Alendronate for Prevention of AntiRetroviral Therapy-associated Bone Loss

Study Overview
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Brief Summary
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Antiretroviral therapy (ART) initiation is associated with a significant loss of bone mineral density (BMD), characterised by increases in bone turnover, which is largely limited to the first 48 weeks of therapy. Bisphosphonates, such as alendronate, decrease bone turnover and can limit loss of bone mineral density. This study aims to determine if a short course of treatment with the oral bisphosphonate alendronate can limit loss of bone mineral density associated with initiation of ART in HIV-1 infected, antiretroviral naive, adult subjects.

Detailed Description
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Multi-centre, prospective, randomised, double-blind, placebo-controlled trial over 50 weeks. The aims of this study include: To determine if short-course treatment with alendronate versus placebo combined with calcium and vitamin D, initiated 2 weeks prior to start of ART and can prevent loss of BMD over 48 weeks of follow-up post ART initiation. To explore the effect of alendronate on bone turnover in the setting of ART initiation. To determine which factors, such as choice of ART, impacts the protective effect of alendronate in preventing BMD loss. To determine the relationship between changes in bone turnover markers, vitamin D, parathyroid hormone and calcium levels. To explore the pathogenesis of BMD loss with initiation of ART by investigating relationships between changes in immune function (T-cells and B-cells subsets), bone turnover and BMD.

Official Title
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A Multi-centre, Prospective, Randomised Trial of Short Course Alendronate Therapy or Placebo Combined With Vitamin D and Calcium to Prevent Loss of Bone Mineral Density in Antiretroviral-naïve, HIV-1 Infected Subjects Initiating Antiretroviral Therapy

Conditions
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Bone Demineralization

Intervention / Treatment
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* Drug: Alendronate
* Drug: Placebo
* Dietary Supplement: calcium carbonate and colecalciferol
* Drug: Tenofovir disoproxil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male>30 years old or female>35 years old HIV-1 antibody positive antiretroviral therapy naïve be presumed to have achieved peak bone mass be eligible for initiation of antiretroviral therapy in the opinion of the investigator be able to provide written, informed consent Exclusion Criteria: subjects unable to comply with the study protocol or unable to stand/sit upright for at least 30 minutes history of osteoporosis history of fragility fracture or previous femoral fracture chronic renal failure hypocalcemia or hypercalcemia at screening history of Paget's disease or known primary hyperparathyroidism previous treatment with or allergy (including hypersensitivity) to bisphosphonates recent history (past 12 months) of peptic or duodenal ulcers or oesophagitis, aspiration or any other abnormality of the oesophagus current therapy with prescribed calcium or vitamin D preparations (other than over-the-counter multivitamin preparations) current therapy with aspirin or other regularly prescribed non-steroidal anti-inflammatory drugs recent dental work (within the past 3 months) or poor oral hygiene (as judged in the opinion of the investigator) recent (within the past three months) significant steroid exposure for female subjects: pregnancy at screening, planning future pregnancies or unwilling to take measures to avoid pregnancy for the duration of the study where in the investigator's opinion, there is a necessity to initiate ART within the pre-ART study window period hepatitis B or hepatitis C co-infection any active illness (including AIDS illness) which in the opinion of the investigator precludes participation in the study subjects concurrently enrolled in another clinical trial of an investigational medical product

Ages Eligible for Study
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Minimum Age: 30 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Alendronate<br>Alendronate 70 mg plus calcium/vitamin D (1250 mg/400iu) plus Truvada® | Drug: Alendronate<br>* alendronate 70 mg tablets to be administered weekly for a total of 14 weeks, commencing 2 weeks prior to ART initiation<br>* Other names: Romax;Dietary Supplement: calcium carbonate and colecalciferol<br>* Calcium carbonate 1250 mg (equivalent to 500 mg of elemental calcium) and colecalciferol 400 iu (equivalent to 10 micrograms of vitamin D3) tablets administered twice daily for a total of 14 weeks, commencing 2 weeks prior to ART initiation<br>* Other names: Ideos;Drug: Tenofovir disoproxil<br>* Emtricitabine / tenofovir disoproxil fumarate 200 / 300 mg tablet administered once-daily with food (open-label) commencing 2 weeks after alendronate initiation and continuing for 48 weeks<br>* Other names: Truvada;|
| Placebo Comparator: Placebo<br>Placebo to alendronate 70mg plus calcium/vitamin D (1250 mg/400iu) plus Truvada® | Drug: Placebo<br>* Sugar pill manufactured to mimic alendronate 70 mg tablet administered weekly for a total of 14 weeks, commencing 2 weeks prior to ART<br>Dietary Supplement: calcium carbonate and colecalciferol<br>* Calcium carbonate 1250 mg (equivalent to 500 mg of elemental calcium) and colecalciferol 400 iu (equivalent to 10 micrograms of vitamin D3) tablets administered twice daily for a total of 14 weeks, commencing 2 weeks prior to ART initiation<br>* Other names: Ideos;Drug: Tenofovir disoproxil<br>* Emtricitabine / tenofovir disoproxil fumarate 200 / 300 mg tablet administered once-daily with food (open-label) commencing 2 weeks after alendronate initiation and continuing for 48 weeks<br>* Other names: Truvada;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of changes in bone mineral density | Between-group differences in percentage change in total hip, lumbar spine, femoral neck BMD and body composition to week 50 among subjects who received at least one dose of the study medication | 50 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of changes in bone turnover markers | Between-group differences in percentage change in bone turnover markers | 50 weeks | 
| Impact of ART choice on alendronate protective effect | Impact of choice of ART on changes in BMD and bone turnover markers | 50 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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human immunodeficiency virus, bone diseases, osteopenia, osteoporosis, fracture, bone turnover, alendronate, antiretroviral