vitamin-k-1 and Osteoporosis

Vitamin K is traditionally connected with blood coagulation, since it is needed for the posttranslational modification of 7 proteins involved in this cascade. However, it is also involved in the maturation of another 11 or 12 proteins that play different roles, encompassing in particular the modulation of the calcification of connective tissues. Since this process is physiologically needed in bones, but is pathological in arteries, a great deal of research has been devoted to finding a possible link between vitamin K and the prevention of osteoporosis and cardiovascular diseases. Unfortunately, the current knowledge does not allow us to make a decisive conclusion about such a link. One possible explanation for this is the diversity of the biological activity of vitamin K, which is not a single compound but a general term covering natural plant and animal forms of vitamin K (K1 and K2) as well as their synthetic congeners (K3 and K4). Vitamin K1 (phylloquinone) is found in several vegetables. Menaquinones (MK4-MK13, a series of compounds known as vitamin K2) are mostly of a bacterial origin and are introduced into the human diet mainly through fermented cheeses. Current knowledge about the kinetics of different forms of vitamin K, their detection, and their toxicity are discussed in this review.

Topics: Animals; Humans; Kinetics; Osteoporosis; Vitamin K; Vitamin K 1; Vitamin K 2

The main function of vitamin K in the human organism is its activity in the blood clotting cascade. Epidemiological studies suggest that reduced intake of vitamin K may contribute to an increased risk of geriatric diseases such as atherosclerosis, dementia, osteoporosis, and osteoarthritis. A growing number of studies also indicate that vitamin K may be involved not only in preventing the development of certain cancers but it may also support classical cancer chemotherapy. This review article summarizes the results of studies on the anticancer effects of vitamin K on selected female malignancies, i.e., breast, cervical, and ovarian cancer, published over the past 20 years. The promising effects of vitamin K on cancer cells observed so far indicate its great potential, but also the need for expansion of our knowledge in this area by conducting extensive research, including clinical trials.

Topics: Aged; Blood Coagulation; Female; Humans; Neoplasms; Osteoporosis; Ovarian Neoplasms; Vitamin K; Vitamin K 1; Vitamin K 2

A protective role for vitamin K in bone health has been suggested based on its role as an enzymatic cofactor. In observational studies, vitamin K insufficiency is generally associated with lower bone mass and increased hip fracture risk. However, these findings are not supported in randomized controlled trials (RCT) of phylloquinone (vitamin K(1)) supplementation and bone loss at the hip in the elderly. This suggests that increased vegetable and legume intakes may simultaneously improve measures of vitamin K status and skeletal health, even though the mechanisms underlying these improvements may be independent of each other. Menaquinone-4 (vitamin K(2)), when given at pharmacological doses, appears to protect against fracture risk and bone loss at the spine. However, there are emerging data that suggest the efficacy of vitamin K supplementation on bone loss is inconclusive.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone and Bones; Bone Density; Child; Child, Preschool; Dietary Supplements; Female; Humans; Male; Middle Aged; Osteoporosis; Randomized Controlled Trials as Topic; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Vitamin K is a collective term for lipid-like naphthoquinone derivatives synthesized only in eubacteria and plants and functioning as electron carriers in energy transduction pathways and as free radical scavengers maintaining intracellular redox homeostasis. Paradoxically, vitamin K is a required micronutrient in animals for protein posttranslational modification of some glutamate side chains to gamma-carboxyglutamate. The majority of gamma-carboxylated proteins function in blood coagulation. Vitamin K shuttles reducing equivalents as electrons between two enzymes: VKORC1, which is itself reduced by an unknown ER lumenal reductant in order to reduce vitamin K epoxide (K>O) to the quinone form (KH2); and gamma-glutamyl carboxylase, which catalyzes posttranslational gamma-carboxylation and oxidizes KH2 to K>O. This article reviews vitamin K synthesis and the vitamin K cycle, outlines physiological roles of various vitamin K-dependent, gamma-carboxylated proteins, and summarizes the current understanding of clinical phenotypes caused by genetic mutations affecting both enzymes of the vitamin K cycle.

