title: Additive bone-protective effects of anabolic treatment when used in conjunction with RANKL and tumor necrosis factor inhibition in two rat arthritis models.
abstract: OBJECTIVE
  To investigate whether the bone-preserving effects of a RANKL antagonist or a tumor necrosis factor (TNF) antagonist could be further improved by the addition of a bone anabolic agent in inflammatory arthritis.
  
  
  METHODS
  Lewis rats with either adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) were treated for 10 days with PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI), interleukin-1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), parathyroid hormone (PTH), or combinations of these agents starting on day 4 after disease onset. Treatment effects were assessed clinically, radiologically, and histologically, and by morphometry for the extent of paw swelling, bone erosive changes, and synovial inflammation.
  
  
  RESULTS
  Paw swelling and synovial inflammation were significantly inhibited by PEG sTNFRI in AIA and CIA, and by IL-1Ra in CIA. OPG and PTH had no significant effect on these parameters. Analysis of bone erosion revealed a significant bone-sparing effect of monotherapy with PEG sTNFRI or OPG in both models, whereas IL-1Ra was only effective in CIA. PTH treatment alone did not show a bone-protective effect in either model. With the combination of PEG sTNFRI and PTH, erosion scores (-74% in AIA and -61% in CIA versus controls) were significantly lower than those elicited by PEG sTNFRI alone (-41% and -29%, respectively, versus controls). Similar results were also obtained with the combination of OPG and PTH (-88% in AIA and -73% in CIA, compared with -70% and -55%, respectively, with OPG monotherapy). Coadministration of IL-1Ra and PTH had no synergistic bone-sparing effect. Morphometric analysis revealed that the addition of PTH to PEG sTNFRI or OPG resulted in higher bone volume and higher osteoblast numbers in both AIA and CIA.
  
  
  CONCLUSIONS
  The bone-protective effects resulting from RANKL or TNF antagonism can be further improved by the addition of a bone anabolic agent.
authors.affiliation: Amgen Inc., Thousand Oaks, California, and Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Scot
authors.initials: S
authors.lastname: Middleton
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Heather
authors.initials: H
authors.lastname: Brown
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Jim
authors.initials: J
authors.lastname: Pretorius
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Paul
authors.initials: P
authors.lastname: Kostenuik
authors.forename: Ulrich
authors.initials: U
authors.lastname: Feige
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy*; D001846:Bone Development / Q000187:drug effects; D001847:Bone Diseases / Q000517:prevention & control*; D001862:Bone Resorption / Q000517:prevention & control; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002452:Cell Count; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D010006:Osteoblasts; D053244:Osteoprotegerin; D010281:Parathyroid Hormone / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D053245:RANK Ligand; D051381:Rats; D011917:Rats, Inbred Lew; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; C496217:PEGylated tumor necrosis factor alpha receptor 1; D010281:Parathyroid Hormone; D053245:RANK Ligand; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C506032:Tnfrsf11b protein, rat; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols