Osteonecrosis of the Jaw Associated with Long-Term Denosumab Therapy: A Review of Published Cases
DOI:
https://doi.org/10.5281/zenodo.22279429Keywords:
Denosumab, Osteonecrosis of the jaw, RANKL, Bone-modifying agents, MRONJAbstract
ackground: Denosumab, a monoclonal antibody against RANKL, is used at high dose for skeletal-related events in oncology and
at low dose for osteoporosis, but both regimens carry a risk of medication-related osteonecrosis of the jaw (MRONJ).Objective: To review published case reports/series and the epidemiologic, mechanistic and guideline literature on denosumab-associated MRONJ, contrasting oncologic and osteoporosis populations. Methods: Narrative review of case reports, case series, randomized trials, retrospective cohorts, and guidelines. Findings: Pooled oncology-trial data show MRONJ in 1.8% of denosumab-treated versus 1.3% of zoledronic acid-treated patients; a 20-year breast cancer cohort found 12% incidence with denosumab versus 3% with bisphosphonates. Published cases span multi-year high-dose oncologic exposure to osteoporosis patients developing MRONJ after a single low dose, often extraction-triggered. Unlike bisphosphonates, denosumab's effect is reversible, informing but not resolving the drug-holiday debate. Conclusions: Pre-therapy dental screening, AAOMS-staged diagnosis, and conservative-first management with surgery reserved for refractory disease remain the evidence base; drug holidays lack proven benefit.
References
Ruggiero, S.L., Dodson, T.B., Aghaloo, T., Carlson, E.R., Ward, B.B., Kademani, D. (2022) American Association of Oral and Maxillofacial Surgeons' Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update. Journal of Oral and Maxillofacial Surgery, 80(5): 920-943.
Saad, F., Brown, J.E., Van Poznak, C., Ibrahim, T., Stemmer, S.M., Stopeck, A.T., et al. (2012) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Annals of Oncology, 23(5): 1341-1347.
Stopeck, A.T., Lipton, A., Body, J.J., Steger, G.G., Tonkin, K., de Boer, R.H., et al. (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. Journal of Clinical Oncology, 28(35): 5132-5139.
Fizazi, K., Carducci, M., Smith, M., Damião, R., Brown, J., Karsh, L., et al. (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. The Lancet, 377(9768): 813-822.
Tomic, J., Jakse, N., Acham, S. (2019) Progress and management of denosumab-related severe osteonecrosis of the entire lower jaw - A case report. Oral Health Care, 4: 1-5.
Brunner, C., Arvandi, M., Marth, C., et al. (2024) Incidence of Medication-Related Osteonecrosis of the Jaw in Patients With Breast Cancer During a 20-Year Follow-Up: A Population-Based Multicenter Retrospective Study. Journal of Clinical Oncology, Published online 20 Aug 2024, doi:10.1200/JCO.24.00171.
Liu, F.C., Luk, K.C., Chen, Y.C. (2023) Risk comparison of osteonecrosis of the jaw in osteoporotic patients treated with bisphosphonates vs. denosumab: a multi-institutional retrospective cohort study in Taiwan. Osteoporosis International, 34: 1729-1737.
Bagan, J., Peydró, A., Calvo, J., Leopoldo, M., Jiménez, Y., Bagan, L. (2016) Medication-related osteonecrosis of the jaw associated with bisphosphonates and denosumab in osteoporosis. Oral Diseases, 22(4): 324-329.
Egloff-Juras, C., Gallois, A., Salleron, J., Massard, V., Dolivet, G., Guillet, J., Phulpin, B. (2018) Denosumab-related osteonecrosis of the jaw: a retrospective study. Journal of Oral Pathology & Medicine, 47(1): 66-70.
Malan, J., Ettinger, K., Naumann, E., Beirne, O.R. (2012) The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 114(6): 671-676.
McClung, M.R., Wagman, R.B., Miller, P.D., Wang, A., Lewiecki, E.M. (2017) Observations following discontinuation of long-term denosumab therapy. Osteoporosis International, 28: 1723-1732.
Otto, S., Hafner, S., Mast, G., Tischer, T., Volkmer, E., Schieker, M., Sturzenbaum, S.R., von Tresckow, E., Kolk, A., Ehrenfeld, M., et al. (2010) Bisphosphonate-related osteonecrosis of the jaw: is pH the missing part in the pathogenesis puzzle? Journal of Oral and Maxillofacial Surgery, 68(5): 1158-1161.
Qaisi, M., Hargett, J., Loeb, M., Brown, J., Caloss, R. (2016) Denosumab Related Osteonecrosis of the Jaw with Spontaneous Necrosis of the Soft Palate: Report of a Life Threatening Case. Case Reports in Dentistry, 2016: 5070187.
Papadimitriou, K., Melakopoulos, I. (2024) Denosumab-related osteonecrosis of the mandible after a single dose - a case report. International Journal of Oral and Maxillofacial Surgery, 52(2): 146-147.
Száraz, D., Peřina, V., Treglerová, J., Macháček, C., Zendulka, O., Bořilová Linhartová, P. (2024) Case Report: single low-dose of denosumab as a trigger of MRONJ development in a patient with osteoporosis after bisphosphonate therapy. Frontiers in Oral Health, 5: 1473049.
Bettini, G., Saia, G., Benetello, F., Bedogni, A. (2022) Temporary Denosumab Discontinuation Promotes Bone Healing of Osteonecrosis of the Jaw and Minimizes the Invasiveness of Surgery: A Case Presentation. Oral, 2(1): 41-48.
Goss, A.N. (2022) Osteonecrosis of the jaw and denosumab. Australian Prescriber, 45(6): 208.
Falinda, D., Malden, N. (2022) Case series: Osteonecrosis of the jaw related to denosumab preceded by bisphosphonates in cancer and osteoporotic patients. Advances in Oral and Maxillofacial Surgery, 5: 100258.
Jung, S., Kim, J., Park, J.H., et al. (2022) A 5-year retrospective cohort study of denosumab induced medication related osteonecrosis of the jaw in osteoporosis patients. Scientific Reports, 12: 8641.
de Sales Lima, M.V., Rizzato, J., Gracindo Marques, D.V., Kitakawa, D., Peralta, F., Scherma, A., Carvalho, L.F.C.S. (2018) Denosumab Related Osteonecrosis of Jaw: a Case Report. Journal of Oral & Maxillofacial Research, 9(4): e5.
Khan, A.A., Morrison, A., Hanley, D.A., Felsenberg, D., McCauley, L.K., O'Ryan, F., et al. (2015) Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. Journal of Bone and Mineral Research, 30(1): 3-23.
Yarom, N., et al. (2025) MASCC/ISOO Clinical Practice Statement: imaging and clinical laboratory tests in the diagnosis and management of medication-related osteonecrosis of the jaw. Supportive Care in Cancer, 33.
Yarom, N., Shapiro, C.L., Peterson, D.E., Van Poznak, C.H., Bohlke, K., Ruggiero, S.L., et al. (2019) Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. Journal of Clinical Oncology, 37(25): 2270-2290.
Aboalela, A.A., Farook, F.F., Alqahtani, A.S., et al. (2022) The Effect of Antiresorptive Drug Holidays on Medication-Related Osteonecrosis of the Jaw: A Systematic Review and Meta-Analysis. Cureus, 14(10): e30485.
Sawada, S., Sakamoto, Y., et al. (2023) Drug holiday of high-dose denosumab and recovery from osteoclast inhibition using immunohistochemical investigation of 7 patients with medication-related osteonecrosis of the jaw undergoing segmental mandibulectomy. Journal of Dental Sciences, 18(4): 1645-1652.
Hoefert, S., Yuan, A., Munz, A., Grimm, M., Elayouti, A., Reinert, S. (2017) Clinical course and therapeutic outcomes of operatively and non-operatively managed patients with denosumab-related osteonecrosis of the jaw (DRONJ). Journal of Cranio-Maxillofacial Surgery, 45(4): 570-578.
Cummings, S.R., San Martin, J., McClung, M.R., Siris, E.S., Eastell, R., Reid, I.R., et al. (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. New England Journal of Medicine, 361(8): 756-765.
Rachner, T.D., Platzbecker, U., Felsenberg, D., Hofbauer, L.C. (2013) Osteonecrosis of the jaw after osteoporosis therapy with denosumab following long-term bisphosphonate therapy. Mayo Clinic Proceedings, 88(4): 418-419.
