Efficacy of Pamidronate in the Treatment of Bone Loss Associated With Liver Transplant

Study Overview
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Brief Summary
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The aims of this study are to prospectively evaluate the efficacy of two intravenous infusions of pamidronate 90 mg, associated with calcium and calcidiol, in the early post-transplant period, on bone loss in liver transplant recipients, and to asses the safety of this treatment.

Detailed Description
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Patients diagnosed with chronic advanced liver disease awaiting orthotopic liver transplantation will be eligible to take part in this study. Patients excluded from the study will be those younger than 18 years, those receiving a multiorgan transplant or retransplant, or patients with a previous allergy to bisphosphonates. Previous treatment with fluoride, estrogens, selective estrogen receptor modulators or bisphosphonates will be another reason for exclusion, as well as therapy with glucocorticoids during the last 6 months before transplantation. None of the patients will have a previous history of disorders, other than liver disease, known to affect bone metabolism. Study Design and Conduct The study will be a 1-year prospective, randomized, double-blind, placebo-controlled trial conducted at 10 centers in Spain. Immunosuppression All patients will receive microemulsion cyclosporine A (CsA) as primary immunosuppressive agent, in combination with glucocorticoids. Additionally, mycophenolate mofetil will be associated according to the usual clinical practice of each center. In all cases, glucocorticoids will be progressively tapered during the first year. Intervention Patients will receive oral calcium (500 mg twice daily) and oral 25-hydroxy vitamin D (16000 UI every 15 days), after informed consent for the study will be obtained and exploratory screening will be done. Within days 7-12 after engraftment, the recruited transplanted patients (will be randomized to either the experimental or placebo group. Patients of the treatment group will receive a single dose of 90 mg disodium pamidronate within days 7-12 and at 3 months after liver transplantation, diluted in 500 ml of 5% glucose serum and administered as a 4-hour continuous intravenous infusion. Patients of the placebo group will receive 500 ml of 5% glucoside serum infusions. Treatment with oral calcium and vitamin D will be maintained for 1 year after transplantation. Study Endpoints The primary endpoints of the study will be changes in bone mineral density (BMD), quantified by dual energy X-ray absorptiometry (DXA) and safety of pamidronate by recording adverse events. Secondary endpoints will include the incidence of skeletal fractures, by assessment of radiological vertebral fractures (symptomatic and asymptomatic), and the development of nonvertebral fractures. Evaluation Five study visits will be scheduled: before transplantation, within day 7-12 after liver transplantation and at 3, 6 and 12 months after liver transplantation.

Official Title
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Prospective, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy of Disodium Pamidronate in the Treatment of Bone Loss Associated With Liver Transplant

Conditions
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Bone Disease, Metabolic

Intervention / Treatment
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* Drug: Disodium pamidronate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosed with chronic advanced liver disease awaiting orthotopic liver transplantation Exclusion Criteria: younger than 18 years receiving a multiorgan transplant or retransplant previous allergy to bisphosphonates Previous treatment with fluoride, estrogens, selective estrogen receptor modulators or bisphosphonates therapy with glucocorticoids during the last 6 months before transplantation previous history of disorders, other than liver disease, known to affect bone metabolism.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pamidronate<br>Single dose of 90 mg disodium pamidronate within days 7-12 and at 3 months after liver transplantation, diluted in 500 ml of 5% glucose serum and administered as a 4-hour continuous intravenous infusion | Drug: Disodium pamidronate<br>* Single dose of 90 mg disodium pamidronate within days 7-12 and at 3 months after liver transplantation, diluted in 500 ml of 5% glucose serum and administered as a 4-hour continuous intravenous infusion<br>* Other names: Aredia;|
| Placebo Comparator: Placebo<br>500 ml of 5% glucoside serum infusions within days 7-12 and at 3 months after liver transplantation and administered as a 4-hour continuous intravenous infusion | Drug: Placebo<br>* 500 ml of 5% glucoside serum infusions within days 7-12 and at 3 months after liver transplantation and administered as a 4-hour continuous intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| bone mineral density (BMD), quantified by dual energy X-ray absorptiometry (DXA) |  | Change during the 1-year of follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| adverse events |  | incidence during 1-year of follow-up | 
| incidence of skeletal fractures, by assessment of radiological vertebral fractures (symptomatic and asymptomatic), |  | 1-year of follow-up | 
| incidence of nonvertebral fractures |  | 1-year follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pamidronate,bone loss, liver transplantation