title: Odanacatib increases mineralized callus during fracture healing in a rabbit ulnar osteotomy model.
abstract: The effects of the cathepsin K inhibitor odanacatib (ODN) on fracture healing were monitored for ~6 and 15 weeks post-fracture in two separate studies using the unilateral transverse mid-ulnar osteotomy model in skeletally mature female rabbits. Rabbits were pre-treated for 3-4 weeks with vehicle (Veh), ODN (2 mg/kg, po, daily), or alendronate (ALN) (0.3 mg/kg, sc, twice-weekly) prior to osteotomy. In Study 1, the animals were maintained on the same respective treatment for ~6 weeks. In Study 2, the animals were also continued on the same therapy or switched from Veh to ODN or ODN to Veh for 15 weeks. No treatment-related impairment of fracture union was seen by qualitative histological assessments in the first study. Cartilage retention was detected in the calluses of ALN-treated rabbits at week-6, while calluses in the ODN and Veh groups contained bony tissue with significantly less residual cartilage. ODN treatment also markedly increased the number of cathepsin K-(+) osteoclasts in the callus, indicating enhanced callus remodeling. From the second study, ex vivo DXA and pQCT confirmed that ODN treatment pre- and post-osteotomy increased callus bone mineral content and bone mineral density (BMD) versus Veh (p < 0.001) and discontinuation of ODN post-surgery returned callus BMD to Veh. Peak load of ODN- or ALN-treated calluses were comparable to Veh. ODN increased callus yield load (20%, p = 0.056) and stiffness (26%, p < 0.05) versus Veh. These studies demonstrated that ODN increased mineralized callus during the early phase of fracture repair without impairing callus formation or biomechanical integrity at the fracture site.
authors.affiliation: Bone Biology, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Pennypacker
authors.affiliation: Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: David
authors.initials: D
authors.lastname: Gilberto
authors.affiliation: Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Gatto
authors.affiliation: Charles River Laboratories, Preclinical Services, Senneville, Quebec, Canada.
authors.forename: Rana
authors.initials: R
authors.lastname: Samadfam
authors.affiliation: Charles River Laboratories, Preclinical Services, Senneville, Quebec, Canada.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Smith
authors.affiliation: Bone Biology, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.affiliation: Bone Biology, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: Le Thi
authors.initials: le T
authors.lastname: Duong
mesh_terms: D019386:Alendronate / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002146:Bony Callus / Q000187:drug effects*; D002113:Calcification, Physiologic / Q000187:drug effects*; D005260:Female; D017102:Fracture Healing / Q000187:drug effects*; D010027:Osteotomy; D011817:Rabbits; D011897:Random Allocation; D014457:Ulna
chemical_list: D001713:Biphenyl Compounds; C527128:odanacatib; D019386:Alendronate
keywords: callus formation; cathepsin K; fracture healing; osteoclast; rabbit