title: The Optimal Duration of PTH(1-34) Infusion Is One Hour per Day to Increase Bone Mass in Rats.
abstract: Parathyroid hormone (PTH) is a potential medicine for osteoporosis, and subcutaneous (s.c.) PTH treatment enhances bone mass; however, continuous infusion of PTH elicits bone resorption and induces bone loss. To clarify this contradictory phenomenon, we examined bone markers and bone mass in rats to assess the optimal duration of PTH(1-34) infusion. Continuous infusion of PTH at 1 µg/kg/h (Css, steady-state concentration ca. 300 pg/mL) for 1-4 h clearly stimulated the expression both of bone formation-related genes (c-fos, Wnt4, EphrinB2) and of bone resorption-related genes (tnfsf11, tnfsf11b, encoding receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG)), but s.c. treatment stimulated these genes only 1-h after the injection. Rats were treated with 1-, 2-, or 4-h infusions of PTH daily using a totally implanted catheter system, and the femoral bone mineral density (BMD) was measured at 4 weeks. The 1-h infusion of PTH significantly stimulated serum bone formation markers (procollagen I N-terminal propeptide (PINP) and osteocalcin) on day 14 and femoral BMD at 2 and 4 weeks, but the 4-h infusion of PTH did not enhance BMD. Since the 4-h infusion increased the levels of both the bone formation markers and a bone resorption marker (urinary C-terminal telopeptide of type 1 collagen (CTx)), the increased bone resorption may predominate over bone formation. The intermittent elevation of plasma PTH to 300 pg/mL for 1-h each day is optimal for increasing bone mass in rats. In osteoporosis therapy in human, using the optimal duration for the clinical dose of PTH may selectively stimulate bone formation.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd.
authors.forename: Masaru
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Noda
authors.forename: Eri
authors.initials: E
authors.lastname: Joyashiki
authors.forename: Chie
authors.initials: C
authors.lastname: Nakagawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Asanuma
authors.forename: Akira
authors.initials: A
authors.lastname: Hayasaka
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nanami
authors.forename: Masaki
authors.initials: M
authors.lastname: Inada
authors.forename: Chisato
authors.initials: C
authors.lastname: Miyaura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D004334:Drug Administration Schedule; D005269:Femur / Q000187:drug effects* / Q000378:metabolism; D007262:Infusions, Intravenous; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000235:genetics
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D014157:Transcription Factors