title: Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing.
abstract: The role of osteoclast-mediated resorption during fracture healing was assessed. The impact of two osteoclast inhibitors with different mechanisms of action, alendronate (ALN) and denosumab (DMAB), were examined during fracture healing. Male human RANKL knock-in mice that express a chimeric (human/murine) form of RANKL received unilateral transverse femur fractures. Mice were treated biweekly with ALN 0.1 mg/kg, DMAB 10 mg/kg, or PBS (control) 0.1 ml until death at 21 and 42 days after fracture. Treatment efficacy assessed by serum levels of TRACP 5b showed almost a complete elimination of TRACP 5b levels in the DMAB-treated animals but only approximately 25% reduction of serum levels in the ALN-treated mice. Mechanical testing showed that fractured femurs from both ALN and DMAB groups had significantly increased mechanical properties at day 42 compared with controls. muCT analysis showed that callus tissues from DMAB-treated mice had significantly greater percent bone volume and BMD than did both control and ALN-treated tissues at both 21 and 42 days, whereas ALN-treated bones only had greater percent bone volume and BMC than control at 42 days. Qualitative histological analysis showed that the 21-and 42-day ALN and DMAB groups had greater amounts of unresorbed cartilage or mineralized cartilage matrix compared with the controls, whereas unresorbed cartilage could still be seen in the DMAB groups at 42 days after fracture. Although ALN and DMAB delayed the removal of cartilage and the remodeling of the fracture callus, this did not diminish the mechanical integrity of the healing fractures in mice receiving these treatments. In contrast, strength and stiffness were enhanced in these treatment groups compared with control bones.
authors.affiliation: Orthopaedic Research Laboratory, Department of Orthopedic Surgery, Boston University School of Medicine, Boston, Massachusetts 02118, USA. lgersten@bu.edu
authors.forename: Louis C
authors.initials: LC
authors.lastname: Gerstenfeld
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sacks
authors.forename: Megan
authors.initials: M
authors.lastname: Pelis
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Mason
authors.forename: Dana T
authors.initials: DT
authors.lastname: Graves
authors.forename: Mauricio
authors.initials: M
authors.lastname: Barrero
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: Elise F
authors.initials: EF
authors.lastname: Morgan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Einhorn
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001696:Biomechanical Phenomena / Q000187:drug effects; D002146:Bony Callus / Q000187:drug effects / Q000473:pathology; D000069448:Denosumab; D004164:Diphosphonates / Q000494:pharmacology*; D005264:Femoral Fractures / Q000473:pathology*; D005269:Femur / Q000187:drug effects / Q000473:pathology*; D017102:Fracture Healing / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013997:Time Factors; D054159:Torsion, Mechanical; D055114:X-Ray Microtomography
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004164:Diphosphonates; D053245:RANK Ligand; D000069448:Denosumab; D019386:Alendronate