MK-7 Supplementation Research Articles

Vitamin K Status Based on K1, MK-4, MK-7, and Undercarboxylated Prothrombin Levels in Adolescent and Adult Patients with Cystic Fibrosis: A Cross-Sectional Study.

The available evidence on vitamin K status in cystic fibrosis (CF) is scarce, lacking data on vitamin K2 (menaquinones-MK). Therefore, we assessed vitamin K1, MK-4 and MK-7 concentrations (LC-MS/MS) in 63 pancreatic insufficient and modulator naïve CF patients, and compared to 61 healthy subjects (HS). Vitamin K1 levels did not differ between studied groups. MK-4 concentrations were higher (median <1st-3rd quartile>: 0.778 <0.589-1.086> vs. 0.349 <0.256-0.469>, p < 0.0001) and MK-7 levels lower (0.150 <0.094-0.259> vs. 0.231 <0.191-0.315>, p = 0.0007) in CF patients than in HS. MK-7 concentrations were higher in CF patients receiving K1 and MK-7 supplementation than in those receiving vitamin K1 alone or no supplementation. Moreover, vitamin K1 concentrations depended on the supplementation regime. Based on multivariate logistic regression analysis, we have found that MK-7 supplementation dose has been the only predictive factor for MK-7 levels. In conclusion, vitamin K1 levels in CF are low if not currently supplemented. MK-4 concentrations in CF patients supplemented with large doses of vitamin K1 are higher than in HS. MK-7 levels in CF subjects not receiving MK-7 supplementation, with no regard to vitamin K1 supplementation, are low. There do not seem to be any good clinical predictive factors for vitamin K status.

Beneficial effects of one-year menaquinone-7 supplementation on vascular stiffness and blood pressure in post-menopausal women

Abstract Background Cardiovascular disease (CVD) is responsible for 35% of total deaths worldwide. Sex hormones, such as oestrogen and progesterone, have a cardiovascular protective role in women. After menopause, women are more prone to hypertension and vascular stiffness, accelerated vascular aging and risk for CVD. Menaquinone-7 (MK-7) is a fat-soluble vitamin K2 and serves as cofactor for vitamin K-dependent protein carboxylation. The vitamin K-dependent matrix Gla protein (MGP) is synthesized in the vasculature and has shown to inhibit vascular calcification and stiffness. Purpose To investigate effects of MK-7 on vascular stiffness in pre/peri- versus post-menopausal women. Methods In a double-blind placebo-controlled clinical intervention trial (NCT02404519), 166 women (age 40-70; dephosphorylated-undercarboxylated MGP (dp-ucMGP) &amp;gt; 400 pmol/L at baseline) received daily 180 µg of MK-7 (n=83) or a matching placebo (n=83) for one year. Blood was sampled during intake (inclusion/exclusion), at baseline and at the end of the study to determine dp-ucMGP levels. Regional carotid-femoral (cf-PWV) and carotid-radial (cr-PWV) pulse wave velocities, vessel wall characteristics (e.g., intima-media thickness, arterial diameter, and local carotid artery PWV (caPWV), and arterial blood pressure were measured at baseline and after one year of vitamin K2 supplementation. Pre/peri- and post-menopausal women were sub-divided according to arterial stiffness (high b-stiffness index: &amp;gt; overall median 9.83). Results Post-hoc analyses showed a significant decrease in dp-ucMGP plasma levels of MK-7 supplemented pre/peri-menopausal (n=34; -8.58% ± 27.65; p=0.009) and post-menopausal women (n=48; -13.40% ± 27.45; p&amp;lt;0.001). At baseline, vascular parameters were significantly increased in post-menopausal women compared to pre/peri-menopausal women, e.g., intima media thickness (p=0.013), carotid artery diameter (p=0.007), and caPWV (p=0.012). MK-7 treatment significantly attenuated vascular stiffness in post-menopausal women (Young’s modulus; placebo +49.14% ± 77.38; MK-7 +9.38% ± 67.10; p=0.044). Post-menopausal women with a high stiffness index showed significantly improved vascular markers after MK-7 treatment, e.g., decreased blood pressure at brachialis (-3.03% ± 9.04; p=0.012), decreased blood pressure at carotid artery (-4.49% ± 11.66; p=0.008), increased distensibility coefficient (+13.25% ± 32.34; p=0.040), and increased compliance coefficient (±12.66% ± 32.64; p=0.040). Conclusions Our results confirm that hormonal changes affect the vasculature, and that post-menopausal women suffer from increased vascular stiffness reflected by functional vascular damage. Further, MK-7 supplementation significantly attenuates arterial stiffness in post-menopausal women, in which women with increased stiffness benefit most on blood pressure. Further research is needed to unravel the mechanisms by which MK-7 executes this beneficial role in post-menopausal women.

