Role of sclerostin deletion in bisphosphonate-induced osteonecrosis of the jaw

Abstract

Purpose: Bone resorption inhibitors, such as bisphosphonates (BP) and denosumab, are frequently used for the management of osteoporosis. Although both drugs reduce the risk of osteoporotic fractures, they are associated with a serious side effect known as medication-related osteonecrosis of the jaw (MRONJ). Sclerostin antibodies (romosozumab) increase bone formation and decrease the risk of osteoporotic fractures: however, their anti-resorptive effect increases ONJ. Thus, this study aimed to elucidate the role of sclerostin deletion in the development of MRONJ.

Methods: Sclerostin knockout (Sost^Δ26/Δ26) mice were used to confirm the development of ONJ by performing tooth extractions. To confirm the role of sclerostin deficiency in a more ONJ-prone situation, we used the BP-induced ONJ model in combination with severe periodontitis to evaluate the development of ONJ and bone formation in wild-type (WT) and Sost^Δ26/Δ26 mice. Wound healing assay using gingival fibroblasts with or without sclerostin stimulation and tooth extraction socket healing were evaluated in the WT and Sost^Δ26/Δ26 mice.

Results: ONJ was not detected in the extraction socket of Sost^Δ26/Δ26 mice. Moreover, the incidence of ONJ was significantly lower in the Sost^Δ26/Δ26 mice treated with BP compared to that of the WT mice. Osteogenic proteins, osteocalcin, and runt-related transcription factor 2, were expressed in the bone surface in Sost^Δ26/Δ26 mice. Recombinant sclerostin inhibited gingival fibroblast migration. The wound healing rate of the extraction socket was faster in Sost^Δ26/Δ26 mice than in WT mice.

Conclusion: Sclerostin deficiency did not cause ONJ and reduced the risk of developing BP-induced ONJ. Enhanced bone formation and wound healing were observed in the tooth extraction socket. The use of romosozumab (anti-sclerostin antibody) has proven to be safe for surgical procedures of the jaw.

Keywords: Bone formation; Extraction socket healing; Medication-induced related osteonecrosis of the jaw; Sclerostin.