Mouse model of anti-RANKL discontinuation reveals reduced bone mass and quality through disruption of bone remodeling
Abstract The discontinuation of denosumab [antibody targeting receptor activator of nuclear factor kappa B ligand (RANKL)] therapy may increase the risk of multiple vertebral fractures; however, the underlying pathophysiology is largely unknown. In patients who underwent discontinuation after multip...
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Nature Publishing Group
2025-05-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-025-00433-0 |
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| author | Koji Ishikawa Soji Tani Nobuhiro Sakai Yoshifumi Kudo Hideyo Horiuchi Hiromi Kimura-Suda Masamichi Takami Mayumi Tsuji Katsunori Inagaki Yuji Kiuchi Takako Negishi-Koga |
| author_facet | Koji Ishikawa Soji Tani Nobuhiro Sakai Yoshifumi Kudo Hideyo Horiuchi Hiromi Kimura-Suda Masamichi Takami Mayumi Tsuji Katsunori Inagaki Yuji Kiuchi Takako Negishi-Koga |
| author_sort | Koji Ishikawa |
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| description | Abstract The discontinuation of denosumab [antibody targeting receptor activator of nuclear factor kappa B ligand (RANKL)] therapy may increase the risk of multiple vertebral fractures; however, the underlying pathophysiology is largely unknown. In patients who underwent discontinuation after multiple injections of denosumab, the levels of tartrate-resistant acid phosphatase 5b increased compared to pretreatment levels, indicating a phenomenon known as “overshoot.” The rate of decrease in bone mineral density during the withdrawal period was higher than the rate of decrease associated with aging, suggesting that the physiological bone metabolism had broken down. Overshoot and significant bone loss were also observed in mice receiving continuous administration of anti-RANKL antibody after treatment was interrupted, resembling the original pathology. In mice long out of overshoot, bone resorption recovered, but osteoblast numbers and bone formation remained markedly reduced. The bone marrow exhibited a significant reduction in stem cell (SC) antigen 1- and platelet-derived growth factor receptor alpha-expressing osteoblast progenitors (PαS cells) and alkaline phosphatase-positive early osteoblasts. Just before the overshoot phase, the osteoclast precursor cell population expands and RANKL-bearing extracellular vesicles (EVs) became abundant in the serum, leading to robust osteoclastogenesis after cessation of anti-RANKL treatment. Thus, accelerated bone resorption due to the accumulation of RANKL-bearing EVs and long-term suppression of bone formation uncoupled from bone resorption leads to the severe bone loss characteristic of denosumab discontinuation. |
| format | Article |
| id | doaj-art-2b7ee06248b945d8a34cff218ec9fb5c |
| institution | DOAJ |
| issn | 2095-6231 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
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| series | Bone Research |
| spelling | doaj-art-2b7ee06248b945d8a34cff218ec9fb5c2025-08-20T03:16:29ZengNature Publishing GroupBone Research2095-62312025-05-0113111410.1038/s41413-025-00433-0Mouse model of anti-RANKL discontinuation reveals reduced bone mass and quality through disruption of bone remodelingKoji Ishikawa0Soji Tani1Nobuhiro Sakai2Yoshifumi Kudo3Hideyo Horiuchi4Hiromi Kimura-Suda5Masamichi Takami6Mayumi Tsuji7Katsunori Inagaki8Yuji Kiuchi9Takako Negishi-Koga10Department of Orthopaedic Surgery, School of Medicine, Showa UniversityDepartment of Orthopaedic Surgery, School of Medicine, Showa UniversityDepartment of Dental Education, School of Dentistry, Showa UniversityDepartment of Orthopaedic Surgery, School of Medicine, Showa UniversityGraduate School of Science and Engineering, Chitose Institute of Science and TechnologyDepartment of Applied Chemistry and Bioscience, Faculty of Science and Technology, Chitose Institute of Science and TechnologyDepartment of Pharmacology, School of Dentistry, Showa UniversityDepartment of Pharmacology, School of Medicine, Showa UniversityDepartment of Orthopaedic Surgery, School of Medicine, Showa UniversityDepartment of Pharmacology, School of Medicine, Showa UniversityDepartment of Community Medicine and Research for Bone and Joint Diseases, Juntendo University Graduate School of MedicineAbstract The discontinuation of denosumab [antibody targeting receptor activator of nuclear factor kappa B ligand (RANKL)] therapy may increase the risk of multiple vertebral fractures; however, the underlying pathophysiology is largely unknown. In patients who underwent discontinuation after multiple injections of denosumab, the levels of tartrate-resistant acid phosphatase 5b increased compared to pretreatment levels, indicating a phenomenon known as “overshoot.” The rate of decrease in bone mineral density during the withdrawal period was higher than the rate of decrease associated with aging, suggesting that the physiological bone metabolism had broken down. Overshoot and significant bone loss were also observed in mice receiving continuous administration of anti-RANKL antibody after treatment was interrupted, resembling the original pathology. In mice long out of overshoot, bone resorption recovered, but osteoblast numbers and bone formation remained markedly reduced. The bone marrow exhibited a significant reduction in stem cell (SC) antigen 1- and platelet-derived growth factor receptor alpha-expressing osteoblast progenitors (PαS cells) and alkaline phosphatase-positive early osteoblasts. Just before the overshoot phase, the osteoclast precursor cell population expands and RANKL-bearing extracellular vesicles (EVs) became abundant in the serum, leading to robust osteoclastogenesis after cessation of anti-RANKL treatment. Thus, accelerated bone resorption due to the accumulation of RANKL-bearing EVs and long-term suppression of bone formation uncoupled from bone resorption leads to the severe bone loss characteristic of denosumab discontinuation.https://doi.org/10.1038/s41413-025-00433-0 |
| spellingShingle | Koji Ishikawa Soji Tani Nobuhiro Sakai Yoshifumi Kudo Hideyo Horiuchi Hiromi Kimura-Suda Masamichi Takami Mayumi Tsuji Katsunori Inagaki Yuji Kiuchi Takako Negishi-Koga Mouse model of anti-RANKL discontinuation reveals reduced bone mass and quality through disruption of bone remodeling Bone Research |
| title | Mouse model of anti-RANKL discontinuation reveals reduced bone mass and quality through disruption of bone remodeling |
| title_full | Mouse model of anti-RANKL discontinuation reveals reduced bone mass and quality through disruption of bone remodeling |
| title_fullStr | Mouse model of anti-RANKL discontinuation reveals reduced bone mass and quality through disruption of bone remodeling |
| title_full_unstemmed | Mouse model of anti-RANKL discontinuation reveals reduced bone mass and quality through disruption of bone remodeling |
| title_short | Mouse model of anti-RANKL discontinuation reveals reduced bone mass and quality through disruption of bone remodeling |
| title_sort | mouse model of anti rankl discontinuation reveals reduced bone mass and quality through disruption of bone remodeling |
| url | https://doi.org/10.1038/s41413-025-00433-0 |
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