**6. Prostate health and vitamin K2**

Patients with chronic kidney disease and those undergoing dialysis have been shown repeatedly to suffer with high levels of uncarboxylated vitamin K–dependent proteins and have high levels of arterial calcification as well. (The most deficient group is the same patients taking vitamin K antagonist drugs concurrently.) In order to prepare for a RCT with a disease endpoint of stabilizing or reversing arterial calcification in this patient group, a supplement trial was conducted in the Netherlands with 50 hemodialysis patients [44]. An age-matched healthy control group was selected also for comparisons. The hemodialysis patients were randomized into groups taking 45, 135, or 360 µg/day of vitamin K2 as MK-7 for 6 weeks. Measurements were taken for the levels of uncarboxylated osteocalcin (ucOC), dp-ucMGP, and PIVKA-II. PIVKA-II is a prothrombin liver protein that is only seen in the circulation under situations of severe vitamin K deficiency, such as found in hemodialysis patients. At baseline hemodialysis, patients, compared to healthy controls, had 4.5-fold higher dp-ucMGP levels and 8.4-fold higher uncarboxylated osteocalcin levels. PIVKA-II levels were detectable in 49 of the 50 hemodialysis patients. There was a dose-dependent response to the MK-7 treatment, with the 45 µg dose being little different than a placebo, the 135 µg dose giving 37%, 11%, and 34% changes in dp-ucMGP, ucOC, and PIVKA-II, respectively, which was almost significant, and the 360 µg dose yielding statistically significant changes of 61%, 34%, and 42% decreases in dp-ucMGP, ucOC, and PIVKA-II. This short trial showed both the severity of the vitamin K deficiency in this hemodialysis patient group as well as the effectiveness of a relatively high dose (360 µg/day) of MK-7 in bringing down functional markers of vitamin K deficiency.

As a follow-up to the Westenfeld Study [44] just reviewed, another larger study with hemodialysis patients was carried out with slightly higher doses, but administered three times a week by a nurse after dialysis [45]. This method was used to increase patient compliance. Doses for the 200 patients were 360, 720, and 1080 µg of MK-7 three times as week for 8 weeks. This works out to equivalent daily doses of 154, 309, and 463 µg/day. After 8 weeks, levels of dpucMGP decreased by 17, 33, and 46% in the three dosage groups, respectively. Results here were similar to those in [44], but with less decrease in relative change in dp-ucMGP at the highest dose (46% vs. 61%). However, the absolute differences before and after intervention were greater in [45]. Absolute changes in dp-upMGP in the Westenfeld Study were −404, −730, and −978 pM at 45, 135, and 360 µg/day [44]. In a study by Caluwé and coworkers [45], absolute changes in dp-ucMGP were −566, −962, and −1487 pM for the equivalent daily doses of 154, 309, and 463 µg/day. So, the outcomes were very similar, especially given that the second trial

How widespread is extrahepatic vitamin K insufficiency? A cross-sectional sample of 896 healthy individuals showed that dp-ucMGP levels increased with age, staying around 200 pM until about age 40 and then increasing up to over 600 pM for those >70 years of age [46]. Levels of dp-ucMGP decreased in children and adults when given supplemental MK-7, again showing that dp-ucMGP was a biomarker that responded to extrahepatic vitamin K status, and that many adults had less than optimal levels of vitamin K. These levels are not optimal, neither are they as severe as hemodialysis patients, who averaged around 3000 pM but ranged to over 7000 pM in some individuals [44, 45]. Hemodialysis patients who took vitamin K antagonists had a mean dp-ucMGP of about 5600 pM [33]. But the values >600 pM in the >70

was 8 weeks long rather than just 6 weeks.

178 Vitamin K2 - Vital for Health and Wellbeing

While the focus of this chapter has been on arterial calcification and cardiovascular health, it has come to the attention of this author that there is evidence that supports a hypothesis that poor prostate health is not a hormone issue, but a cardiovascular issue [51]. The first piece of evidence comes from interventional radiologists Dr. Gat and coworkers, who were initially working on reversing infertility in men by relieving varicoceles, or varicose veins in the pampiniform venous plexus. They discovered that varicose veins in the internal spermatic vein, which normally returns blood from the testes to the kidneys, prevented normal blood flow. The one-way valves had failed in this vein, possibly causing the varicose vein, or as part of the process of forming varicose veins—the exact mechanism is debated. So instead of normal blood flow, the blood flowed retrograde through the prostatic veins. When testosterone levels were measured near the prostate gland in 12 infertile men with varicocele, the mean concentration was 3632 pmol/l compared to 27.33 pmol/l in the serum, or about 130 times higher [52]. By occluding the internal spermatic vein, Dr. Gat was able to relieve the physical pressure due to the elevated blood pressure caused by the height of the column of blood sitting in the internal spermatic vein and also made a pathway through normal venous pathways for blood to drain away from the testes without retrograde flow past the prostate. This venous occlusion surgery led to relief of benign prostatic hyperplasia (BPH), and possibly prevention of prostate cancer as well [52].

before prostate cancer diagnosis and nonusers of warfarin showed an odds ratio of 2.2 (95% CI 1.03–4.81) of poor prognosis disease. This would seem to agree with the hypothesis that vitamin K antagonists would increase the possibility of forming varicoceles, leading to poor

Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate...

http://dx.doi.org/10.5772/63413

181

At this point, the role of vitamin K2 in prostate health is a good hypothesis but needs further confirmation by interventional radiologists and other researchers before the link between prostate health and cardiovascular function, especially the role of vitamin K2 plays, is certain.

