Vitamin K Abstracts 9

©

 

Menaquinone-7 as a novel pharmacological therapy in the treatment of rheumatoid arthritis: A clinical study.
            (Abdel-Rahman et al., 2015) Download
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.


 

Role of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia.
            (Aziz and Patil, 2015) Download
OBJECTIVE:  To determine prophylactic role of single dose of vitamin K in prevention of antibiotic induced hypoprothrombinemia. METHODS:  This prospective comparative study included critically ill children in age group 2 mo to 12 y, admitted to a tertiary care hospital in India, likely to receive prolonged antibiotic therapy. One hundred twenty children, 60 in each group (A & B) were enrolled in the study. Patient allocation was done on alternate basis. Group A children received prophylactic vitamin K while group B did not. Baseline coagulation studies and other investigations were done in all children. Coagulation studies were repeated on day 10 and day 14 of antibiotic therapy and in between if required clinically. Children who developed deranged INR were given therapeutic vitamin K. If deranged INR returns to normal at 12 h of vitamin K administration then it indirectly confirms vitamin K deficiency. Analysis was done by fisher's t test and chi square test. RESULTS:  In children on prolonged antibiotic therapy, vitamin K deficiency was a common problem (15%). It was common in male sex, severe grade of protein energy malnutrition (PEM), N-methylthiotetrazole (NMTT) group containing antibiotics use and duration of antibiotic more than 10 d. It was same in children whether they received or did not receive prophylactic vitamin K on day 1 of antibiotic therapy (95% CI; p value 0.79). CONCLUSIONS:  Vitamin K deficiency is common problem in patients on prolonged antibiotic therapy. There is no role of single dose of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia.

Impact of menaquinone-4 supplementation on coronary artery calcification and arterial stiffness: an open label single arm study.
            (Ikari et al., 2016) Download
BACKGROUND:  Dietary intake of vitamin K has been reported to reduce coronary artery calcification (CAC) and cardiovascular events. However, it is unknown whether supplemental menaquinone (MK)-4 can reduce CAC or arterial stiffness. To study the effect of MK-4 supplementation on CAC and brachial ankle pulse wave velocity (baPWV). METHODS:  This study is a single arm design to take 45 mg/day MK-4 daily as a therapeutic drug for 1 year. Primary endpoint was CAC score determined using 64-slice multislice CT (Siemens), and the secondary endpoint was baPWV measured before and 1 year after MK-4 therapy. RESULTS:  A total of 26 patients were enrolled. The average age was 69 ± 8 years and 65 % were female. Plasma levels of phylloquinone (PK), MK-7, and MK4 were 1.94 ± 1.38 ng/ml, 14.2 ± 11.9 ng/ml and 0.4 ± 2.0 ng/ml, respectively, suggesting that MK-7 was the dominant vitamin K in the studied population. Baseline CAC and baPWV were 513 ± 773 and 1834 ± 289 cm/s, respectively. At 1 year following MK-4 supplementation, the values were 588 ± 872 (+14 %) and 1821 ± 378 cm/s (-0.7 %), respectively. In patients with high PIVKA-2, -18 % annual reduction of baPWV was observed. CONCLUSION:  Despite high dose MK-4 supplementation, CAC increased +14 % annually, but baPWV did not change (-0.7 %). The benefits of MK-4 supplementation were only observed in patients with vitamin K insufficiencies correlated with high PIVKA-2 baseline levels, reducing baPWV but not CAC. TRIAL REGISTRATION:  This study was registered as UMIN 000002760.

