The Effects Of Zoledronic Acid On Bone Metabolism In Osteprotegerin Knock-out Mice

Objective To study the effects of Zoledronic acid(Zol) on the bone mineral density(BMD),bone biomechanical properties and serum biochemical markers of bone turnover in osteoprotegerin-knockout mice (OPG^-/-),so as to explore the relationship between regulatory effect of Zoledronic acid on bone metabolism and OPG pathway.Methods 9-week-old female OPG^-/- mice(n=30) and wild-type mice (n=10) were involved in the study. OPG^-/- mice were randomly divided into three groups(10 for each group), and treated with zoledronic acid at a dose of 0μg/kg (H2O group), 50μg/kg( low dose zoledronic acid, L-ZOL) and 150μg/kg (high dose zoledronic acid, H-ZOL) subcutaneously twice per week. All the OPG^-/- and WT mice were reproduced by heterozygotes(OPG^+/-) matings with a mixed C57BL/6J×129/SV background. The mice were killed 6 weeks after intervention. The bone mineral density (BMD) and bone mineral content (BMC) of the left femur was measured using DXA. The biomechanical properties of the right femur was determined by a three-point bending test. Serum bone alkaline phosphatase(B-ALP) and tartrate-resistant acid phosphatase-5b (TRACP-5b) were determined by ELISA.Results 1. Compared with the mice in H₂O group, the zoledronic acid-treated mice showed an increased total BMD and BMC, almost equal to the levels of wild-type mice. There was no significant differences in BMD and BMC between L- ZOL and H- ZOL groups.2. Ultimate load, elastic modulus and stress index of femur in both of L-ZOL and H-ZOL groups were significant higher than that of H₂O group. Furthermore, the ultimate load was higher than that of WT group. There were no significant differences in all three biomechanical parameters between L-ZOL and H-ZOL groups.3. Compared with the mice in H₂O group, the zoledronic acid-treated mice showed an decreased serum B-ALP and TRACP-5b . Furthermore, the serum TRACP-5b was lower than that of WT group. There was no significant differences in B-ALP and TRACP-5b between L-ZOL and H-ZOL groups.Conclusions 1. Zoledronic acid could effectively improve bone mineral density and biomechanical strength properties as well as decrease the rate of bone turnover in OPG -knockout mice, suggesting that the in vivo anti-bone resorption effect of zoledronic acid is triggered via an OPG-independent pathway.2. The anti-bone resorption effects of low dose and high dose zoledronic acid in OPG knock-out mice were nearly equivalent, suggesting that the low does zoledronic acid therapy is more suitable in the treatment of osteoporosis.