Abstract: The aim of this study is to investigate the method of ultrasound tomography of bone based on ultrasonic full-waveform inversion (FWI), and to dynamically monitor the progression of osteoporotic micro-structural deterioration. Female mice are injected with 4-vinylcyclohexene diepoxide (VCD) to induce premature ovarian failure and establish the mice osteoporosis model. The mice are scanned by Micro-CT in vivo at different osteoporosis progression (the 0, 2, 4 and 6 weeks), and bone micro-structure in the femurs of mice are reconstructed. Taking the initial bone micro-structure of mice (at the 0 week) as the baseline input model, the effects of FWI on monitoring bone micro-structure deterioration in osteoporosis progression are numerically analyzed, with different ultrasound transmitting and receiving modes (transmission, reflection and transmission-reflection dual mode). The results show that FWI failed to reconstruct bone micro-structure when using the uniform medium (pure water) as the initial model. Compared with the initial model with uniform medium (pure water), the FWI using the baseline bone (at the 0 week) model could accurately monitor the bone micro-structure deterioration in different osteoporotic processes (at the 2, 4, 6 week), the ultrasound velocity inversion is with a root-mean-square error (RMSE) < 17 m/s, mean relative error (MRE) < 7.2%, and structural correlation coefficient (CC) > 0.85. Compared with different ultrasound transmitting and receiving modes, the combination of transmission-reflection dual-mode in FWI is significantly superior to the single transmission or reflection FWI in monitoring bone micro-structural deterioration. This study demonstrate that FWI using the baseline bone model can be used to dynamically monitor bone micro-structural deterioration and might have some significance in assessing the progression of osteoporosis.