Introduction: Recently, uncoupled bone remodeling in the subchondral bone (SB) has been considered an important process to promote knee osteoarthritis (KOA). However, it is unclear how SB metabolism in the early stage of KOA affects the initiation and progression of the disease. This study aimed to investigate the relationship between the early changes in SB and the disease process, using wild-type (WT) mice and Tsukuba hypertensive mice (THM) with high-turnover bone metabolism. Methods Destabilization of the medial meniscus (DMM) or sham surgery was performed on the left knee of male 40-week-old THM and WT mice (n = 7 in each group). Bone volume/tissue volume (BV/TV), bone mineral density (BMD), and mean height (Hm, µm) in the medial tibial SB were longitudinally measured in vivo using micro-computed tomography (µCT) at 0, 1, 2, 4, 8, and 12 weeks postoperatively. Tibial cartilage degeneration was evaluated histologically using the OARSI score at 0, 1, 2, 4, 8, and 12 weeks postoperatively (n = 7 in each group). Results Significant decreases in BV/TV in both WT + DMM and THM + DMM groups were evident at 1 and 4 weeks postoperatively, respectively. Notably, significant decreases in the BMD (at 2 and 8 weeks postoperatively) and Hm (at 4 and 12 weeks postoperatively), and significant increases in the Osteoarthritis Research Society International (OARSI) score (at 2 and 8 weeks postoperatively) in the THM + DMM and WT + DMM groups were observed, respectively. A strong correlation was noted between the Hm and the BMD. These time-dependent changes in the BV/TV, BMD, Hm in the SB, and OARSI score were significantly enhanced in the THM + DMM group compared to the WT + DMM group. Conclusions These results indicate that SB loss at the early stage and the subsequent uncoupled bone remodeling, which can be enhanced by high-turnover osteoporosis, play an important role in the initiation and progression of KOA in the mouse DMM model. SB loss in the early stage could be a key target for preventing the initiation and progression of the disease.