vitamin-k-1 and menaquinone-7

Vitamin K acts as a cofactor and is required for post-translational γ-carboxylation of vitamin K-dependent proteins (VKDP). The current recommended daily intake (RDI) of vitamin K in most countries has been established based on normal coagulation requirements. Vitamin K1 and menaquinone (MK)-4 has been shown to decrease osteocalcin (OC) γ-carboxylation at RDI levels. Among the several vitamin K homologs, only MK-7 (vitamin K2) can promote γ-carboxylation of extrahepatic VKDPs, OC, and the matrix Gla protein at a nutritional dose around RDI. MK-7 has higher efficacy due to its higher bioavailability and longer half-life than other vitamin K homologs. As vitamin K1, MK-4, and MK-7 have distinct bioactivities, their RDIs should be established based on their relative activities. MK-7 increases bone mineral density and promotes bone quality and strength. Collagen production, and thus, bone quality may be affected by MK-7 or MK-4 converted from MK-7. In this review, we comprehensively discuss the various properties of MK-7.

Topics: Biological Availability; Bone and Bones; Bone Density; Collagen; Dietary Supplements; Humans; Osteocalcin; Recommended Dietary Allowances; Vitamin K 1; Vitamin K 2

Vitamin K and its essential role in coagulation (vitamin K [Koagulation]) have been well established and accepted the world over. Many countries have a Recommended Daily Intake (RDI) for vitamin K based on early research, and its necessary role in the activation of vitamin K-dependent coagulation proteins is known. In the past few decades, the role of vitamin K-dependent proteins in processes beyond coagulation has been discovered. Various isoforms of vitamin K have been identified, and vitamin K2 specifically has been highlighted for its long half-life and extrahepatic activity, whereas the dietary form vitamin K1 has a shorter half-life. In this review, we highlight the specific activity of vitamin K2 based upon proposed frameworks necessary for a bioactive substance to be recommended for an RDI. Vitamin K2 meets all these criteria and should be considered for a specific dietary recommendation intake.

Topics: Diet; Dietary Supplements; Humans; Recommended Dietary Allowances; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

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.

Topics: Animals; Anticoagulants; Diet; Dietary Supplements; Drug Evaluation, Preclinical; Drug Interactions; Humans; Models, Animal; Nutritional Requirements; Randomized Controlled Trials as Topic; Terminology as Topic; Vitamin K; Vitamin K 1; Vitamin K 2

Intervention studies and meta-analyses have shown that vitamin D(3) at 700-800 IU/day decreases the fracture incidence. Higher phylloquinone (vitamin K(1)) intake or "natto" intake was associated with lower fracture incidence. In contrast, current intake of vitamin D and K in Japanese is likely to be unsatisfactory for preventing fracture. The intake of fish, abundant in vitamin D(3) is encouraged. Regarding vitamin K, "natto" intake is strongly recommended, since it contains extraordinary amount of menaquinone-7. Phylloquinone in green vegetables would be efficiently absorbed when cooked with oil. Thus Japanese traditional foods seem to be appropriate for bone health.

Topics: Cholecalciferol; Dietary Fats; Female; Food Analysis; Fractures, Bone; Humans; Male; Risk; Solubility; Soy Foods; Vitamin K 1; Vitamin K 2

Haemodialysis patients suffer from accelerated vascular calcification. The vitamin K-dependent matrix Gla protein (MGP) is one of the most powerful inhibitors of vascular calcification. Haemodialysis patients have high levels of the inactive form of MGP (desphosphorylated-uncarboxylated-MGP, dp-uc-MGP) and may benefit from pharmacological doses of vitamin K2 (menaquinone) to improve the calcification inhibitory activity of MGP.. To determine the optimal dose of menaquinone-7 (MK-7) for MGP activation, 200 chronic haemodialysis patients were recruited to randomly receive 360, 720 or 1080 µg of MK-7 thrice weekly for 8 weeks. Dp-uc-MGP was measured at baseline and after 8 weeks. Dietary intake of vitamin K1 (phylloquinone) and menaquinone was estimated based on a detailed questionnaire.. At baseline, dp-uc-MGP was not associated with phylloquinone intake (P = 0.92), but correlated inversely with menaquinone intake (P = 0.023). MK-7 supplementation dose dependently reduced dp-uc-MGP. The levels decreased by 17, 33 and 46% in the respective groups. Drop-outs were mainly due to gastrointestinal side-effects related to the unpleasant smell of the tablets.. Chronic haemodialysis patients have high levels of inactive MGP, possibly related to a low dietary vitamin K intake. Pharmacological doses of MK-7 dose-dependently reduce dp-uc-MGP. Menaquinone supplementation may be a novel approach to prevent vascular calcifications in chronic haemodialysis patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Calcium-Binding Proteins; Dietary Supplements; Dose-Response Relationship, Drug; Extracellular Matrix Proteins; Female; Follow-Up Studies; Hemostatics; Humans; Male; Matrix Gla Protein; Middle Aged; Prognosis; Prospective Studies; Renal Dialysis; Single-Blind Method; Surveys and Questionnaires; Vascular Calcification; Vitamin K 1; Vitamin K 2; Vitamins; Young Adult

