High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties.
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.
Pozzi
Samantha
S
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
Vallet
Sonia
S
Mukherjee
Siddhartha
S
Cirstea
Diana
D
Vaghela
Nileshwari
N
Santo
Loredana
L
Rosen
Eyal
E
Ikeda
Hiroshi
H
Okawa
Yutaka
Y
Kiziltepe
Tanyel
T
Schoonmaker
Jesse
J
Xie
Wanling
W
Hideshima
Teru
T
Weller
Edie
E
Bouxsein
Mary L
ML
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
Raje
Noopur
N
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
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid