Vitamin K status in Children with Osteogenesis Imperfecta

Osteogenesis Imperfecta is a rare genetic disease where, in about 90% of the cases, a mutation is present in collagen-1-related genes [1,2]. Collagen type 1 is the most abundant type of collagen in bone and accounts for about 20-25% of the bone mass [3][4]. It determines the elasticity of the bone [3]. In Osteogenesis imperfecta the mild type 1 form is mainly caused by quantitative lack of collagen, which is further structurally normal. Most other types are a result of misfolding of the collagen, because of a substituted amino acid [4], or - to a lesser extend - because of exon skipping, leading to a truncated collagen molecule [2]. Misfolded and truncated collagen lead to a more disorganized bone structure [4].
The body tries to ‘fix’ the problem by discharging the defect molecules from the bone. Because the problem is genetic and not just an incidental mistake, this leads to chronic increased bone turnover [5][6]. This is shown in children with O.I., where osteoblast activity was decreased and osteoclast activity was increased [5].
Another general characteristic of Osteogenesis Imperfecta is the hypermineralized bone [7][8], which contributes to more fragile bones, because of increased stiffness [4]. This is independent of the type of O.I.[7]. The mineral compound of bone matrix forms plates that fill the free space within the matrix. The packing density needs to be higher in Osteogenesis Imperfecta bone in order to fill the larger spaces present [9] [7], due to lower collagen content [9].
Osteocalcin, a small bone-specific matrix protein is synthesized by osteoblasts [10] [11] and plays an important role in mineralization of bone matrix. It is available in the human body in two forms: carboxylated and uncarboxylated. The uncarboxylated form of osteocalcin is found to be a hormone, stimulating insulin-secretion and thereby mediating glucose homeostasis [12][11]. The carboxylated form of osteocalcin is important in the formation of maturated hydroxyapatite, the mineral component of bone [10][11]. The exact role of carboxylated osteocalcin in bone matrix is not yet completely clear, but it likely plays an important role in prevention of cracks in bone after fracturing and improving bone toughness [13]. Carboxylation of osteocalcin is mediated by vitamin K [10].
The Matrix Gla protein (MGP), most abundantly found in bone and cartilage, also is dependent on vitamin K for its carboxylation. Carboxylation of MGP prevents growth plate cartilage mineralization [14][15] and thereby calcification. Bone growth is consequently enhanced. When MGP is insufficiently present (i.e. higher undercarboxylated concentrations), this will result in early calcification of cartilage, leading to short stature, osteopenia and fractures [16].
Vitamin K is found in leafy vegetables (phylloquinone) and as a product of bacterial fermentation (menaquinone)[17]. Dietary intake of vitamin K varies greatly among populations [17]. Since it was proposed that healthy children may already have a suboptimal vitamin K intake [18], it may be even more so for children with O.I.
We aim to assess whether vitamin K levels in children with O.I. are even lower than in healthy children. If this proves to be true, the next step will be starting vitamin K supplementation therapy in a clinical trial. Van Summeren et al. already showed that vitamin K levels in prepubertal children can be improved by vitamin K supplementation [18]. Therefore, this is a potential very easy treatment option to achieve better bone health and growth in children with O.I.