Vitamin K is a cofactor in the production of blood coagulation factors (in the liver), osteocalcin (in bone), and matrix Gla protein (cartilage and vessel wall). Accumulating evidence suggests that for optimal bone and vascular health, relatively high intakes of vitamin K are required. The synthetic short-chain vitamin K(1) is commonly used in food supplements, but recently the natural long-chain menaquinone-7 (MK-7) has also become available as an over-the-counter (OTC) supplement. The purpose of this paper was to compare in healthy volunteers the absorption and efficacy of K(1) and MK-7. Serum vitamin K species were used as a marker for absorption and osteocalcin carboxylation as a marker for activity. Both K(1) and MK-7 were absorbed well, with peak serum concentrations at 4 hours after intake. A major difference between the 2 vitamin K species is the very long half-life time of MK-7, resulting in much more stable serum levels, and accumulation of MK-7 to higher levels (7- to 8-fold) during prolonged intake. MK-7 induced more complete carboxylation of osteocalcin, and hematologists should be aware that preparations supplying 50 mug/d or more of MK-7 may interfere with oral anticoagulant treatment in a clinically relevant way.

Topics: Absorption; Adult; Blood Coagulation Factors; Bone and Bones; Cartilage; Coenzymes; Dietary Supplements; Female; Humans; Liver; Male; Osteocalcin; Time Factors; Vitamin K 1; Vitamin K 2; Vitamins

Significant reduction in bone mineral density (BMD) occurs in stroke patients on the hemiplegic and contralateral sides, correlating with the degree of paralysis and vitamin D and K deficiency due to malnutrition, and increasing the risk of hip fracture. We evaluated the efficacy of vitamin K2 (menatetrenone: menaquinone-4; MK-4) in maintaining BMD by comparing serum biochemical indices of bone metabolism between treated and untreated patients. In a random and prospective study, of 108 hemiplegic patients following stroke, 54 received 45 mg menatetrenone daily (MK-4 group, n = 54) for 12 months, and the remaining 54 (untreatment group) did not. Nine patients excluded from the study. The BMD in the second metacarpals and serum indices of bone metabolism were determined. BMD on the hemiplegic side increased by 4.3% in the MK-4 group and decreased by 4.7% in the untreated group (p < 0.0001), while BMD on the intact side decreased by 0.9% in the MK-4 group and by 2.7% in the untreated group (p < 0.0001). At baseline, patients of both groups showed vitamin D and K1 deficiencies, high serum levels of ionized calcium, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), and low levels of parathyroid hormones (PTH) and bone Gla proteins (BGP), indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1, 25-dihydroxyvitamin D (1, 25-[OH]2D) and compensatory PTH secretion. Both vitamins K1 and K2 increased by 97.6% and 666.9%, respectively, in the MK-4 group. Correspondingly, a significant increase in BGP and decreases in both ICTP and calcium were observed in the MK-4 group, in association with a simultaneous increase in both PTH and 1, 25-[OH]2D. One patient in the untreated group suffered from a hip fracture, compared with none in the MK-4 group. The treatment with MK-4 can increase the BMD of disused and vitamin D- and K-deficient hemiplegic bone by increasing the vitamin K concentration, and it also can decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1, 25-[OH]2D concentration.

Topics: Aged; Biomarkers; Bone Density; Bone Diseases, Metabolic; Cerebrovascular Disorders; Female; Hemiplegia; Hemostatics; Humans; Male; Metacarpus; Middle Aged; Prospective Studies; Vitamin D Deficiency; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Patients (40 cases) were treated with daily dosage of warfarin of 2-7 mg after being undergone artificial valve replacements. Twenty one days after administration of warfarin, we examined the patients for kinetics of K vitamins and vitamin K-dependent coagulation factors in blood, and intestinal flora in feces, as well as the relationship between K vitamins and coagulation activity. The following results were obtained. (1) In warfarin-administered patients (Group B), blood levels of vitamin K1 and menaquinone-7, a vitamin K2 homologue, were similar to those in non-warfarin-administered patients. Therefore, administration of warfarin did not significantly decreased the levels. (2) In patients selected randomly from Group B (Group C), the vitamin K1 level in feces was higher than that in non-warfarin-administered patients. The menaquinone-7 level in feces was similar to that in non-warfarin-administered patients. For the total counts of bacteria and the detection rate of vitamin K2-producing bacteria, there was no significant difference between Group C and non-warfarin-administered patients. (3) The above mentioned results of (1) and (2) suggest that it is important for development of anticoagulant effects by warfarin to inhibit conversion from vitamin K1 to reduced vitamin K1, as well as to inhibit the reducing process from vitamin K1-epoxide to vitamin K1. (4) Vitamin K1-epoxide, a metabolite of vitamin K1, appeared in blood after administration of warfarin; there was a lower correlation between the blood level of vitamin K1-epoxide and the warfarin dosage. Further, PIVKA-II appeared in blood after administration of warfarin; there was a inverse lower correlation between the level of PIVKA-II and HPT, and between PIVIKA-II and TT. In conclusion, it has been clarified that vitamin K1-epoxide and PIVKA-II are useful parameters to evaluate anticoagulant effect of warfarin.

