title: Transient retention of endochondral cartilaginous matrix with bisphosphonate treatment in a long-term rabbit model of distraction osteogenesis.
abstract: Bisphosphonates induce major increases in strength of callus in distraction osteogenesis in the short term. Poor understanding of the underlying mechanism, however, raises concerns about long-term consequences. In this long-term study in 32 rabbits, zoledronic acid transiently increased trabeculae by delayed temporal progression of endochondral bone remodeling but did not prevent radiographic completion of bone repair.
  
  
  BACKGROUND
  We hypothesized that bisphosphonate inhibition of osteoclast-mediated resorption would retain bone during repair, producing a larger callus in the short term. However, if remodeling was not restored, completion of the bone repair process in the long term could be jeopardized.
  
  
  METHODS
  Juvenile rabbits underwent right tibial osteotomy and 2 weeks of distraction, followed by a period of consolidation. Animals received saline (controls) or zoledronic acid (ZA; 0.1 mg/kg at surgery and again 2 weeks later), and distracted tibias were examined by radiograph, DXA, histology, and histomorphometry at 2, 4, 6, 18, and 44 weeks after surgery.
  
  
  RESULTS
  Regenerated bone in ZA-treated animals was denser than controls on radiographs at 6 weeks and had more distinct radiodense trabeculae and retention of original cortices at 18 weeks. By 44 weeks, controls and ZA-treated animals were radiographically healed and indistinguishable. Regenerate BMD and BMC increased between 2 and 4 weeks in all animals, with a greater effect in ZA. At 6 weeks, BMD and BMC in ZA-treated animals were 1.6- and 2-fold greater, respectively, than controls (p < 0.01). From 6 to 44 weeks, the control values gradually increased and approached the ZA-treated values. Regenerate bone volume and trabecular number by histomorphometry were from 1.6- to 2-fold greater in ZA-treated animals at 6 and 18 weeks (p < 0.05). Endochondral cartilaginous matrix volume was up to 2.4-fold greater in ZA-treated animals at 2 and 4 weeks (p < 0.05). TRACP+ cells in ZA-treated animals were larger with more nuclei. Mineral apposition rate and osteoblast number and surface were lower in ZA-treated animals at 6 weeks (p < 0.01) but not at later times.
  
  
  CONCLUSIONS
  Disruption of TRACP+ cell function by ZA during bone regeneration seems to lead to an accretion of cancellous bone built on a larger endochondral cartilaginous matrix and increased bone mass, consistent with reported increases in short-term callus strength. This increase in bone mass, caused by a delay in remodeling, provided a transient advantage without preventing radiographic completion of the bone repair process in the long term. Noncontinuous treatment with nitrogen-containing bisphosphonates thus can have short-term beneficial effects without preventing long-term bone repair.
authors.affiliation: Orthopaedic Research Unit, Children's Hospital at Westmead, Sydney, Australia. e.smith@garvan.org.au
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Smith
authors.forename: Anthony
authors.initials: A
authors.lastname: McEvoy
authors.forename: David G
authors.initials: DG
authors.lastname: Little
authors.forename: Paul A
authors.initials: PA
authors.lastname: Baldock
authors.forename: John A
authors.initials: JA
authors.lastname: Eisman
authors.forename: Edith M
authors.initials: EM
authors.lastname: Gardiner
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D015519:Bone Density; D001861:Bone Regeneration; D002146:Bony Callus; D002356:Cartilage / Q000378:metabolism*; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology; D019857:Osteogenesis, Distraction; D011817:Rabbits; D000071681:Tartrate-Resistant Acid Phosphatase; D013977:Tibia / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D013997:Time Factors; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D007527:Isoenzymes; D000077211:Zoledronic Acid; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase