Effect of Intravenous Zoledronic Acid on Tibiofemoral Cartilage Volume Among Patients With Knee Osteoarthritis With Bone Marrow Lesions: A Randomized Clinical Trial

Abstract

Importance: A proof-of-principle study suggested that intravenous zoledronic acid may reduce knee pain and the size of bone marrow lesions in people with knee osteoarthritis, but data from large trials are lacking.

Objective: To determine the effects of intravenous zoledronic acid on knee cartilage volume loss in patients with symptomatic knee osteoarthritis and bone marrow lesions.

Design, setting, and participants: A 24-month multicenter, double-blind placebo-controlled randomized clinical trial conducted at 4 sites in Australia (1 research center and 3 hospitals). Adults aged 50 years or older with symptomatic knee osteoarthritis and subchondral bone marrow lesions detected by magnetic resonance imaging (MRI) were enrolled from November 2013 through September 2015. The final date of follow-up was October 9, 2017.

Interventions: Intravenous infusion with either 5 mg of zoledronic acid in a 100-mL saline solution (n = 113) or a placebo saline solution (n = 110) at baseline and 12 months.

Main outcomes and measures: The primary outcome was absolute change in tibiofemoral cartilage volume assessed using MRI over 24 months (the minimum clinically important difference [MCID] has not been established). Three prespecified secondary outcomes were change in knee pain assessed by a visual analog scale (0 [no pain] to 100 [unbearable pain]; MCID, 15) and the Western Ontario and McMaster Universities Osteoarthritis Index (0 [no pain] to 500 [unbearable pain]; MCID, 75) over 3, 6, 12, 18, and 24 months and change in bone marrow lesion size over 6 and 24 months (the MCID has not been established).

Results: Of 223 participants enrolled (mean age, 62.0 years [SD, 8.0 years]; 52% were female), 190 (85%) completed the trial. Change in tibiofemoral cartilage volume was not significantly different between the zoledronic acid group and the placebo group over 24 months (-878 mm3 vs -919 mm3; between-group difference, 41 mm3 [95% CI, -79 to 161 mm3]; P = .50). No significant between-group differences were found for any of the prespecified secondary outcomes, including changes in knee pain assessed by a visual analog scale (-11.5 in the zoledronic acid group vs -16.8 in the placebo group; between-group difference, 5.2 [95% CI, -2.3 to 12.8]; P = .17), changes in knee pain assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (-37.5 vs -58.0, respectively; between-group difference, 20.5 [95% CI, -11.2 to 52.2]; P = .21), and changes in bone marrow lesion size (-33 mm2 vs -6 mm2; between-group difference, -27 mm2 [95% CI, -127 to 73 mm2]; P = .60) over 24 months. Adverse events were more common with zoledronic acid than with placebo (96% vs 83%, respectively) and consisted mainly of acute reactions (defined as symptoms within 3 days of administration of infusion; 87% vs 56%).

Conclusions and relevance: Among patients with symptomatic knee osteoarthritis and bone marrow lesions, yearly zoledronic acid infusions, compared with placebo, did not significantly reduce cartilage volume loss over 24 months. These findings do not support the use of zoledronic acid in the treatment of knee osteoarthritis.

Trial registration: anzctr.org.au Identifier: ACTRN12613000039785.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Aitken reported being a recipient of a level 1 National Health and Medical Research Council of Australia (NHMRC) future fund career development fellowship. Dr Laslett reported being a recipient of an NHMRC early career fellowship. Dr Pelletier reported being a shareholder in ArthroLab Inc; and receiving grants and speaker’s fees from Mylan and TRB Chemedica. Dr Martel-Pelletier reported being a shareholder in ArthroLab Inc; and receiving grants and speaker’s fees from TRB Chemedica. Dr Wluka reported being a recipient of an NHMRC translating research into practice fellowship. Dr Wang reported receiving grants from Monash University. Dr Jones reported being a recipient of an NHMRC practitioner fellowship; and receiving personal fees for serving as a consultant to multiple unnamed pharmaceutical companies. No other disclosures were reported.

Figures

Figure 1.. Examples of the Measurement of Femoral (A, B, C, and D) and Tibial (E and F) Cartilage Volume and Bone Marrow Lesion Size (G and H)

A, Delineation of an initial estimate of the bone cartilage interfaces. B, Automatic deformation of the bone cartilage contour estimates by the 2- or 3-dimensional active contour process. C, Delineation of an initial estimate of the cartilage soft tissue interfaces. D, Automatic deformation of the cartilage soft contour estimates by the 2- or 3-dimensional active contour process. E, The manual drawing process of disarticulation contours around the tibial cartilage boundaries. This was done on a section-by-section basis, and then a 3-dimensional rendering (F) was conducted to calculate the volume of the tibial cartilage. G, A hyperintensity in the subchondral bone at the medial femoral compartment. H, The manual drawing process of the hyperintense area. Bone marrow lesions on adjacent slices were measured and compared to locate the slice with the maximum lesion size. This was done for the medial femoral, medial tibial, lateral femoral, lateral tibial, and patellar compartments. The total size of the bone marrow lesion was calculated as the sum of every lesion within each compartment.

Figure 2.. Population Eligibility and Inclusion in the Zoledronic Acid for Osteoarthritis Knee Pain (ZAP2) Study

aOne participant allocated to the placebo group incorrectly received zoledronic acid at both baseline and 12 months. bParticipants who had major surgery (eg, heart surgery, hip replacement, back surgery) or wished to have an antiresorptive treatment (denosumab). cParticipants who did not receive the second infusion but continued with the study visits and assessments. dFor change in cartilage volume, 194 participants with data on both tibial and femoral cartilage volume at baseline were included in the primary analysis (93 in the zoledronic acid group and 101 in the placebo group) and 163 were included in the per-protocol analysis (79 and 84, respectively).

Figure 3.. Effect of Zoledronic Acid on Knee Pain and Bone Marrow Lesion Size Compared With Placebo

A, C, and E show changes from baseline in bone marrow lesion size, visual analog scale pain score, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. Results were estimated using linear mixed-effects modeling (no imputation). The models included treatment, month, and treatment × month interaction with adjustment for the baseline value of the corresponding outcome. Error bars indicate 95% CIs. The red arrows indicate infusions at baseline and at 12 months. B, D, and F show the raw data for the outcomes at each point. The boxes indicate 25th and 75th percentiles; horizontal lines and “+” within boxes indicate median and mean, respectively; whiskers indicate the highest and lowest values within 1.5 × interquartile range; and points beyond the whiskers indicate outliers. The WOMAC index relies on a self-administered questionnaire reflecting pain, stiffness, and limitations to physical function. The WOMAC pain subscale measures 5 dimensions: walking on a flat surface, going up and down stairs, at night while in bed, sitting or lying, and standing. Higher WOMAC and visual analog scale knee pain scores indicate more severe symptoms.