Zoledronic Acid Not Associated With Reduced Cartilage Loss in Knee Osteoarthritis

knee osteoarthritis xray
knee osteoarthritis xray
Researchers determined the effects of zoledronic acid on knee cartilage volume loss in knee osteoarthritis and bone marrow lesions.

Yearly intravenous zoledronic acid does not significantly reduce cartilage volume loss in patients with knee osteoarthritis (OA), according to results of a 2-year clinical trial reported in JAMA.1

Results of a pilot study indicated that intravenous bisphosphonate zoledronic acid reduced knee pain and bone marrow lesion size in patients with knee OA after 6 months.2 In this multicenter, double-blind, placebo-controlled, randomized controlled trial (Zoledronic Acid for Osteoarthritis Knee Pain; Anzctr.org.au Identifier: ACTRN12613000039785), the researchers aimed to determine whether zoledronic acid reduced knee pain, bone marrow lesion size, and loss of cartilage volume in adults aged ≥50 years with knee OA after 24 months.

A total of 223 patients (mean age, 62.0 years; 52% women) with knee OA were enrolled in the study from 4 sites in the OA Clinical Trial Network of Australia. Patients were randomly assigned 1:1 to receive intravenous infusion of zoledronic acid (5 mg in a 100 mL saline solution) or placebo (100 mL saline solution) at baseline and 12 months. The primary outcome was absolute change in tibiofemoral cartilage volume at 24 months as assessed by MRI. Secondary outcomes included the change in bone marrow lesion size at 6 and 24 months and change in knee pain at regular intervals between 3 and 24 months. Knee pain was assessed using the visual analog scale (VAS; from 0 to 100) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; from 0 to 500).

Over the course of the study, 33 patients (15%) withdrew from the trial, including 23 in the treatment group and 10 in the placebo group. At 24 months, tibiofemoral cartilage volume decreased by a mean value of 878 mm3 and 919 mm3 in the treatment and control groups, respectively. The between-group difference was not statistically significant (41 mm3; 95% CI, -79 to 161 mm3; P =.50). Knee pain improved in both groups, with no significant difference at any time point. At 24 months, the between-group difference for VAS score was 5.2 (95% CI, -2.3 to 12.8; P =.17) and 20.5 for the WOMAC score (95% CI, -11.2 to 52.2; P =.21). There was no difference observed in bone marrow lesion size at 24 months (P =.60).

Adverse events were experienced by 96% vs 83% of participants in the zoledronic acid and placebo groups. The difference in frequency of adverse events was primarily driven by a higher rate of acute reactions within 3 days of infusion in the treatment group compared with the control group (87% vs 56%). Acute reactions included musculoskeletal pain and stiffness, fever, and headache and dizziness.

Researchers noted that the planned study size (n=264) was not achieved because of budgetary restrictions. In addition, 1 patient assigned to the placebo group incorrectly received zoledronic acid.

Related Articles

“Among patients with symptomatic knee [OA] and bone marrow lesions, yearly zoledronic acid infusions, compared with placebo, did not significantly reduce cartilage volume loss over 24 months,” the researchers concluded. “These findings do not support the use of zoledronic acid in the treatment of knee [OA].”

Disclosures: Several authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.


  1. Cai G, Aitken D, Laslett LL, et al. Effect of intravenous zoledronic acid on tibiofemoral cartilage volume among patients with knee osteoarthritis with bone marrow lesions: A randomized clinical trial. JAMA. 2020;323(15):1456-1466.
  2. Laslett LL, Doré DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis. 2012;71(8):1322-1328.