Denosumab Sequential Therapy

Study Overview
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Brief Summary
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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
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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.

Official Title
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Department of Orthopedics, National Taiwan University Hospital

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: Zoledronic Acid
* Drug: Denosumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lumbar spine bone mineral density | Change in lumbar spine bone mineral density from baseline | 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, 1 year, 1.5 years, 2 year | 
| Clinical osteoporotic fracture | Incidence of clinical osteoporotic fracture | baseline, 1 year, 2 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoporosis, Denosumab, Zoledronate, Bone mineral density