Vitamin K2 and Bone Quality

Vitamin K is a cofactor required for post-translational gamma-carboxylation of vitamin K-dependent proteins, including coagulation and anti-coagulation factors; osteocalcin (OC), essential for bone metabolism; and matrix Gla proteins (MGP), an inhibitor of artery calcification. In addition to activation of OC, vitamin K2 induces collagen accumulation in the bone matrix. The principle effects of vitamin K on bone health are not to increase bone mineral density but to promote bone quality and bone strength. Vitamin K2, as menaquinone-7 (MK-7), is the only major vitamin K homolog which can activate OC at nutritional doses. The higher efficacy of MK-7 is due to its better bioavailability and longer half-life compared to other vitamin K homologs. Furthermore, a normal nutritional intake of MK-7 has been shown to activate MGP, which inhibit artery calcification, and has been associated with prevention of cardiovascular diseases. Thus, MK-7 is thought to contribute to calcium homeostasis in arteries as well as bones. *Corresponding author: Toshiro Sato, Fine Chemical Laboratory, Nakashinden, Fukuroi-city, Shizuoka, Japan, E-mail: [email protected] Received February 09, 2013; Accepted February 11, 2013; Published February 28, 2013 Citation: Sato T (2013) Vitamin K2 and Bone Quality. Vitam Trace Elem S6: 001. doi:10.4172/2167-0390.S6-001 Copyright: © 2013 Sato T. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Vitamin K acts as a cofactor for the endoplasmic enzyme γ-glutamyl carboxylase, during post-translational conversion of glutamic acid residues to γ-carboxyglutamic acid (Gla) in specific proteins. These proteins are referred to as vitamin K-dependent proteins, and include several blood coagulation factors and anti-coagulation factors, which are synthesized in the liver; Osteocalcin(OC), a bone-specific protein synthesized by osteoblasts; and Matrix Gla Protein (MGP), which is synthesized in several organs. Recently, considerable attention has been directed towards these vitamin K-dependent Gla proteins; their role in bone metabolism; and their inhibitory effect on artery calcification. The current average intake of vitamin K from a normal diet in healthy adults is greater than that required for normal blood coagulation, but is insufficient for extra hepatic tissue requirements [1,2]. Vitamin K2 has been found to be highly effective in bone metabolism compared to vitamin K1. In Japan, a high dose of vitamin K2 (45 mg/day), as menaquinone-4 (MK-4), is used as therapeutic treatment for osteoporosis. The principle effect of vitamin K2 on osteoporosis is prevention of bone fracture by improving bone quality, and not increasing bone mineral density. Recently, attention has been directed towards another vitamin K2 homolog; menaquinone-7 (MK7) extracted from Bacillus subtilis natto. This has been found to be highly effective in carboxylation of osteocalcin at nutritional doses. This review focuses on the effects of vitamin K2 as MK-7 on bone quality. Structure of Vitamin K and its Distribution in Foods There are two naturally occurring forms of vitamin K: vitamin K1 (phylloquinone), derived from green plants; and vitamin K2 (menaquinones, MK-n), which are a series of vitamers with multi-isoprene units at position 3 of the common 2-methyl-1,4naphthoquinone ring structure. In food, vitamin K1 is bound to the chloroplast membrane of leafy green vegetables; whereas, MK-4 is found in animal products, such as eggs, meat, and liver. MK-4 is derived from menadione (a synthetic analog of vitamin K, consisting only of the 2-methyl-1,4naphthoquinone ring structure), which is given to animals as a feed additive nutrient and converted to MK-4 in animal tissues. Long chain menaquinones (e.g., MK-7, MK-8, and MK-9) are found in fermented foods such as cheese, curd, and sauerkraut [3]. The Japanese fermented food “natto” contains MK-7 at an exceptionally high concentration [3]. Vitamin K1, MK-4, and MK-7 are currently used as nutritional supplements and by the food industry (Figure 1). Osteocalcin and Vitamin K OC is produced by osteoblasts and forms bone matrix. Fullycarboxylated OC binds to calcium and shows affinity for hydroxyl apatite in bone [4]. The exact function of OC in bone is unclear, but is thought to be involved in calcium modulation. The first study using OC-knockout mice found that bone formation was accelerated in the knockout mice [5]; in contrast, bone structure turned fragile in OCknockout mice after ovariectomy treatment [6]. This suggested that OC is important for bone maturation and bone quality. OC has been used as a biomarker for bone metabolism: deficiency in vitamin K, elevates serum undercarboxylated OC (ucOC) levels; and high serum ucOC has been associated with hip fracture [7,8], and has been recognized as independent risk factor of fracture. In Japan, serum ucOC has been used as diagnostic marker to evaluate vitamin K deficiency in bone, since 2007. Bone Quality and Vitamin K2 Murasawa et al. [9] conducted a study on ovariectomized rats fed with MK-7 (30 mg/kg bw per day) for 5 months. They observed