title: Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model.
abstract: Sclerostin antibody has demonstrated a bone-forming effect in pre-clinical models of osteogenesis imperfecta, where mutations in collagen or collagen-associated proteins often result in high bone fragility in pediatric patients. Cessation studies in osteoporotic patients have demonstrated that sclerostin antibody, like intermittent PTH treatment, requires sequential anti-resorptive therapy to preserve the anabolic effects in adult populations. However, the persistence of anabolic gains from either drug has not been explored clinically in OI, or in any animal model. To determine whether cessation of sclerostin antibody therapy in a growing OI skeleton requires sequential anti-resorptive treatment to preserve anabolic gains in bone mass, we treated 3week old Brtl/+ and wild type mice for 5weeks with SclAb, and then withdrew treatment for an additional 6weeks. Trabecular bone loss was evident following cessation, but was preserved in a dose-dependent manner with single administration of pamidronate at the time of cessation. In vivo longitudinal near-infrared optical imaging of cathepsin K activation in the proximal tibia suggests an anti-resorptive effect of both SclAb and pamidronate which is reversed after three weeks of cessation. Cortical bone was considerably less susceptible to cessation effects, and showed no structural or functional deficits in the absence of pamidronate during this cessation period. In conclusion, while SclAb induces a considerable anabolic gain in the rapidly growing Brtl/+ murine model of OI, a single sequential dose of antiresorptive drug is required to maintain bone mass at trabecular sites for 6weeks following cessation.
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Perosky
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States.
authors.forename: Basma M
authors.initials: BM
authors.lastname: Khoury
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States.
authors.forename: Terese N
authors.initials: TN
authors.lastname: Jenks
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States.
authors.forename: Ferrous S
authors.initials: FS
authors.lastname: Ward
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States.
authors.forename: Kai
authors.initials: K
authors.lastname: Cortright
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States.
authors.forename: Bethany
authors.initials: B
authors.lastname: Meyer
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States.
authors.forename: David K
authors.initials: DK
authors.lastname: Barton
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Sinder
authors.affiliation: Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Disorders, NIH, Bethesda, MD, United States.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Caird
authors.affiliation: University of Michigan Department of Orthopaedic Surgery, Ann Arbor, MI, United States; University of Michigan Department of Biomedical Engineering, Ann Arbor, MI, United States. Electronic address: kenkoz@umich.edu.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kozloff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D001696:Biomechanical Phenomena; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D006023:Glycoproteins / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D019265:Spectroscopy, Near-Infrared; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D004164:Diphosphonates; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse
keywords: Bisphosphonate; Cessation; Osteogenesis imperfecta; Osteoporosis; Sclerostin antibody