vitamin K3. Anticancer Res. 2001 Sep-Oct;21(5):3439–44.
14. Calderon PB, Cadrobbi J, Marques C, et al. Potential therapeutic application of the association of vitamins C and K3 in cancer treatment. Curr Med Chem. 2002 Dec;9(24):2271–85.
15. von Gruenigen VE, Jamison JM, Gilloteaux J, et al. The in vitro antitumor activity of vitamins C and K3 against ovarian carcinoma. Anticancer Res. 2003 Jul-Aug;23(4):3279–87.
16. Verrax J, Cadrobbi J, Delvaux M, et al. The association of vitamins C and K3 kills cancer cells mainly by autoschizis, a novel form of cell death. Basis for their potential use as coadjuvants in anticancer therapy. Eur J Med Chem. 2003 May;38(5):451–7.
17. Tareen B, Summers JL, Jamison JM, et al. A 12 Week, Open Label, Phase I/IIa Study Using Apatone® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy. Int J Med Sci. 2008; 5(2):62–67
18. Lamson DW, Plaza SM. The anticancer effects of vitamin K. ­Altern Med Rev. 2003 Aug;8(3):303–18.

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