Observation of the neuroprotective efficacy of vitamin K in a streptozocin-induced diabetes model in chick embryos.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia due to insulin deficiency and/or resistance. Vitamin K (VK) is a group of fat-soluble molecules, including naturally occurring vitamin K1 (phylloquinone). vitamin K2 (menaquinone), and synthetic vitamin K3 (menadione). Beyond coagulation, the health benefits of VK have been described to play different roles in both physiological and pathological processes such as inflammation, energy metabolism, neuroprotection, cellular growth, and survival. It was aimed to observe the antioxidant and/or neuroprotective activity of vitamin K1 in our model of chick embryo diabetic neuropathy (DN) induced by streptozotocin (STZ). Ninety White Leghorn, fertile and 0-day-old SPF (specific pathogen-free) eggs (57 ± 4 gr) were used in the study. Chick embryo blood brain tissues were taken for biochemical evaluation. Plasma insulin and glucose levels were measured. In addition, brain tissue total antioxidant level (TAS), total oxidant level (TOS), malondialdehyde (MDA), and vascular endothelial growth factor (VEGF) levels were measured. Plasma glucose levels were higher in the STZ-treated groups and lower in the treatment groups. Plasma insulin levels were observed to be higher in STZ groups in groups treated with high VK. Low TAS, high MDA, TOS, and VEGF levels were recorded in brain tissue STZ groups. Low VEGF, TOS, and MDA levels were recorded in the group treated with the highest VK, while high TAS levels were observed. In our STZ-induced chick embryo diabetic neuropathy model, we observed that VK1 reduced oxidant damage by showing antioxidant properties or by modulating antioxidant enzymes.

Vitamin K2 (MK-7) attenuates LPS-induced acute lung injury via inhibiting inflammation, apoptosis, and ferroptosis.

Acute lung injury (ALI) is a life-threatening disease that has received considerable critical attention in the field of intensive care. This study aimed to explore the role and mechanism of vitamin K2 (VK2) in ALI. Intraperitoneal injection of 7 mg/kg LPS was used to induce ALI in mice, and VK2 injection was intragastrically administered with the dose of 0.2 and 15 mg/kg. We found that VK2 improved the pulmonary pathology, reduced myeloperoxidase (MPO) activity and levels of TNF-α and IL-6, and boosted the level of IL-10 of mice with ALI. Moreover, VK2 played a significant part in apoptosis by downregulating and upregulating Caspase-3 and Bcl-2 expressions, respectively. As for further mechanism exploration, we found that VK2 inhibited P38 MAPK signaling. Our results also showed that VK2 inhibited ferroptosis, which manifested by reducing malondialdehyde (MDA) and iron levels, increasing glutathione (GSH) level, and upregulated and downregulated glutathione peroxidase 4 (GPX4) and heme oxygenase-1 (HO-1) expressions, respectively. In addition, VK2 also inhibited elastin degradation by reducing levels of uncarboxylated matrix Gla protein (uc-MGP) and desmosine (DES). Overall, VK2 robustly alleviated ALI by inhibiting LPS-induced inflammation, apoptosis, ferroptosis, and elastin degradation, making it a potential novel therapeutic candidate for ALI.

VItamin K In PEritonial DIAlysis (VIKIPEDIA): Rationale and study protocol for a randomized controlled trial.

Vascular calcification (VC) is an active process, resulting from the disturbance of balance between inhibitors and promoters of calcification, in favor of the latter. Matrix Gla Protein, a powerful inhibitor of VC, needs vitamin K to become active. In vitamin K depletion, plasma levels of the inactive form of MGP, dephosphorylated, uncarboxylated MGP (dp-ucMGP) are increased and associated with VC and cardiovascular (CV) outcomes. End Stage Renal Disease (ESRD) patients have increased circulating dp-ucMGP levels and accelerated VC. VItamin K In PEritoneal DIAlysis (VIKIPEDIA) is a prospective, randomized, open label, placebo-controlled trial, evaluating the effect of vitamin K2 supplementation on arterial stiffness and CV events in ESRD patients undergoing peritoneal dialysis (PD). Forty-four PD patients will be included in the study. At baseline, dp-ucMGP and pulse-wave velocity (PWV) will be assessed and then patients will be randomized (1:1 ratio) to vitamin K (1000 µg MK-7/day) or placebo for 1.5 years. The primary endpoint of this trial is the change in PWV in the placebo group as compared to the treatment group. Secondary endpoints are the occurrence of CV events, mortality, changes in PD adequacy, change in 24-hour ambulatory blood pressure indexes and aortic systolic blood pressure and changes in calcium/phosphorus/parathormone metabolism. VIKIPEDIA is a new superiority randomized, open label, placebo-controlled trial aiming to determine the effect of vitamin K2 supplementation on VC, CV disease and calcium/phosphorus metabolism, in PD patients. Trial registration: The protocol of this study is registered at ClinicalTrials.gov with identification number NCT04900610 (25 May 2021).

Efficacy and safety of vitamin K2 for postmenopausal women with osteoporosis at a long-term follow-up: meta-analysis and systematic review.

INTRODUCTION: Vitamin K2 supplementation has been revealed to be effective in the prevention and treatment of osteoporosis in Japan, but further proof for the effectiveness of this practice is still needed. OBJECTIVE: To investigate whether vitamin K2 supplementation plays a role in maintaining bone mineral density (BMD) and reducing the incidence of fractures for postmenopausal women with osteoporosis at a long-term follow-up. MATERIALS AND METHODS: We searched systematically throughout the databases of PubMed, Cochrane library, and EMBASE from the dates of their inception to November 16 2021 in this meta-analysis and systematic review, using keywords vitamin K2 and osteoporosis. RESULTS: Nine RCTs with 6853 participants met the inclusion criteria. Vitamin K2 was associated with a significantly increased percentage change of lumbar BMD and forearm BMD (WMD 2.17, 95% CI [1.59-2.76] and WMD 1.57, 95% CI [1.15-1.99]). There were significant differences in undercarboxylated osteocalcin (uc-OC) reduction (WMD -0.96, 95% CI [-0.70 to 0.21]) and osteocalcin (OC) increment (WMD 26.52, 95% CI [17.06-35.98]). Adverse reaction analysis showed that there seemed to be higher adverse reaction rates in the vitamin K2 group (RR = 1.33, 95% CI [1.11-1.59]), but no serious adverse events related to vitamin K2 supplementation. CONCLUSION: This meta-analysis and systematic review seemed to support the hypothesis that vitamin K2 plays an important role in the maintenance and improvement of BMD, and it decreases uc-OC and increases OC significantly at a long-term follow-up. Vitamin K2 supplementation is beneficial and safe in the treatment of osteoporosis for postmenopausal women.

Safety and Efficacy of Vitamin K Antagonists versus Rivaroxaban in Hemodialysis Patients with Atrial Fibrillation: A Multicenter Randomized Controlled Trial.

