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Background/objective: Denosumab is a monoclonal antibody that inhibits bone resorption and is indicated for the treatment of osteoporosis, bone metastases, and giant cell tumor of bone. We describe a woman with symptomatic Paget disease of the skull whose headaches and monostotic disease of the skull improved after receiving denosumab for concomitant low bone density., Case Report: A 75-year-old woman presented with unremitting headache of 1 month. She had a medical history of polymyalgia rheumatica, osteopenia, hypothyroidism, and gastroesophageal reflux disease. She reported taking prednisone 1 to 20 mg daily for polymyalgia rheumatica for 1 year and received a dose of denosumab 60 mg for osteopenia 1 month before presentation. The calcium, alkaline phosphatase, and bone-specific alkaline phosphatase levels were 8.2 mg/dL (reference range [RR], 8.5-10.5 mg/dL), 132 U/L (RR, 40-129 U/L), and 17.8 μg/L (RR, 7-22.4 μg/L), respectively. Skull radiography revealed sclerosis/hyperostosis, lytic lesions, and expansion of bone, consistent with Paget disease of bone (PDB). Five months after the initial presentation, her headache resolved, and her calcium and alkaline phosphatase levels were 9.7 U/L and 96 U/L, respectively., Discussion: Denosumab neutralizes the receptor activator of nuclear factor-kappa B ligand. To date, there have been 2 case reports reported in the English literature of denosumab used successfully in patients with PDB who could not tolerate or were not eligible for bisphosphonates. This case report describes a patient with PDB treated with denosumab for osteopenia who experienced improvement in PDB-related symptoms., Conclusion: Although denosumab was originally approved for the treatment of osteoporosis, the inhibition of bone resorption via inhibition of the receptor activator of nuclear factor-kappa B ligand may be potentially effective in the treatment of PDB., Competing Interests: The authors have no multiplicity of interest to disclose., (© 2023 AACE. Published by Elsevier Inc.)