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

Abstract

BackgroundBisphosphonates 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.MethodsTwo 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.DiscussionThis 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 registrationAustralian New Zealand Clinical Trials Registry: ACTRN12613000039785, registered on 14 January 2013.

Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis

“…96 Alendronate treatment improved the Western Ontario and McMaster University Osteoarthritis Index pain score, decreased biochemical markers and increased the BMD in a prospective 2-year trial 97 Moreover, compared with those receiving placebo, patients with symptomatic knee OA who received intravenous zoledronic acid yearly did not show a significant reduction in cartilage volume loss, the size of BMOLs or the pain score over 24 months. 98 There are other antiresorptive agents (such as OPG, cathepsin K (CTSK) inhibitors and strontium ranelate) that may exert protective effects on subchondral bone and cartilage in animal models and serve as disease-modifying OA drugs for clinical treatment of OA. [99][100][101] Intriguingly, calcitonin, which is known for targeting subchondral bone remodelling, also leads to intracellular cAMP accumulation and then promotes chondrocyte anabolism by binding to its receptors on human OA chondrocytes.…”

Effect of Preoperative Zoledronic Acid Administration on Pain Intensity after Percutaneous Vertebroplasty for Osteoporotic Vertebral Compression Fractures

“…ZOL has the advantages of long-acting, obvious, and fast-acting effect, and significantly improving bone density. A multicenter, randomized, double-blind, controlled trial that administered ZOL and placebo at 6, 12, 18, and 24 months ultimately concluded that ZOL administration reduced bone mass loss and pain [ 18 ]. Cai et al conducted a trial in patients aged >40 years who had low back pain and vertebral modic changes for 6 months.…”

Zoledronic acid plus methylprednisolone versus zoledronic acid or placebo in symptomatic knee osteoarthritis: a randomized controlled trial

“…Third, some baseline characteristics were not well balanced, but we have taken this into account by adjusting for them in data analyses according to the trial protocol. 28 Four, the sample size was calculated based on the primary hypothesis. The noninferiority test between ZA and VOLT01 and superiority tests of ZA and VOLT01 with placebo on knee symptoms and BMLs may be underpowered, making the results hypothesis generating.…”

“…Exclusion criteria were the same as for the ZAP2 trial as previously published. 28 Briefly, we excluded patients with prior use of bisphosphonates except according to a washout schedule, a history of nontraumatic iritis or uveitis, abnormal blood tests (i.e. serum calcium >2.75 mmol/l or <2.00 mmol/l, creatinine clearance <35 ml/min or 25-hydroxyvitamin D concentrations <40 nmol/l), cancer, poor dental health, severe knee osteoarthritis [defined as a joint space narrowing on X-ray of Grade 3 using the Osteoarthritis Research Society International (OARSI) atlas 30 ], knee surgery or arthroscopy in the last 12 month, a corticosteroid injection in the last 3 months, or a hyaluronic acid injection in the last 6 months in the study knee.…”