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

Nakashima Fuminori

Matsuda Shinji

Ninomiya Yurika

Ueda Tomoya

Yasuda Keisuke

Hatano Saki

Shimada Shogo

Furutama Daisuke

Memida Takumi

Kajiya Mikihito

Shukunami Chisa

Ouhara Kazuhisa

Mizuno Noriyoshi

Bone

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 (SostΔ26/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 SostΔ26/Δ26 mice. Wound healing assay using gingival fibroblasts with or without sclerostin stimulation and tooth extraction socket healing were evaluated in the WT and SostΔ26/Δ26 mice.
Results
ONJ was not detected in the extraction socket of SostΔ26/Δ26 mice. Moreover, the incidence of ONJ was significantly lower in the SostΔ26/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 SostΔ26/Δ26 mice. Recombinant sclerostin inhibited gingival fibroblast migration. The wound healing rate of the extraction socket was faster in SostΔ26/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.

Medication-induced related osteonecrosis of the jaw

Sclerostin

Bone formation

Extraction socket healing

英語

Elsevier

© 2024. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/

This is not the published version. Please cite only the published version.

この論文は出版社版ではありません。引用の際には出版社版をご確認、ご利用ください。

[DOI] https://doi.org/10.1016/j.bone.2024.117200 ～の異版である

日本学術振興会

Japan Society for the Promotion of Science

[Crossref Funder] https://doi.org/10.13039/501100001691

ロモソズマブによる顎骨壊死発症の検証およびそのメカニズム解明の研究

ロモソズマブによる顎骨壊死発症の検証およびそのメカニズム解明の研究

23K15973

科学技術振興機構

Japan Science and Technology Agency

広島大学創発的 次世代 研究者育成・支援プログラム

広島大学創発的 次世代 研究者育成・支援プログラム

JPMJSP2132