Topics: Adult; Aged; Biomarkers; Blood Coagulation; Blood Coagulation Factors; Feces; Female; Humans; Male; Middle Aged; Protein Precursors; Prothrombin; Vitamin K; Vitamin K 1; Vitamin K 2; Warfarin

Vitamin K and metabolites have a beneficial role in blood coagulation, bone metabolism and growth. However, the determination of vitamin K concentrations in the blood in patients consuming a diet with naturally occurring vitamin K is currently challenging. We aim to develop a cost-effective and rapid method to measure vitamin K metabolites with potential application for clinics and research.. We developed a simple liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the determination of vitamin K1, menaquinone-4 (MK-4), menaquinone-7 (MK-7) and vitamin K1-2,3 epoxide in human serum and validated the method in a study cohort of 162 patients tested for carbohydrate malabsorption and in 20 patients with oral phenprocoumon intake.. The overall precision (CVs) ranged between 4.8 and 17.7% in the specified working range (0.06-9.0 nmol/L for all analytes except for MK-7 with 0.04-6.16 nmol/L). In the malabsorption cohort samples, measured values were obtained for all different vitamin K metabolites except for vitamin K1-2,3 epoxide. This metabolite could be detected only in patients with phenprocoumon intake. The good performance of the method is especially achieved by the interaction of three factors: the use of lipase in the sample preparation, the use of an atypical fluorinated reversed phase column, and a logarithmic methanol gradient.. The described method is able to determine the concentration of four vitamin K metabolites in a time-efficient, simple and cost-effective manner. It can be suitable for both routine clinics and research.

Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Epoxy Compounds; Humans; Phenprocoumon; Tandem Mass Spectrometry; Vitamin K; Vitamin K 1; Vitamin K 2

We have reported that vitamin E intake lowers phylloquinone (PK) concentration in extrahepatic tissues of rats. In this study, we aimed to clarify the characteristic of the distribution of menaquinone-7 (MK-7), a vitamin K contained in fermented foods, by comparison with other vitamin K distributions and to clarify the effect of vitamin E intake on MK-7 concentration in rats. Rats were fed a vitamin K-free diet (Free group), a diet containing 0.75 mg PK/kg (PK group), a 0.74 mg menaquinone-4 (MK-4)/kg diet (MK-4 group), a 1.08 mg MK-7/kg diet (MK-7 group), or a 0.29 mg menadione (MD)/kg diet (MD group) for 16 wk. MK-7 mainly accumulated in the liver, spleen, and adrenal gland of the MK-7 group, although PK accumulated in the serum and all tissues of the PK group. Conversely, MK-4 was present in all tissues of the PK, MK-4, MK-7, and MD groups. MK-4 concentration in the serum, liver, adipose tissue, and spleen was higher in the MK-4 group than in the other groups; however, MK-4 concentration in the kidney, testis, tibia, and brain was lower in the MK-4 group than in the PK, MK-7, and MD groups. Next, vitamin E- and K-deficient rats were orally administered MK-7 with or without α-tocopherol. α-Tocopherol did not affect MK-7 or MK-4 concentration in the serum and various tissues. These results suggested that MK-7 is particularly liable to accumulate in the liver, and MK-7 concentration is not affected by vitamin E intake.

Topics: alpha-Tocopherol; Animals; Diet; Fermented Foods; Liver; Male; Nutritional Status; Rats, Wistar; Tissue Distribution; Vitamin K 1; Vitamin K 2; Vitamin K 3; Vitamin K Deficiency

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).. 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.. 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.. 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.. This study was registered as UMIN 000002760.

Topics: Aged; Ankle Brachial Index; Body Mass Index; Cardiomyopathies; Coronary Vessels; Dietary Supplements; Endpoint Determination; Female; Hemostatics; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Pulse Wave Analysis; Risk Factors; Vascular Stiffness; Vitamin K 1; Vitamin K 2

To further understand the correlation between vitamin K and bone metabolism, the effects of vitamins K1, menaquinone-4 (MK-4), and menaquinone-7 (MK-7) on RANKL-induced osteoclast differentiation and bone resorption were comparatively investigated. Vitamin K2 groups (MK-4 and MK-7) were found to significantly inhibit RANKL-medicated osteoclast cell formation of bone marrow macrophages (BMMs) in a dose-dependent manner, without any evidence of cytotoxicity. The mRNA expression of specific osteoclast differentiation markers, such as c-Fos, NFATc1, OSCAR, and TRAP, as well as NFATc1 protein expression and TRAP activity in RANKL-treated BMMs were inhibited by vitamin K2, although MK-4 exhibited a significantly greater efficiency compared to MK-7. In contrast, the same dose of vitamin K1 had no inhibitory effect on RANKL-induced osteoclast cell formation, but increased the expression of major osteoclastogenic genes. Interestingly, vitamins K1, MK-4 and MK-7 all strongly inhibited osteoclastic bone resorption (p < 0.01) in a dose dependent manner. These results suggest that vitamins K1, MK-4 and MK-7 have anti-osteoporotic properties, while their regulation effects on osteoclastogenesis are somewhat different.

