**2. Vitamin K‐dependent proteins in the bone building process**

Osteocalcin is produced by osteoblasts during bone formation, and serves as the most abundant protein in bone after collagen. Furthermore, it is crucial for bone mineralization. Activated osteocalcin is located within hydroxyapatite crystals and binds calcium strongly to facilitate mineralization of the hydroxyapatite crystal grid [24]. Osteocalcin production is regulated by a plethora of factors including retinoic acid (RA), estrogens, glucocorticoids, as well as vitamin D [25–27]. In 1995, Douglas et al. showed the percentage of carboxylated osteocalcin (cOC), as calculated from total osteocalcin, was found to be less than 60% in osteoporotic postmenopausal women compared to 70–80% in young, healthy adults [28]. The osteocalcin production is increased by vitamin D but also increased by both MK‐4 and MK‐7 in a synergistic fashion. From 2007, as used by Knapen et al., osteocalcin has been employed as a marker for the deficiency of vitamin K in bone. Today, the specific osteocalcin molecules are total Osteocalcin (tOC), ucOsteocalcin (ucOC), and cOsteocalcin (cOC) [28, 44]. A secon‐ dary action of MK‐4 and MK‐7 is the ensuing increased collagen production by cells of the osteoblastic lineage. Collagen should make the structural fundament, on which calcium and other minerals are accumulated within the bone matrix. Increased deposition of collagen makes the bone more flexible and this is very important for the attainment of "higher" or better bone quality [24]. In 2001, Yamaguchi et al. unraveled the stimulatory effect of MK‐7 on osteoblastic bone formation *in vitro*, but they also discovered the suppressive effect of MK‐7 on osteoclast‐like cell formation and osteoclastic bone resorption in rat bone tissues *in vitro* [29]. Furthermore, in 2001, Yamaguchi and Ma [30] confirmed the dual effects of MK‐7 but also a significant decrease number of osteoclasts. Finally, in 2011, Yamaguchi and Weilzmann showed that MK‐7 reinforces the synthesis of various bone‐specific proteins, mediated through the pathways of calcium‐dependent protein kinase C signaling, as well as cyclic AMP‐dependent signaling. MK‐7 also antagonizes the "receptor activator of NF‐κB (RANK) ligand (RANKL)" induced NF‐κB activation on osteoclast precursors. This concept now makes up the basis for the search of novel antiosteoporotic medication regimens, mimicking the plethora of effects induced by MK‐7 [31].
