PMID- 32315057 OWN - NLM STAT- MEDLINE DCOM- 20200512 LR - 20201022 IS - 1538-3598 (Electronic) IS - 0098-7484 (Print) IS - 0098-7484 (Linking) VI - 323 IP - 15 DP - 2020 Apr 21 TI - Effect of Intravenous Zoledronic Acid on Tibiofemoral Cartilage Volume Among Patients With Knee Osteoarthritis With Bone Marrow Lesions: A Randomized Clinical Trial. PG - 1456-1466 LID - 10.1001/jama.2020.2938 [doi] AB - 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. FAU - Cai, Guoqi AU - Cai G AD - Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. FAU - Aitken, Dawn AU - Aitken D AD - Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. FAU - Laslett, Laura L AU - Laslett LL AD - Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. FAU - Pelletier, Jean-Pierre AU - Pelletier JP AD - Osteoarthritis Research Unit, University of Montreal Hospital Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada. FAU - Martel-Pelletier, Johanne AU - Martel-Pelletier J AD - Osteoarthritis Research Unit, University of Montreal Hospital Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada. FAU - Hill, Catherine AU - Hill C AD - Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia. FAU - March, Lyn AU - March L AD - University of Sydney, Royal North Shore Hospital, Sydney, Australia. FAU - Wluka, Anita E AU - Wluka AE AD - Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Australia. FAU - Wang, Yuanyuan AU - Wang Y AD - Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Australia. FAU - Antony, Benny AU - Antony B AD - Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. FAU - Blizzard, Leigh AU - Blizzard L AD - Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. FAU - Winzenberg, Tania AU - Winzenberg T AD - Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. FAU - Cicuttini, Flavia AU - Cicuttini F AD - Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Australia. FAU - Jones, Graeme AU - Jones G AD - Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. LA - eng PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - JAMA JT - JAMA JID - 7501160 RN - 0 (Bone Density Conservation Agents) RN - 6XC1PAD3KF (Zoledronic Acid) SB - IM MH - Aged MH - Bone Density Conservation Agents/administration & dosage/*therapeutic use MH - Bone Marrow/pathology MH - Bone Marrow Diseases/complications/diagnostic imaging/*drug therapy MH - Cartilage, Articular/diagnostic imaging/*drug effects/pathology MH - Double-Blind Method MH - Female MH - Humans MH - Infusions, Intravenous MH - Knee Joint/diagnostic imaging/pathology MH - Male MH - Middle Aged MH - Osteoarthritis, Knee/complications/*drug therapy/pathology MH - Treatment Failure MH - Zoledronic Acid/administration & dosage/*therapeutic use PMC - PMC7175085 COIS- 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. EDAT- 2020/04/22 06:00 MHDA- 2020/05/19 06:00 PMCR- 2020/10/21 CRDT- 2020/04/22 06:00 PHST- 2020/04/22 06:00 [entrez] PHST- 2020/04/22 06:00 [pubmed] PHST- 2020/05/19 06:00 [medline] PHST- 2020/10/21 00:00 [pmc-release] AID - 2764707 [pii] AID - joi200025 [pii] AID - 10.1001/jama.2020.2938 [doi] PST - ppublish SO - JAMA. 2020 Apr 21;323(15):1456-1466. doi: 10.1001/jama.2020.2938.