title: Comparable outcomes in fracture reduction and bone properties with RANKL inhibition and alendronate treatment in a mouse model of osteogenesis imperfecta.
abstract: We report a direct comparison of receptor activator of nuclear factor kappa B ligand (RANKL) inhibition (RANK-Fc) with bisphosphonate treatment (alendronate, ALN) from infancy through early adulthood in a mouse model of osteogenesis imperfecta. Both ALN and RANK-Fc decreased fracture incidence to the same degree with increases in metaphyseal bone volume via increased number of thinner trabeculae.
  
  
  BACKGROUND
  The potential therapeutic benefit of RANKL inhibitors in osteogenesis imperfecta (OI) is under investigation. We report a direct comparison of RANKL inhibition (RANK-Fc) with bisphosphonate treatment (ALN) from infancy through early adulthood in a model of OI, the oim/oim mouse.
  
  
  METHODS
  Two-week-old oim/oim, oim/+, and wildtype (+/+) mice were treated with RANK-Fc 1.5 mg/kg twice per week, ALN 0.21 mg/kg/week or saline (n = 12-20 per group) for 12 weeks.
  
  
  RESULTS
  ALN and RANK-Fc both decreased fracture incidence (9.0 ± 3.0 saline 4.4 ± 2.7 ALN, 4.3 ± 3.0 RANK-Fc fractures per mouse). Serum TRACP-5b activity decreased to 65% after 1 month in all treated mice, but increased sacrifice with RANK-Fc to 130-200% at sacrifice. Metaphyseal density was significantly increased with ALN in +/+ and oim/oim mice (p < 0.05) and tended to increase with RANK-Fc in +/+ mice. No changes in oim/oim femur biomechanical parameters occurred with treatment. Both ALN and RANK-Fc significantly increased trabecular number (3.73 ± 0.77 1/mm for oim/oim saline vs 7.93 ± 0.67 ALN and 7.34 ± 1.38 RANK-Fc) and decreased trabecular thickness (0.045 mm ± 0.003 for oim/oim saline vs 0.034 ± 0.003 ALN and 0.032 ± 0.002 RANK-Fc) and separation in all genotypes (0.28 ± 0.08 mm for oim/oim saline vs 0.12 ± 0.010 ALN and 13 ± 0.03 RANK-Fc)., with significant increase in bone volume fraction (BVF) with ALN, and a trend towards increased BVF in RANK-Fc.
  
  
  CONCLUSIONS
  Treatment of oim/oim mice with either a bisphosphonate or a RANK-Fc causes similar decreases in fracture incidence with increases in metaphyseal bone volume via increased number of thinner trabeculae.
authors: NYPH-Weill Cornell Medical Center, New York, NY, USA. rbargman@numc.edu
authors: R
authors: R
authors: Bargman
authors: R
authors: R
authors: Posham
authors: A L
authors: AL
authors: Boskey
authors: E
authors: E
authors: DiCarlo
authors: C
authors: C
authors: Raggio
authors: N
authors: N
authors: Pleshko
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D019386:Alendronate / Q000627:therapeutic use*; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D007527:Isoenzymes / Q000097:blood; D008297:Male; D051379:Mice; D010013:Osteogenesis Imperfecta / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D058866:Osteoporotic Fractures / Q000209:etiology / Q000517:prevention & control*; D053245:RANK Ligand / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D000071681:Tartrate-Resistant Acid Phosphatase; D015430:Weight Gain / Q000187:drug effects; D055114:X-Ray Microtomography / Q000379:methods
chemical_list: D050071:Bone Density Conservation Agents; D007527:Isoenzymes; D053245:RANK Ligand; C517736:Rank-Fc; D011993:Recombinant Fusion Proteins; C505689:Tnfsf11 protein, mouse; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D019386:Alendronate