TY - JOUR
T1 - High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties
AU - Pozzi, Samantha
AU - Vallet, Sonia
AU - Mukherjee, Siddhartha
AU - Cirstea, Diana
AU - Vaghela, Nileshwari
AU - Santo, Loredana
AU - Rosen, Eyal
AU - Ikeda, Hiroshi
AU - Okawa, Yutaka
AU - Kiziltepe, Tanyel
AU - Schoonmaker, Jesse
AU - Xie, Wanling
AU - Hideshima, Teru
AU - Weller, Edie
AU - Bouxsein, Mary L.
AU - Munshi, Nikhil C.
AU - Anderson, Kenneth C.
AU - Raje, Noopur
PY - 2009/9/15
Y1 - 2009/9/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=70349439276&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-09-0426
DO - 10.1158/1078-0432.CCR-09-0426
M3 - Journal article
C2 - 19737962
AN - SCOPUS:70349439276
SN - 1078-0432
VL - 15
SP - 5829
EP - 5839
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -