Vitamin K supplementation and arterial calcification in dialysis: results of the double-blind, randomised, placebo-controlled RenaKvit trial

Abstract Background Arterial calcification is associated with cardiovascular mortality in dialysis patients. Active matrix Gla-protein (MGP) is a vitamin K-dependent inhibitor of arterial calcification. Elevated plasma concentrations of inactive MGP, i.e. dephosphorylated-uncarboxylated MGP (dp-ucMGP), is prevalent in dialysis patients. MGP inactivity might contribute to arterial calcification. We investigated if vitamin K supplementation had an effect on arterial calcification in chronic dialysis patients. Methods In a two-year double-blind, placebo-controlled intervention trial, 48 dialysis patients were randomised to vitamin K (menaquinone-7 (MK-7), 360 µg daily), or placebo. MK-7 in serum and dp-ucMGP in plasma were used to assess vitamin K status. Carotid-femoral pulse wave velocity (cfPWV) and scores of coronary arterial calcification (CAC) and abdominal aorta calcification (AAC) were used to assess arterial calcification. Results Thirty-seven participants completed year one, 21 completed year two. At year two, serum MK-7 was 40-fold higher, and plasma dp-ucMGP 40% lower after vitamin K supplementation compared with placebo (mean dp-ucMGP difference: -1380 pmol/L (95% CI: -2029;-730)). There was no significant effect of vitamin K supplementation on cfPWV (mean difference at year two: 1.2 m/s (95% CI: -0.1; 2.4)). CAC Agatston score increased significantly in vitamin K supplemented participants, but not significantly different from placebo (mean difference at year two: 664 (95% CI: -554; 1881)). AAC scores increased in both groups, significantly so within the placebo group at year 1, but with no significant between-group differences. Conclusion Vitamin K supplementation improved vitamin K status, but did not hinder or modify the progression of arterial calcification in dialysis patients.

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

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqz147 ◽

2019 ◽

Vol 110 (4) ◽

pp. 883-890 ◽

Cited By ~ 18

Author(s):

S R Zwakenberg ◽

P A de Jong ◽

J W Bartstra ◽

R van Asperen ◽

J Westerink ◽

...

Keyword(s):

Type 2 Diabetes ◽

Vascular Calcification ◽

Vitamin K ◽

Controlled Trial ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Secondary Outcome ◽

Double Blind

ABSTRACT Background Vitamin 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. Objectives The 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. Methods In 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. Results We 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. Conclusion MK-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.

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Periostin promotes arterial calcification through PPARγ-related glucose metabolism reprogramming

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01009.2020 ◽

2021 ◽

Author(s):

Yi Zhu ◽

Jing-Jing Ji ◽

Xiao-Dong Wang ◽

Xue-Jiao Sun ◽

Min Li ◽

...

Keyword(s):

Coronary Artery ◽

Ex Vivo ◽

Matrix Gla Protein ◽

Calcium Deposition ◽

Arterial Calcification ◽

Agatston Score ◽

Respiratory Chain Complexes ◽

Ecm Remodeling ◽

Pparγ Agonist ◽

Lactate Levels

Extracellular matrix (ECM) exerts a list of biological functions, contributing to almost 30% of the osteogenic process. Periostin is a secreted protein that can alter ECM remodeling in response to vascular injury. However, the functional role of periostin in vascular calcification has yet to be fully described. Ex vivo, recombinant periostin accelerated thoracic aortas calcification, increased the expression of glycolysis key enzymes, and disturbed the normal oxidative phosphorylation (OXPHOS), which could be alleviated by the peroxisome proliferation-activated receptor γ (PPARγ) agonist pioglitazone. In vascular smooth muscle cells (VSMCs), recombinant periostin promoted VSMC-osteoblastic phenotype transition and calcium deposition, and suppressed PPARγ expression. Mechanistically, recombinant periostin caused over-activation of glycolysis and mitochondrial dysfunction in VSMCs, as assessed by extracellular acidification rate (ECAR), oxygen consumption rate, and mitochondrial respiratory chain complexes activities. Targeted glycolysis inhibitors reduced mitochondrial calcium overload, apoptosis, and periostin-induced VSMCs calcification. PPARγ agonists preserved glycolysis and OXPHOS in the stimulated microenvironment, and reversed periostin-promoted VSMC calcification. Furthermore, plasma periostin, lactate, and matrix Gla protein levels were measured in 274 patients who underwent computed tomography to determine coronary artery calcium score (Agatston score). Plasma periostin and lactate levels were both linked to an Agatston score of more than zero in patients with coronary artery calcification. There is also a positive correlation between plasma periostin and lactate levels. This study suggests that downregulation of PPARγ is involved in the mechanism by which periostin accelerates arterial calcification, partly through excessive glycolysis activation and unbalanced mitochondrial homeostasis.

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Matrix Gla-protein: The calcification inhibitor in need of vitamin K

Thrombosis and Haemostasis ◽

10.1160/th08-02-0087 ◽

2008 ◽

Vol 100 (10) ◽

pp. 593-603 ◽

Cited By ~ 145

Author(s):

Ellen C. M. Cranenburg ◽

Cees Vermeer ◽

Leon J. Schurgers

Keyword(s):

Vitamin K ◽

Potent Inhibitor ◽

Dominant Role ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Healthy Population ◽

Alternative Mechanism ◽

Vascular Health ◽

Calcification Detection ◽

Apparently Healthy

SummaryAmong the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. With the aid of conformation-specific antibodies MGP species in both tissue and the circulation have been detected in the healthy population, and significant differences were found in patients with cardiovascular disease (CVD). Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection. These assays may have potential value for identifying patients as well as apparently healthy subjects at high risk for CVD and/or cardiovascular calcification and for monitoring the treatment of CVD and vascular calcification.

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Cardiovascular Calcification and Bone: A Comparison of the Effects of Dietary and Serum Vitamin K and its Dependent Proteins

International Cardiovascular Forum Journal ◽

10.17987/icfj.v4i0.119 ◽

2015 ◽

Vol 4 ◽

pp. 6 ◽

Cited By ~ 1

Author(s):

Rachel Nicoll ◽

John McLaren Howard ◽

Michael Henein

Keyword(s):

Vitamin K ◽

Bone Health ◽

Animal Studies ◽

Oral Anticoagulants ◽

Human Study ◽

Serum Vitamin ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Font Size ◽

Considerable Uncertainty

This review compares the effect of vitamin K on cardiovascular (CV) calcification and bone health and shows that, in principal, the γ-carboxylation of the vitamin K-dependent proteins matrix Gla protein (MGP) and its bone equivalent osteocalcin (OC), generally ensures that hydroxyapatite is kept out of the CV system and is deposited in bone. This is an important finding, since there is currently no reliable treatment for CV calcification.Vitamin K2 (menaquinone) may be more effective in the arteries, while vitamin K1 (phylloquinone) is more active in bone. Nevertheless, there remains considerable uncertainty over the precise scope of the functions of MGP and OC, and their carboxylated and under-carboxylated forms, as well as the newly discovered vitamin K-dependent proteins. Although a diet high in vegetables could deliver adequate phylloquinone, supplementation of menaquinone may be necessary for those at risk of CV calcification. Several animal studies and one human study have demonstrated that arterial calcification could be reduced with vitamin K supplementation and there are further trials in progress. Patients on warfarin are particularly prone to CV calcification but there has been concern that supplementation would either counter warfarin treatment or destabilise INR. In fact, studies suggest that low dose phylloquinone did not increase coagulation and may improve the stability of anticoagulant therapy. Furthermore, use of oral anticoagulants which do not affect vitamin K metabolism, such as ximelagatran, could be used when there is a need for vitamin K supplementation for artery or bone health.

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P1283BASELINE CHARACTERISTICS IN THE “IPACK-HD” STUDY (INHIBIT PROGRESSION OF CORONARY ARTERY CALCIFICATION WITH VITAMIN K IN HEMODIALYSIS PATIENTS): A PHASE 2, MULTI-CENTRE, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED PILOT TRIAL

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1283 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Corinne Babiolakis ◽

Deborah Zimmerman ◽

Louise Moist ◽

Andrew Day ◽

Patrick Norman ◽

...