Menaquinone-4 prevents medication-related osteonecrosis of the jaw through the SIRT1 signaling-mediated inhibition of cellular metabolic stresses-induced osteoblast apoptosis.

Long-term usage of bisphosphonates, especially zoledronic acid (ZA), induces osteogenesis disorders and medication-related osteonecrosis of the jaw (MRONJ) in patients, thereby contributing to the destruction of bone remodeling and the continuous progression of osteonecrosis. Menaquinone-4 (MK-4), a specific vitamin K2 isoform converted by the mevalonate (MVA) pathway in vivo, exerts the promotion of bone formation, whereas ZA administration suppresses this pathway and results in endogenous MK-4 deficiency. However, no study has evaluated whether exogenous MK-4 supplementation can prevent ZA-induced MRONJ. Here we showed that MK-4 pretreatment partially ameliorated mucosal nonunion and bone sequestration among ZA-treated MRONJ mouse models. Moreover, MK-4 promoted bone regeneration and inhibited osteoblast apoptosis in vivo. Consistently, MK-4 downregulated ZA-induced osteoblast apoptosis in MC3T3-E1 cells and suppressed the levels of cellular metabolic stresses, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and DNA damage, which were accompanied by elevated sirtuin 1 (SIRT1) expression. Notably, EX527, an inhibitor of the SIRT1 signaling pathway, abolished the inhibitory effects of MK-4 on ZA-induced cell metabolic stresses and osteoblast damage. Combined with experimental evidences from MRONJ mouse models and MC3T3-E1 cells, our findings suggested that MK-4 prevents ZA-induced MRONJ by inhibiting osteoblast apoptosis through suppression of cellular metabolic stresses in a SIRT1-dependent manner. The results provide a novel translational direction for the clinical application of MK-4 for preventing MRONJ.

Effects of Menaquinone-7 on the Bone Health of Growing Rats under Calcium Restriction: New Insights from Microbiome-Metabolomics.

Insufficient calcium intake during growth is a global public health concern. The aim of this study was to investigate the effects of dietary menaquinone-7 (MK-7) on bone accrual in growing Sprague-Dawley rats under calcium restriction. Following 13 weeks of treatment, various bone quality parameters, including microarchitecture, were measured. Fecal and cecal samples were subjected to microbiome (16S rRNA gene sequencing) analyses, while metabolomics analysis of the cecum and humerus samples was analyzed based on UHPLC-Q/TOF-MS. We found that calcium deficiency diminished the richness of the microbiome and disrupted microbiome composition, accompanied by an elevation in the relative abundance of Parasutterella. Furthermore, calcium insufficiency escalated the level of isovaleric acid and modified the metabolic profiles. MK-7 supplementation significantly increased the cortical thickness, cortical bone area, and the calcium content of the femur. Apart from improving bone calcium deposition and diminishing bone resorption, the mechanisms underlying the beneficial effects of MK on bone quality also involve the modulation of the host's metabolic pathways and the composition of gut microbiota. The gut-bone axis holds promise as an efficacious target for ameliorating calcium deficiency in children's bone quality, and MK-7 is a promising dietary supplement from this perspective.

