title: Zoledronic acid suppresses callus remodeling but enhances callus strength in an osteoporotic rat model of fracture healing.
abstract: CONCLUSIONS
  In this study, we demonstrated that the use of zoledronic acid does not impair fracture healing, but results in superior callus size and resistance at the fracture site, which could be the consequence of a lower rate of bone turnover due to its anti-catabolic effect.
  
  
  OBJECTIVE
  To investigate the effect of inhibition of bone remodeling by the bisphosphonate, zoledronic acid, on callus properties in an osteoporotic rat model of fracture healing.
  
  
  METHODS
  Ovariectomized (OVX) rats were randomly divided into four treatment groups (n=24 per group): saline control (CNT); and three systemic zoledronic acid-injected groups (0.1mg/kg), administered 1 day (ZOLD1), 1 week (ZOLW1), and 2 weeks (ZOLW2) after fracture. Rats were killed at either 6 or 12 weeks postoperatively. Postmortem analyses included radiography, microcomputed tomography, histology, histomorphometry, biomechanical tests, and nanoindentation tests.
  
  
  RESULTS
  Treatment with zoledronic acid led to a significant increase in trabecular bone volume within the callus, as well as in callus resistance, compared to those in the saline control rats; delayed administration (ZOLW2) reduced intrinsic material properties, including ultimate stress and elastic modulus, and microarchitecture parameters, including bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), and connectivity density (Conn.D), compared with ZOLD1 at 12 weeks after surgery. OVX had a negative effect on the progression of endochondral ossification at 6 weeks. Zoledronic acid administration at an early stage following fracture may bind to early callus, and thus not affect subsequent callus formation and endochondral ossification, while delayed administration (ZOLW2) mildly suppresses bony callus remodeling.
  
  
  CONCLUSIONS
  The superior results obtained with zoledronic acid (ZOLD1, ZOLW1, and ZOLW2) compared to CNT in terms of callus size and resistance could be the consequence of a lower rate of bone turnover at the fracture site due to the anti-catabolic effect of zoledronic acid. Mild suppression of callus remodeling by delayed administration did not impair the initial phase of the fracture healing process.
authors.affiliation: Department of Orthopaedics, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, People's Republic of China. Electronic address: hao_yongqiang@hotmail.com.
authors.forename: Y
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Orthopaedics, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Orthopaedics, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Ge
authors.affiliation: Department of Orthopaedics, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, People's Republic of China.
authors.forename: K
authors.initials: K
authors.lastname: Dai
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016723:Bone Remodeling / Q000187:drug effects; D002146:Bony Callus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005264:Femoral Fractures / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D021621:Imaging, Three-Dimensional; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D010024:Osteoporosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Callus remodeling; Callus resistance; Fracture healing; Osteoporosis; Ovariectomized rats; Zoledronic acid