title: High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties.
abstract: OBJECTIVE
  The increasing incidence of osteonecrosis of the jaw and its possible association with high cumulative doses of bisphosphonate led us to study the effects of high doses of zoledronic acid (ZA) on bone remodeling.
  
  
  METHODS
  Five-week-old C57BL6 mice were treated with saline or ZA weekly for 3 weeks at increasing doses (0.05-1 mg/Kg). Effects of ZA on bone remodeling were studied using standard assays.
  
  
  RESULTS
  We observed an increase in bone mineral density and content in treated animals at doses of 0.05 mg/Kg, which was not further enhanced at higher doses of ZA. Trabecular bone volume at the proximal tibia and the distal femur assessed by histomorphometry and microCT, respectively, increased significantly in ZA-treated groups. There was however no difference between 0.5 and 1 mg/kg, suggesting a ceiling effect for ZA. ZA led to decreased numbers of osteoclasts and osteoblasts per bone perimeter that paralleled a significant reduction of serum levels of TRAC5b and osteocalcin in vivo. Effects on osteoblasts were confirmed in in vitro assays. Mechanical testing of the femur showed increased brittleness in ZA-treated mice.
  
  
  CONCLUSIONS
  High doses of ZA inhibit both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties. No dose response was noted beyond 0.5 mg/kg suggesting that lower doses of ZA may be adequate in inhibiting bone resorption. Our data may help inform future studies of ZA use with respect to alternate and lower doses in the treatment of patients with cancer bone disease.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Pozzi
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Diana
authors.initials: D
authors.lastname: Cirstea
authors.forename: Nileshwari
authors.initials: N
authors.lastname: Vaghela
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.forename: Eyal
authors.initials: E
authors.lastname: Rosen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okawa
authors.forename: Tanyel
authors.initials: T
authors.lastname: Kiziltepe
authors.forename: Jesse
authors.initials: J
authors.lastname: Schoonmaker
authors.forename: Wanling
authors.initials: W
authors.lastname: Xie
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Edie
authors.initials: E
authors.lastname: Weller
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
mesh_terms: D000328:Adult; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology*; D019070:Cell Lineage / Q000187:drug effects*; D004164:Diphosphonates / Q000008:administration & dosage* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid