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Introduction The purpose of this study was to evaluate a protocol for systemic administration of rosiglitazone in mice in order to stimulate apoptosis of osteocytes in the jaws and to evaluate the effect of osteocyte apoptosis induced by rosiglitazone in the progression of periapical lesions in mice at 7, 21, and 42 days. Methods C57BL/6 mice at 4–5 weeks of age were used. In phase 1, mice (n = 24) were treated with rosiglitazone (gavage, 10 mg/kg dose) or without (phosphate‐buffered saline + 10% dimethyl sulfoxide) for 1, 2, or 3 weeks. We used the terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick‐end labeling and 4′‐6‐diamidino‐2‐phenylindole methods for quantification of apoptotic cells. In phase 2, mice (n = 30) received rosiglitazone for 2 weeks or just vehicle for 1 week (n = 30), and periapical lesions were induced for 7, 21, or 42 days. We performed the measurement of periapical lesions, tartrate‐resistant acid phosphatase staining, dual‐energy x‐ray absorptiometry for the evaluation of bone mineral density (BMD) in long bone, and gene evaluation using real time quantitative polymerase chain reaction of osteocyte markers (Sost, Hyou1, and Dmp1) and receptor activator of nuclear factor kappa‐B ligand (RANKL) (Tnfsf11). Results It was observed that systemic administration of rosiglitazone for 2 weeks showed apoptosis of osteocytes in a more expressive manner. In phase 2, in the groups that received rosiglitazone, a trend toward larger periapical lesions was observed (P > .05). Rosiglitazone also induced a greater number of osteoclasts and a greater expression of Sost and Hyou1 at 21 days of lesions. Moreover, there were no statistically significant differences in RANKL and Dmp1 expression or in the BMD of femurs. Conclusions Rosiglitazone stimulated apoptosis of osteocytes, interfering in the progression of periapical lesions in mice. HIGHLIGHTSOsteocytes are considered the orchestrators of many bone functions.Thiazolidinediones (TZDs) (diabetes medicine) lead to increased apoptosis in osteocytes.TZDs stimulated the apoptosis of osteocytes in jaws interfering in the progression of periapical lesions in mice.