title: Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis.
abstract: OBJECTIVE
  Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast-targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions.
  
  
  METHODS
  Human tumor necrosis factor (TNF)-transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti-TNF, at the onset of arthritis.
  
  
  RESULTS
  Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (-60%) and was almost completely blocked by repeated administration of ZA (-95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti-TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass.
  
  
  CONCLUSIONS
  ZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.
authors.affiliation: University of Vienna, Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Herrak
authors.forename: Birgit
authors.initials: B
authors.lastname: Görtz
authors.forename: Silvia
authors.initials: S
authors.lastname: Hayer
authors.forename: Kurt
authors.initials: K
authors.lastname: Redlich
authors.forename: Erika
authors.initials: E
authors.lastname: Reiter
authors.forename: Jürg
authors.initials: J
authors.lastname: Gasser
authors.forename: Helga
authors.initials: H
authors.lastname: Bergmeister
authors.forename: Giorgos
authors.initials: G
authors.lastname: Kollias
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001168:Arthritis / Q000150:complications* / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D001175:Arthrography; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D002116:Calcitonin / Q000494:pharmacology; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D004164:Diphosphonates / Q000494:pharmacology*; D006614:Hindlimb; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000069285:Infliximab; D007596:Joints / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D014057:Tomography, X-Ray Computed; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000077211:Zoledronic Acid
chemical_list: D000911:Antibodies, Monoclonal; D004164:Diphosphonates; D007093:Imidazoles; D014409:Tumor Necrosis Factor-alpha; D000077211:Zoledronic Acid; D002116:Calcitonin; D000069285:Infliximab