BACKGROUND: In patients with normal renal function or early stage CKD, the risk-benefit profile of direct oral anticoagulants (DOACs) is superior to that of vitamin K antagonists (VKAs). In patients on hemodialysis, the comparative efficacy and safety of DOACs versus VKAs are unknown. METHODS: In the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a VKA with a target INR of 2-3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. Patients continued the originally assigned treatment and follow-up was extended for at least an additional 18 months. The primary efficacy end point was a composite of fatal and nonfatal cardiovascular events. Secondary efficacy end points were individual components of the composite outcome and all-cause death. Safety end points were life-threatening, major, and minor bleeding. RESULTS: Median (IQR) follow-up was 1.88 (1.01-3.38) years. Premature, permanent discontinuation of anticoagulation occurred in 25% of patients. The primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group. The estimated competing risk-adjusted hazard ratio for the primary end point was 0.41 (95% CI, 0.25 to 0.68; P=0.0006) in the rivaroxaban group and 0.34 (95% CI, 0.19 to 0.61; P=0.0003) in the rivaroxaban and vitamin K2 group, compared with the VKA group. Death from any cause, cardiac death, and risk of stroke were not different between the treatment arms, but symptomatic limb ischemia occurred significantly less frequently with rivaroxaban than with VKA. After adjustment for competing risk of death, the hazard ratio for life-threatening and major bleeding compared with the VKA group was 0.39 (95% CI, 0.17 to 0.90; P=0.03) in the rivaroxaban group, 0.48 (95% CI, 0.22 to 1.08; P=0.08) in the rivaroxaban and vitamin K2 group and 0.44 (95% CI, 0.23 to 0.85; P=0.02) in the pooled rivaroxaban groups. CONCLUSIONS: In patients on hemodialysis with atrial fibrillation, a reduced dose of rivaroxaban significantly decreased the composite outcome of fatal and nonfatal cardiovascular events and major bleeding complications compared with VKA. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Oral Anticoagulation in Hemodialysis, NCT03799822.

The efficacy and safety of menatetrenone in the management of osteoporosis: a systematic review and meta-analysis of randomized controlled trials.

In our systematic review and meta-analysis, we comprehensively evaluated menatetrenone in the management of osteoporosis. We found that menatetrenone decreased the ratio of undercarboxylated osteocalcin to osteocalcin (ucOC/OC) and improved lumbar BMD compared with placebo based on the 18 studies assessed. However, its benefit in fracture risk control was uncertain. INTRODUCTION: We performed a systematic review and meta-analysis of the efficacy and safety of menatetrenone in managing osteoporosis. METHODS: PubMed, Cochrane Library, Embase, ClinicalTrials.gov , and three Chinese literature databases (CNKI, CBM, Wanfang) were searched for relevant randomized controlled trials (RCTs) published before October 5, 2017, comparing menatetrenone with other anti-osteoporotic drugs or placebo in treating osteoporosis. The pooled risk ratio (RR) or mean difference (MD) and 95% confidence interval (CI) were calculated using fixed-effects or random-effects meta-analysis. RESULTS: Eighteen RCTs (8882 patients) were included. Pooled analyses showed that menatetrenone was more effective than placebo in improving lumbar bone mineral density (BMD) (five studies, N = 658, MD = 0.05 g/cm2, 95% CI 0.01 to 0.09 g/cm2) and decreasing ucOC/OC (two studies, N = 75, MD = - 21.78%, 95% CI - 33.68 to - 9.87%). Compared with placebo, menatetrenone was associated with a nonsignificantly decreased risk of vertebral fracture (five studies, N = 5508, RR = 0.87, 95% CI 0.64 to 1.20). Evidence on other anti-osteoporotic drugs as comparators was limited and revealed no significantly different effects of menatetrenone on BMD or fracture risks. Furthermore, compared with placebo, menatetrenone significantly increased the incidence of adverse events (AEs) (two studies, N = 1949, RR = 1.47, 95% CI 1.07 to 2.02) and adverse drug reactions (four studies, N = 6102, RR = 1.29, 95% CI 1.07 to 1.56). However, no significant difference in the incidence of serious AEs was found between menatetrenone and placebo. CONCLUSIONS: Menatetrenone significantly decreases ucOC and might improve lumbar BMD in osteoporotic patients. However, its benefit in fracture risk control is uncertain.

Controllable vitamin K deficiency under high-dose oral menatetrenone administration - a case report.

Vitamin (V) K deficiency may cause severe bleeding tendencies, which necessitates extreme caution. We report a case of a 30-year-old man diagnosed with VK deficiency of unknown etiology. He was treated with intravenous menatetrenone three times a week in an outpatient setting for about 1 year and 9 months. Eventually, he developed an allergic reaction to intravenous menatetrenone and was under steroid therapy. In order to reduce his hospital visits and discontinue steroid use, the pharmacist proposed to change the method of menatetrenone administration from intravenous to oral (high dose). The change in treatment method has greatly improved the patient's quality of life.

Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using 18F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design.

BASIK2 is a prospective, double-blind, randomized placebo-controlled trial investigating the effect of vitamin K2 (menaquinone-7;MK7) on imaging measurements of calcification in the bicuspid aortic valve (BAV) and calcific aortic valve stenosis (CAVS). BAV is associated with early development of CAVS. Pathophysiologic mechanisms are incompletely defined, and the only treatment available is valve replacement upon progression to severe symptomatic stenosis. Matrix Gla protein (MGP) inactivity is suggested to be involved in progression. Being a vitamin K dependent protein, supplementation with MK7 is a pharmacological option for activating MGP and intervening in the progression of CAVS. Forty-four subjects with BAV and mild-moderate CAVS will be included in the study, and baseline 18F-sodiumfluoride (18F-NaF) positron emission tomography (PET)/ magnetic resonance (MR) and computed tomography (CT) assessments will be performed. Thereafter, subjects will be randomized (1:1) to MK7 (360 mcg/day) or placebo. During an 18-month follow-up period, subjects will visit the hospital every 6 months, undergoing a second 18F-NaF PET/MR after 6 months and CT after 6 and 18 months. The primary endpoint is the change in PET/MR 18F-NaF uptake (6 months minus baseline) compared to this delta change in the placebo arm. The main secondary endpoints are changes in calcium score (CT), progression of the left ventricularremodeling response and CAVS severity (echocardiography). We will also examine the association between early calcification activity (PET) and later changes in calcium score (CT).

US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K.

Vitamin K plays important biological roles in maintaining normal blood coagulation, bone mineralization, soft tissue physiology, and neurological development. Menaquinone-7 is a form of vitamin K2 that occurs naturally in some animal-derived and fermented foods. It is also available as an ingredient of dietary supplements. Menaquinone-7 has greater bioavailability than other forms of vitamin K, which has led to increasing sales and use of menaquinone-7 supplements. This special article reviews the chemistry, nomenclature, dietary sources, intake levels, and pharmacokinetics of menaquinones, along with the nonclinical toxicity data available and the data on clinical outcomes related to safety (adverse events). In conclusion, the data reviewed indicate that menaquinone-7, when ingested as a dietary supplement, is not associated with any serious risk to health or with other public health concerns. On the basis of this conclusion, US Pharmacopeia monographs have been developed to establish quality standards for menaquinone-7 as a dietary ingredient and as a dietary supplement in various dosage forms.

Comparison of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis: Japanese Osteoporosis Intervention Trial-03.

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65 years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate (2.5 mg/day or 17.5 mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95 % confidence interval 0.811-1.422, p = 0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81 ± 3.93 ng/mL to 2.59 ± 1.52 ng/mL at 6 months in the risedronate and vitamin K2 group, whereas the change in the risedronate alone group was minimal (from 5.96 ± 4.36 ng/mL to 4.05 ± 3.40 ng/mL at 6 months) (p < 0.01). The treatment discontinuation rate was higher in the risedronate and vitamin K2 group than in the risedronate alone group (10.0 % vs 6.7 %). No unknown adverse drug reactions were reported. In conclusion, concurrent treatment with vitamin K2 and risedronate was not efficacious compared with monotherapy with risedronate in terms of fracture prevention.

Menaquinone-7 as a novel pharmacological therapy in the treatment of rheumatoid arthritis: A clinical study.

Menaquinones (MKs) have been reported to induce apoptosis in rheumatoid arthritis (RA) synovial cells. Recently, menaquinone-4 (MK-4) was proven as a new potential agent for the treatment of RA. However, menaquinone-7 (MK-7) has greater bioavailability and efficacy than MK-4 after oral administration. Yet, the therapeutic benefits of MK-7 in the management of patients with RA have never been addressed. This study was designed to clarify the therapeutic role of MK-7 added to normal therapeutic regimen of RA in patients with different stages of the disease with a clinical follow up through a randomized clinical trial. In a cross sectional study, 84 RA patients (24 male, 60 female) (average age=47.2 years) were enrolled in this study. The patients were divided into MK-7 treated group (n=42) and MK-7 naïve group (n=42). MK-7 capsules were administered in a dose of 100µg/day for three months in the first group without changing in other medications. The clinical and biochemical markers on RA patients treated with MK-7 and naïve group were assessed. In MK-7 treated group, serum concentrations of MK-7 were monitored before and after three months of MK-7 administration. In the cross sectional study, a significant decrease in MK-7 treated group for the levels of undercarboxylated osteocalcin (ucOC), erythrocyte sedimentation rate (ESR), disease activity score assessing 28 joints with ESR (DAS28-ESR), C-reactive protein (CRP) and matrix metalloproteinase (MMP-3) was found. In MK-7 treated group, a marked decrease in RA clinical and biochemical markers for moderate and good response compared to non-responders was observed in ucOC, ESR and DAS28-ESR. A marked increase in the levels of MK-7 for the moderate and good responders compared to non-responders was observed. The results suggest that MK-7 improves disease activity in RA patients. Therefore, MK-7 represents a new promising agent for RA in combination therapy with other disease modifying antirheumatic drugs.

Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma.

AIM: To evaluate the chemopreventive efficacy of vitamin K2 (VK2) analog in patients with hepatocellular carcinoma (HCC) after curative hepatic resection or local ablation, since a recent randomized control trial (RCT) and systematic review have given contradictory results. METHODS: MEDLINE, EMBASE and Cochrane library databases were systematically searched through the end of May 2012. Meta-analysis of RCTs and cohort studies was performed to estimate the effects of the VK2 analog on tumor recurrence rate and overall survival (OS). Risk ratios (RRs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Six RCTs and one cohort study involving a total of 930 patients were included. VK2 analog therapy did not reduce the 1-year recurrence rate, with a pooled RR of 0.67 (95% CI 0.39-1.13, p = 0.13). However, VK2 analog therapy was associated with a significant reduction in the 2- and 3-year tumor recurrence rates, with respective pooled RRs of 0.65 (95% CI 0.51-0.83, p<0.001) and 0.70 (95% CI = 0.58-0.85, p<0.001). The therapy was also associated with a significant improvement in 1-, 2-, and 3-year OS, with respective pooled RRs of 1.03 (95% CI 1.01-1.05, p = 0.02), 1.11 (95% CI 1.03-1.19, p = 0.005) and 1.14 (95% CI 1.02-1.28, p = 0.02). None of the studies reported adverse effects attributable to VK2 analog therapy. CONCLUSION: The VK2 analog may reduce recurrence rate after 1 year and improve OS in HCC patients as early as 1 year. However, these findings should be considered preliminary since the majority of patients came from an RCT with survival data out to only 1 year. More extensive studies with larger sample sizes and longer follow-up are needed.

Menatetrenone for the treatment of osteoporosis.

INTRODUCTION: The effect of the anti-osteoporosis medicine, menatetrenone (vitamin K(2); menaquinone-4) on the skeleton remains a matter of controversy. The objective of the present review study was to evaluate the effect of menatetrenone on the skeleton of postmenopausal women, men and glucocorticoid-treated patients. METHODS: PubMed was used to search the literature for randomized controlled trials (RCTs), meta-analyses and systematic reviews. Thirteen RCTs, one meta-analysis and one systematic review were available for analysis. RESULTS: Except for one large Japanese RCT (Phase IV trial: Osteoporotic Fracture (OF) study, n = 4378), RCTs with small sample size showed non-significant or modest effect on bone mineral density (BMD) in postmenopausal women and patients treated with glucocorticoid, positive effect on hip geometry in postmenopausal women and efficacy against fractures (mainly vertebral fractures) in postmenopausal women with osteoporosis. A post hoc analysis of the OF study showed that the incidence of vertebral fractures decreased in postmenopausal women with at least five vertebral fractures. A meta-analysis study, but not a systematic review study, showed efficacy against vertebral and non-vertebral fractures mainly in postmenopausal women with osteoporosis. There was no available evidence for men with osteoporosis. CONCLUSION: The present review of the literature revealed some evidence of a positive effect of menatetrenone on the skeleton of postmenopausal women and in patients treated with glucocorticoid. EXPERT OPINION: Menatetrenone is considered to be a second-line medicine for postmenopausal osteoporotic women with an increased risk for vertebral fractures.

Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized controlled trial.

The aim of this study was to investigate whether menatetrenone (MNT) suppresses hepatocellular carcinoma (HCC) recurrence in patients undergoing hepatectomy. Between January 2005 and September 2009, 101 patients who underwent curative hepatectomy for primary HCC were enrolled in the study. Patients were divided into two groups: a non-MNT group (n=51), and an MNT group (n=50) that was administered 45 mg of MNT daily. During the observation period, recurrence was observed in 33 patients in the non-MNT group and in 28 patients of the MNT group (p=0.545). In patients with a preoperative Des-γ-carboxy-prothrombin (DCP) level lower than 40 AU/l (n=38), the cumulative disease-free survival rates at 12, 36, and 60 months in the non-MNT group, were 81.3%, 0.0%, and 0.0%, respectively, while those in the MNT group were 78.3%, 58.1%, and 31.0%, respectively (p=0.060). MNT has a moderately suppressive effect on HCC recurrence after hepatectomy, especially in patients with a normal preoperative DCP level.

Amelioration of pregnancy-associated osteoporosis after treatment with vitamin K2: a report of four patients.

Abstract We demonstrate for the first time therapeutic effects of vitamin K2 (menatetrenone) on pregnancy-associated osteoporosis with multiple vertebral fractures in four cases. Due to its safety, vitamin K2 presents itself as a treatment option for women with pregnancy-associated osteoporosis. Desirably, future controlled studies should verify these findings.

Hypotension associated with menaquinone.

PURPOSE: A case of mild symptomatic hypotension after treatment with menaquinone (vitamin K(2)) is reported. SUMMARY: A 62-year-old white man with a medical history of hyperlipidemia, coronary artery disease, and benign prostatic hyperplasia was started on a regimen of menaquinone 100 µg daily as a supplement to his medications for coronary artery disease. Approximately two hours after taking the first dose of menaquinone, the patient experienced sudden weakness and dizziness. At that time, his blood pressure was 110/55 mm Hg. On day 2 of treatment, his blood pressure was 105/50 mm Hg two hours after taking menaquinone; however the patient was asymptomatic. On day 3, the patient's blood pressure was 100/50 mm Hg two hours after menaquinone ingestion, with symptoms of generalized weakness and dizziness, at which point menaquinone was discontinued. All of the patient's heart rate measurements were within normal limits during this time. The day after discontinuing menaquinone, the patient's blood pressure was 115/65 mm Hg, after which his readings were within normal limits on subsequent days. After a 10-day menaquinone-free period, the patient was rechallenged. On rechallenge day 1, the patient's blood pressure was 115/60 mm Hg two hours after menaquinone ingestion; on rechallenge day 2, his blood pressure was 100/55 mm Hg. The patient was asymptomatic on both days of the rechallenge. The Naranjo et al. adverse drug reaction probability scale score was 7, indicating a probable adverse reaction to menaquinone. The drug interaction probability scale score for this case was 6, indicating that a drug interaction was probable. CONCLUSION: A 62-year-old white man developed mild symptomatic hypotension while receiving menaquinone therapy.

Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects.

