FRI0523 Zoledronic acid plus prednisolone versus zoledronic acid alone or placebo in the treatment of knee osteoarthritis: a randomised trial
Authors: G. Cai, L. Laslett, D. Aitken, T. Winzenberg, G. Jones
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Disease-modifying therapeutic options are needed for patients with osteoarthritis (OA). Zoledronic acid (ZA) is a potential option as it reduced both knee pain and knee bone marrow lesion (BML) size over 6 months in patients with knee OA. However, ZA infusions are often accompanied by a suite of side effects within 3 days of infusion (acute phase reactions (APRs)), which include flu-like symptoms. These may be caused by upregulation of pro-inflammatory cytokines. A preliminary study (n=20) suggested that a combination of ZA and prednisolone (VOLT01) was superior to ZA alone in reducing APR and knee pain in knee OA patients. A larger study was needed to confirm these findings and examine the new combination's effect on OA outcomes. <h3>Objectives</h3> To compare the effect of once-off infusion of ZA, VOLT01 and placebo on APRs, knee BML size and knee pain symptoms over 6 months in knee OA patients with significant knee pain and BMLs. <h3>Methods</h3> Knee OA patients≥50 years with significant knee pain (defined as a 100 mm Visual Analogue Scale (VAS) ≥40 mm) and knee BMLs visualised on proton density weighted MRI were randomised to receive one infusion of ZA (5 mg in 100 ml saline), VOLT01 (5 mg ZA in 100 ml saline plus a 10 mg prednisolone bolus) or placebo (100 ml saline). Co-primary hypotheses were that VOLT01 would significantly reduce APRs compared to ZA, and that VOLT01 would be non-inferior to ZA in reducing BML size over 6 months. Secondary hypothesis was that VOLT01 would be non-inferior to ZA in improving knee pain and dysfunction (assessed using the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) and VAS) over 6 months. Mixed effect models were performed for data analyses. Analyses for change in knee pain and function scores were adjusted for baseline imbalanced values (baseline pain and utility scores, and pain medications). Non-inferiority margins were defined as 140 mm<sup>2</sup> for change in knee BML size and 8 mm for change in knee pain and function scores (WOMAC pain and function scores were averaged to a 100 mm VAS). <h3>Results</h3> 117 knee OA patients (63 females, mean ±standard deviation (SD) age 62.2±8.1 years) were enrolled. At baseline, mean ±SD knee pain VAS score was 50.1±18.9 mm and median BML size 370 mm<sup>2</sup>. APRs were more frequent in the two active treatment groups (ZA: 87%; VOLT01: 90%) than the placebo group (55%) (both p&lt;0.01). Compared to placebo, neither ZA nor VOLT01 significantly reduced BML size (ZA mean difference [95% CI] −21.6 [-103.0 to +59.9], VOLT01 −62.0 [-142.5 to +18.4]) or knee pain scores (WOMAC pain: ZA 2.6 [-8.5 to +13.8], VOLT01 −8.1 [-18.8 to +2.6]; VAS pain: ZA 5.4 [-6.4 to +17.1], VOLT01 −7.7 [-19.0 to +3.6]) over 6 months, but WOMAC knee function improved significantly (−9.9 [-18.2 to −1.6], p=0.02) in VOLT01-treated group. VOLT01 was non-inferior to ZA in reducing knee BML size and superior to ZA in reducing knee pain and function scores (figure 1). <h3>Conclusions</h3> Combining prednisolone with ZA does not appear useful for reducing APRs, though there may be a small benefit over ZA alone for knee symptoms. Neither showed evidence of disease modification by changing BML size. <h3>Disclosure of Interest</h3> None declared