Topics: Acid Phosphatase; Animals; Bone Marrow Cells; Bone Resorption; Cell Differentiation; Isoenzymes; Macrophages; Male; Mice; Mice, Inbred ICR; NFATC Transcription Factors; Osteoclasts; Proto-Oncogene Proteins c-fos; RANK Ligand; Receptors, Cell Surface; RNA, Messenger; Signal Transduction; Tartrate-Resistant Acid Phosphatase; Vitamin K; Vitamin K 1; Vitamin K 2

It has been demonstrated that single nucleotide polymorphism (SNP) (R325Q, 974G>A) in the gamma-glutamyl carboxylase (GGCX) gene is associated with the bone mineral density (BMD). In the present study, we investigated the effect of GGCX polymorphism (974G>A) on the correlations among the vitamin K in-take, level of serum vitamin K, and ratio of undercarboxylated osteocalcin (ucOC) to intact osteocalcin (OC) in healthy young Japanese subjects.. Healthy young adult subjects (n=189) were genotyped for the poly-morphism, and we measured the levels of serum vitamin K, intact OC, ucOC, and dietary nutrient intakes.. Dietary vitamin K intake from vegetables was significantly correlated with the level of serum phylloquinone (PK), and vitamin K intake from fermented beans, natto, was also significantly correlated with the level of serum menaquinone-7 (MK-7). Moreover, the total dietary vitamin K intake showed a significant negative correlation with the ratio of ucOC to intact OC. Interestingly, on grouping by the GGCX genotype, there was a significant interaction between the ratio of ucOC to intact OC with vitamin K intake in homozygotes (GG-type) and heterozygotes (GA-type) (p<0.001). These results suggest that an adequate nutritional strategy is necessary for people with high-risk genotypes (GG- or GA-type).. We demonstrated the effects of SNP (974G>A) in the GGCX gene on the correlation between dietary vitamin K intake and gamma-carboxylation of serum OC. Our data may be useful for planning strategies to prevent osteoporosis.. 前言：γ-麩胺醯羧化酶(GGCX)基因的單核苷酸多型性(SNP)與骨骼礦物質密度 (BMD)之相關性已被證實。本篇研究探討，在日本的健康年輕受試者中，其 GGCX 多型性(974G>A)對於維生素K 攝取、血清中維生素K 濃度和羧化不全骨 鈣素(ucOC)與完整骨鈣素(OC)比值之間關聯性的影響。方法：共有189 位健康 年輕成人進行基因多型性檢測，並測量其血清中維生素K、OC、ucOC 濃度和 飲食中營養素攝取量。結果：飲食中攝取來自蔬菜的維生素K 與血清中維生素 K1(PK；葉綠醌)有顯著相關；而攝取來自發酵豆類-納豆的維生素K 也與血清中 維生素K2(MK-7；甲萘醌-7)有顯著相關。此外，從飲食中攝取的總維生素K 和 ucOC 與OC 比值有顯著負相關。值得注意的是，將GGCX 基因型分組時發現， 同型結合子(GG-type)和異型結合子(GA-type)兩組的ucOC 與OC 比值和維生素 K 攝取有顯著交互作用(p<0.001)。以上結果顯示，適當的營養策略對於具有高 風險基因型(GG-或GA-type)的人是必要的。結論：本研究證實GGCX 基因中的 SNP(974G>A)多型性對於飲食維生素K 攝取與血清骨鈣素γ-羧化相關性之效 應。本資料對於規劃預防骨質疏鬆症之策略也許會有幫助。

Topics: Carbon-Carbon Ligases; Diet; Genotype; Humans; Japan; Male; Nutritional Status; Osteocalcin; Polymorphism, Single Nucleotide; Soy Foods; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Young Adult

The objective of the present study was to examine the effect of dairy products enriched with calcium, vitamin D(3), and phylloquinone (vitamin K(1)) or menaquinone-7 (vitamin K(2)) on parameters of bone metabolism in postmenopausal women following a 12-month intervention. Postmenopausal women were divided into three intervention groups and a control group (CG). All three intervention groups attended biweekly sessions and received fortified dairy products providing daily 800 mg of calcium and 10 μg of vitamin D(3) (CaD). Furthermore, in two of the three intervention groups the dairy products were also enriched with vitamin K, providing daily 100 μg of either phylloquinone (CaDK1) or menaquinone-7 (CaDK2). The increase observed for serum 25(OH)D levels in all intervention groups and the increase observed for serum IGF-I levels in the CaDK2 group differed significantly compared to the changes observed in CG (P = 0.010 and P = 0.028, respectively). Furthermore, both the CaDK1 and CaDK2 groups had a significantly lower mean serum undercarboxylated osteocalcin to osteocalcin ratio and urine deoxypyridinoline levels at follow-up compared to the CaD and CG groups (P = 0.001 and P = 0.047, respectively). Significant increases in total-body BMD were observed in all intervention groups compared to CG (P < 0.05), while significant increases in lumbar spine BMD were observed only for CaDK1 and CaDK2 compared to CG (P < 0.05) after controlling for changes in serum 25(OH)D levels and dietary calcium intake. In conclusion, the present study revealed more favorable changes in bone metabolism and bone mass indices for the two vitamin K-supplemented groups, mainly reflected in the suppression of serum levels of bone remodeling indices and in the more positive changes in lumbar spine BMD for these two study groups.

Topics: Aged; Bone and Bones; Bone Density; Bone Density Conservation Agents; Calcium, Dietary; Dairy Products; Dietary Supplements; Female; Follow-Up Studies; Humans; Middle Aged; Osteoporosis, Postmenopausal; Postmenopause; Vitamin D; Vitamin K 1; Vitamin K 2; Vitamins

Although hip fracture is considered to be associated with hypovitaminosis D and K, few reports have previously studied both of them. We have studied the vitamin D- and K-status as well as the general nutritional status in ninety-nine patients with hip fracture. Mean serum concentration of 25hydroxy-vitamin D (25OH-D) in female fractured patients was only approximately 9 ng/mL, suggesting severe vitamin D deficiency. There was no significant difference between the two groups in serum concentration of intact parathyroid hormone in both genders and serum 25OH-D levels in the male subjects. Plasma concentrations of phylloquinone (vitamin K1; PK) and menaquinone-7 (MK-7) were significantly lower in the fractured group than in the control group in both genders. Logistic regression analysis indicated that circulating concentrations of albumin, PK and 25OH-D were the significant and independent determinants of fracture risk, with their higher concentrations associated with decreased fracture risk. Finally, principal component analysis (PCA) was performed to summarize the clinical parameters into smaller numbers of independent components. Three components were obtained, each representing the overall nutritional status, the vitamin D status, and the vitamin K status. In conclusion, our study has shown that patients with hip fracture have vitamin D and K deficiency independent of general malnutrition.

Topics: Aged; Aged, 80 and over; Female; Hip Fractures; Humans; Logistic Models; Male; Parathyroid Hormone; Risk Factors; Vitamin D; Vitamin D Deficiency; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

There have been methodological problems for studying hypovitaminosis D and K in the elderly. First, studies were done either by evaluating food intake or measuring their circulating levels, but rarely by both in Japan. In this paper, vitamin D and K intakes and their circulating levels were simultaneously determined. Second issue is whether hypovitaminosis D and K are independent of general malnutrition, prevalent in the elderly. We tried to statistically discriminate them by principal component analysis (PCA). Fifty institutionalized elderly were evaluated for their circulating 25 hydroxy-vitamin D (25OH-D), intact parathyroid hormone (PTH), phylloquinone (PK), menaquinone-7 (MK-7) levels, and their food intake. Although average vitamin D intake (7.0 microg/day) exceeded the Japanese Adequate Intake (AI) of 5.0 microg/day, average serum 25OH-D concentration was in the hypovitaminosis D range (11.1 ng/mL). Median vitamin K intake was 168 microg/day, approximately 2.5 times as high as AI for vitamin K. Nevertheless, plasma PK and MK-7 concentrations were far lower than those of healthy Japanese elderly over 70 years old. PCA yielded four components; each representing overall nutritional, vitamin K2, vitamin D, and vitamin K1 status, respectively. Since these components are independent of each other, vitamin D- and K-deficiency in these subjects could not be explained by overall malnutrition alone. In summary, institutionalized elderly had a high prevalence of hypovitaminosis D and K, and the simultaneous determination of their circulating level and dietary intake is mandatory in such studies. PCA would yield fruitful results for eliminating the interference by confounders in a cross-sectional study.

Topics: 25-Hydroxyvitamin D 2; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Calcifediol; Diet; Female; Humans; Institutionalization; Japan; Male; Malnutrition; Nutritional Status; Parathyroid Hormone; Principal Component Analysis; Sex Characteristics; Vitamin D Deficiency; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

It has been reported that vitamin K supplementation effectively prevents fractures and sustains bone mineral density in osteoporosis. However, there are only limited reported data concerning the association between vitamin K nutritional status and bone mineral density (BMD) or fractures in Japan. The objectives were to evaluate the association between plasma phylloquinone (K1) or menaquinone (MK-4 and MK-7) concentration and BMD or fracture in Japanese women prospectively. A total of 379 healthy women aged 30-88 years (mean age, 63.0 years) were consecutively enrolled. Plasma K1, MK-4, MK-7, and serum undercarboxylated osteocalcin (ucOC) concentrations, BMD, and incidence of vertebral fractures were evaluated. In stepwise multiple linear regression analyses, L2-4 BMD and a bone turnover marker, log K1, concentrations were independently correlated with vertebral fracture incidence. When subjects were divided into low and high K1 groups by plasma K1 concentration, the incidence of vertebral fracture in the low K1 group (14.4%) was significantly higher than that in the high K1 group (4.2%), and its age-adjusted RR was 3.58 (95% CI, 3.26-3.93). L2-4 BMD was not different between the two groups. These results suggest that subjects with vitamin K1 insufficiency in bone have increased susceptibility for vertebral fracture independently from BMD.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Asian People; Female; Fractures, Bone; Humans; Incidence; Japan; Middle Aged; Spinal Injuries; Vitamin K 1; Vitamin K 2

