title: Vitamin K-dependent carboxylation of osteocalcin affects the efficacy of teriparatide (PTH(1-34)) for skeletal repair.
abstract: Teriparatide (PTH1-34) promotes skeletal repair and increases bone mass. Vitamin K is involved in bone mineralization as a coenzyme of γ-carboxylase for Gla proteins, and therefore vitamin K insufficiency caused by malnutrition or therapeutic intake of the vitamin K antagonist warfarin could affect the efficacy of PTH1-34 therapy for bone repair. In the present study, we investigated whether vitamin K influences the efficacy of PTH1-34 therapy for bone repair in a rat osteotomy model. Female 12-week-old Sprague-Dawley rats were subjected to a closed midshaft osteotomy of the femur and randomized into four groups (n=10 per group): vehicle, PTH1-34 (daily 30 μg/kg/day subcutaneous injection)+solvent (orally, three times a week), PTH1-34+warfarin (0.4 mg/kg/day orally, three times a week), and PTH1-34+vitamin K2 (menatetrenone, 30 mg/kg/day orally, three times a week). Serum γ-carboxylated and uncarboxylated osteocalcin (Gla-OC and Glu-OC) levels and radiographic healing were monitored every 2 weeks. Skeletal repair was assessed by micro-computed tomography, mechanical testing, and histology at 8weeks after surgery. PTH1-34 amplified the osteotomy-induced increase in Gla-OC and improved the mechanical properties as well as the volumetric bone mineral tissue density of the fracture callus. Concurrent use of warfarin decreased the response to PTH1-34 therapy in terms of mechanical recovery, probably by impairing mineralization due to the lack of Gla-OC. Although the effects of combination therapy with PTH1-34 and vitamin K2 on bone repair did not significantly exceed those of PTH1-34 monotherapy in rats fed sufficient dietary vitamin K, postoperative Gla-OC levels were correlated with the mechanical properties of the osteotomized femur in PTH1-34-treated rats regardless of the use of warfarin or vitamin K2. These findings suggest the importance of vitamin K dependent γ-carboxylation of OC for realizing the full effects of PTH1-34 on skeletal repair.
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan. Electronic address: takamasa@med.hokudai.ac.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takahata
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kameda
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hamano
authors.affiliation: Chitose Institute of Science of Technology, Chitose, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Ito
authors.affiliation: Chitose Institute of Science of Technology, Chitose, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kimura-Suda
authors.affiliation: Division of Human Mechanical Systems and Design, Faculty of Engineering, Hokkaido University, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Todoh
authors.affiliation: Division of Human Mechanical Systems and Design, Faculty of Engineering, Hokkaido University, Sapporo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tadano
authors.affiliation: Hokkaido University, Department of Orthopedic Surgery, School of Medicine, Sapporo, Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Iwasaki
mesh_terms: D000818:Animals; D001846:Bone Development; D002264:Carboxylic Acids / Q000378:metabolism*; D005260:Female; D015675:Osteocalcin / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019379:Teriparatide / Q000494:pharmacology*; D014812:Vitamin K / Q000494:pharmacology*
chemical_list: D002264:Carboxylic Acids; D015675:Osteocalcin; D019379:Teriparatide; D014812:Vitamin K
keywords: Fracture; Gla-osteocalcin; Mineralization; Parathyroid hormone (1–34); Teriparatide; Vitamin K