Vitamin K2 supplementation and arterial stiffness among renal transplant recipients-a single-arm, single-center clinical trial.
            (Mansour et al., 2017) Download
Subclinical vitamin K deficiency is prevalent among renal transplant recipients and is associated with an increased risk of cardiovascular disease. However, the association between vitamin K supplementation and improvement of arterial stiffness has not been explored in the renal transplant population. The KING trial (vitamin K2 In reNal Graft) is a single-arm study that evaluated the association between the change in vitamin K status and indices of arterial stiffness following 8 weeks of menaquinone-7 (vitamin K2) supplementation (360 μg once daily) among renal transplant recipients (n = 60). Arterial stiffness was measured using carotid-femoral pulse wave velocity (cfPWV). Subclinical vitamin K deficiency was defined as plasma concentration of dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) >500 pmol/L.At baseline, 53.3% of the study subjects had subclinical vitamin K deficiency. Supplementation was associated with a 14.2% reduction in mean cfPWV at 8 weeks (cfPWV pre-vitamin K2 = 9.8 ± 2.2 m/s vs. cfPWV post-vitamin K2 = 8.4 ± 1.5 m/s; P < .001). Mean dp-ucMGP concentrations were also significantly reduced by 55.1% following menaquinone-7 supplementation with a reduction in the prevalence of subclinical deficiency by 40% (P = .001). When controlled for age, durations of hemodialysis and transplantation, and the change in 24-hour mean arterial pressure, the improvement in arterial stiffness was independently associated with the reduction in dp-ucMGP concentration (P = .014).Among renal transplant recipients with stable graft function, vitamin K2 supplementation was associated with improvement in subclinical vitamin K deficiency and arterial stiffness. (Clinicaltrials.gov: NCT02517580).

Oral Consumption of Vitamin K2 for 8 Weeks Associated With Increased Maximal Cardiac Output During Exercise.
            (McFarlin et al., 2017) Download
Background • Vitamin K1 and K2 are not typically common in a Western diet because they are found in a variety of fermented foods. Vitamin K2 in particular has been demonstrated to restore mitochondrial function and has a key role in production of mitochondrial adenosine triphosphate. Thus, it is reasonable to speculate that dietary supplementation with vitamin K2 could increase the function of muscle with high mitochondrial content (ie, skeletal and cardiac muscle). Objective • The purpose of this study was to determine if 8 wk of dietary supplementation with Vitamin K2 could alter cardiovascular responses to a graded cycle ergometer test. Design • The study was a randomized controlled trial. Setting • The study took place in the Applied Physiology Laboratory of the Department of Biological Sciences at the University of North Texas (Denton, TX, USA). Participants • Participants were aerobically trained males and female athletes (N = 26). Intervention • Participants were randomly assigned either to a control group that received a rice flour placebo or to an intervention group that received vitamin K2. For weeks 1 to 4, participants received 300 mg/d; for weeks 5 to 8, they received 150 mg/d. Subjects assigned to the control group received similar doses to mirror the intervention group. Subjects consumed the supplements during an 8-wk period while they maintained their typical exercise habits. Outcome Measures • At baseline and postintervention, participants completed a standard, graded exercise test on an electronically braked cycle ergometer. Before the test, participants were fitted with a mouth piece, and their oxygen consumption, carbon dioxide production, respiratory rate, and respiratory exchange ratio were measured. In addition, participants were fitted with skin-mounted electrodes that measured noninvasive cardiac output, stroke volume, and heart rate. To assess the cumulative exercise change, an area-under-the-curve (AUC) value was calculated separately for each outcome variable at each treatment time point. Results • Vitamin K2 supplementation was associated with a 12% increase in maximal cardiac output, with P = .031, with a trend toward an increase in heart-rate AUC, with P = .070. No significant changes occurred in stroke volume. Conclusions • Although vitamin K2 supplementation has previously been reported to improve cardiovascular function in diseased patients, to the research team's knowledge, the current study is the first to report its potential in active individuals. More research is needed to fully evaluate the potential effects of the observed effects.

