A protocol for a multicentre, randomised, double-blind, placebo-controlled trial to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change and knee pain over 24 months in knee osteoarthritis patients - ZAP2

Dawn Aitken, Laura L Laslett, Guoqi Cai, Catherine Hill, Lyn March, Anita E Wluka, Yuanyuan Wang, Leigh Blizzard, Flavia Cicuttini, Graeme Jones, Dawn Aitken, Laura L Laslett, Guoqi Cai, Catherine Hill, Lyn March, Anita E Wluka, Yuanyuan Wang, Leigh Blizzard, Flavia Cicuttini, Graeme Jones

Abstract

Background: Bisphosphonates are a class of drugs that slow bone loss and are a promising candidate to treat knee osteoarthritis (OA) patients. In a pilot study, we demonstrated that zoledronic acid reduced knee pain and size of subchondral bone marrow lesions (BMLs) over 6 months in knee OA patients with significant knee pain and BMLs. A longer, larger study is required to assess whether decreases in BML size will translate to reductions in cartilage loss over time. We are currently conducting a multicentre, randomised, double-blind, placebo-controlled trial over 24 months that aims to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change (assessed using magnetic resonance imaging (MRI)) and knee pain in knee OA patients.

Methods: Two hundred sixty-four patients with clinical knee OA, significant knee pain and subchondral BMLs present on MRI will be recruited in Hobart, Melbourne, Sydney and Adelaide. They will be randomly allocated to the two arms of the study, receiving an annual identical intravenous infusion of either 100 mL of fluid containing zoledronic acid (5 mg/100 mL) or placebo (0.9% NaCl 100 mL), at baseline and 1 year later. MRI of the study knee will be performed at screening, month 6 and 24. Knee structure, symptoms and function will be assessed using validated methods. The primary outcome is absolute change in tibiofemoral cartilage volume (mm3) over 24 months. Secondary outcomes include improvement in knee pain over 3, 6, 12, 18, and 24 months and reductions in BML size over 6 and 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses will be performed as the secondary analyses.

Discussion: This study will provide high-quality evidence to assess whether zoledronic acid has a novel disease modifying effect in OA by slowing cartilage loss and reducing pain. If zoledronic acid proves effective, it suggests great potential for cost savings through a delay or reduced need for joint replacement surgery, and potential for great improvements in quality of life for OA suffers.

Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12613000039785 , registered on 14 January 2013.

Keywords: Cartilage; Magnetic resonance imaging (MRI); Osteoarthritis; Pain; Zoledronic acid.

Conflict of interest statement

Ethics approval and consent to participate

Ethics approval has been obtained from the Tasmania Health and Medical Human Research Ethics Committee (H0012941), The Alfred Hospital Ethics Committee (03/13), Monash University Human Research Ethics Committee (CF14/1064–2,014,000,452), Northern Sydney Local Health District Ethics Committee (HREC/13/HAWKE/80) and Human Research Ethics Committee (TQEH/LMH/MH) (HREC/13/TQEHLMH/134). Written informed consent will be obtained from all patients by the study doctor (i.e. a rheumatologist or supervised rheumatology advanced registrar).

Consent for publication

Not applicable.

Competing interests

Voltarra Pharmaceuticals provided part funding for the VOLT01 sub-study but has no role in the design, implementation, data collection, data analysis, interpretation of data, or writing of the manuscript related to this study. Anita Wluka and Flavia Cicuttini are members of the Editorial Board of BMC Musculoskeletal Disorders. None of the other authors have any competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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