title: Effect of alendronate on post-traumatic osteoarthritis induced by anterior cruciate ligament rupture in mice.
abstract: BACKGROUND
  Previous studies in animal models of osteoarthritis suggest that alendronate (ALN) has antiresorptive and chondroprotective effects, and can reduce osteophyte formation. However, these studies used non-physiologic injury methods, and did not investigate early time points during which bone is rapidly remodeled prior to cartilage degeneration. The current study utilized a non-invasive model of knee injury in mice to investigate the effect of ALN treatment on subchondral bone changes, articular cartilage degeneration, and osteophyte formation following injury.
  
  
  METHODS
  Non-invasive knee injury via tibial compression overload or sham injury was performed on a total of 90 mice. Mice were treated with twice weekly subcutaneous injections of low-dose ALN (40 μg/kg/dose), high-dose ALN (1,000 μg/kg/dose), or vehicle, starting immediately after injury until sacrifice at 7, 14 or 56 days. Trabecular bone of the femoral epiphysis, subchondral cortical bone, and osteophyte volume were quantified using micro-computed tomography (μCT). Whole-joint histology was performed at all time points to analyze articular cartilage and joint degeneration. Blood was collected at sacrifice, and serum was analyzed for biomarkers of bone formation and resorption.
  
  
  RESULTS
  μCT analysis revealed significant loss of trabecular bone from the femoral epiphysis 7 and 14 days post-injury, which was effectively prevented by high-dose ALN treatment. High-dose ALN treatment was also able to reduce subchondral bone thickening 56 days post-injury, and was able to partially preserve articular cartilage 14 days post-injury. However, ALN treatment was not able to reduce osteophyte formation at 56 days post-injury, nor was it able to prevent articular cartilage and joint degeneration at this time point. Analysis of serum biomarkers revealed an increase in bone resorption at 7 and 14 days post-injury, with no change in bone formation at any time points.
  
  
  CONCLUSIONS
  High-dose ALN treatment was able to prevent early trabecular bone loss and cartilage degeneration following non-invasive knee injury, but was not able to mitigate long-term joint degeneration. These data contribute to understanding the effect of bisphosphonates on the development of osteoarthritis, and may support the use of anti-resorptive drugs to prevent joint degeneration following injury, although further investigation is warranted.
authors.affiliation: Department of Orthopaedic Surgery, University of California-Davis Medical Center, 4635 2nd Ave, Suite 2000, Sacramento, CA, 95817, USA. mokhoras@yahoo.com.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Khorasani
authors.affiliation: Department of Orthopaedic Surgery, University of California-Davis Medical Center, 4635 2nd Ave, Suite 2000, Sacramento, CA, 95817, USA. sdiko26@gmail.com.
authors.forename: Sindi
authors.initials: S
authors.lastname: Diko
authors.affiliation: Department of Orthopaedic Surgery, University of California-Davis Medical Center, 4635 2nd Ave, Suite 2000, Sacramento, CA, 95817, USA. alwhsia@ucdavis.edu.
authors.forename: Allison W
authors.initials: AW
authors.lastname: Hsia
authors.affiliation: Department of Orthopaedic Surgery, University of California-Davis Medical Center, 4635 2nd Ave, Suite 2000, Sacramento, CA, 95817, USA. mjanderson@ucdavis.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Anderson
authors.affiliation: Department of Orthopaedic Surgery, University of California-Davis Medical Center, 4635 2nd Ave, Suite 2000, Sacramento, CA, 95817, USA. dgenetos@ucdavis.edu.
authors.forename: Damian C
authors.initials: DC
authors.lastname: Genetos
authors.affiliation: Department of Orthopaedic Surgery, University of California-Davis Medical Center, 4635 2nd Ave, Suite 2000, Sacramento, CA, 95817, USA. drhaudenschild@ucdavis.edu.
authors.forename: Dominik R
authors.initials: DR
authors.lastname: Haudenschild
authors.affiliation: Department of Orthopaedic Surgery, University of California-Davis Medical Center, 4635 2nd Ave, Suite 2000, Sacramento, CA, 95817, USA. bchristiansen@ucdavis.edu.
authors.forename: Blaine A
authors.initials: BA
authors.lastname: Christiansen
mesh_terms: D019386:Alendronate / Q000627:therapeutic use*; D000818:Animals; D000070598:Anterior Cruciate Ligament Injuries; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001862:Bone Resorption / Q000517:prevention & control; D002357:Cartilage Diseases / Q000517:prevention & control; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D005260:Female; D007279:Injections, Subcutaneous; D007718:Knee Injuries / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D020370:Osteoarthritis, Knee / Q000517:prevention & control*
chemical_list: D050071:Bone Density Conservation Agents; D019386:Alendronate