Effect of phylloquinone (vitamin K1) supplementation for 12 months on the indices of vitamin K status and bone health in adult patients with Crohn's disease.
            (O'Connor et al., 2014) Download
Although epidemiological findings support a role for vitamin K status in the improvement of bone indices in adult patients with Crohn's disease (CD), this needs to be confirmed in double-blind, randomised controlled trials (RCT) with phylloquinone (vitamin K1). By conducting two RCT, the present study aimed to first establish whether supplementation with 1000 μg of phylloquinone daily near-maximally suppresses the percentage of undercarboxylated osteocalcin in serum (%ucOC; marker of vitamin K status) in adult patients with CD currently in remission as it does in healthy adults and second determine the effect of supplementation with phylloquinone at this dose for 12 months on the indices of bone turnover and bone mass. The initial dose-ranging RCT was conducted in adult patients with CD (n 10 per group) using 0 (placebo), 1000 or 2000 μg of phylloquinone daily for 2 weeks. In the main RCT, the effect of placebo v. 1000 μg vitamin K/d (both co-administered with Ca (500 mg/d) and vitamin D3 (10 μg/d)) for 12 months (n 43 per group) on the biochemical indices of bone turnover (determined by enzyme immunoassay) and bone mass (determined by dual-energy X-ray absorptiometry) were investigated. At baseline, the mean %ucOC was 47 %, and this was suppressed upon supplementation with 1000 μg of phylloquinone daily ( - 81 %; P< 0·01) and not suppressed further by 2000 μg of phylloquinone daily. Compared with the placebo, supplementation with 1000 μg of phylloquinone daily for 12 months had no significant effect (P>0·1) on bone turnover markers or on the bone mass of the lumbar spine or femur, but modestly increased (P< 0·05) the bone mass of the total radius. Despite near maximal suppression of serum %ucOC, supplementation with 1000 μg of phylloquinone daily (with Ca and vitamin D3) had no effect on the indices of bone health in adult CD patients with likely vitamin K insufficiency.

The effect of vitamin K1 supplementation on sensitivity and insulin resistance via osteocalcin in prediabetic women: a double-blind randomized controlled clinical trial.
            (Rasekhi et al., 2015) Download
BACKGROUND/OBJECTIVES:  A relationship between osteocalcin (OC) levels and factors associated with energy metabolism and insulin resistance has been reported recently. The aim of this study was to investigate whether modulation of ostecalcin isoforms via vitamin K1 supplementation would affect glucose metabolism or insulin sensitivity in prediabetic and premenopause women. SUBJECTS/METHODS:  Eighty-two prediabetic women were randomized to consume vitamin K1 supplement (n = 39) or placebo (n = 43) for 4 weeks. Participants in the vitamin K1 supplement group received one pearl softgel capsule containing 1000 μm of phylloquinone, and the placebo group received one placebo capsule daily for 4 weeks. Blood samples were collected at baseline and after the 4-week intervention period to quantify carboxylated OC (cOC), undercarboxylated OC (ucOC) and relevant variables. RESULTS:  Phylloquinone supplementation increased the serum levels of cOC and decreased ucOC, compared with placebo (12.53 ± 5.95 compared with 7.43 ± 4.85 ng/ml and 2.47 ± 1.91 compared with 4.79 ± 2.43 ng/ml, respectively; P < 0.001). Furthermore, intake of phylloquinone supplement led to significant decreases in %ucOC (17.97 ± 12.24 compared with 43.80 ± 19.86) and 2-h post-oral glucose tolerance test (OGTT) glucose (7.32 ± 1.50 compared with 8.62 ± 1.45 mmol/l), and 2-h post-OGTT insulin level (80.34 ± 42.24 compared with 112.43 ± 53.19 μIU/ml) and increased insulin sensitivity index (2.46 ± 0.71 compared with 1.75 ± 0.61) compared with placebo. Overall, a significant association was found between changes in %ucOC and changes in 2-h post-OGTT glucose (r = 0.308, P = 0.028). CONCLUSIONS:  The results of this study demonstrated that vitamin K1 supplementation for 4 weeks did not affect insulin resistance in premenopausal and prediabetic women but had beneficial effects on glycemic status and insulin sensitivity.