Topics: Animals; Blood Coagulation; Calcium; Carbon-Carbon Ligases; Coumarins; Homeostasis; Humans; Mixed Function Oxygenases; Osteoporosis; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Epoxide Reductases

Vitamin K is receiving more attention in relation to its role in bone metabolism. Vitamin K is a coenzyme for glutamate carboxylase, which mediates the conversion of glutamate to gamma-carboxyglutamate (Gla). The gamma-carboxylation of the Gla proteins is essential for the proteins to attract Ca2+ and to incorporate these into hydroxyapatite crystals. The best known of the three known bone-related Gla proteins is osteocalcin (OC). Even though the exact role of OC is not known, a number of studies have shown that vitamin K insufficiency or high levels of undercarboxylated osteocalcin (ucOC) is associated with an increase in the concentration of circulating ucOC. Furthermore, several studies have demonstrated that vitamin K insufficiency is associated with low bone mineral density (BMD) and increased fractures. Vitamin K supplementation, on the other hand, has been shown to improve the bone turnover profile and decrease the level of circulating ucOC. Dietary recommendations are based on saturation of the coagulation system, and in most countries the dietary intake is sufficient to obtain the amount recommended. In relation to bone, requirements might be higher. The aim of this chapter is to give an overview of the importance of vitamin K in relation to bone health in adult humans and thereby in the prevention of osteoporosis. Furthermore, I will shortly discuss the interaction with vitamin D and the paradox in relation to warfarin treatment.

Topics: Adult; Anticoagulants; Bone and Bones; Diet; Glutamic Acid; Humans; Nutritional Status; Osteocalcin; Osteoporosis; Vitamin K; Vitamin K 1; Vitamin K 2

Vitamin K is a nutrient originally identified as an essential factor for blood coagulation. Recently, vitamin K has emerged as a potential protector against osteoporosis and hepatocarcinoma. Accumulated evidence indicates that subclinical non-hemostatic vitamin K deficiency in extrahepatic tissues, particularly in bone, exists widely in the otherwise healthy adult population. Both vitamin K(1) and K(2) have been shown to exert protective effects against osteoporosis. Moreover, therapeutic potential of vitamin K(2) as an anti-hepatoma drug has been recently highlighted. Most of the new biological functions of vitamin K in bone and hepatoma cells are considered to be attributable to promotion of gamma-carboxylation of glutamic acid residues in vitamin K-dependent proteins, which is shared by both vitamins K(1) and K(2). In contrast, vitamin K(2)-specific, gamma-carboxylation-unrelated functions have also been demonstrated. These functions include stimulation of steroid and xenobiotic receptor (SXR)-mediated transcription and anti-oxidant property. Thus, biological differences between vitamins K(1) and K(2), and a potential involvement of gamma-carboxylation-independent actions in the new roles of vitamin K remain open issues. Molecular bases of coagulation-unrelated pleiotropic actions of vitamin K and its implications in human health deserve further investigations.

Topics: 1-Carboxyglutamic Acid; Antioxidants; Carcinoma, Hepatocellular; Fractures, Bone; Humans; Liver Neoplasms; Osteoporosis; Pregnane X Receptor; Receptors, Steroid; Soy Foods; Transcription, Genetic; Vitamin K; Vitamin K 1; Vitamin K 2

Vitamin K has been implicated in bone health, primarily in observational studies. However, little is known about the role of phylloquinone supplementation on prevention of bone loss in men and women.. The objective of this study was to determine the effect of 3-yr phylloquinone supplementation on change in bone mineral density (BMD) of the femoral neck bone in older men and women who were calcium and vitamin D replete.. In this 3-yr, double-blind, controlled trial, 452 men and women (60-80 yr) were randomized equally to receive a multivitamin that contained either 500 mug/d or no phylloquinone plus a daily calcium (600 mg elemental calcium) and vitamin D (400 IU) supplement.. Measurements of the femoral neck, spine (L2-L4), and total-body BMD, bone turnover, and vitamins K and D status were measured every 6-12 months. Intent-to-treat analysis was used to compare change in measures in 401 participants who completed the trial.. There were no differences in changes in BMD measurements at any of the anatomical sites measured between the two groups. The group that received the phylloquinone supplement had significantly higher phylloquinone and significantly lower percent undercarboxylated osteocalcin concentrations compared with the group that did not receive phylloquinone. No other biochemical measures differed between the two groups.. Phylloquinone supplementation in a dose attainable in the diet does not confer any additional benefit for bone health at the spine or hip when taken with recommended amounts of calcium and vitamin D.

Topics: Aged; Aged, 80 and over; Bone Density; Dietary Supplements; Double-Blind Method; Female; Humans; Male; Osteoporosis; Vitamin K 1

The administration of menaquinone-4 (MK-4), one of subclasses of vitamin K2, significantly reduces bone loss in postmenopausal osteoporotic women. However, concerns have been raised about whether vitamin K administration alters the hemostatic balance by inducing a thrombotic tendency. We investigated were whether the administration of vitamin K in the form of MK-4 induced a thrombotic tendency in 29 elderly patients with osteoporosis (5 men, 24 women; age range 78.7+/-5.1 years). Patients were administered 45 mg/day (three times a day, 30 min after each meal) of MK-4 for 12 weeks. Blood samples were obtained from the patients at 0, 4 and 12 weeks after the start of MK-4 administration. A number of hemostatic parameters remained stable under the markedly increased plasma levels of MK-4. However, in patients with suspected vitamin K deficiency, whose plasma levels of vitamin K or factor VII were low, vitamin-K-dependent clotting factors such as factor VII and prothrombin were gradually increased after administration of MK-4. No changes in the sensitive molecular markers such as TAT and F1+2, which reflect the amount of thrombin generated in the blood stream, were observed, even in those patients with suspected vitamin K deficiency. These results indicate that MK-4 can be administered safely, with regard to maintaining the hemostatic balance, to osteoporotic patients receiving no anticoagulant therapy.

Topics: Aged; Aged, 80 and over; Blood Coagulation Factors; Cyanoacrylates; Female; Hemostasis; Hemostatics; Humans; Male; Osteoporosis; Osteoporosis, Postmenopausal; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Vitamin K (VK) as well as vitamin D (VD) plays an important role in osteoporosis. Vitamin K1 (VK1), vitamin K2 (VK2, menaquinone-4 (MK-4), and menaquinone-7 (MK-7)) are significant for the metabolism of skeletal muscle. 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 (25(OH)D2 and 25(OH)D3) reflect circulating VD levels. More sensitive measurements remain to be developed. In the present study, a new high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of VK1, VK2 (MK-4 and MK-7), as well as 25(OH)D2 and 25(OH)D3 levels in human serum.. We developed a simple LC-MS/MS method for the determination of VK1, MK-4, MK-7, 25(OH)D2, and 25(OH)D3 levels in human serum and validated the method in a study cohort of 200 patients divided into the premenopausal women group and postmenopausal osteoporosis patient group.. The overall precision (coefficient of variation) ranged from 2.66 to 10.11% in the specified working range (0.05-5 ng/mL) for VK1, MK-4, and MK-7. Serum VK1, MK-4, and MK-7 levels in postmenopausal women with osteoporosis were 1.187 ± 0.094 ng/mL, 0.058 ± 0.009 ng/mL, and 0.885 ± 0.064 ng/mL, respectively (mean ± standard deviation). Serum VK1, MK-4, and MK-7 levels in premenopausal women were 1.143 ± 0.103 ng/mL, 0.028 ± 0.003 ng/mL, and 1.553 ± 0.226 ng/mL, respectively. Serum 25(OH)D2 and 25(OH)D3 levels in postmenopausal women with osteoporosis were 0.757 ± 0.056 ng/mL and 11.72 ± 0.632 ng/mL, respectively. Serum 25(OH)D2 and 25(OH)D3 levels in premenopausal were 1.793 ± 0.575 ng/mL and 12.42 ± 1.069 ng/mL, respectively.. A new LC-MS/MS method for determination of serum VK and VD levels was evaluated and validated. MK-7 in plasma decreased earlier than VD in postmenopausal osteoporosis patients. MK-7 status is significantly associated with osteoporosis and could be considered a predictable biomarker in the diagnosis of osteoporosis in postmenopausal women.

Topics: 25-Hydroxyvitamin D 2; Calcifediol; Chromatography, Liquid; Female; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Tandem Mass Spectrometry; Vitamin D; Vitamin K 1; Vitamins

Topics: Bone and Bones; Diet, Healthy; Dietary Supplements; Humans; Osteocalcin; Osteoporosis; Vegetables; Vitamin K 1; Vitamin K 2

Susceptibility to osteoporosis seems to be influenced genetically. Previous studies on the effects of genetic polymorphisms on bone mineral density (BMD) showed controversial results. Vitamin K hydrochinon is an important cofactor for gamma carboxylation of osteocalcin. The reduction of vitamin K to vitamin K hydrochinon depends on the vitamin K epoxide reductase complex subunit 1 (VKORC1). We evaluated the impact of polymorphisms in VKORC1 on BMD and fractures. In this single-center study, 184 individuals (141 female subjects and 43 male subjects, mean age: 63.2 +/- 14.3 years) were recruited. In all, 149 of 184 could be genotyped by allele-specific polymerase chain reaction (PCR) for the VKORC1 variants 3673G>A or 9041G>A. The genotypes were correlated with clinical parameters. Vitamin K(1) concentrations were determined by high-performance liquid chromatography (HPLC); carboxylated (GlaOC) and undercarboxylated osteocalcin (GluOC) was determined by enzyme-linked immunosorbent assays (ELISAs). The 9041 GG and GA genotypes were significantly more frequent in patients with low BMD (P = 0.012). Thus, carriers of at least 1 G-allele seem to have a higher risk for low BMD. No statistically significant association was found for the 3673 G>A variant and BMD. GluOC concentrations were higher in patients who carried a 3673 GA and GG genotypes (P = 0.07). For both variants, no association with fractures could be observed. In our cohort, a genetic variation in the 3'-region of the VKORC1 gene (9041 AG and GG) was associated significantly with low BMD. This finding suggests that VKORC1 may play a role in osteoporosis. The results of our pilot study should be confirmed as our findings may be important for treatment decisions.

Topics: Aged; Bone Density; Female; Fractures, Bone; Gene Expression Regulation; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Mixed Function Oxygenases; Osteocalcin; Osteoporosis; Pilot Projects; Polymorphism, Single Nucleotide; RNA, Messenger; Vitamin K 1; Vitamin K Epoxide Reductases

The findings of a number of cross-sectional studies suggest benefits of high phylloquinone (vitamin K(1)) intake on bone health in later life. Until recently these observational data were supported by the findings of an intervention study that showed a protective role for vitamin K(1) (together with calcium, magnesium, zinc, and vitamin D(3)) on bone loss over 3 years in early postmenopausal women. Over the last 18 months, two further important intervention studies have been published, which investigated the effect of vitamin K(1) on bone loss in older subjects. These two studies add to the evidence-base but cast some doubt on the benefits of high vitamin K(1) intake on bone health in later life.

Topics: Aged; Aged, 80 and over; Bone Density; Female; Humans; Male; Middle Aged; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause; Randomized Controlled Trials as Topic; Vitamin K 1

We report here the development of a precise and sensitive method for the determination of vitamin K homologues including phylloquinone (PK), menaquinone-4 (MK-4), and menaquinone-7 (MK-7) in human plasma using HPLC-tandem mass-mass spectrometry with atmospheric pressure chemical ionization (LC-APCI-MS/MS). The method involves the use of stable isotope (18)O-labeled internal standard compounds, which were synthesized in our laboratory, and the selection of a precursor and product ion with a MS/MS multiple reaction monitoring method. The average intraassay and interassay variation values for PK, MK-4, and MK-7 were <10%. Average spiked recoveries from authentic compounds added to normal human plasma samples for PK, MK-4, and MK-7 were 98-102%. Mean plasma concentrations of PK, MK-4, and MK-7 from healthy subjects (n = 20) were 1.22 +/-0.57, 0.39 +/- 0.46, and 6.37 +/- 7.45 ng/mL, respectively. We conclude that this novel LC-APCI-MS/MS method should be useful for the evaluation of vitamin K status in postmenopausal women and elderly subjects and provides useful information for the treatment and prevention of osteoporosis with vitamin K.

Topics: Calibration; Chromatography, High Pressure Liquid; Humans; Mass Spectrometry; Osteoporosis; Oxygen Isotopes; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Fluorescence; Vitamin K; Vitamin K 1; Vitamin K 2

1. Female chicks of a White Leghorn strain were fed three different diets from one day old: control, additional vitamin K3 (10 mg/kg), and a diet containing a combination of additional vitamin K3, sodium fluoride (10 mg/kg) and limestone in particulate rather than powdered form. At 16 weeks photoperiod was increased for half the birds from 8:16 L:D to 16:8 L:D immediately or by one hour per week to the same ultimate photoperiod for the other half. 2. Age at first egg was lower by 4.0 d for birds on the fast lighting regime but there were no overall effects of lighting on bone quality at either 25 or 70 weeks. 3. Additional vitamin K3 resulted in higher proximal tarsometatarsus cancellous bone volumes at 15 weeks and throughout the laying period compared with controls. Plasma osteocalcin concentrations were unaffected by vitamin K3 supplementation during growth. 4. The combination diet resulted in beneficial responses of 12 to 20% in most bone characteristics in hens at 70 weeks. The magnitude of these effects was similar to a previous study involving a particulate calcium source alone (Fleming et al., Poultry Science, 39: 434-440, 1998b). We conclude that the beneficial effects of the combined treatment over the lifetime of the hens were attributable mainly to the presence in the diet of a calcium source in particulate form.