The additive effect of vitamin K supplementation and bisphosphonate on fracture risk in post-menopausal osteoporosis: a randomised placebo controlled trial

SummaryThis study assessed whether vitamin K, given with oral bisphosphonate, calcium and/or vitamin D has an additive effect on fracture risk in post-menopausal women with osteoporosis. No difference in bone density or bone turnover was observed although vitamin K1 supplementation led to a modest effect on parameters of hip geometry.PurposeSome clinical studies have suggested that vitamin K prevents bone loss and may improve fracture risk. The aim was to assess whether vitamin K supplementation has an additive effect on bone mineral density (BMD), hip geometry and bone turnover markers (BTMs) in post-menopausal women with osteoporosis (PMO) and sub-optimum vitamin K status receiving bisphosphonate, calcium and/or vitamin D treatment.MethodsWe conducted a trial in 105 women aged 68.7[12.3] years with PMO and serum vitamin K1 ≤ 0.4 µg/L. They were randomised to 3 treatment arms; vitamin K1 (1 mg/day) arm, vitamin K2 arm (MK-4; 45 mg/day) or placebo for 18 months. They were on oral bisphosphonate and calcium and/or vitamin D. We measured BMD by DXA, hip geometry parameters using hip structural analysis (HSA) software and BTMs. Vitamin K1 or MK-4 supplementation was each compared to placebo. Intention to treat (ITT) and per protocol (PP) analyses were performed.ResultsChanges in BMD at the total hip, femoral neck and lumbar spine and BTMs; CTX and P1NP did not differ significantly following either K1 or MK-4 supplementation compared to placebo. Following PP analysis and correction for covariates, there were significant differences in some of the HSA parameters at the intertrochanter (IT) and femoral shaft (FS): IT endocortical diameter (ED) (% change placebo:1.5 [4.1], K1 arm: -1.02 [5.07], p = 0.04), FS subperiosteal/outer diameter (OD) (placebo: 1.78 [5.3], K1 arm: 0.46 [2.23] p = 0.04), FS cross sectional area (CSA) (placebo:1.47 [4.09],K1 arm: -1.02[5.07], p = 0.03).ConclusionThe addition of vitamin K1 to oral bisphosphonate with calcium and/or vitamin D treatment in PMO has a modest effect on parameters of hip geometry. Further confirmatory studies are needed.Trial registrationThe study was registered at Clinicaltrial.gov:NCT01232647.

Study protocol of the InterVitaminK trial: a Danish population-based randomised double-blinded placebo-controlled trial of the effects of vitamin K (menaquinone-7) supplementation on cardiovascular, metabolic and bone health

IntroductionVitamin K has been suggested to have protective effects against progression of vascular calcification and development of cardiovascular disease (CVD). However, few well-powered randomised controlled trials have examined whether vitamin...

Vitamin K supplementation and bone mineral density in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis. In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360µg or placebo for 2years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1-L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status. After 2years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo -0.023g/cm2 [95% confidence interval (CI) -0.039 to -0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050g/cm2 (95% CI 0.015-0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants. Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.

The Effects of Vitamin K2 (Menaquinone-7) on the Leptin and Adiponectin Levels in Overweight/Obese Type 2 Diabetes Patients: A Randomized Clinical Trial

Background: Type 2 diabetes mellitus (T2DM) is a prevalent disease with metabolic consequences. Lower levels of adiponectin and higher levels of leptin were reported in T2DM. This study aimed to evaluate the effect of menaquinone-7 (MK-7) supplementation on adiponectin and leptin in overweight/obese T2DM patients. Methods: Sixty men and women with T2DM and 27 ≤ body mass index &lt; 35 kg/m2 , participated in this double-blind placebo-controlled randomized clinical trial for 12 weeks. The subjects were allocated into intervention (200 µg/day MK-7) or placebo groups. Three-day food records, anthropometrics and physical activity were assessed and fasting blood samples were collected at the pre- and post-intervention. Serum adiponectin, leptin, fasting blood sugar (FBS) and fasting insulin (FI) were measured and adiponectin to leptin ratio (A/L ratio) was calculated. Results: MK-7 decreased fasting blood sugar (P: 0.018) and fasting insulin (P: 0.012), according to a within group analysis of the 45 patients who finished the research. Fasting blood sugar (P: 0.024) and leptin levels (P: 0.032) were lower in the MK-7 group, but there were no significant changes between the groups in terms of adiponectin or the adiponectin to leptin (A/L) ratio. Conclusion: Current study showed that MK-7 supplementation could lead to significant reduction in leptin and FBS, but it has no effect on the adiponectin and A/L ratio in overweight/ obese T2DM patients.