 

Reducing Undercarboxylated Osteocalcin With Vitamin K Supplementation Does Not Promote Lean Tissue Loss or Fat Gain Over 3 Years in Older Women and Men: A Randomized Controlled Trial.
            (Shea et al., 2017) Download
Osteocalcin (OC) is a vitamin K-dependent protein synthesized during bone formation. Mice injected with the undercarboxylated form of OC (ucOC) had more skeletal muscle mass and less fat mass than sham-treated controls, suggesting a unique metabolic role for ucOC. UcOC decreases in response to vitamin K supplementation. Our objective was to determine the effect of reducing ucOC on change in lean tissue and fat mass in older community-dwelling adults (n = 401, mean ± SD 69 ± 6 years) using data from a randomized controlled trial of vitamin K supplementation. Over 3 years, serum ucOC was reduced by 58% in women and by 61% in men randomized to vitamin K, whereas in the control group, ucOC decreased by 1% in women and 4% in men (supplementation*time p < 0.001 in men and women). However, there were no differences in the change in appendicular lean mass (calculated as arm lean mass + leg lean mass) or total body fat mass between women randomized to vitamin K and control over 3 years (supplementation*time p values all ≥ 0.18) or between men randomized to vitamin K and control (supplementation*time p values all ≥ 0.54). Consistent with these findings, ucOC was not associated cross-sectionally with appendicular lean mass or fat mass in men or women after adjustment for total OC at baseline (all p ≥ 0.12). These findings indicate the undercarboxylated form of OC is not implicated in age-related changes in skeletal muscle or adipose tissue mass in older community-dwelling adults. © 2016 American Society for Bone and Mineral Research.

Efficacy of Vitamin K2 for Glucocorticoid-induced Osteoporosis in Patients with Systemic Autoimmune Diseases.
            (Shikano et al., 2016) Download
Objective Vitamin K2 (menatetrenone) is an effective treatment for patients with postmenopausal osteoporosis. We herein performed a subanalysis of patients with systemic autoimmune diseases undergoing glucocorticoid therapy in our previous prospective study. Methods Sixty patients were categorized into a group with vitamin K2 treatment (n=20, Group A) and a group without vitamin K2 treatment (n=40, Group B). All patients were treated with bisphosphonates. Results Serum levels of osteocalcin and undercarboxylated osteocalcin decreased significantly after the start of glucocorticoid therapy in both groups, while the serum osteocalcin level was significantly higher in Group A than Group B during the third (p=0.0250) and fourth weeks (p=0.0155). The serum level of the N-terminal peptide of type I procollagen, a bone formation marker, decreased during glucocorticoid therapy, but was significantly higher in Group A than Group B during the fourth week (p=0.0400). The bone mineral density and fracture rate showed no significant differences between the two groups. Conclusion Although vitamin K2 improves bone turnover markers in patients with osteoporosis on glucocorticoid therapy, it has no significant effect on the bone mineral density and fracture rate after 1.5 years of treatment.