Keyword(s):

Coronary Artery ◽

Kidney Disease ◽

Vitamin K ◽

Coronary Artery Calcification ◽

Pilot Trial ◽

Matrix Gla Protein ◽

Phase 2 ◽

Double Blind ◽

Baseline Characteristics ◽

Very High

Abstract Background and Aims The leading cause of mortality for patients with end-stage kidney disease (ESKD) is cardiovascular disease (CVD). This is due, in part, to vascular calcification (VC) where calcium becomes deposited within arterial walls causing narrowing of the arteries and altering their flexibility. Matrix Gla protein (MGP), a vitamin k-dependent protein, is a key local inhibitor of VC and becomes up-regulated adjacent to sites of calcification. There is a very high prevalence of vitamin K deficiency in patients across the chronic kidney disease (CKD) spectrum and vitamin K has been shown to prevent VC in experimental models. To date, no trial has examined whether vitamin K supplementation prevents the progression of coronary artery calcification in patients with ESKD, a group in which high risk has been established. The aim of the iPACK-HD pilot study is to determine whether a trial to determine whether vitamin K has a favourable effect on coronary artery calcium (CAC) scores in patients with ESKD is feasible. Method The iPACK-HD pilot trial is a phase 2 multi-centre, double-blind, randomized, placebo-controlled clinical trial conducted in three sites (Kingston, Ottawa and London) in Ontario, Canada. Adult patients with ESKD on chronic dialysis with a baseline CAC score of ≥30 Agatston units (AUs) are randomized to receive 10 mg of vitamin K1 or matching placebo administered post-hemodialysis 3x/week for a total of 12 months. Exclusions include medical conditions that require anticoagulation and a history of either coronary artery bypass, grafting or stenting. Randomization is stratified based on diabetes and study centre. Baseline CAC scores are determined by computed tomography (CT) and demographic and laboratory data at study entry are obtained by participant interview and medical chart review. Results A total of 85 participants are randomized into this trial. Baseline characteristics of trial participants are reported as mean ± SD, median [IQR], or %. The mean age is 63 ± 13 years. There are a higher proportion of males (57%) than females and whites (85%) compared to all other ethnicities. Forty-four percent of participants have diabetes and 77% have hypertension. Dialysis vintage is 0.9 [0.4,2.7] years. Most participants take calcium-based phosphate binders (89%) and over half of participants take an HMG-CoA reductase inhibitor (53%) or vitamin D (61%). Clinical laboratory values are presented in Table 1. Total median CAC and volume calcium scores are 587 [252,1416] AUs and 482 [206,1170] mm3, respectively. Sixty-five (76%) participants had a study exit CT scan performed upon completion of the study. Of 156 doses, a median of 150 [123,155] were received and 2 [1,6] were missed. Conclusion Participants in the iPACK-HD study have a high burden of calcification but are similar in baseline characteristics to the Canadian hemodialysis population. Loss to trial completion is 24%, but the most frequent reason is kidney transplantation. Adherence to study drug is very high with few reported side effects.

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Effect of 6-Month Vitamin D Supplementation on Plasma Matrix Gla Protein in Older Adults

Nutrients ◽

10.3390/nu11020231 ◽

2019 ◽

Vol 11 (2) ◽

pp. 231 ◽

Cited By ~ 4

Author(s):

Adriana van Ballegooijen ◽

Joline Beulens ◽

Leon Schurgers ◽

Elisa de Koning ◽

Paul Lips ◽

...

Keyword(s):

Vitamin D ◽

Vitamin K ◽

Controlled Trial ◽

Vitamin K Antagonists ◽

Functional Limitation ◽

Vitamin D Supplementation ◽

Vitamin K Antagonist ◽

Matrix Gla Protein ◽

Double Blind

Vitamin D supplementation has been widely promoted to restore 25-hydroxyvitamin D concentrations; however, experimental evidence suggests a nutrient interaction with vitamin K. We assessed the effects of 1200 IU vitamin D3 per day versus placebo for six months on vitamin K status in a randomized, double-blind, placebo-controlled trial with participants aged 60–80 years with depressive symptoms and ≥1 functional limitation for a secondary analysis. Stored baseline and six-month follow-up blood samples were available for 131 participants (n = 65 placebo vs. n = 66 vitamin D supplementation). We measured dephosphorylated uncarboxylated matrix gla protein (MGP) (dp-ucMGP) concentrations—a marker of vitamin K deficiency. Mean age was 68 years, and 89 participants (68%) were women. Vitamin K antagonists were used by 16 participants and multivitamin supplements by 50 participants. No differences in change between intervention and placebo were found (−38.5 ± 389 vs. 4.5 ± 127 (pmol/L), p = 0.562). When excluding vitamin K antagonist users and multivitamin users, dp-ucMGP at follow-up was significantly higher in the vitamin D group (n = 40) compared to placebo (n = 30), with a difference of 92.8 (5.7, 180) pmol/L, adjusting for baseline dp-ucMGP and sex. In conclusion, vitamin D supplementation for six months did not affect vitamin K status; however, among participants without vitamin K antagonist or multivitamin use, vitamin D supplementation influenced dp-ucMGP concentrations.

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Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1258 ◽

2020 ◽

Cited By ~ 3

Author(s):

Anton S M Dofferhoff ◽

Ianthe Piscaer ◽

Leon J Schurgers ◽

Margot P J Visser ◽

Jody M W van den Ouweland ◽

...

Keyword(s):

Vitamin K ◽

Elastic Fiber ◽

Protein S ◽

Coagulation Factors ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Fiber Damage ◽

Fiber Degradation ◽

Factor Ii ◽

Poor Outcomes

Abstract Background Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2–infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. Methods A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K–dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography. Results dp-ucMGP was elevated in COVID-19 patients compared with controls (P < .001), with even higher dp-ucMGP in patients with poor outcomes (P < .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P < .001) and with coronary artery (P = .002) and thoracic aortic (P < .001) calcification scores. Conclusions dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.

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Role of Vitamin K in CKD: Is Its Supplementation Advisable in CKD Patients?

Kidney & Blood Pressure Research ◽

10.1159/000516611 ◽

2021 ◽

pp. 1-8

Author(s):

Patrycja Grzejszczak ◽

Ilona Kurnatowska

Keyword(s):

Vitamin K ◽

Disease Risk ◽

Active Form ◽

Serum Markers ◽

Vitamin K2 ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Increased Risk ◽

Wall Calcification ◽

Bone Complications

Background: Patients with CKD are at an increased risk of developing vascular calcification (VC) and bone complications which translate into a higher morbidity and mortality. The dephosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP) is considered to be an indicator of vitamin K2 status and correlates with markers of VC. It is activated by γ-glutamyl carboxylase that converts inactive MGP into an active form, and vitamin K2 is a cofactor of this reaction. The active form of MGP is a known inhibitor of arterial wall calcification and plays an important role in bone turnover. Recent studies show poor vitamin K2 status in CKD patients. We aimed to review the literature for the association between vitamin K2 status and calcification and bone disease risk and the efficacy of vitamin K2 supplementation in CKD population. Summary: Most CKD patients, including those on renal replacement therapy, have vitamin K2 deficiency. The dp-ucMGP level, a marker of vitamin K2 status, is decreased by vitamin K2 supplementation in CKD patients, but there is no unequivocal proof that it influences arterial calcification progression and bone complications. Key Messages: CKD population are at risk of vitamin K deficiency. Supplementation of vitamin K2 is safe and improves the serum markers of its deficiency. There is lack of strong evidence that vitamin K2 supplementation slows progression of calcification or reduces the frequency of bone complications. More prospective studies are needed.

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456Risk of arterial calcification by conventional vitamin K antagonist treatment

European Heart Journal ◽

10.1093/eurheartj/ehz747.0115 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Hasific ◽

K A Oevrehus ◽

O Gerke ◽

J Hallas ◽

M Busk ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Vitamin K ◽

Treatment Duration ◽

Oral Anticoagulants ◽

Statin Treatment ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Plaque Burden

