title: Acute development of cortical porosity and endosteal naïve bone formation from the daily but not weekly short-term administration of PTH in rabbit.
abstract: Teriparatide [human parathyroid hormone (1-34)], which exerts an anabolic effect on bone, is used for the treatment of osteoporosis in patients who are at a high risk for fracture. That the once-daily administration of teriparatide causes an increase in cortical porosity in animal models and clinical studies has been a matter of concern. However, it is not well documented that the frequency of administration and/or the total dose of teriparatide affect the cortical porosity. The present study developed 4 teriparatide regimens [20 μg/kg/day (D20), 40 μg/kg/day (D40), 140 μg/kg/week (W140) and 280 μg/kg/week (W280)] in the rabbit as a model animal with a well-developed Haversian system and osteons. The total weekly doses were equivalent in the low-dose groups (D20 and W140) and in the high-dose groups (D40 and W280). After the short-term (1 month) administration of TPDT, micro-CT, histomorphometry and three-dimensional second harmonic generation (3D-SHG) imaging to visualize the bone collagen demonstrated that daily regimens but not weekly regimens were associated with the significant development of cortical porosity and endosteal naïve bone formation by marrow fibrosis. We concomitantly monitored the pharmacokinetics of the plasma teriparatide levels as well as the temporal changes in markers of bone formation and resorption. The analyses in the present study suggested that the daily repeated administration of teriparatide causes more deleterious changes in the cortical microarchitecture than the less frequent administration of higher doses. The findings of the present study may have some implications for use of teriparatide in clinical treatment.
authors.affiliation: Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamane
authors.affiliation: Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan.|Division of Analytical Bio-Medicine, Graduate School of Medicine, Ehime University, Shitukawa, Toon city, Ehime, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Takakura
authors.affiliation: Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Shimadzu
authors.affiliation: Laboratory for Safety Assessment and ADME, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Division of Bio-Imaging, Proteo-Science Center (PROS), Ehime University, Shitukawa, Toon city, Ehime, Japan.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan.|Medical Affairs Department, Pharmaceutical Business Administration Division, Asahi Kasei Pharma Corporation, Tokyo, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Isogai
authors.affiliation: Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ishizuya
authors.affiliation: Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takao-Kawabata
authors.affiliation: Division of Analytical Bio-Medicine, Graduate School of Medicine, Ehime University, Shitukawa, Toon city, Ehime, Japan.|Division of Bio-Imaging, Proteo-Science Center (PROS), Ehime University, Shitukawa, Toon city, Ehime, Japan.|Division of Analytical Bio-Medicine, Advanced Research Support Center (ADRES), Ehime University, Shitukawa, Toon city, Ehime, Japan.|Artificial Joint Integrated Center, Ehime University Hospital, Shitukawa, Toon city, Ehime, Japan.
authors.forename: Tadahiro
authors.identifier: http://orcid.org/0000-0002-1431-0689
authors.initials: T
authors.lastname: Iimura
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D001862:Bone Resorption / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000166:cytology / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D021621:Imaging, Three-Dimensional; D008856:Microscopy, Fluorescence; D008857:Microscopy, Interference; D023421:Models, Animal; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D016062:Porosity / Q000187:drug effects; D011817:Rabbits; D019379:Teriparatide / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D055114:X-Ray Microtomography
chemical_list: D050071:Bone Density Conservation Agents; D019379:Teriparatide; D003094:Collagen