The Effect of Zoledronate Treatment Timing on Lumbar and Caudal Vertebrae in Ovariectomized Rats

Introduction: While there have been numerous studies demonstrating the effect of bisphosphonates in rats as either a preventative treatment or recovering treatment for osteoporosis, few have directly compared the two treatment alternatives with respect to their effects on bone microstructure and strength. This paper, then, investigates the effects of treatment timing using Zoledronate [ZOL], a potent bisphosphonate, on the lumbar and caudal vertebrae in ovariectomized [OVX], female Wistar rats. Methods: Twenty nine rats were divided into four groups according to their treatment: OVX at week 0 (n=5), OVX+earlyZOL (20 gg/kg s.c. week 0, n=8), OVX+late ZOL (20 gg/kg s.c. week 8, n=7), and SHAM-OVX (n=9). Results: Micro-computed tomography (gCT) evaluation of six parameters characterizing bone morphology [BV/TV, ConnD, SMI, TbTh, TbNr, and TbSp] showed slightly favorable effects with early ZOL treatment in the fourth lumbar [L4] vertebrae. Compared to SHAM-OVX, OVX has a significantly (p<0.05) lower BV/TV, higher SMI, and TbSp. OVX+earlyZOL had a significantly higher BV/TV than OVX and SHAMOVX and a lower TbSp than OVX. Decreasing trends but no statistically significant differences were reached in the cortical thickness with treatment, nor were there any differences in bone morphology between the groups in the sixth caudal vertebrae [CD6]. A two-way ANOVA revealed an interaction between the vertebral site and treatment group for BV/TV and TbSp. jCT and static compression tests on the L3 and L4 of rats in a secondary study revealed significant correlations in architectural parameters and biomechanical properties between the two vertebrae. L4 had a higher BV/TV, SMI, and minimum area [minA] and a lower TbNr and TbSp than L3, but L4 had lower values for stiffness, energy to failure [energy], and ultimate load. Regression analysis also showed statistically significant correlations between ultimate load [Uload] and total bone volume [BV], energy and BV, Uload and minA, stiffness and minA, and energy and minA. Conclusion: Results showed slightly favorable trends on bone microstructure for early treatment and demonstrated the potential for clinical advantages using preventative therapy. Upon further research in understanding the vertebrae's response to ZOL at different time points after OVX, treatment for osteoporosis may be better directed. Thesis Supervisor: Kimberly Hamad-Schifferli Title: Esther and Harold E. Assistant Professor of Mechanical Engineering and Biological Engineering M OVX Jý.Irrwtaryt 200-77 MaiCllill Ztflllril 2 sSUr. i~l:` ?3 i