title: Short-term glucocorticoid treatment causes spinal osteoporosis in ovariectomized rats.
abstract: OBJECTIVE
  In humans, glucocorticoid-induced osteoporosis is the most common cause of medication-induced osteoporosis. Recent clinical data suggest that glucocorticoid therapy increases the risk of vertebral fractures within a short treatment period. Therefore, this study aimed at investigating vertebral bone in a rat model of glucocorticoid-induced postmenopausal osteoporosis.
  
  
  METHODS
  Fifty Sprague-Dawley rats were randomly assigned into three groups: 1) untreated controls, 2) Sham-operated group, and 3) ovariectomized rats treated with glucocorticoid (dexamethasone) for 3 months (3M) after recovery from bilateral ovariectomy. Osteoporotic bone status was determined by means of the gold standard dual energy X-ray absorptiometry (DEXA) scan. Vertebral bodies were examined using µCT, histological analysis, mRNA expression analysis, and biomechanical compression testing. Further systemic effects were studied biochemically using serum marker analysis.
  
  
  RESULTS
  Dexamethasone treatment showed at 3M a significantly lower bone mineral density in ovariectomized rats compared to Sham-operated control (p < 0.0001) as analyzed in vivo by DEXA. Furthermore, Z scores reached levels of -5.7 in the spine indicating sever osteoporotic bone status. Biomechanical testing of compression stability indicated a lower functional competence (p < 0.0001) in the spine of treated rats. µCT analysis showed significant reduction of bone volume density (BV/TV%; p < 0.0001), significantly enhanced trabecular spacing (Tb.Sp; p < 0.0001) with less trabecular number (Tb.N; p < 0.001) and complete loss of trabecular structures in glucocorticoid-treated ovariectomized rats. Histological analysis by osteoblast and osteoclast activities reflected a higher bone catabolism reflected by osteoclast counts by TRAP (p < 0.019) and lower bone catabolism indicated by ALP-stained area (p < 0.035).Serum analysis showed a significant increase in osteocalcin (p < 0.0001), osteopontin (p < 0.01) and insulin (p < 0.001) at 3M. Expression analysis of molecular markers in the vertebral body revealed lower expression in tenascin C in the OVX-steroid animals at 3M.
  
  
  CONCLUSIONS
  Short-term glucocorticoid treatment of ovariectomized rats indicates according to DEXA standards a severe osteoporotic bone status in vertebral bone. Nonetheless, dysfunctional bone anabolism and enhanced bone catabolism are observed. Alterations of bone extracellular matrix proteins that correlate to inferior mechanical stability and affected microstructure were noticed and suggest further investigation. Treatment with dexamethasone was also seen to affect insulin and osteopontin levels and thus osteoblast function and maturation. This described animal model presents a recapitulation of clinically obtained data from early phase glucocorticoid-induced osteoporosis observed in patients.
authors: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany, wolfgang.boecker@chiru.med.uni-giessen.de.
authors: W
authors: W
authors: Böcker
authors: T
authors: T
authors: El Khassawna
authors: N
authors: N
authors: Bauer
authors: K
authors: K
authors: Brodsky
authors: D
authors: D
authors: Weisweiler
authors: P
authors: P
authors: Govindarajan
authors: G
authors: G
authors: Schlewitz
authors: M
authors: M
authors: Kampschulte
authors: L
authors: L
authors: Dürselen
authors: U
authors: U
authors: Thormann
authors: G
authors: G
authors: Szalay
authors: R
authors: R
authors: Schnettler
authors: A C
authors: AC
authors: Langheinrich
authors: C
authors: C
authors: Heiss
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density; D002452:Cell Count; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D007328:Insulin / Q000097:blood; D023421:Models, Animal; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000473:pathology; D053495:Osteopontin / Q000097:blood; D010024:Osteoporosis / Q000139:chemically induced* / Q000473:pathology; D010052:Ovariectomy; D017207:Rats, Sprague-Dawley
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D015675:Osteocalcin; D053495:Osteopontin; D003907:Dexamethasone