The effect of menaquinone-7 supplementation on dp-ucMGP, PIVKAII, inflammatory markers, and body composition in type 2 diabetes patients: a randomized clinical trial

BackgroundType 2 diabetes mellitus (T2DM) is a common disorder that is characterized by chronic hyperglycemia and chronic inflammation, which also have a reinforcing effect on each other. The present research studied the effects of menaquinone (MK-7) supplementation on serum dp-ucMGP (dephospho uncarboxylated Matrix Gla Protein), PIVKAII (Prothrombin Induced by Vitamin K Absence), inflammatory markers and body composition indices in type 2 diabetes mellitus (T2DM) patients.MethodsThis 12-week double-blind placebo-controlled randomized clinical trial allocated 60 T2DM patients equally into a MK-7 (200 mcg/day) group or a placebo group. All patients also received dietary advice at the beginning of study and their dietary intakes were checked using a 3-day food record. The body composition of each patient was also measured and their vitamin K status was assessed using the ELISA method to measure serum dp-ucMGP and PIVKAII. In addition, inflammatory status indices were also measured, including hsCRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6) and TNF-α (tumor necrosis factor alpha). All measurements were made both before and after the intervention period.ResultsIn total 45 patients completed the trial (MK-7 group = 23 and placebo group = 22). The calorie and macronutrient intake of the two groups were similar pre and post intervention. There were statistically significant increases in dietary vitamin K intake for both groups over the course of the study (p < 0.05), but the intergroup differences were not significant. The body composition indices (i.e., body fat percentage, fat mass, fat free mass, muscle mass, bone mass and total body water) were not significantly different between groups or across the trial. The serum levels of the vitamin K markers, PIVKAII and dp-ucMGP, decreased significantly in the MK-7 group over the course of the study (p < 0.05), but there was no decrease in the placebo group. However, after adjusting for the baseline levels and changes in vitamin K intake, the between group differences were only significant for PIVKAII (p < 0.05). Following the intervention, the serum levels of the inflammatory markers (hsCRP, IL-6, and TNF-α) were significantly lower in the MK-7 group (p < 0.05), but not in the placebo group. However, the between group differences in the inflammatory markers were not statistically significant.ConclusionsAlthough further studies are needed, it appears that MK-7 supplementation can be effective in improving PIVKAII levels, but not for improving dp-ucMGP, inflammatory status or the body composition indices of T2DM patients.Trial registration numberThis study was prospectively registered at the Iranian Registry of Clinical Trials on the 20th of May 2019 (ID: IRCT20100123003140N22).

Vitamin K Epoxide Reductase Complex Subunit 1-Like 1 (VKORC1L1) Inhibition Induces a Proliferative and Pro-inflammatory Vascular Smooth Muscle Cell Phenotype.

Background: Vitamin K antagonists (VKA) are known to promote adverse cardiovascular remodeling. Contrarily, vitamin K supplementation has been discussed to decelerate cardiovascular disease. The recently described VKOR-isoenzyme Vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) is involved in vitamin K maintenance and exerts antioxidant properties. In this study, we sought to investigate the role of VKORC1L1 in neointima formation and on vascular smooth muscle cell (VSMC) function.Methods and Results: Treatment of wild-type mice with Warfarin, a well-known VKA, increased maladaptive neointima formation after carotid artery injury. This was accompanied by reduced vascular mRNA expression of VKORC1L1. In vitro, Warfarin was found to reduce VKORC1L1 mRNA expression in VSMC. VKORC1L1-downregulation by siRNA promoted viability, migration and formation of reactive oxygen species. VKORC1L1 knockdown further increased expression of key markers of vascular inflammation (NFκB, IL-6). Additionally, downregulation of the endoplasmic reticulum (ER) membrane resident VKORC1L1 increased expression of the main ER Stress moderator, glucose-regulated protein 78 kDa (GRP78). Moreover, treatment with the ER Stress inducer tunicamycin promoted VKORC1L1, but not VKORC1 expression. Finally, we sought to investigate, if treatment with vitamin K can exert protective properties on VSMC. Thus, we examined effects of menaquinone-7 (MK7) on VSMC phenotype switch. MK7 treatment dose-dependently alleviated PDGF-induced proliferation and migration. In addition, we detected a reduction in expression of inflammatory and ER Stress markers.Conclusion: VKA treatment promotes neointima formation after carotid wire injury. In addition, VKA treatment reduces aortal VKORC1L1 mRNA expression. VKORC1L1 inhibition contributes to an adverse VSMC phenotype, while MK7 restores VSMC function. Thus, MK7 supplementation might be a feasible therapeutic option to modulate vitamin K- and VKORC1L1-mediated vasculoprotection.

Vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) inhibition induces a proliferative and pro-inflammatory vascular smooth muscle cell phenotype

Abstract Background Vitamin K antagonists (VKA) like Warfarin are known to promote adverse cardiovascular remodelling. Contrarily, vitamin K supplementation has been discussed to decelerate cardiovascular disease. The recently described VKOR-isoenzyme Vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) is involved in vitamin K maintenance and exerts antioxidant properties. In this study, we sought to investigate the role of VKORC1L1 in neointima formation and on vascular smooth muscle cell (VSMC) function. Methods and results Treatment of wild-type mice with Warfarin increased maladaptive neointima formation after carotid artery injury. This was accompanied by reduced vascular mRNA expression of VKORC1L1. In vitro, Warfarin was found to reduce VKORC1L1 mRNA expression in VSMC. VKORC1L1 downregulation by siRNA promoted viability, migration and formation of reactive oxygen species. VKORC1L1 knockdown further increased expression of key markers of vascular inflammation (NFκB, IL-6). Additionally, downregulation of the endoplasmic reticulum (ER) membrane resident VKORC1L1 increased expression of the main ER Stress moderator, glucose-regulated protein 78 kDa (GRP78). Moreover, treatment with the ER Stress inducer Tunicamycin promoted VKORC1L1, but not VKORC1 expression. Finally, we sought to investigate, if treatment with vitamin K can mediate the protective properties of VKORC1L1. Thus, we examined effects of menaquinone-7 (MK7) on VSMC phenotype switch. MK7 treatment dose-dependently alleviated PDGF-induced proliferation and migration. In addition, we detected a reduction in expression of inflammatory and ER Stress markers. Conclusion VKA-induced neointima formation is associated with reduced vascular VKORC1L1 expression. VKORC1L1 inhibition contributes to an adverse VSMC phenotype while MK7 restores VSMC function. Thus, MK7 supplementation might be a feasible therapeutic option to modulate vitamin K- and VKORC1L1-mediated vasculoprotection. Funding Acknowledgement Type of funding sources: None.

Menaquinone 4 Reduces Bone Loss in Ovariectomized Mice through Dual Regulation of Bone Remodeling.

Epidemiologic studies showed that higher vitamin K (VK) consumption correlates with a reduced risk of osteoporosis, yet the dispute remains about whether VK is effective in improving bone mineral density (BMD). We sought to discover the anti-osteoporotic effect of menaquinone-4 (MK-4) and evaluate the expression of critical genes related to bone formation and bone resorption pathways in the body. Fifty female C57BL/6 mice (aged 13 weeks) were randomly arranged to a sham-operated group (SHAM, treated with corn oil) and four ovariectomized groups that were administered corn oil (OVX group), estradiol valerate (EV, 2 mg/kg body weight as the positive control), low or high doses of VK (LVK and HVK; 20 and 40 mg MK-4/kg body weight, respectively) by gavage every other day for 12 weeks. Body and uterine weight, serum biochemical indicators, bone microarchitecture, hematoxylin-eosin (HE) staining, and the mRNA expression of critical genes related to bone formation and bone resorption pathways were assessed. Either dose of MK-4 supplementation increased the alkaline phosphatase (ALP), decreased the undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase (TRACP, p < 0.05) levels, and presented higher BMD, percent bone volume (BV/TV), trabecular thickness (Tb.Th), and lower trabecular separation (Tb.Sp) and structure model index (SMI, p < 0.05) compared with the OVX group. Additionally, both doses of MK4 increased the mRNA expression of Runx2 and Bmp2 (p < 0.05), whereas the doses down-regulated Pu.1 and Nfatc1 (p < 0.05) mRNA expression, the high dose decreased Osx and Tgfb (p < 0.05) mRNA expression, and the low dose decreased Mitd and Akt1 (p < 0.05) mRNA expression. These data show the dual regulatory effects of MK-4 on bone remodeling in ovariectomized mice: the promotion of bone anabolic activity and inhibition of osteoclast differentiation, which provides a novel idea for treating osteoporosis.

Sodium [18F]Fluoride PET Can Efficiently Monitor In Vivo Atherosclerotic Plaque Calcification Progression and Treatment.

Given the high sensitivity and specificity of sodium [18F]Fluoride (Na[18F]F) for vascular calcifications and positive emerging data of vitamin K on vascular health, the aim of this study is to assess the ability of Na[18F]F to monitor therapy and disease progression in a unitary atherosclerotic mouse model. ApoE−/− mice were placed on a Western-type diet for 12-weeks and then split into four groups. The early stage atherosclerosis group received a chow diet for an additional 12-weeks, while the advanced atherosclerosis group continued the Western-type diet. The Menaquinone-7 (MK-7) and Warfarin groups received MK-7 or Warfarin supplementation during the additional 12-weeks, respectively. Control wild type mice were fed a chow diet for 24-weeks. All of the mice were scanned with Na[18F]F using a small animal positron emission tomography (PET)/computed tomography (CT). The Warfarin group presented spotty calcifications on the CT in the proximal aorta. All of the spots corresponded to dense mineralisations on the von Kossa staining. After the control, the MK-7 group had the lowest Na[18F]F uptake. The advanced and Warfarin groups presented the highest uptake in the aortic arch and left ventricle. The advanced stage group did not develop spotty calcifications, however Na[18F]F uptake was still observed, suggesting the presence of micro-calcifications. In a newly applied mouse model, developing spotty calcifications on CT exclusively in the proximal aorta, Na[18F]F seems to efficiently monitor plaque progression and the beneficial effects of vitamin K on cardiovascular disease.

Beneficial health effects of Menaquinone-7 on body composition, glycemic indices, lipid profile, and endocrine markers in polycystic ovary syndrome patients.

ObjectiveThe aim of this study was to investigate the effect of oral vitamin K2 (Menaquinone‐7 [MK‐7]) on clinical and biochemical parameters in polycystic ovary syndrome (PCOS) patients.MethodsIn this randomized, double‐blind, placebo‐controlled clinical trial, 84 PCOS patients were randomly assigned into the treatment (90 µg Menaquinone‐7 daily for 8 weeks) and placebo groups. Insulin resistance, lipid profile, endocrine biomarkers, and body composition of the participants were measured before and after the intervention. This study was performed in Ghadir Mother & Child Hospital affiliated to Shiraz University of Medical Sciences, Shiraz, Iran.ResultsMenaquinone‐7 supplementation, when compared to placebo, significantly decreased serum fasting insulin (p = .002), homeostasis model of assessment insulin resistance (p = .002), and homeostasis model of assessment β‐cell function (p = .02) in addition to a significant increase in quantitative insulin sensitivity check index (p = .001). Also, MK‐7 administration led to significant declines in serum triglyceride (p = .003) and dihydrotestosterone (DHT; p = .03) levels, free androgen index (p < .001), waist circumference (p = .03), and body fat mass (p < .001) as well as significant increases in skeletal muscle (p < .001) and sex hormone binding globulin (SHBG, p < .001).ConclusionsThis study highlights the beneficial effects of MK‐7 on insulin resistance, fat mass, skeletal muscle, and serum levels of triglyceride, DHT, and SHBG in PCOS patients. Therefore, it seems that MK‐7 supplementation might be an appropriate additive treatment for PCOS patients.

Effects of MK-7 Supplementation on Glycemic Status, Anthropometric Indices and Lipid Profile in Patients with Type 2 Diabetes: A Randomized Controlled Trial.

BackgroundType 2 diabetes mellitus (T2DM) is a prevalent disorder which accounts for 90–95% of diabetic patients. The aim of this study was to assess the effects of menaquinone (MK-7) supplementation on glycemic indices, anthropometric indices and lipid profile, among patients with T2DM.MethodsIn this double-blind placebo-controlled randomized clinical trial, 60 men and women with T2DM were allocated equally into either the MK-7 (200 µg/day) or the placebo group. Physical activity level and dietary intake were assessed using the international physical activity questionnaire-short form (IPAQ-SF) and a 3-day food record, pre- and post-intervention. Anthropometric measures, blood pressure, glycemic indices and lipid profile including fasting blood sugar (FBS), hemoglobin A1c (HBA1C), fasting insulin (FI), homeostatic model assessment insulin resistance index (HOMA-IR), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) were measured at baseline and after twelve weeks.ResultsForty-five patients completed the trial. There were no significant between-group differences for calorie intake, macronutrient intake, physical activity level or anthropometric measures at baseline and at the end of the study. Dietary vitamin K intake increased significantly at the end of the study in the MK-7 (p: 0.02) and placebo (p: 0.001) groups, but intergroup differences were not significant (p: 0.86). FBS (p: 0.01), HbA1c (p: 0.002), fasting insulin (p: 0.01) and HOMA-IR (p: 0.007) decreased significantly in the MK-7 group. Furthermore, after adjustment for the baseline values and changes of vitamin K intake at the end of study, FBS and HbA1C showed significant intergroup changes, and they were significantly lower in the MK-7 group compared to the placebo group. Lipid profile (TG, TC, LDL-C, HDL-C and LDL-C/HDL-C) did not change significantly within or between groups.ConclusionMK-7 supplementation seems to be effective in the improvement of glycemic indices, but not the lipid profile of patients with T2DM.Clinical Trial RegistrationThe present study was prospectively registered at the Iranian Registry of Clinical Trials on May 2019 (ID: IRCT20100123003140N22).

The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial

ABSTRACTBackgroundVitamin K occurs in the diet as phylloquinone and menaquinones. Observational studies have shown that both phylloquinone and menaquinone intake might reduce cardiovascular disease (CVD) risk. However, the effect of vitamin K on vascular calcification is unknown.ObjectivesThe aim of this study was to assess if menaquinone supplementation, compared to placebo, decreases vascular calcification in people with type 2 diabetes and known CVD.MethodsIn this double-blind, randomized, placebo-controlled trial, we randomly assigned men and women with type 2 diabetes and CVD to 360 µg/d menaquinone-7 (MK-7) or placebo for 6 mo. Femoral arterial calcification at baseline and 6 mo was measured with 18sodium fluoride positron emission tomography (18F-NaF PET) scans as target-to-background ratios (TBRs), a promising technique to detect active calcification. Calcification mass on conventional computed tomography (CT) scan was measured as secondary outcome. Dephosphorylated–uncarboxylated matrix Gla protein (dp-ucMGP) concentrations were measured to assess compliance. Linear regression analyses were performed with either TBR or CT calcification at follow-up as the dependent variable, and treatment and baseline TBR or CT calcification as independent variables.ResultsWe randomly assigned 35 patients to the MK-7 group (33 completed follow-up) and 33 to the placebo group (27 completed follow-up). After the 6-mo intervention, TBR tended to increase in the MK-7 group compared with placebo (0.25; 95% CI: −0.02, 0.51; P = 0.06), although this was not significant. Log-transformed CT calcification mass did not increase in the intervention group compared with placebo (0.50; 95% CI: −0.23, 1.36; P = 0.18). MK-7 supplementation significantly reduced dp-ucMGP compared with placebo (−205.6 pmol/L; 95% CI: −255.8, −155.3 pmol/L). No adverse events were reported.ConclusionMK-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared with placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary. This trial was registered at clinicaltrials.gov as NCT02839044.

Maximal dose-response of vitamin-K2 (menaquinone-4) on undercarboxylated osteocalcin in women with osteoporosis.

Low concentrations of serum vitamin K accompany high concentrations of undercarboxylated osteocalcin (ucOC) and osteoporotic fractures. Although vitamin K2 (MK-4) is approved as a therapeutic agent for the treatment of osteoporosis in some countries, the dose-response is unknown. The objective of this study was to assess the improvement in carboxylation of osteocalcin (OC) in response to escalating doses of MK-4 supplementation. A nine-week, open-labeled, prospective cohort study was conducted in 29 postmenopausal women who suffered hip or vertebral compression fractures. Participants took low-dose MK-4 (0.5mg) for 3 weeks (until the second visit), then medium-dose MK-4 (5mg) for 3 weeks (until the third visit), then high-dose MK-4 (45mg) for 3 weeks. The mean±SD age of the participants was 69±9years. MK-4 dose (p<0.0001), but neither age nor other relevant medications (e.g. bisphosphonates) correlated with improvement in %ucOC. As compared to baseline concentrations (geometric mean±SD) of 16.8±2.4, 0.5mg supplementation halved %ucOC to 8.7±2.2 (p<0.0001) and the 5-mg dose halved %ucOC again (to 3.9±2.2; p=0.0002 compared to 0.5-mg dose). However, compared to 5mg/day, there was no additional benefit of 45mg/day (%ucOC 4.6; p=NS vs. 5-mg dose). MK-4 supplementation resulted in borderline increases in γ-carboxylated osteocalcin (glaOC; p=0.07). There were no major side effects of MK-4 supplementation. In postmenopausal women with osteoporotic fractures, supplementation with either 5 or 45mg/day of MK-4 reduces ucOC to concentrations typical of healthy, pre-menopausal women.

