Comparative Effect of Zoledronic Acid Versus Denosumab on Serum Sclerostin of Postmenopausal Women With Low Bone Mass

Study Overview
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Brief Summary
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The primary aim of the study is the comparative effect of zolendronic acid versus denosumab on serum sclerostin levels in postmenopausal women with low bone mass. Secondary aims are their comparative effect on serum dickkopf-1, osteoprotegerin, receptor activator of nuclear factor kappaB ligand (RANKL) and bone turnover markers (procollagen type I N-terminal peptide [PINP] and C-terminal cross-linking telopeptide of type I collagen [CTX]).

Detailed Description
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Osteoporosis is the most common bone disease, caused by a relatively increased rate of bone resorption by the osteoclasts that exceeds the rate of bone formation by the osteoblasts, resulting in net loss of bone mass. To-date, antiresorptive agents, which inhibit osteoclast activity and induce their apoptosis, are considered as the cornerstone of osteoporosis prevention and treatment. Bisphosphonates currently represent the first line antiresorptive agents for the management of postmenopausal osteoporosis. Zoledronic acid is considered to-date the most potent bisphosphonate. A once-yearly infusion of intravenous zoledronic acid decreases bone turnover, improves bone density and decreases the vertebral and non-vertebral fracture risk. Most recently, denosumab (AMG-162) has been launched for the treatment of postmenopausal osteoporosis. Denosumab, a fully human monoclonal IgG2 antibody against human RANKL, specifically binds and neutralizes the receptor activator of nuclear factor kappaB ligand (RANKL) in order to decrease bone resorption and subsequent bone loss. Subcutaneous administration of denosumab every six months decreases bone turnover markers, increases bone mineral density and reduces the vertebral and non-vertebral fracture risk. The role of sclerostin in bone metabolism is emerging. Sclerostin is the secreted expression of the SOST gene. In adult human bone, sclerostin is expressed only by osteocytes and inhibits bone formation by osteoblasts. It has been proposed that sclerostin expression by newly embedded osteocytes at the onset of osteoid mineralization may serve as a negative feedback signal on osteoblasts to prevent overfilling of the basic multicellular unit. Although zoledronic acid and denosumab are currently regarded as the most potent antiresorptive agents, there is no head-to-head comparative study. This study primarily aims to the comparative effect of zoledronic acid and denosumab on serum sclerostin levels and secondarily on serum dickkopf-1, osteoprotegerin, RANKL and bone turnover markers (procollagen type I N-terminal peptide [PINP] and C-terminal cross-linking telopeptide of type I collagen [CTX]).

Official Title
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Comparative Effect of Zoledronic Acid Versus Denosumab on Serum Sclerostin Levels of Postmenopausal Women With Low Bone Mass: A Multicenter, Randomized, Head-to-head Clinical Trial

Conditions
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Postmenopausal Osteoporosis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian postmenopausal women older than 40 years Low bone mass at lumbar spine (L2-L4) or femoral neck (BMD T-score of ≤ -2.0) or BMD T-score of > -2.0 coexistent with low-energy fracture of vertebral, femoral neck or forearm Patient's informed consent to participate Exclusion Criteria: Secondary osteoporosis Any bone and mineral disorder other than osteoporosis, including primary or secondary hyperparathyroidism, Paget's disease of bone, osteogenesis imperfecta, rheumatologic diseases, paraplegia, chronic immobilization Severe liver or kidney disease (creatinine clearance < 60ml/min/1.73m2) or liver or kidney transplantation Premature ovarian failure Uncontrolled thyroid disease Any malignancy Any musculoskeletal injury or surgical procedure 6 months prior to baseline Dental surgery or teeth removed 3 months prior to baseline or plan to History or concomitant medications that could affect bone metabolism, including immunosuppressive, anticonvulsant, antiviral and anti-tuberculosis agents, addictive drugs, corticosteroids, non-steroidal anti-inflammatory drugs, amiodarone, thiazolidinediones, interferon, metronidazole, and tamoxifen

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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Female

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denosumab<br> | Drug: Denosumab<br>* Denosumab (injection), 60 mg, administered as a single subcutaneous injection once<br>* Other names: Prolia;|
| Experimental: Zoledronic Acid<br> | Drug: Zoledronic acid<br>* Zoledronic acid (vial), 5 mg, administered once as a single 15- to 30-minute intravenous infusion<br>* Other names: Aclasta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sclerostin | Serum sclerostin levels | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dickkopf-1 | Serum dickkopf-1 (DKK-1) levels | 12 weeks | 
| OPG/RANKL | Serum osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) levels | 12 weeks | 
| Calcium metabolism | Serum calcium, phosphate, intact parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25OHD) | 12 weeks | 
| Bone turnover | Serum bone turnover markers (total alkaline phosphatase [TSAP], type I N-terminal peptides [PINP] και C-terminal cross-linking telopeptide of type I collagen [CTX]) | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bone turnover, denosumab, postmenopausal osteoporosis, sclerostin, zolendronic acid