Abstract Background Vitamin K antagonists (VKA) are the most frequently prescribed oral anticoagulants worldwide although new oral anticoagulants (NOAC) have become an important alternative. VKA inhibits Vitamin K1 necessary to produce coagulation factors but also Vitamin K2, which is essential in the activation of matrix-Gla protein, thought to be a strong local inhibitor of arterial calcifications. Purpose The aim was to investigate, whether VKA treatment is associated with coronary artery calcification (CAC) in a population with no prior cardiovascular disease (CVD). Methods We collected data on cardiovascular risk factors and CAC scores from cardiac CT scans performed as part of clinical examinations (n=9,672) or research studies (n=14,166) in the period 2007–2017. Data on use of VKA and NOAC was obtained from the Danish National Health Service Prescription Database. The association between VKA treatment duration and categorized CAC score was investigated by ordered logistic regression while adjusting for covariates. The independent variables included in the model were: age, gender, smoking, body mass index (BMI), diabetes mellitus, hypertension, hypercholesterolemia and/or statin treatment, family history of CVD, estimated glomerular filtration rate, VKA treatment duration and NOAC treatment duration. The categorisation of CAC was: 0, 1–99, 100–399 and ≥400 AU, corresponding to no, mild, moderate and severe atherosclerotic plaque burden, respectively. Results The final study population consisted of 17,254 participants (median 67 years old, 75% males) with no prior CVD, of which 1,748 (10%) and 1,144 (7%) had been treated with VKA or NOAC, respectively. A longer duration of VKA treatment was associated with higher CAC categories (Figure). For each cumulative year of VKA treatment, the odds of being in a higher CAC category, i.e. having more severe atherosclerosis, increased (odds ratio (OR)=1.032, 95% CI 1.009–1.057). All traditional cardiovascular risk factors were also associated with CAC. In contrast, NOAC treatment duration was not associated with CAC category (OR=1.004, 95% CI 0.937–1.075). In a sensitivity analysis of patients without statin treatment (n=12,143), the association between VKA treatment and CAC category remained unchanged. There was no significant interaction between VKA treatment duration and age on CAC category. Conclusion Adjusted for cardiovascular risk factors, VKA treatment – in contrast to NOAC - is associated with more severe CAC. Additional studies are required to clarify the clinical importance of this association in terms of hard cardiovascular endpoints. Acknowledgement/Funding Novo Nordisk Foundation and Independent Research Fund Denmark

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Abstract P071: The Effect of Menaquinone -7 Supplementation on Circulating Species of Matrix-Gla Protein

Circulation ◽

10.1161/circ.125.suppl_10.ap071 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Gerdien W Dalmeijer ◽

Yvonne T van der Schouw ◽

Elke Magdeleyns ◽

Cees Vermeer ◽

Joline W Beulens

Keyword(s):

Risk Factors ◽

Vitamin K ◽

Controlled Trial ◽

Placebo Treatment ◽

Matrix Gla Protein ◽

Blood Lipid Profile ◽

Double Blind ◽

Time Treatment ◽

Changes Over Time ◽

Over Time

Background: Menaquinones intake is associated with a reduced risk of coronary calcification and coronary heart disease. This association may be explained by increased carboxylation of matrix-Gla protein (MGP) by menaquinones. However, the effect of menaquinone supplementation on MGP carboxylation has not been investigated to date. Objective: To investigate if 180 µg/day and 360 µg/day menaquinone supplementation may increase carboxylation of MGP. Design: A randomized, double-blind, placebo-controlled trial was performed. Sixty subjects aged 40–65 years were randomly allocated to supplementation of 180 μg/d, 360 μg/d of menaquinone-7 (MK-7) or placebo during 12 weeks. At baseline, after 4 and 12 weeks, desphospho-uncarboxylated MGP (dp-ucMGP), desphospho-carboxylated MGP (dp-cMGP) and total uncarboxylated MGP (t-ucMGP) were measured by ELISA techniques. Furthermore, uncarboxylated osteocalcin (ucOC), carboxylated osteocalcin (cOC) and various cardiovascular risk factors were measured. The ratio of ucOC to cOC was used as proxy of vitamin K status. Results: Dp-ucMGP, decreased significantly and dose-dependently in the 180 μg and 360 mg MK-7 supplementation groups ( P time*treatment <0.001) by 31% (400 pM to 276 pM) and 46% (391 pM to 210 pM) respectively after 12 weeks, while dp-ucMGP circulation levels remained unchanged after placebo treatment. The osteocalcin ratio also decreased significantly and dose-dependently in the 180 μg and 360 mg MK-7 treatment ( P time*treatment <0.001) by 57% (0.44 to 0.19) and 74% (0.42 to 0.11) respectively after 12 weeks, while osteocalcin ratio remained unchanged after placebo treatment, showing improved vitamin K status and indicating good compliance to the study treatment. Changes over time of dp-cMGP (p=0.42) and t-ucMGP (p=0.23) levels did not differ between treatment arms. Also the prothrombin time did not differ between treatments arms ( P time*treatment=0.92). Furthermore, changes over time in other risk factors of cardiovascular disease like blood lipid profile or blood pressure did not differ between treatments. Conclusions: Supplementation with MK-7 decreased dp-ucMGP with 31% to 46%. Like the osteocalcin ratio, dp-ucMGP can be used as a sensitive marker of vitamin K status. MK-7 supplementation has no effect on dp-cMGP and t-ucMGP concentrations.

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