Topics: Animal Feed; Animals; Bone Development; Calcium Carbonate; Chickens; Dietary Supplements; Female; Fluorides; Light; Osteoporosis; Oviposition; Poultry Diseases; Vitamin K 1

Rapid bone loss is a serious health problem for astronauts during long lasting missions in space. We have recorded the changes of biochemical markers for bone metabolism in one of the astronauts during the 6-month space flight of the EUROMIR-95 mission. Immediately after launch both bone resorption markers and urinary calcium excretion increased about two fold, whereas bone formation markers remained unchanged. After 12 1/2 weeks the astronaut received vitamin K1 (10 mg/day for 6 weeks). Vitamin K is known to be involved in the formation of gamma-carboxyglutamate (Gla) in proteins, such as the calcium-binding bone Gla-proteins osteocalcin and matrix Gla-protein. Concomitant with the start of vitamin K treatment, the calcium-binding capacity of osteocalcin increased, and so did the urinary excretion of free Gla. This is suggestive for a subclinical vitamin K-deficiency in the astronaut before vitamin K-supplementation. During periods of high vitamin K status markers for bone formation (osteocalcin and bone alkaline phosphatase) had increased as compared to the first part of the flight. The mean increases were 14 and 23%, respectively. Our data suggest that increased intake of vitamin K may contribute to counteracting microgravity-induced loss of bone mass during long lasting space missions, but need confirmation in more astronauts.

Topics: 1-Carboxyglutamic Acid; Adult; Aerospace Medicine; Alkaline Phosphatase; Amino Acids; Biomarkers; Bone and Bones; Bone Development; Bone Resorption; Calcium; Humans; Osteocalcin; Osteoporosis; Parathyroid Hormone; Space Flight; Vitamin K; Vitamin K 1; Weightlessness; Weightlessness Countermeasures

The rapid loss of bone mass is one of the serious problems which have to be solved before long-lasting manned spaceflights may be considered. In this paper we describe investigations in which we have checked whether the bone loss in astronauts as well as in osteoporotic patients may be related to abnormalities in a recently discovered calcium-binding protein, named osteocalcin. It was observed that in all subjects of a limited number of osteoporotic patients, the amount of calcium-binding groups (Gla-residues) in the circulating osteocalcin was substantially reduced. The Gla-content could be normalized, however, by the oral administration of vitamin K (1 mg/day). We also analyzed the Gla-content of plasma-osteocalcin from 4 astronauts before and after the D-1 mission. The amount of Gla-residues was reduced by more than 50% in the post-flight samples. It seems probable, that an increased vitamin K-intake by the astronauts will correct the observed abnormality, but whether this will lead to a decrease of the microgravity-induced bone-loss remains to be seen.

Topics: 1-Carboxyglutamic Acid; Adult; Aerospace Medicine; Aged; Bone and Bones; Humans; Middle Aged; Osteocalcin; Osteoporosis; Space Flight; Vitamin K; Vitamin K 1; Weightlessness; Weightlessness Countermeasures

If gamma-carboxylation, by the vitamin K1 - cycle, of glutamate residues of bone-matrix peptides is essential for the formation of bone, the circulating levels of this vitamin might indicate the potential efficiency of this process. Methods involving HPLC with electrochemical detection have very recently been developed for assaying the low levels of vitamin K1 that occur in normal plasma. Using such methods, we found that the circulating levels of vitamin K1 in osteoporotic patients (who had sustained either spinal crush-fractures or fractures of the neck of the femur) were significantly lower than those of age-matched control subjects.

Topics: Aged; Electrochemistry; Female; Humans; Male; Middle Aged; Osteoporosis; Vitamin K 1

Topics: Adolescent; Adult; Aged; Female; Femoral Neck Fractures; Humans; Male; Middle Aged; Osteoporosis; Vitamin K 1