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Possible Involvements of Vitamin K in Bone Quality

Possible Involvements of Vitamin K in Bone Quality Oral high-dose vitamin K2 (menaquinone-4, 45 mg/d) has been approved for the treatment of osteoporosis in Japan since 1995, and Cockayne and colleagues1 recently provided a meta-analysis of randomized controlled trials investigating the effects of vitamin K therapy on fracture risk. This analysis showed the strong effect of high-dose vitamin K2 on fracture prevention among Japanese patients. There is no evidence that vitamin K has extraskeletal effects on fracture risk, indicating that this vitamin would restrict bone fragility, which depends on its quantity and quality.2 However, the mechanisms by which vitamin K reduces fracture incidence have been poorly understood. In postmenopausal Japanese women with osteoporosis, it is well known that high-dose vitamin K2 therapy slightly prevents reduction of areal bone mineral density (BMD) measured by dual-energy x-ray absorptiometry but does not actually increase the areal BMD, suggesting that vitamin K2 improves bone quality. For example, vitamin K promotes osteocalcin incorporation into bone tissue through γ-carboxylation, and higher bone mass but similar bone stiffness in osteocalcin-deficient mice compared with wild-type mice indicates that osteocalcin increases bone tissue stiffness.3 In fact, circulating noncarboxylated osteocalcin above the normal range is a strong risk factor for hip fracture in Swedish women independent of areal BMD.4 In addition, it was recently shown that vitamin K2 use increased collagen accumulation through the small leucine-rich proteoglycan, tsukushi, in osteoblastic cells.5 Consistent with this finding, vitamin K2 was previously reported to improve elastic modulus and toughness without affecting BMD, with an accompanying increase in collagen with proper physiological function in bone, in diabetic aged rat femur.6 The stiffness and toughness of bone tissue are determined by mineral crystals and collagen fibrils, respectively, and therefore vitamin K appears to strengthen bone material properties effectively. Finally, there are also several lines of preclinical evidence indicating that vitamin K2 use promotes bone formation and suppresses bone resorption,7 although high-dose vitamin K2 therapy does not change serum and urinary bone turnover markers, except serum osteocalcin, in Japanese women with osteoporosis. Therefore, it might be possible that vitamin K2 improves trabecular bone microarchitecture and/or increases cortical bone size through promotion of periosteal bone formation because these changes are not detected properly as areal BMD. Further investigations are required to clarify the effects of vitamin K on bone quality, and combination therapy with vitamin K may be useful for preventing fractures. Correspondence: Dr Sugiyama, Department of Orthopaedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Yamaguchi 755-8505, Japan; and Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, England (tsugiyama@rvc.ac.uk). References 1. Cockayne SAdamson JLanham-New SShearer MJGilbody STorgerson DJ Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 2006;1661256- 1261PubMedGoogle ScholarCrossref 2. Seeman EDelmas PD Bone quality: the material and structural basis of bone strength and fragility. N Engl J Med 2006;3542250- 2261PubMedGoogle ScholarCrossref 3. Sugiyama TKawai S Quantitative ultrasound, skeletal quality, and fracture risk. Lancet 2004;3631076- 1077PubMedGoogle ScholarCrossref 4. WHO Scientific Group, Prevention and Management of Osteoporosis. Geneva, Switzerland World Health Organization2003;WHO Technical Report Series No. 921 5. Ichikawa THorie-Inoue KIkeda KBlumberg BInoue S Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells. J Biol Chem 2006;28116927- 16934PubMedGoogle ScholarCrossref 6. Saito MSoshi STanaka TFujii K Effects of vitamins B6 and K2 on bone mechanical properties and collagen cross-links in spontaneously diabetic WBN/Kob rats [abstract]. J Bone Miner Res 2005;20 ((suppl 1)) S286Google ScholarCrossref 7. Iwamoto JTakeda TSato Y Effects of vitamin K2 on osteoporosis. Curr Pharm Des 2004;102557- 2576PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Possible Involvements of Vitamin K in Bone Quality

Archives of Internal Medicine , Volume 167 (1) – Jan 8, 2007

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Publisher
American Medical Association
Copyright
Copyright © 2007 American Medical Association. All Rights Reserved.
ISSN
0003-9926
DOI
10.1001/archinte.167.1.93
pmid
17210884
Publisher site
See Article on Publisher Site

Abstract

Oral high-dose vitamin K2 (menaquinone-4, 45 mg/d) has been approved for the treatment of osteoporosis in Japan since 1995, and Cockayne and colleagues1 recently provided a meta-analysis of randomized controlled trials investigating the effects of vitamin K therapy on fracture risk. This analysis showed the strong effect of high-dose vitamin K2 on fracture prevention among Japanese patients. There is no evidence that vitamin K has extraskeletal effects on fracture risk, indicating that this vitamin would restrict bone fragility, which depends on its quantity and quality.2 However, the mechanisms by which vitamin K reduces fracture incidence have been poorly understood. In postmenopausal Japanese women with osteoporosis, it is well known that high-dose vitamin K2 therapy slightly prevents reduction of areal bone mineral density (BMD) measured by dual-energy x-ray absorptiometry but does not actually increase the areal BMD, suggesting that vitamin K2 improves bone quality. For example, vitamin K promotes osteocalcin incorporation into bone tissue through γ-carboxylation, and higher bone mass but similar bone stiffness in osteocalcin-deficient mice compared with wild-type mice indicates that osteocalcin increases bone tissue stiffness.3 In fact, circulating noncarboxylated osteocalcin above the normal range is a strong risk factor for hip fracture in Swedish women independent of areal BMD.4 In addition, it was recently shown that vitamin K2 use increased collagen accumulation through the small leucine-rich proteoglycan, tsukushi, in osteoblastic cells.5 Consistent with this finding, vitamin K2 was previously reported to improve elastic modulus and toughness without affecting BMD, with an accompanying increase in collagen with proper physiological function in bone, in diabetic aged rat femur.6 The stiffness and toughness of bone tissue are determined by mineral crystals and collagen fibrils, respectively, and therefore vitamin K appears to strengthen bone material properties effectively. Finally, there are also several lines of preclinical evidence indicating that vitamin K2 use promotes bone formation and suppresses bone resorption,7 although high-dose vitamin K2 therapy does not change serum and urinary bone turnover markers, except serum osteocalcin, in Japanese women with osteoporosis. Therefore, it might be possible that vitamin K2 improves trabecular bone microarchitecture and/or increases cortical bone size through promotion of periosteal bone formation because these changes are not detected properly as areal BMD. Further investigations are required to clarify the effects of vitamin K on bone quality, and combination therapy with vitamin K may be useful for preventing fractures. Correspondence: Dr Sugiyama, Department of Orthopaedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Yamaguchi 755-8505, Japan; and Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, England (tsugiyama@rvc.ac.uk). References 1. Cockayne SAdamson JLanham-New SShearer MJGilbody STorgerson DJ Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 2006;1661256- 1261PubMedGoogle ScholarCrossref 2. Seeman EDelmas PD Bone quality: the material and structural basis of bone strength and fragility. N Engl J Med 2006;3542250- 2261PubMedGoogle ScholarCrossref 3. Sugiyama TKawai S Quantitative ultrasound, skeletal quality, and fracture risk. Lancet 2004;3631076- 1077PubMedGoogle ScholarCrossref 4. WHO Scientific Group, Prevention and Management of Osteoporosis. Geneva, Switzerland World Health Organization2003;WHO Technical Report Series No. 921 5. Ichikawa THorie-Inoue KIkeda KBlumberg BInoue S Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells. J Biol Chem 2006;28116927- 16934PubMedGoogle ScholarCrossref 6. Saito MSoshi STanaka TFujii K Effects of vitamins B6 and K2 on bone mechanical properties and collagen cross-links in spontaneously diabetic WBN/Kob rats [abstract]. J Bone Miner Res 2005;20 ((suppl 1)) S286Google ScholarCrossref 7. Iwamoto JTakeda TSato Y Effects of vitamin K2 on osteoporosis. Curr Pharm Des 2004;102557- 2576PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Jan 8, 2007

References