A sensitive and highly selective high-performance liquid chromatography (HPLC) method was developed for the determination of vitamin K homologues including phylloquinone (PK), menaquinone-4 (MK-4) and menaquinone-7 (MK-7) in human plasma using post-column peroxyoxalate chemiluminescence (PO-CL) detection following on-line ultraviolet (UV) irradiation. The method was based on ultraviolet irradiation (254 nm, 15 W) of vitamin K to produce hydrogen peroxide and a fluorescent product at the same time, which can be determined with PO-CL detection. The separation of vitamin K by HPLC was accomplished isocratically on an ODS column within 35 min. The method involves the use of 2-methyl-3-pentadecyl-1,4-naphthoquinone as an internal standard. The detection limits (signal-to-noise ratio = 3) were 32, 38 and 85 fmol for PK, MK-4 and MK-7, respectively. The recoveries of PK, MK-4 and MK-7 were greater than 82% and the inter- and intra-assay R.S.D. values were 1.9-5.4%. The sensitivity and selectivity of this method were sufficient for clinical and nutritional applications.

Topics: Chromatography, High Pressure Liquid; Female; Humans; Luminescence; Male; Oxalates; Reproducibility of Results; Ultraviolet Rays; Vitamin K 1; Vitamin K 2; Vitamins

Several reports indicate an important role for vitamin K in bone health as well as blood coagulation. However, the current Adequate Intakes (AI) might not be sufficient for the maintenance of bone health. To obtain a closer estimate of dietary intake of phylloquinone (PK) and menaquinones (MKs), PK, MK-4 and MK-7 contents in food samples (58 food items) were determined by an improved high-performance liquid chromatography method. Next, we assessed dietary vitamin K intake in young women living in eastern Japan using vitamin K contents measured here and the Standard Tables of Food Composition in Japan. PK was widely distributed in green vegetables and algae, and high amounts were found in spinach and broccoli (raw, 498 and 307 microg/100 g wet weight, respectively). Although MK-4 was widely distributed in animal products, overall MK-4 content was lower than PK. MK-7 was observed characteristically in fermented soybean products such as natto (939 microg/100 g). The mean total vitamin K intake of all subjects (using data from this study and Japanese food composition tables) was about 230 microg/d and 94% of participants met the AI of vitamin K for women aged 18-29 y in Japan, 60 microg/d. The contributions of PK, MK-4 and MK-7 to total vitamin K intake were 67.7, 7.3 and 24.9%, respectively. PK from vegetables and algae and MK-7 from pulses (including fermented soybean foods) were the major contributors to the total vitamin K intake of young women living in eastern Japan.

Topics: Adolescent; Adult; Chromatography, High Pressure Liquid; Dairy Products; Edible Grain; Eukaryota; Fabaceae; Female; Food Analysis; Humans; Japan; Meat; Nutrition Assessment; Spices; Tea; Vegetables; Vitamin K 1; Vitamin K 2

Phylloquinone is converted into menaquinone-4 and accumulates in extrahepatic tissues. Neither the route nor the function of the conversion is known. One possible metabolic route might be the release of menadione from phylloquinone by catabolic activity. In the present study we explored the presence of menadione in urine and the effect of vitamin K intake on its excretion. Menadione in urine was analysed by HPLC assay with fluorescence detection. Urine from healthy male volunteers was collected before and after administration of a single dose of K vitamins. Basal menadione excretion in non-supplemented subjects (n 6) was 5.4 (sd 3.2) microg/d. Urinary menadione excretion increased greatly after oral intake of the K vitamins, phylloquinone and menaquinone-4 and -7. This effect was apparent within 1-2 h and peaked at about 3 h after intake. Amounts of menadione excreted in 24 h after vitamin K intake ranged, on a molar basis, from 1 to 5 % of the administered dose, indicating that about 5-25 % of the ingested K vitamins had been catabolized to menadione. Menadione excretion was not enhanced by phylloquinone administered subcutaneously or by 2',3'-dihydrophylloquinone administered orally. In archived samples from a depletion/repletion study (Booth et al. (2001) Am J Clin Nutr 74, 783-790), urinary menadione excretion mirrored dietary phylloquinone intake. The present study shows that menadione is a catabolic product of K vitamins formed after oral intake. The rapid appearance in urine after oral but not subcutaneous administration suggests that catabolism occurs during intestinal absorption. The observations make it likely that part of the menaquinone-4 in tissues results from uptake and prenylation of circulating menadione.

