The aim of this study is to investigate the histopathological findings of drill hole healing and interactions of parathyroid hormone (PTH), β-catenin and transcription factor-4 (TCF7L2/Tcf-4) after local application of recombinant human bone morphogenic protein-2 (rhBMP-2). Sprague Dawley rats were used in two groups of femoral cortex hole model. In the non-treated group, a hole was opened with a 3 mm K-wire in the distal and mid third junction of the right femur. In the treated group, local rhBMP-2 protein was injected into the similar femoral hole. Sterile 18M H2O was injected into the femoral hole at contralateral femur. There was more subperiosteal membranous bone reaction in the group treated with rhBMP-2 injection compared to the non-treated group. This was also proven immunohistochemically in both ipsilateral and contralateral femur with increased anti bone morphogenic protein-2 (anti BMP-2) expression. Moreover, there was an increased subperiosteal reaction at the contralateral femur. Also, in the treated group, PTH expression was increased in cells that form callus, and nuclear beta-catenin expression was increased in chondrocytes of periosteal ossification. Future studies should try to find whether the effects of rhBMP-2 on PTH and Wnt signaling pathway changes with different fracture models, also the systemic effects of local rhBMP-2 application should be investigated.