Clinical trial NCT03868033: Denosumab Sequential Therapy
Official title: Department of Orthopedics, National Taiwan University Hospital
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Osteoporosis
Keywords: Osteoporosis
Denosumab
Zoledronate
Bone mineral density
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
First posted: 2019-03-08
Enrollment: 101
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Postmenopausal women
2. Men \>50-year-old
3. After Denosumab treatment ≥ 2 years due to osteoporosis

Exclusion Criteria:

1. Patientshadeverusedantiosteoporosismedications other than Dmab
2. Estimated glomerular filtration rate \<35 ml/min.
3. Malignancy
4. Continuous steroid treatment, hormone therapy or other medical treatment affecting bone metabolism
5. Secondary osteoporosis
6. Metabolic bone diseases
7. Contraindications to ZOL
8. Patients older than 80 years old
9. Hypocalcemia

Primary outcomes:
measure: Changes of lumbar spine, total hip and femoral neck bone mineral density
timeFrame: baseline, 1 year, 2 year
Secondary outcomes:
measure: Change of bone turnover marker
timeFrame: baseline, 6 months, 12 months, 15 months, 18 months, 24 months
measure: Clinical osteoporotic fracture
timeFrame: baseline, 1 year, 2 year
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: Department of Orthopedics, National Taiwan University Hospital
state: N/A = Not Applicable
Study officials:
affiliation: Department of Orthopedics, National Taiwan University Hospital Yunlin Branch
name: Shau-Huai Fu, doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Orthopedics, National Taiwan University Hospital
name: Chia-Che Lee
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.