Topics: Administration, Cutaneous; Administration, Oral; Cell Line; Cells, Cultured; Dietary Supplements; Hemostatics; Humans; Male; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K 3; Vitamins

Vitamin K deficiency is associated with low bone mineral density and increased risk of bone fracture. Phylloquinone (K1) and menaquinone 4 (MK-4) and 7 (MK-7) are generally observed in human plasma; however, data are limited on their circulating concentrations and their associations with bone metabolism or with gamma-carboxylation of the osteocalcin molecule.. The objectives were to measure the circulating concentrations of K1, MK-4, and MK-7 in women and to ascertain whether each form of vitamin K is significantly associated with bone metabolism.. Plasma concentrations of K1, MK-4, MK-7, undercarboxylated osteocalcin (ucOC; measured by using the new electrochemiluminescence immunoassay), intact osteocalcin (iOC), calcium, and phosphorus; bone-derived alkaline phosphatase activity; and concentrations of urinary creatinine, N-terminal telopeptide, and deoxypyridinoline were measured in healthy women (n = 396).. On average, MK-7 and MK-4 were the highest and lowest, respectively, of the 3 vitamers in all age groups. K1 and MK-7 correlated inversely with ucOC, but associations between nutritional basal concentration of MK-4 and ucOC were not observed. Multiple regression analysis indicated that not only K1 and MK-7 concentrations but also age were independently correlated with ucOC concentration and the ratio of ucOC to iOC. The plasma K1 or MK-7 concentration required to minimize the ucOC concentration was highest in the group aged > or =70 y, and it decreased progressively for each of the younger age groups.. The definite role of ucOC remains unclear. However, if submaximal gamma-carboxylation is related to the prevention of fracture or bone mineral loss, circulating vitamin K concentrations in elderly people should be kept higher than those in young people.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aging; Biomarkers; Bone and Bones; Bone Density; Carboxylic Acids; Female; Fractures, Bone; Humans; Japan; Middle Aged; Nutritional Requirements; Nutritional Status; Osteocalcin; Risk Factors; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Vitamins

The difference between vitamin K metabolism in the liver and that in the bone of vitamin K-deficient rats was examined. After 17 d administration of vitamin K-deficient food, vitamin K in the liver was almost depleted, and prothrombin time (PT) was prolonged. Serum total osteocalcin level was slightly decreased by vitamin K deficiency, whereas serum undercarboxylated osteocalcin level did not change. The level of menaquinone (MK)-4 as well as that of phylloquinone was decreased, but approximately 40 % of the initial level still existed in the femur after the 17 d period. A single-dose administration of vitamin K (250 nmol/kg body weight) markedly increased vitamin K level in the liver but not in the femur. These results suggest that the turnover of vitamin K in the bone is slower than that in the liver, and bone metabolism may be little affected by the short period of intake of vitamin K-deficient food. However, intake of a larger amount of vitamin K is required for its accumulation in the bone than in the liver. Furthermore, the counteracting effect of MK-7 on prolonged PT in vitamin K-deficient rats was found to be higher than phylloquinone or MK-4.

Topics: Animals; Bone and Bones; Cyanoacrylates; Indoleacetic Acids; Liver; Male; Osteocalcin; Partial Thromboplastin Time; Prothrombin Time; Rats; Rats, Sprague-Dawley; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Increasing evidence indicates a significant role for vitamin K in bone metabolism and osteoporosis. In this study, we found a large geographic difference in serum vitamin K2 (menaquinone-7; MK-7) levels in postmenopausal women. Serum MK-7 concentrations were 5.26 +/- 6.13 ng/mL (mean +/- SD) in Japanese women in Tokyo, 1.22 +/- 1.85 in Japanese women in Hiroshima, and 0.37 +/- 0.20 in British women. We investigated the effect of Japanese fermented soybean food, natto, on serum vitamin K levels. Natto contains a large amount of MK-7 and is eaten frequently in eastern (Tokyo) but seldom in western (Hiroshima) Japan. Serum concentrations of MK-7 were significantly higher in frequent natto eaters, and natto intake resulted in a marked, sustained increase in serum MK-7 concentration. We analyzed the relation between the regional difference in natto intake and fracture incidence. A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption in each prefecture throughout Japan. These findings indicate that the large geographic difference in MK-7 levels may be ascribed, at least in part, to natto intake and suggest the possibility that higher MK-7 level resulting from natto consumption may contribute to the relatively lower fracture risk in Japanese women.

