title: Local treatment of a bone graft by soaking in zoledronic acid inhibits bone resorption and bone formation. A bone chamber study in rats.
abstract: BACKGROUND
  Bone grafts are frequently used in orthopaedic surgery. Graft remodelling is advantageous but can occur too quickly, and premature bone resorption might lead to decreased mechanical integrity of the graft. Bisphosphonates delay osteoclastic bone resorption but may also impair formation of new bone. We hypothesize that these effects are dose dependent. In the present study we evaluate different ways of applying bisphosphonates locally to the graft in a bone chamber model, and compare that with systemic treatment.
  
  
  METHODS
  Cancellous bone grafts were placed in titanium chambers and implanted in the tibia of 50 male rats, randomly divided into five groups. The first group served as negative control and the grafts were rinsed in saline before implantation. In the second and third groups, the grafts were soaked in a zoledronic acid solution (0.5 mg/ml) for 5 seconds and 10 minutes respectively before being rinsed in saline. In the fourth group, 8 μL of zoledronic acid solution (0.5 mg/ml) was pipetted onto the freeze-dried grafts without rinsing. The fifth group served as positive control and the rats were given zoledronic acid (0.1 mg/kg) systemically as a single injection two weeks after surgery. The grafts were harvested at 6 weeks and analysed with histomorphometry, evaluating the ingrowth distance of new bone into the graft as an equivalent to the anabolic osteoblast effect and the amount (bone volume/total volume; BV/TV) of remaining bone in the remodelled graft as equivalent to the catabolic osteoclast effect.
  
  
  RESULTS
  In all chambers, almost the entire graft had been revascularized but only partly remodelled at harvest. The ingrowth distance of new bone into the graft was lower in grafts soaked in zoledronic acid for 10 minutes compared to control (p = 0.007). In all groups receiving zoledronic acid, the BV/TV was higher compared to control.
  
  
  CONCLUSIONS
  This study found a strong inhibitory effect on bone resorption by bisphosphonates but also a limited inhibition of the ingrowth of new bone. Local treatment at surgery resulted in stronger inhibition of both resorption and bone formation compared to systemic treatment.
authors.affiliation: Department of Orthopedics, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden. ola.belfrage@med.lu.se
authors.forename: Ola
authors.initials: O
authors.lastname: Belfrage
authors.forename: Hanna
authors.initials: H
authors.lastname: Isaksson
authors.forename: Magnus
authors.initials: M
authors.lastname: Tägil
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001862:Bone Resorption / Q000473:pathology / Q000517:prevention & control*; D015194:Diffusion Chambers, Culture; D004164:Diphosphonates / Q000008:administration & dosage*; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D013977:Tibia / Q000187:drug effects / Q000502:physiology / Q000601:surgery; D014025:Titanium / Q000008:administration & dosage; D014184:Transplantation, Homologous / Q000379:methods; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D014025:Titanium