Alendronate for Prevention of AntiRetroviral Therapy-associated Bone Loss (APART)

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

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.

Study Overview

• Status: Terminated
• Conditions: Bone Demineralization
• Intervention / Treatment: Drug: Alendronate; Dietary supplement: calcium carbonate and colecalciferol; Drug: Tenofovir disoproxil; Drug: Placebo

Detailed Description

Multi-centre, prospective, randomised, double-blind, placebo-controlled trial over 50 weeks. The aims of this study include:

1. 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.
2. To explore the effect of alendronate on bone turnover in the setting of ART initiation.
3. To determine which factors, such as choice of ART, impacts the protective effect of alendronate in preventing BMD loss.
4. To determine the relationship between changes in bone turnover markers, vitamin D, parathyroid hormone and calcium levels.
5. 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.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 4

Contacts and Locations

Study Locations

• Ireland
  • Dublin, Ireland, 9
    • Beaumont Hospital
  • Dublin, Ireland, 7
    • Mater Misericordiae University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Alendronate; Alendronate 70 mg plus calcium/vitamin D (1250 mg/400iu) plus Truvada®	Drug: Alendronate; alendronate 70 mg tablets to be administered weekly for a total of 14 weeks, commencing 2 weeks prior to ART initiation; Other Names: Fosamax; Romax; Dietary supplement: calcium carbonate and colecalciferol; 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; Other Names: Calcichew D3 forte; Ideos; Drug: Tenofovir disoproxil; 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; Other Names: Truvada
Placebo Comparator: Placebo; Placebo to alendronate 70mg plus calcium/vitamin D (1250 mg/400iu) plus Truvada®	Dietary supplement: calcium carbonate and colecalciferol; 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; Other Names: Calcichew D3 forte; Ideos; Drug: Tenofovir disoproxil; 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; Other Names: Truvada; Drug: Placebo; Sugar pill manufactured to mimic alendronate 70 mg tablet administered weekly for a total of 14 weeks, commencing 2 weeks prior to ART

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathogenesis of BMD loss with initiation of ART	Relationship between changes in T-cell and B-cell subsets, bone turnover and BMD with ART initiation	50 weeks

Collaborators and Investigators

• Sponsor: University College Dublin
• Collaborators: Rush University Medical Center; Royal College of Surgeons, Ireland; Mater Misericordiae University Hospital; Health Research Board, Ireland; Beaumont Hospital
• Investigators: Principal Investigator: Patrick WG Mallon, MB BCh BAO,PhD,FRCPI, University College Dublin

Publications and helpful links

General Publications

• Cotter AG, Sabin CA, Simelane S, Macken A, Kavanagh E, Brady JJ, McCarthy G, Compston J, Mallon PW; HIV UPBEAT Study Group. Relative contribution of HIV infection, demographics and body mass index to bone mineral density. AIDS. 2014 Sep 10;28(14):2051-60. doi: 10.1097/QAD.0000000000000353.
• McComsey GA, Kendall MA, Tebas P, Swindells S, Hogg E, Alston-Smith B, Suckow C, Gopalakrishnan G, Benson C, Wohl DA. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS. 2007 Nov 30;21(18):2473-82. doi: 10.1097/QAD.0b013e3282ef961d.

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Actual): September 1, 2019
• Study Completion (Actual): September 1, 2019

Study Registration Dates

• First Submitted: December 17, 2014
• First Submitted That Met QC Criteria: December 17, 2014
• First Posted (Estimate): December 22, 2014

Study Record Updates

• Last Update Posted (Actual): May 26, 2022
• Last Update Submitted That Met QC Criteria: May 20, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: bone diseases; osteoporosis; fracture; osteopenia; alendronate; bone turnover; antiretroviral; human immunodeficiency virus
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Bone Demineralization, Pathologic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Gastrointestinal Agents; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antacids; Tenofovir; Vitamin D; Cholecalciferol; Calcium; Alendronate; Calcium Carbonate
• Other Study ID Numbers: APART_2014