Vitamin K and Osteoporosis

Vitamin K acts as a coenzyme of carboxylase, catalyzing the carboxylation of several vitamin K dependent proteins. Beyond its well-known effects on blood coagulation, it also exerts relevant effects on bone and the vascular system. In this review, we point out the relevance of an adequate vitamin K intake to obtain sufficient levels of carboxylated (active form) vitamin K dependent proteins (such as Osteocalcin and matrix Gla protein) to prevent bone health. Another bone-related action of Vitamin K is being a ligand of the nuclear steroid and xenobiotic receptor (SXR). We also discuss the recommended intake, deficiency, and assessment of vitamin K. Furthermore, we review the few available studies that have as pre-specified outcome bone fractures, indicating that we need more clinical studies to confirm that vitamin K is a potential therapeutic agent for bone fractures.

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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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PROX1 suppresses vitamin K-induced transcriptional activity of steroid and xenobiotic receptor

Genes to Cells ◽

10.1111/j.1365-2443.2011.01551.x ◽

2011 ◽

Vol 16 (11) ◽

pp. 1063-1070 ◽

Cited By ~ 7

Author(s):

Kotaro Azuma ◽

Tomohiko Urano ◽

Tetsuro Watabe ◽

Yasuyoshi Ouchi ◽

Satoshi Inoue

Keyword(s):

Vitamin K ◽

Transcriptional Activity ◽

Steroid And Xenobiotic Receptor ◽

Xenobiotic Receptor

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Multiple Modes of Vitamin K Actions in Aging-Related Musculoskeletal Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms20112844 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2844 ◽

Cited By ~ 8

Author(s):

Kotaro Azuma ◽

Satoshi Inoue

Keyword(s):

Protective Effect ◽

Blood Coagulation ◽

Musculoskeletal Disorders ◽

Vitamin K ◽

Clinical Studies ◽

Protective Role ◽

Covalent Modification ◽

Conditional Knockout ◽

Matrix Gla Protein ◽

Regulation Of Transcription

Vitamin K is a fat-soluble vitamin that was originally found as an essential factor for blood coagulation. With the discovery of its role as a co-factor for γ-glutamyl carboxylase (GGCX), its function for blood coagulation was understood as the activation of several blood coagulation factors by their γ-carboxylation. Over the last two decades, other modes of vitamin K actions have been discovered, such as the regulation of transcription by activating the steroid and xenobiotic receptor (SXR), physical association to 17β-Hydroxysteroid dehydrogenase type 4 (17β-HSD4), covalent modification of Bcl-2 antagonist killer 1 (Bak), and the modulation of protein kinase A (PKA) activity. In addition, several epidemiological studies have revealed that vitamin K status is associated with some aging-related diseases including osteoporosis, osteoarthritis, and sarcopenia. Clinical studies on single nucleotide polymorphisms of GGCX suggested an association between higher GGCX activity and bone protective effect, while recent findings using conditional knockout mice implied that a contribution in protective effect for bone loss by GGCX in osteoblastic lineage was unclear. GGCX in other cell lineages or in other tissues might play a protective role for osteoporosis. Meanwhile, animal experiments by our groups among others revealed that SXR, a putative receptor for vitamin K, could be important in the bone metabolism. In terms of the cartilage protective effect of vitamin K, both GGCX- and SXR-dependent mechanisms have been suggested. In clinical studies on osteoarthritis, the γ-carboxylation of matrix Gla protein (MGP) and gla-rich protein (GRP) may have a protective role for the disease. It is also suggested that SXR signaling has protective role for cartilage by inducing family with sequence similarity 20a (Fam20a) expression in chondrocytes. In the case of sarcopenia, a high vitamin K status in plasma was associated with muscle strength, large muscle mass, and high physical performance in some observational studies. However, the basic studies explaining the effects of vitamin K on muscular tissue are limited. Further research on vitamin K will clarify new biological mechanisms which contribute to human longevity and health through the prevention and treatment of aging-related musculoskeletal disorders.

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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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The Connection Between Vitamin K and Bone Health

Journal of Student Science and Technology ◽

10.13034/jsst.v8i2.64 ◽

2015 ◽

Vol 8 (2) ◽

Author(s):

Jamy (Ning) Fu

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Vitamin K ◽

Bone Health ◽

Bone Fractures ◽

The Body ◽

Mineral Density ◽

Densité Minérale Osseuse ◽

The Impact ◽

Viable Method

Vitamin K is essential to the body because it is known to help blood coagulate and activate osteocalcin, a protein involved in maintaining healthy bones. In this review, one study observing the impact of vitamin K supplementation on patients’ bone mineral densities and three studies focusing on the effects of vitamin K supplementation on the incidence of bone fractures are discussed to determine whether the vitamin may be important for maintaining bone health. While some promising results, such as an increase in bone mineral density of subjects after vitamin K supplementation arose, the conclusions reached by the four studies were not statistically significant enough to justify the importance of vitamin K in maintaining bone health. Well-controlled studies that are unbiased, statistically powerful, and focused on vitamin K’s effects on bone density are required in the future to provide further insight on whether vitamin K supplementation is a viable method of improving bone health. La vitamine K est essentielle pour le corps, car il est connu pour assister dans la coagulation du sang ainsi qu’activer l'ostéocalcine, une protéine impliquée dans le maintien de la santé des os. Ici, une étude dirigé vers les observations de l'impact de la consommation de suppléments de la vitamine K sur la densité minérale osseuse de patients, puis trois autres études portant sur les effets de la consommation de suppléments de la vitamine K sur l'incidence des fractures osseuses sont examinées afin de déterminer si la vitamine soit une facteur important dans le maintien de la santé des os. Tandis que des résultats sont révélés prometteurs, comme ceux montrant une augmentation de la densité minérale osseuse des sujets après la consommation des suppléments de la vitamine K, l’ensemble de conclusions tirées des quatre études ne présente pas suffisamment de données qui pourraient suggérer une corrélation entre la consommation des suppléments de la vitamine K et la santé des os. Des études supplémentaires portant sur les effets de la vitamine K sur la densité osseuse, mené dans des conditions contrôlés, bien conçus, impartiales, qui produiront des résultats persuasifs, sont nécessaires à être effectuer à l'avenir afin de donner un meilleur aperçu de l’effet de la supplémentation en vitamine K comme une méthode viable dans l’entretien de la santé des os.

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Synthesis of New Vitamin K Analogues as Steroid and Xenobiotic Receptor (SXR) Agonists: Insights into the Biological Role of the Side Chain Part of Vitamin K

Journal of Medicinal Chemistry ◽

10.1021/jm200201k ◽

2011 ◽

Vol 54 (13) ◽

pp. 4918-4922 ◽

Cited By ~ 20

Author(s):

Yoshitomo Suhara ◽

Masato Watanabe ◽

Sayaka Motoyoshi ◽

Kimie Nakagawa ◽

Akimori Wada ◽

...

Keyword(s):

Vitamin K ◽

Biological Role ◽

Side Chain ◽

Steroid And Xenobiotic Receptor ◽

Xenobiotic Receptor

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Structure-Activity Relationship of Novel Vitamin K Analogues as Steroid and Xenobiotic Receptor (SXR) Agonists

YAKUGAKU ZASSHI ◽

10.1248/yakushi.132.881 ◽

2012 ◽

Vol 132 (8) ◽

pp. 881-886 ◽

Cited By ~ 1

Author(s):

Yoshitomo Suhara ◽

Sayaka Motoyoshi ◽

Yoshihisa Hirota ◽

Natsumi Sawada ◽

Kimie Nakagawa ◽

...

Keyword(s):

Vitamin K ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Structure Activity ◽

Steroid And Xenobiotic Receptor ◽

Xenobiotic Receptor ◽

Relationship Of

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Energy Metabolism and Ketogenic Diets: What about the Skeletal Health? A Narrative Review and a Prospective Vision for Planning Clinical Trials on this Issue

International Journal of Molecular Sciences ◽

10.3390/ijms22010435 ◽

2021 ◽

Vol 22 (1) ◽

pp. 435

Author(s):

Daniela Merlotti ◽

Roberta Cosso ◽

Cristina Eller-Vainicher ◽

Fabio Vescini ◽

Iacopo Chiodini ◽

...

Keyword(s):

Energy Metabolism ◽

Ketogenic Diet ◽

Bone Health ◽

Clinical Studies ◽

Bone Fractures ◽

Mesenchymal Cell ◽

Narrative Review ◽

Mineral Density ◽

Skeletal Health ◽

Ketogenic Diets

The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, bone fragility could also be seen as a consequence of a “poor” quality in nutrition. Ketogenic diet was originally proven to be effective in epilepsy, and long-term follow-up studies on epileptic children undergoing a ketogenic diet reported an increased incidence of bone fractures and decreased bone mineral density. However, the causes of such negative impacts on bone health have to be better defined. In these subjects, the concomitant use of antiepileptic drugs and the reduced mobilization may partly explain the negative effects on bone health, but little is known about the effects of diet itself, and/or generic alterations in vitamin D and/or impaired growth factor production. Despite these remarks, clinical studies were adequately designed to investigate bone health are scarce and bone health related aspects are not included among the various metabolic pathologies positively influenced by ketogenic diets. Here, we provide not only a narrative review on this issue, but also practical advice to design and implement clinical studies on ketogenic nutritional regimens and bone health outcomes. Perspectives on ketogenic regimens, microbiota, microRNAs, and bone health are also included.

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Vitamin K Nutrition and Bone Health

Nutrients ◽

10.3390/nu12071909 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1909 ◽

Cited By ~ 2

Author(s):

Naoko Tsugawa ◽

Masataka Shiraki

Keyword(s):

Energy Metabolism ◽

Fracture Risk ◽

Vitamin K ◽

Bone Health ◽

Bone Fractures ◽

Vitamin K Deficiency ◽

Protein Levels ◽

K Deficiency ◽

Dependent Protein

Vitamin K is essential for blood coagulation and plays an important role in extrahepatic metabolism, such as in bone and blood vessels, and in energy metabolism. This review discusses the assessment of vitamin K sufficiency and the role of vitamin K in bone health. To elucidate the exact role of vitamin K in other organs, accurate tools for assessing vitamin K deficiency or insufficiency are crucial. Undercarboxylated vitamin K-dependent protein levels can be measured to evaluate tissue-specific vitamin K deficiency/insufficiency. Vitamin K has genomic action through steroid and xenobiotic receptor (SXR); however, the importance of this action requires further study. Recent studies have revealed that the bone-specific, vitamin K-dependent protein osteocalcin has a close relationship with energy metabolism through insulin sensitivity. Among the organs that produce vitamin K-dependent proteins, bone has attracted the most attention, as vitamin K deficiency has been consistently associated with bone fractures. Although vitamin K treatment addresses vitamin K deficiency and is believed to promote bone health, the corresponding findings on fracture risk reduction are conflicting. We also discuss the similarity of other vitamin supplementations on fracture risk. Future clinical studies are needed to further elucidate the effect of vitamin K on fracture risk.

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Metabolism and cell biology of vitamin K

Thrombosis and Haemostasis ◽

10.1160/th08-03-0147 ◽

2008 ◽

Vol 100 (10) ◽

pp. 530-547 ◽

Cited By ~ 205

Author(s):

Paul Newman ◽

Martin J. Shearer

Keyword(s):

Vitamin K ◽

Cell Biology ◽

Side Chain ◽

Local Synthesis ◽

Anticoagulant Drugs ◽

Clinical Benefits ◽

Steroid And Xenobiotic Receptor ◽

Plant Form ◽

Specific Tissue ◽

Xenobiotic Receptor

SummaryNaturally occurring vitamin K compounds comprise a plant form, phylloquinone (vitamin K1) and a series of bacterial menaquinones (MKs) (vitamin K2). Structural differences in the isoprenoid side chain govern many facets of metabolism of K vitamins including the way they are transported, taken up by target tissues, and subsequently excreted. In the post-prandial state, phylloquinone is transported mainly by triglyceride-rich lipoproteins (TRL) and long-chain MKs mainly by low-density lipoproteins (LDL). TRL-borne phylloquinone uptake by osteoblasts is an apoE-mediated process with the LRP1 receptor playing a predominant role. One K2 form, MK-4, has a highly specific tissue distribution suggestive of local synthesis from phylloquinone in which menadione is an intermediate. Both phylloquinone and MKs activate the steroid and xenobiotic receptor (SXR) that initiates their catabolism, but MK-4 specifically upregulates two genes suggesting a novel MK-4 signalling pathway. Many studies have shown specific clinical benefits of MK-4 at pharmacological doses for osteoporosis and cancer although the mechanism(s) are poorly understood. Other putative non-cofactor functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and thereby the availability of reduced vitamin K. Under extreme blockade, vitamin K can bypass the inhibition of Gla synthesis in the liver but not in the bone and the vessel wall. In humans, MK-7 has a greater efficacy than phylloquinone in carboxylating both liver and bone Gla proteins. A daily supplement of phylloquinone has shown potential for improving anticoagulation control.

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