Effects of Vitamin K on Matrix Metalloproteinase-3 and Rheumatoid Factor in Women with Rheumatoid Arthritis: A Randomized, Double-Blind, Placebo-Controlled Trial.
            (Shishavan et al., 2016) Download
OBJECTIVES:  Rheumatoid arthritis (RA) is an autoimmune disease characterized by an increase in some autoantibodies and proteolytic enzymes, leading to joint destruction. Although recent investigations have considered vitamin K as an anti-inflammatory nutrient with an important role in bone metabolism, there is currently limited information on its efficacy in RA. We aimed to examine the effects of vitamin K1 (phylloquinone) on the biomarker of joint destruction and autoantibody in patients with RA. MATERIALS AND METHODS:  This was a randomized clinical trial in which 64 women with RA who fulfilled the eligibility criteria were randomly allocated to an intervention or a control group. Vitamin K1 or placebo was administered to the participants for 8 weeks. Baseline characteristics and anthropometric measures were obtained. Clinical status using disease activity score in 28 joints (DAS-28), serum levels of matrix metalloproteinase-3 (MMP-3), and rheumatoid factor (RF) were assessed before and after the intervention. RESULTS:  The serum level of MMP-3 compared with the baseline values did not change significantly in the groups. However, the serum concentration of RF decreased significantly in the vitamin K1 group (p = 0.041). Intergroup comparison showed no significant change in RF serum level after adjusting for relevant confounders (p > 0.05). CONCLUSIONS:  Vitamin K1 supplementation at 10 mg/day for 8 weeks did not alter joint destruction and immune status in the patients with RA compared with the controls.

Comparison of concurrent treatment with vitamin K
            (Tanaka et al., 2017) Download
The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and rise- dronate 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, undercar- boxylated 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 min- eral 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 vita- min K2 group than in the risedronate alone group.

 


References

Abdel-Rahman, MS, EA Alkady, and S Ahmed (2015), ‘Menaquinone-7 as a novel pharmacological therapy in the treatment of rheumatoid arthritis: A clinical study.’, Eur J Pharmacol, 761 273-78. PubMed: 26073022
Aziz, F and P Patil (2015), ‘Role of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia.’, Indian J Pediatr, 82 (4), 363-67. PubMed: 25297643
Ikari, Y, et al. (2016), ‘Impact of menaquinone-4 supplementation on coronary artery calcification and arterial stiffness: an open label single arm study.’, Nutr J, 15 (1), 53. PubMed: 27175730
Mansour, AG, et al. (2017), ‘Vitamin K2 supplementation and arterial stiffness among renal transplant recipients-a single-arm, single-center clinical trial.’, J Am Soc Hypertens, 11 (9), 589-97. PubMed: 28756183
McFarlin, BK, AL Henning, and AS Venable (2017), ‘Oral Consumption of Vitamin K2 for 8 Weeks Associated With Increased Maximal Cardiac Output During Exercise.’, Altern Ther Health Med, 23 (4), 26-32. PubMed: 28646812
O’Connor, EM, et al. (2014), ‘Effect of phylloquinone (vitamin K1) supplementation for 12 months on the indices of vitamin K status and bone health in adult patients with Crohn’s disease.’, Br J Nutr, 112 (7), 1163-74. PubMed: 25181575
Rasekhi, H, et al. (2015), ‘The effect of vitamin K1 supplementation on sensitivity and insulin resistance via osteocalcin in prediabetic women: a double-blind randomized controlled clinical trial.’, Eur J Clin Nutr, 69 (8), 891-95. PubMed: 25782427
Shea, MK, et al. (2017), ‘Reducing Undercarboxylated Osteocalcin With Vitamin K Supplementation Does Not Promote Lean Tissue Loss or Fat Gain Over 3 Years in Older Women and Men: A Randomized Controlled Trial.’, J Bone Miner Res, 32 (2), 243-49. PubMed: 27604070
Shikano, K, et al. (2016), ‘Efficacy of Vitamin K2 for Glucocorticoid-induced Osteoporosis in Patients with Systemic Autoimmune Diseases.’, Intern Med, 55 (15), 1997-2003. PubMed: 27477405
Shishavan, NG, et al. (2016), ‘Effects of Vitamin K on Matrix Metalloproteinase-3 and Rheumatoid Factor in Women with Rheumatoid Arthritis: A Randomized, Double-Blind, Placebo-Controlled Trial.’, J Am Coll Nutr, 35 (5), 392-98. PubMed: 26156560
Tanaka, S, et al. (2017), ‘Comparison of concurrent treatment with vitamin K’, J Bone Miner Metab, 35 (4), 385-95. PubMed: 27484436