Vitamin K is required for the carboxylation of Gla-proteins in the liver (coagulation factors) and extra-hepatic tissues, such as bone (osteocalcin, OC), and arterial wall (matrix Gla-protein, MGP). Although the coagulation factors are essentially fully carboxylated under normal conditions, 10-40 % of OC and MGP remains undercarboxylated. We were therefore interested to study the dose-response effects of extra intake of menaquinones on the carboxylation of the extra-hepatic Gla-proteins. A total of forty-two healthy Dutch men and women aged between 18 and 45 years were randomised into seven groups to receive: placebo capsules or menaquinone-7 (MK-7) capsules at a daily dose of 10, 20, 45, 90, 180 or 360 µg. Circulating uncarboxylated OC (ucOC), carboxylated OC (cOC) and desphospho-uncarboxylated MGP were measured by ELISA. The ucOC:cOC ratio was calculated from circulating ucOC and cOC values. Endogenous thrombin potential and peak height were determined by calibrated automated thrombography. To increase the statistical power, we collapsed the treatment groups into three dosage groups: placebo, low-dose supplementation (doses below RDA, Commission Directive 2008/100/EC), and high-dose supplementation (doses around RDA, Commission Directive 2008/100/EC). MK-7 supplementation at doses in the order of the RDA (Commission Directive 2008/100/EC) increased the carboxylation of circulating OC and MGP. No adverse effects on thrombin generation were observed. Extra MK-7 intake at nutritional doses around the RDA (Commission Directive 2008/100/EC) improved the carboxylation of the extra-hepatic vitamin K-dependent proteins. Whether this improvement contributes to public health, i.e. increasing the protection against age-related diseases needs further investigation in specifically designed intervention trials.

Intake of vitamin K1 and K2 and risk of hip fractures: The Hordaland Health Study.

BACKGROUND: Evidence of the effect of vitamin K on bone health is conflicting. The aim was to investigate the association between intake of vitamins K1 and K2 and subsequent risk of hip fracture in a general population sample, as well as potential effect modification by apolipoprotein E gene (APOE) status by presence of the E4 allele. METHODS: 1238 men and 1569 women 71-75 years of age were included in the community-based Hordaland Health Study 1997-1999 in Western Norway. Information on hip fracture was obtained from hospitalizations in the region from enrolment until 31 December 2009. Information on intake of vitamins K1 and K2 collected at baseline was used as potential predictors of hip fracture in Cox proportional hazards regression analyses. RESULTS: Participants in the lowest compared to the highest quartile of vitamin K1 intake had increased risk of suffering a hip fracture (hazard ratio (HR)=1.57 [95% CI 1.09, 2.26]). Vitamin K2 intake was not associated with hip fracture. Presence of APOE4-allele did not increase the risk of hip fracture, nor was there any effect modification with vitamin K1 in relation to risk of hip fracture. CONCLUSIONS: A low intake of vitamin K1, but not K2, was associated with an increased risk of hip fractures.

Prospective evaluation of Vitamin K2, Raloxifene and their co-administration in osteoporotic rats.

In this study, therapeutic effects of Vitamin K2, Raloxifene and their co-administration on bone, uterus, blood and weight profiles were investigated with an ovariectomized rat model. Forty Wistar rats were divided into five groups (n=8): Raloxifene (R), Vitamin K2 (K), Raloxifene+Vitamin K2 (R+K), ovariectomized controls (OVX) and Sham-operated controls (Sham). Treatment began 3 months after ovariectomy. Vitamin K2 and Raloxifene were administered 30 and 1.5 mg/kg/day separately and in combination five times per week for 12 weeks. All treatment groups had significantly higher ultimate strength and energy absorption capacity (P<0.05) than ovariectomized controls in both femur and tibia. Histological results showed that treatment groups had healthy lumen structure, whereas OVX had degeneration. Adverse effects which were seen in individual treatments (myometrium weakening in K, endometrium weakening in R, and ALP increase in group R) were not observed in the R+K group implying a synergistic effect of these two agents when they are co-administered. According to blood analysis, ALP values were significantly high in Raloxifene-only group (P<0.0001). This effect is suppressed in the co-administered group. In summary, the groups R, K and R+K had significantly higher ultimate strength and less susceptibility to fracture than ovariectomized controls. In summation, Vitamin K2 treated groups (either in single or combined with Raloxifene) had considerable biomechanical performance and reproductive tissue profile indicating that this agent is prospectively effective in osteoporosis management.