Denosumab Sequential Therapy (DST)

Department of Orthopedics, National Taiwan University Hospital

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.

Study Overview

• Status: Completed
• Conditions: Osteoporosis
• Intervention / Treatment: Drug: Denosumab; Drug: Zoledronic Acid

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.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Shau-Huai Fu; Phone Number: +886972655734; Email: b90401045@gmail.com

Study Locations

• Taiwan
  • N/A = Not Applicable
    • Taipei, N/A = Not Applicable, Taiwan, 64041
      • Department of Orthopedics, National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Continuous Denosumab; Continuous anti-resorptive therapy by Denosumab for 2 years	Drug: Denosumab; Continuous Denosumab treatment in arm 1 for two years or as a 2nd year treatment in arm 2 for one year; Other Names: Prolia
Experimental: Zoledronic acid to Denosumab; treat with Zoledronic acid for one year and then shift to Denosumab for another one year	Drug: Denosumab; Continuous Denosumab treatment in arm 1 for two years or as a 2nd year treatment in arm 2 for one year; Other Names: Prolia; Drug: Zoledronic Acid; Use Zoledronic acid as a sequential therapy after denosumab treatment for more than 2 years; Other Names: Aclasta
Experimental: Continuous Zoledronic acid; Continuous anti-resorptive therapy by Zoledronic acid for 2 years	Drug: Zoledronic Acid; Use Zoledronic acid as a sequential therapy after denosumab treatment for more than 2 years; Other Names: Aclasta
Experimental: 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	Drug: Zoledronic Acid; Use Zoledronic acid as a sequential therapy after denosumab treatment for more than 2 years; Other Names: Aclasta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of lumbar spine, total hip and femoral neck bone mineral density	Changes of lumbar spine, total hip and femoral neck bone mineral density from baseline	baseline, 1 year, 2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical osteoporotic fracture	Incidence of clinical osteoporotic fracture	baseline, 1 year, 2 year
Change of bone turnover marker	Changes of bone turnover marker, including C-terminal telopeptide of type I collagen (CTX) and propeptide of procollagen type I (P1NP)	baseline, 6 months, 12 months, 15 months, 18 months, 24 months

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Shau-Huai Fu, doctor, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch; Principal Investigator: Chia-Che Lee, Department of Orthopedics, National Taiwan University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2019
• Primary Completion (Actual): July 1, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: March 6, 2019
• First Submitted That Met QC Criteria: March 7, 2019
• First Posted (Actual): March 8, 2019

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 21, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Osteoporosis; Bone mineral density; Denosumab; Zoledronate
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid; Denosumab
• Other Study ID Numbers: 201811067MIPC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes