title: Dexrazoxane shows cytoprotective effects in zoledronic acid-treated human cells in vitro and in the rabbit tibia model in vivo.
abstract: BACKGROUND
  Bisphosphonates are important and effective drugs in oncology and osteoporosis therapy. They accumulate in the bone matrix becoming released and active by bone resorption. This leads to effective inhibition of tumor cells and bone degradation. A side effect of bisphosphonates similar to other drugs like denosumab is osteonecrosis of the jaws (ONJ). This problem mostly occurs after tooth extraction. We studied the cytoprotectant dexrazoxane known from anthracycline chemotherapy for cytoprotection in nitrogen-containing bisphosphonate treated cells and in the rabbit tibia model to evaluate a possible value in ONJ management.
  
  
  METHODS
  Human osteoblasts (HOB) P2 cells and Human ginigiva fibroblasts (HGF) P2 cells were treated with zoledronic acid (50 μmol/L) and the cytoprotectant dexrazoxane (600 μmol/L). Analysis included cell viability testing with MTT assay and morphology analysis using CellTracker™ Green CMFDA. A biomaterial carrier (Bio-Oss Collagen) was implanted in the rabbit tibia of 6 female chinchilla bastard rabbits on both sides with drill hole defects (d: 3.2mm). Implants were loaded with 25 nmol zoledronic acid, with and without 300 nmol dexrazoxane and unloaded in a control group. Analysis included histological examination of undecalcified samples with toloudine blue staining after 10 days.
  
  
  RESULTS
  In vitro experiments showed a significantly higher MTT activity in cells treated with zoledronic acid together with dexrazoxane compared to the same cells treated with the bisphosphonate alone in t-test (HOB: p=0.0003; HGF: p below 0.0001) and one-way ANOVA. Cell morphology changes were consistent with these results. In vivo results showed newly formed bone trabeculae directly growing towards the implanted hydroxylapatite particles and cortical bone interface resorption activities in the control and the experimental group only.
  
  
  CONCLUSIONS
  The study suggests a possible value of this patented technology for ONJ therapy and prevention with local or systemic application.
authors.affiliation: Clinic for Maxillofacial Surgery, University of Marburg, Georg-Voigt-Str. 3, 35039 Marburg, Germany. draenert@draenert.net
authors.forename: G F
authors.initials: GF
authors.lastname: Draenert
authors.forename: D O
authors.initials: DO
authors.lastname: Huetzen
authors.forename: P W
authors.initials: PW
authors.lastname: Kämmerer
authors.forename: V
authors.initials: V
authors.lastname: Palarie
authors.forename: V
authors.initials: V
authors.lastname: Nacu
authors.forename: W
authors.initials: W
authors.lastname: Wagner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001862:Bone Resorption / Q000473:pathology; D018929:Cell Culture Techniques; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen; D004396:Coloring Agents; D019610:Cytoprotection / Q000187:drug effects*; D004164:Diphosphonates / Q000494:pharmacology*; D004337:Drug Carriers; D017886:Durapatite; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D023421:Models, Animal; D010006:Osteoblasts / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D011817:Rabbits; D011929:Razoxane / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013977:Tibia / Q000187:drug effects*; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004396:Coloring Agents; D004164:Diphosphonates; D004337:Drug Carriers; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007093:Imidazoles; D020011:Protective Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; C069306:5-chloromethylfluorescein; D011929:Razoxane; D000077211:Zoledronic Acid; D003094:Collagen; D017886:Durapatite; C022616:thiazolyl blue