Denosumab Versus Zoledronic Acid in Thalassemia-Induced Osteoporosis

Study Overview
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Brief Summary
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This study is to compare the two medications Denosumab and Zoledronic Acid For Patients With Beta Thalassemia Major Induced Osteoporosis. Patients with B-thalassemia major induce osteoporosis will undergo baseline assessment of the bone densitometry by Dual-energy X-ray absorptiometry scan as a standard of care by the radiology department, then a blood test for bone specific Alkaline phosphatase and type-1 Carboxy Telopeptide will be measured by the chemistry lab. Patients with B-Thalassemia Major induced osteoporosis, who are 18 years of age or more and willing to participate in the study will be enrolled after consenting by the primary investigator in hematology outpatient clinic. Patients with osteoporosis will receive one of the two medications, at the end of the year Dual-energy X-ray absorptiometry scan will be done to compare the response of the two medications. The potential risks include the drug-related side effects

Detailed Description
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Despite the significant improvements in the therapeutic management of beta thalassemia major (BTM) over the past few decades, osteoporosis is still a common finding, even in optimally treated patients. The relationships between bone mineral densities (BMD) and several clinical characteristics or hematological markers have been described. Chronic anemia, bone marrow expansion due to ineffective erythropoiesis, iron toxicity, calcium and zinc deficiencies, low vitamin D levels and endocrine complications have been suggested to contribute to the etiology of bone diseases in BTM. Nevertheless, the complex etiological mechanisms of this heterogeneous osteopathy remain incompletely clarified. A complex mechanism controls bone remodeling in human. This mechanism includes the receptor activator of nuclear factor kappa B ligand (RANKL), its natural receptor (RANK) and osteoprotegerin (OPG). The RANK/RANKL pathway is an essential to promote osteoclast formation and activation and prolongs osteoclast survival. OPG acts as a decoy receptor for RANKL and prevents its interaction with RANK thereby inhibiting osteoclast formation, function, and survival. Alteration of the RANK/RANKL/OPG system for increased osteoclastic activity and enhanced osteoblastic dysfunction is proposed as an important mechanism in the etiology of osteoporosis in BTM. Hypogonadism, a common finding in BTM, is associated with enhanced RANKL activity. The sex steroid hormones, androgen, and estrogens, via their respective nuclear receptors, regulate BMD in humans and mice. Testosterone is likely to have direct and indirect inhibitory effects on human osteoclast formation and bone resorption. Animal model and cell culture studies suggest a direct inhibitory effect of androgens on the OPG/RANKL cytokines system. In human osteoblastic cells, testosterone and 5-dihydrotestosterone mediate an androgen receptor-induced specific inhibition of OPG messenger ribonucleic acid (mRNA) expression. Androgens have also been shown to block RANKL-induced osteoclastic formation while RANKL expression was found to be up-regulated in osteoblastic cells from androgen receptor-deficient mice. The effect of oestradiol (E2) on osteoclast precursors and osteoclasts seems to be mediated by osteoblastic cells. Inhibitory effect of E2 is associated with the stimulated secretion of OPG by osteoblasts. Previous studies have focused on the characteristics of thalassemic patients with osteoporosis and their response to therapy with bisphosphonate. Because RANK-RANKL and OPG play a significant role in bone resorption and seem to be the principal implicated mechanism for the development of osteoporosis in BTM, we will conduct this prospective study to evaluate the anti-RANKL denosumab versus zoledronic acid on TM-induced osteoporosis.

Official Title
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Denosumab Versus Zoledronic Acid for Patients With Beta-Thalassemia Major-Induced Osteoporosis

Conditions
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Thalassemia Majors (Beta-Thalassemia Major), Osteoporosis

Intervention / Treatment
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* Drug: Denosumab 60 MG/ML Prefilled Syringe
* Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to participate in the study Age 18 years old or older Eastern Cooperative Oncology Group Performance Status less than or equal 2 Exclusion Criteria: Age less than 18 years old Not willing to participate in the study Vulnerable subjects or Eastern Cooperative Oncology Group Performance Status 3 or 4

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Denosumab<br>Denosumab 60 MG/ML Prefilled Syringe Denosumab Dose: 60 milligrams, subcutaneous injection, every 6 months (twice a year) | Drug: Denosumab 60 MG/ML Prefilled Syringe<br>* Denosumab 60 MG/ML will be administered to 20 patients with b-thalassemia major<br>* Other names: Prolia;|
| Active Comparator: Zoledronic Acid<br>Zoledronic Acid 5Mg/Bag 100Ml Inj Zoledronic acid will be 5 milligrams, Intravenous injection, once a year | Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj<br>* Zoledronic Acid 5Mg/Bag 100Ml Inj will be administered to 20 patients with b-thalassemia major<br>* Other names: Aclasta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with a 50 percent or greater reduction in type-1 collagen carboxy telopeptide from the baseline | Number of patients with a 50 percent or greater reduction in type-1 collagen carboxy telopeptide from the baseline | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with a 50 percent or greater improvement in Dual-energy X-ray absorptiometry scan from the baseline | Number of patients with a 50 percent or greater improvement in Dual-energy X-ray absorptiometry scan from the baseline | 12 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoporosis, Beta-Thalassemia Major, Denosumab, Zoledronic Acid