Denosumab Sequential Therapy (DST)

Denosumab is a potent anti-resorptive agent and is now widely used in the treatment of osteoporosis. Although denosumab has excellent effect to increase bone mass and prevent fracture in FREEDOM study with very low complications, even up to ten years, it's effect is reversible. After holding the drug, circulating denosumab levels fall rapidly, and bone resorption reaching twice baseline levels for about 6 months. How to prevent bone loss after denosumab therapy is an important issue, especially when considering the compliance, persistence, or other comorbidities of the patient. We want to verify if zoledronic acid could be used as a sequential therapy after denosumab to prevent rapid bone loss by randomized clinical trial.

Denosumab is a monoclonal antibody directed against the protein RANK-L, the principal regulator of osteoclast development. Thus, it acts as a potent anti-resorptive agent and is now widely used in the treatment of osteoporosis. Because it's easily to be used with very low risk of complications, patient has better compliance and persistence of denosumab than bisphosphonates. It's market share increasing very rapidly in Taiwan. Although denosumab has excellent effect to increase bone mass and prevent fracture in FREEDOM study with very low complications, even up to ten years, it's effect is reversible. After holding the drug, circulating denosumab levels fall rapidly, and bone resorption reaching twice baseline levels for about 6 months. Over the first 12 months off therapy, all the bone density gained on treatment is lost4. According to previous meta-analysis study, although the persistence of denosumab therapy is better than bisphosphonates, only 62% patients keep the treatment after two years. We could image how low the persistence is after five-year or ten-year treatment in the real world. How to prevent bone loss after denosumab therapy is an important issue, especially when considering the compliance, persistence, or other comorbidities of the patient. There is only one randomized controlled trial dealing with this problem, although the primary goal of the study is designed to compare the compliance and persistence1. After switching from denosumab to alendronate for one year, bone mineral density does not decrease rapidly, although there is mild elevation of bone turn over marker. We want to verify if zoledronic acid could be used as a sequential therapy after denosumab to prevent rapid bone loss by randomized clinical trial.

treat with Zoledronic acid for one year and then close follow up by bone turn over marker. resume another dose of Zoledronic acid if elevated CTX level above normal range

Continuous Denosumab treatment in arm 1 for two years or as a 2nd year treatment in arm 2 for one year

Changes of bone turnover marker, including C-terminal telopeptide of type I collagen (CTX) and propeptide of procollagen type I (P1NP)

Inclusion Criteria: Postmenopausal women Men >50-year-old After Denosumab treatment ≥ 2 years due to osteoporosis Exclusion Criteria: secondary osteoporosis metabolic bone disease cancer history continuous steroid therapy hormone replacement therapy ever used any other kind of anti-resorptive treatment 6.estimated Glomerular filtration rate< 35 mL/min 7.allergy to Zoledronic acid 8.hypocalcaemia 9.any contraindications to use Zoledronic acid

Lee CC, Wang CY, Hung CC, Huang CC, Li CY, Chen HY, Chang YL, Tseng WJ, Wang TM, Yang RS, Wong TH, Fu SH. A Multi-Institutional Randomized Controlled Trial to Investigate Whether Zoledronate Prevents Bone Loss After Discontinuation of Denosumab: The Study Protocol of Denosumab Sequential Therapy (DST) Trial. Front Med (Lausanne). 2021 Sep 8;8:717168. doi: 10.3389/fmed.2021.717168. eCollection 2021.