Topics: Aged; Aged, 80 and over; Bacillus; Feces; Female; Femoral Neck Fractures; Fermentation; Glycine max; Humans; Incidence; Japan; Middle Aged; Osteoporosis, Postmenopausal; Risk Factors; Triglycerides; United Kingdom; Vitamin K 1; Vitamin K 2

Recently, vitamin K has become increasingly of interest in the bone metabolism field because of its role as a cofactor in the carboxylation of osteocalcin. Although the role of osteocalcin is not clear, noncarboxylated osteocalcin is one risk factor in hip fractures. It has been reported that the circulating levels of vitamin K1 in osteoporotic patients were significantly lower than those of age-matched control subjects. In this study, we measured circulating levels of vitamin K1, menaquinone-4 (MK-4) and menaquinone-7 (MK-7) in 23 normal healthy women aged 52-93 years (mean +/- SD: 80.1 +/- 3.5), 13 female patients with vertebral fractures aged 66-93 years (80.3 +/- 7.8) and 38 female patients with hip fractures aged 76-87 years (79.8 +/- 9.2), (all Japanese), in order to make sure whether these vitamin K levels were different in these three groups. Serum circulating levels of MK-4 was undetectable in most subjects (only one out of 74). Appreciable numbers from these three groups had undetectable levels of MK-7 (52% of the control group, 23% of the vertebral fracture group and 24% of the hip fracture group). Eight subjects from the normal control group (35%) and five patients from the vertebral group (38%) had undetectable levels of vitamin K1. We did not find a significant difference in the measurable levels of vitamin K1, MK-4 and MK-7 in patients with vertebral fractures or patients with hip fractures compared to age-matched normal controls. Undetectable levels of measured vitamin K1, MK-4 and MK-7 in most of subjects may significantly affect the results.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Female; Hip Fractures; Humans; Japan; Middle Aged; Osteocalcin; Serum Albumin; Spinal Fractures; Vitamin K 1; Vitamin K 2

Changes in the circulating factors participating in involutional osteoporosis have been intensively investigated in women, but little is known about this in men. We investigated the possible participation of circulating factors including testosterone, vitamin D metabolites, and vitamins K1 and K2 in osteopenia in elderly men. In a group of 27 ambulatory men aged 74 +/- 10 years (mean +/- SD; range, 60 to 90), the bone mineral density (BMD) of the second to fourth lumbar vertebrae was measured by dual-energy x-ray absorptiometry (DXA) and expressed as a Z score, the age-adjusted BMD value for the Japanese population (mean +/- SD, 0 +/- 1). Although the plasma level of total testosterone significantly decreased with age in the group, it did not significantly correlate with the Z score. However, the plasma levels of 25-hydroxyvitamin D (25-OHD), phylloquinone, menaquinone-7 (MK-7), and albumin were significantly positively correlated with the Z score. Moreover, plasma 25-OHD and both phylloquinone and MK-7 were significantly positively correlated in the subjects. These observations suggest that depressed circulating levels of 25-OHD and vitamin K concomitantly and cooperatively participate in osteopenia in elderly men, which may reflect the etiology of the type II moiety of involutional osteoporosis.

Topics: Aged; Aged, 80 and over; Bone Density; Bone Diseases, Metabolic; Cyanoacrylates; Humans; Male; Middle Aged; Testosterone; Vitamin D; Vitamin K; Vitamin K 1; Vitamin K 2

Vitamin K plays an essential role in the gamma carboxylation of the gla-containing proteins of bone matrix, such as osteocalcin. We have measured the concentration of vitamin K1 (VK) and of the menaquinones MK-6, MK-7, and MK-8, the three major vitamin K2 moieties, in trabecular and cortical bone taken from the femoral neck of patients undergoing hip replacement. Both bone compartments were found to contain large amounts of VK, MK-6, MK-7, and MK-8. Concentrations were as high as those reported for the liver, the major storage organ for vitamin K. Further research is required to examine the association between vitamin K in bone and the gamma carboxylation of vitamin K-dependent bone proteins.

Topics: Aged; Bone and Bones; Chromatography, High Pressure Liquid; Female; Femur Neck; Humans; Male; Middle Aged; Vitamin K; Vitamin K 1; Vitamin K 2

1. Through the vitamin K1 cycle, phylloquinone is now known to play an active role, not only in relation to prothrombin, but also in the synthesis of bone peptides. 2. The recent development of a sensitive method allowed the demonstration of a deficit of vitamin K1 in the circulation of osteoporotic subjects. 3. Vitamin K2, namely the menaquinones of various chain-lengths, has been shown by others to be more effective than vitamin K1 in the curative rat bioassay. 4. Earlier reports had shown that the concentration of menaquinones in human liver may exceed that of vitamin K1. But previous methods were too insensitive for testing the normal circulating levels of menaquinones in the human. 5. The new sensitive method has now been applied to measuring the circulating levels of vitamin K1 and of two of the menaquinones, namely menaquinone-7 and menaquinone-8. 6. In normal individuals, the circulating levels of vitamin K1 were the same, irrespective of age. 7. In young normal subjects, the combined levels of menaquinone-7 and menaquinone-8 were at least the same as the level of vitamin K1. In elderly normal subjects, there was a marked deficit of menaquinone-8.

Topics: Adult; Aged; Aged, 80 and over; Aging; Chromatography, High Pressure Liquid; Female; Humans; Male; Middle Aged; Vitamin K; Vitamin K 1; Vitamin K 2