title: Zoledronate induces bisphosphonate-related osteonecrosis of the jaw in osteopenic sheep.
abstract: OBJECTIVE
  Bisphosphonate-related osteonecrosis of the jaw (BP-ONJ) occurs in 1 % of patients with medication-induced osteoporosis treated with bisphosphonates. Sheep are an established large animal model for investigating osteoporotic skeletal changes. Zoledronate significantly reduces tissue mineral variability in ovariectomized sheep. The aim of this study was to analyze bone healing after tooth extraction in sheep with induced osteopenia and zoledronate administration.
  
  
  METHODS
  Eight adult ewes were randomly divided into two groups of four animals. All sheep underwent ovariectomy and a low-calcium diet. Dexamethasone was administered weekly for 16 weeks. Zoledronate was then given every third week for a further 16 weeks in four sheep; these infusions were repeated after extraction of two lower premolars. Four sheep without zoledronate administrations served as controls.
  
  
  RESULTS
  Due to general health conditions, two sheep of the zoledronate group had to be excluded before surgery. The remaining two sheep of this group developed BP-ONJ lesions at the extraction site and various other sites in both jaws. Control group animals showed uneventful wound healing. Histology of the alveolar processes as well as lumbar spine revealed larger portions of old bone and smaller portions of new bone in the zoledronate group.
  
  
  CONCLUSIONS
  This animal study showed uneventful wound healing after tooth extraction in osteopenic sheep whereas zoledronate treatment leads to development of BP-ONJ-like lesions.
  
  
  CONCLUSIONS
  As bisphosphonate administration is a standard treatment for glucocorticoid-induced osteoporosis, this model can be used for further research in pathogenesis and management of bisphosphonate-related adverse events.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. pit.voss@uniklinik-freiburg.de.
authors.forename: Pit J
authors.initials: PJ
authors.lastname: Voss
authors.affiliation: AO Research Institute Davos, Clavadelerstr. 8, 7270, Davos, Switzerland. martin.stoddart@aofoundation.org.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stoddart
authors.affiliation: Department of Orthopedics and Traumatology, University Medical Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. anke.bernstein@uniklinik-freiburg.de.
authors.forename: Anke
authors.initials: A
authors.lastname: Bernstein
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. rainer.schmelzeisen@uniklinik-freiburg.de.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schmelzeisen
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. katja.nelson@uniklinik-freiburg.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Nelson
authors.affiliation: AO Research Institute Davos, Clavadelerstr. 8, 7270, Davos, Switzerland. vincent.stadelmann@aofoundation.org.
authors.forename: Vincent
authors.initials: V
authors.lastname: Stadelmann
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Mainz, Augustusplatz 2, 55131, Mainz, Germany. ziebart@mkg.klinik.uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ziebart
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany. philipp.poxleitner@uniklinik-freiburg.de.|AO Research Institute Davos, Clavadelerstr. 8, 7270, Davos, Switzerland. philipp.poxleitner@uniklinik-freiburg.de.
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Poxleitner
mesh_terms: D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000473:pathology*; D001851:Bone Diseases, Metabolic / Q000139:chemically induced; D003907:Dexamethasone / Q000633:toxicity; D004164:Diphosphonates / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000633:toxicity*; D010052:Ovariectomy; D011897:Random Allocation; D034561:Sheep, Domestic; D014081:Tooth Extraction; D014945:Wound Healing / Q000502:physiology*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D003907:Dexamethasone
keywords: Bisphosphonates; Large animal study; Oral and maxillofacial surgery; Oral pathology; Osteoporosis; Ovariectomy; Wound healing
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