title: Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength.
abstract: Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI-causing defect.
  
  
  BACKGROUND
  Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1.
  
  
  METHODS
  Six-month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2×/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed.
  
  
  RESULTS
  Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength.
  
  
  CONCLUSIONS
  Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI.
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, 2015 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Sinder
authors.forename: L E
authors.initials: LE
authors.lastname: White
authors.forename: J D
authors.initials: JD
authors.lastname: Salemi
authors.forename: M S
authors.initials: MS
authors.lastname: Ominsky
authors.forename: M S
authors.initials: MS
authors.lastname: Caird
authors.forename: J C
authors.initials: JC
authors.lastname: Marini
authors.forename: K M
authors.initials: KM
authors.lastname: Kozloff
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D048868:Adaptor Proteins, Signal Transducing; D045930:Anabolic Agents / Q000627:therapeutic use*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D015992:Body Mass Index; D015519:Bone Density / Q000187:drug effects* / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005269:Femur / Q000473:pathology / Q000503:physiopathology; D005819:Genetic Markers / Q000276:immunology*; D007527:Isoenzymes / Q000097:blood; D008297:Male; D008817:Mice, Mutant Strains; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D010013:Osteogenesis Imperfecta / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013314:Stress, Mechanical; D000071681:Tartrate-Resistant Acid Phosphatase; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D045930:Anabolic Agents; D057134:Antibodies, Neutralizing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D007527:Isoenzymes; C422903:SOST protein, human; D015675:Osteocalcin; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase