title: Mechanisms of bone fragility in a mouse model of glucocorticoid-treated rheumatoid arthritis: implications for insufficiency fracture risk.
abstract: OBJECTIVE
  Glucocorticoid (GC) therapy is associated with increased risk of fracture in patients with rheumatoid arthritis (RA). To elucidate the cause of this increased risk, we examined the effects of chronic erosive inflammatory arthritis and GC treatment on bone quality, structure, and biomechanical properties in a murine model.
  
  
  METHODS
  Mice with established arthritis and expressing human tumor necrosis factor α (TNFα) transgene (Tg) and their wild-type (WT) littermates were continually treated with GC (prednisolone 5 mg/kg/day via subcutaneous controlled-release pellet) or placebo for 14, 28, or 42 days. Microstructure, biomechanical properties, chemical composition, and morphology of the tibiae and lumbar vertebral bodies were assessed by micro-computed tomography, biomechanical testing, Raman spectroscopy, and histology, respectively. Serum markers of bone turnover were also determined.
  
  
  RESULTS
  TNF-Tg and GC treatment additively decreased mechanical strength and stiffness in both the tibiae and the vertebral bodies. GC treatment in the TNF-Tg mice increased the ductility of tibiae under torsional loading. These changes were associated with significant alterations in the biochemical and structural composition of the mineral and organic components of the bone matrix, a decrease in osteoblast activity and bone formation, and an increase in osteoclast activity.
  
  
  CONCLUSIONS
  Our findings indicate that the concomitant decrease in bone strength and increase in bone ductility associated with chronic inflammation and GC therapy, coupled with the significant changes in the bone quality and structure, may increase the susceptibility of the bone to failure under low-energy loading. This may explain the mechanism of symptomatic insufficiency fractures in patients with RA receiving GC therapy who do not have radiographic manifestations of fracture.
authors: University of Rochester, New York, USA.
authors: Masahiko
authors: M
authors: Takahata
authors: Jason R
authors: JR
authors: Maher
authors: Subhash C
authors: SC
authors: Juneja
authors: Jason
authors: J
authors: Inzana
authors: Lianping
authors: L
authors: Xing
authors: Edward M
authors: EM
authors: Schwarz
authors: Andrew J
authors: AJ
authors: Berger
authors: Hani A
authors: HA
authors: Awad
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology*; D001696:Biomechanical Phenomena / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D004195:Disease Models, Animal; D050723:Fractures, Bone / Q000453:epidemiology / Q000473:pathology*; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011239:Prednisolone / Q000008:administration & dosage / Q000009:adverse effects*; D012307:Risk Factors; D013059:Spectrum Analysis, Raman; D013131:Spine / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D019076:Transgenes / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: D005938:Glucocorticoids; D014409:Tumor Necrosis Factor-alpha; D011239:Prednisolone