Denosumab Sequential Therapy

NCT ID: NCT03868033

Last Updated: 2024-04-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 101 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-04-12
• Study Completion Date: 2023-12-31

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.

Conditions

Osteoporosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Continuous Denosumab

Continuous anti-resorptive therapy by Denosumab for 2 years

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: DRUG

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

Zoledronic acid to Denosumab

treat with Zoledronic acid for one year and then shift to Denosumab for another one year

Group Type: EXPERIMENTAL

Zoledronic Acid

Intervention Type: DRUG

Use Zoledronic acid as a sequential therapy after denosumab treatment for more than 2 years

Denosumab

Intervention Type: DRUG

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

Continuous Zoledronic acid

Continuous anti-resorptive therapy by Zoledronic acid for 2 years

Group Type: EXPERIMENTAL

Zoledronic Acid

Intervention Type: DRUG

Use Zoledronic acid as a sequential therapy after denosumab treatment for more than 2 years

Zoledronic acid to observation

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

Group Type: EXPERIMENTAL

Zoledronic Acid

Intervention Type: DRUG

Use Zoledronic acid as a sequential therapy after denosumab treatment for more than 2 years

Interventions

Zoledronic Acid

Use Zoledronic acid as a sequential therapy after denosumab treatment for more than 2 years

Intervention Type: DRUG

Denosumab

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

Intervention Type: DRUG

Other Intervention Names

Aclasta; Prolia

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

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Taiwan University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Shau-Huai Fu, doctor

Role: PRINCIPAL_INVESTIGATOR

Department of Orthopedics, National Taiwan University Hospital Yunlin Branch

Chia-Che Lee

Role: PRINCIPAL_INVESTIGATOR

Department of Orthopedics, National Taiwan University Hospital

Locations

Department of Orthopedics, National Taiwan University Hospital

Taipei, N/A = Not Applicable, Taiwan

Countries

Taiwan

References

Lee CC, Wang CY, Yen HK, Hung CC, Lai CY, Hu MH, Wang TM, Li CY, Fu SH. Zoledronate Sequential Therapy After Denosumab Discontinuation to Prevent Bone Mineral Density Reduction: A Randomized Clinical Trial. JAMA Netw Open. 2024 Nov 4;7(11):e2443899. doi: 10.1001/jamanetworkopen.2024.43899.

Reference Type: DERIVED

PMID: 39527056 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34568375 (View on PubMed)

Other Identifiers

201811067MIPC

Identifier Type: -

Identifier Source: org_study_id