Abstract: Denosumab (Dmab) is a receptor activator of NF-kappaB ligand (RANKL) inhibitor with better efficacy and safety. Dmab has been approved to treat patients with osteoporosis (OP), giant cell tumor of bone (GCTB), multiple myeloma (MM) and bone metastases from solid tumors. However, in clinical practice, Dmab is faced with problems such as drug duration, drug withdrawal sequence and local recurrence. This article reviewed the clinical application and challenges of Dmab in OP and neoplastic bone disease, aiming to provide evidence for clinical treatment.