High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties

Samantha Pozzi, Sonia Vallet, Siddhartha Mukherjee, Diana Cirstea, Nileshwari Vaghela, Loredana Santo, Eyal Rosen, Hiroshi Ikeda, Yutaka Okawa, Tanyel Kiziltepe, Jesse Schoonmaker, Wanling Xie, Teru Hideshima, Edie Weller, Mary L. Bouxsein, Nikhil C. Munshi, Kenneth C. Anderson, Noopur Raje*

*Corresponding author for this work

Research output: Journal article (peer-reviewed)Journal article

87 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish
Pages (from-to)5829-5839
Number of pages11
JournalClinical Cancer Research
Volume15
Issue number18
DOIs
Publication statusPublished - 15 Sept 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties'. Together they form a unique fingerprint.

Cite this