Reversal of atherosclerosis by a plant-based diet has already been mentioned in this chapter [27]. Dr. Esselstyn has also shown that a plant-based diet very low in fat can reverse coronary artery disease [57]. Of 198 subjects in the lifestyle intervention study, 177 were adherent to the program while 21 formed a control group of non-adherent comparison subjects. There was reversal of angiographic-verified blockages in 39 adherent subjects. Disease progression occurred in 4 (2.3%) adherent subjects, but in 11 (52.4%) of the non-adherent subjects. Coronary

There is abundant evidence that increased consumption of fruits and vegetables in conjunction with exercise and a healthy lifestyle is beneficial for cardiovascular health and lower cardiovascular mortality. Healthy diets have been reported to lower cardiovascular mortality risk by about 30–40% [14, 58, 59]. When combined with other lifestyle factors, the risk plummets to

The point here is that all available resources should be used to counter the disease process and to promote healthy aging. While vitamin K2 is a valuable nutrient that is generally in short supply in the global diet, the context of the entire diet must be kept in mind. The best results will be obtained by a full complement of healthy foods. Population studies have shown that even 40–50 µg/day of menaquinones from the diet is associated with cardioprotection [6, 7]

Is vitamin K2 compatible with a plant-based diet? While most of the common sources of menaquinones are cheese, fermented dairy products, eggs, and meats, there are plant sources as well. While these are animal products, judicial selection could be used to maximize K2 intake without consuming a large amount of any animal-based foods. Natto is a well-known Japanese food that is very rich in MK-7, though not very popular outside of Japan. The menaquinone in natto is made by fermentation with *Bacillus subtilis var. natto*. Fermented vegetables such as sauerkraut contain a small amount of menaquinones as well. By selecting probiotic bacteria based on their production of menaquinones, the amount of vitamin K2 from a serving of fermented vegetables could be significant. More product development is needed in this area.

about 20% or less compared to the least healthy fraction of the population [60–63].

and lower risk of advanced prostate cancer and lung cancer [54, 55, 64].

prostate health. But there could be other mechanisms of action as well.

**7. Vitamin K2 and a plant-based diet?**

artery calcification was not measured.

Varicose veins and destruction of the one-way valves in the internal spermatic vein were the direct cause of BPH, but what causes varicose veins? Work by Cario-Toumaniantz and coworkers [53] on the differentially expressed genes and gene products in varicose vein tissue showed an overexpression of genes involved in extracellular remodeling, including matrix Gla protein. Smooth muscle cells were seen proliferating in varicose vein tissue with high expression of MGP, particularly the uncarboxylated form of MGP. Overexpression of MGP and proliferation of smooth muscle cells have been seen before, reported by Price and coworkers investigating the effects of warfarin on arterial calcification in rats [15], and by Schurgers and coworkers reporting the reversal of warfarin-induced arterial calcification in rats [28]. In areas of calcification of arteries, there is proliferation of smooth muscle cells and increased expression of uncarboxylated MGP, similar to what was seen in varicose vein tissue [53]. It is likely then that vitamin K is involved in the mechanism by which varicose veins form, just as it has been implicated in the formation of arterial calcifications. When varicose vein tissue culture was treated with warfarin, mineralization increased, which could be inhibited by the inclusion of vitamin K in the culture media [53], indicating a direct role for vitamin K in the prevention of varicose veins.

In addition to this evidence from cellular biology, evidence from a prospective observational study showed an association between intake of vitamin K2 and poor prostate health manifested as prostate cancer. There was a significant association between menaquinone intake and advanced prostate cancer in the EPIC-Heidelberg cohort [54]. A nested case-control follow-up study also found an association between the ratio of undercarboxylated osteocalcin to carboxylated osteocalcin and high-grade prostate cancer and advanced prostate cancer [55]. Neither of these reports found a connection with vitamin K1 intake. Further evidence comes from a retrospective study of warfarin use and clinical stage of prostate cancer at diagnosis [56]. While some of the evidence for intermediate or short-term use of warfarin is conflicting, the comparison between those men who had used warfarin for at least 4 years in the 5 years before prostate cancer diagnosis and nonusers of warfarin showed an odds ratio of 2.2 (95% CI 1.03–4.81) of poor prognosis disease. This would seem to agree with the hypothesis that vitamin K antagonists would increase the possibility of forming varicoceles, leading to poor prostate health. But there could be other mechanisms of action as well.

At this point, the role of vitamin K2 in prostate health is a good hypothesis but needs further confirmation by interventional radiologists and other researchers before the link between prostate health and cardiovascular function, especially the role of vitamin K2 plays, is certain.