Effects of menaquinone-7 supplementation in patients with aortic valve calcification: study protocol for a randomised controlled trial

IntroductionAortic stenosis is a common heart valve disease, and due to the growing elderly population, the prevalence is increasing. The disease is progressive with increasing calcification of the valve cusps....

Vitamin K-induced effects on body fat and weight: results from a 3-year vitamin K2 intervention study.

Vitamin K status has been linked to fat and glucose metabolism by several authors, but whether high vitamin K intake influences body weight or composition has remained unclear. Here we tested the hypothesis that increased vitamin K intake decreases body fat or fat distribution. In a randomized placebo-controlled human intervention trial, 214 postmenopausal women, 55-65 years of age, received either 180 mcg/day of vitamin K2 (menaquinone-7, MK-7) or placebo for 3 years. Osteocalcin (OC) carboxylation was used as a marker for vitamin K status, and fat distribution was assessed by dual-energy X-ray absorptiometry total body scan. In the total cohort, MK-7 supplementation increased circulating carboxylated OC (cOC) but had no effect on body composition. In those with an above-median response in OC carboxylation ('good responders'), MK-7 treatment resulted in a significant increase in total and human molecular weight adiponectin and a decrease in abdominal fat mass and in the estimated visceral adipose tissue area compared with the placebo group and the poor responders. The fact that changes in body composition measures or markers for fat or glucose metabolism were not associated with changes in uncarboxylated OC (ucOC) does not support the assumption that ucOC stimulates fat metabolism in humans. Instead, high vitamin K2 intake may support reducing body weight, abdominal and visceral fat, notably in subjects showing a strong increase in cOC. A causal relation between the changes in cOC and body fat or distribution cannot be concluded from these data.

Bioavailability and Chemical/Functional Aspects of Synthetic MK-7 vs Fermentation-Derived MK-7 in Randomised Controlled Trials.

We investigated the bioavailability of a synthetic form of the vitamin K2 molecule menaquinone-7 (MK-7) in a randomised single-blinded two-way cross-over study. Healthy subjects (20 - 66 years of age) took a single 180 μg dose of synthetic MK-7 or fermentation-derived MK-7, and serum MK-7 concentrations were monitored for 72 hours to calculate AUC(0 - 72 h) and Cmax. We also compared the biological effects of placebo, fermentation-derived MK-7 (90 μg) and 3 doses of synthetic MK-7(45, 90 and 180 μg) in a randomised double-blinded parallel study. Healthy subjects (20 - 60 years of age) took one of the supplements daily for 43 days, and the fraction of carboxylated osteocalcin (OC) was compared between day 1 and day 43 as a marker for vitamin K activity. In the bioavailability study, the 90 % confidence interval for the ratio of the AUC(0-72 h) values for synthetic and fermentationderived MK-7 was 83 - 111, indicating bioequivalence. The 90 % confidence interval for the Cmax ratio was 83 - 131. The serum concentrations of carboxylated OC and undercarboxylated OC were increased (p = 0.01) and reduced (p = 0.02), respectively, after daily intake of 180 μg of synthetic MK-7 for 43 days, indicating increased vitamin K activity. Across both studies, only 1 participant reported an adverse event (dry mouth; 180 μg synthetic MK-7 group, functional study) that was considered possibly related to synthetic MK-7 supplementation. Our findings provide evidence that the tested synthetic form of MK-7 is bioequivalent to fermentation-derived MK-7, exhibits vitamin K activity and is well tolerated in healthy subjects.