Clinical, Bone Mineral Density and Spinal Remodelling Responses to Zoledronate Treatment in Chronic Recurrent Multifocal Osteomyelitis

<b>Background:</b> Chronic Recurrent Multifocal Osteomyelitis (CRMO) is a rare auto-inflammatory condition affecting the growing skeleton. The standard first-line treatment of high-dose NSAIDs (non-steroidal anti-inflammatory drugs) is adequate only in a subset of patients. The American College of Rheumatology Consensus Guidelines suggest considering bisphosphonates in a certain category of patients based on evidence from a handful of case series reporting the outcome of pamidronate use. <b>Aims:</b> The aim of this study was to report the efficacy and safety of bisphosphonate, predominantly zoledronate, use in CRMO. <b>Methods:</b> A retrospective cohort study of children with CRMO receiving bisphosphonates was conducted between January 2008 and September 2023 at a single tertiary referral centre. We described the baseline characteristics; clinical indication, regimen and response to bisphosphonate treatment; changes in bone mineral density (BMD) and spine remodelling on dual-energy X-ray absorptiometry (DXA) scans; and safety data. <b>Results:</b> During the study period, 64 (72%, <i>n</i> = 46 females) patients with CRMO with a median age at diagnosis of 10 years (range: 3 to 16 years) were identified. Approximately 31% (<i>n</i> = 20) received either pamidronate (<i>n</i> = 2) or zoledronate (<i>n</i> = 14) or both (<i>n</i> = 4) due to changes in local protocols. The most frequent indications for bisphosphonate use were refractory pain [55%, <i>n</i> = 11/20], pain + spine involvement [35% (<i>n</i> = 7/20)] and spine involvement only [10% (<i>n</i> = 2)]. Prior to bisphosphonate therapy, 100% took regular NSAIDs (<i>n</i> = 19/19), 21% (<i>n</i> = 4/19) used opioids, 47% (<i>n</i> = 9/19) received oral steroid courses, and 10% (<i>n</i> = 2/19) received methotrexate. The median age at bisphosphonate treatment initiation was 12 years (range 6-18 years), and the duration of treatment was 2 years (range: 6 months to 5 years). Improvement in pain was reported by 88% of patients (<i>n</i>= 15/17, 1 was excluded as they had not started treatment yet). All non-responders (<i>n</i> = 2/17;) to bisphosphonate therapy were later recognised clinically to have pain amplification syndrome and were referred to the chronic pain multi-disciplinary team. This correlated to the complete treatment de-escalation of opioids (<i>n</i> = 3/3; 1 was excluded as they had not yet started treatment), steroids (<i>n</i> = 8/8) and methotrexate (<i>n</i> = 2/2). NSAIDs were discontinued in 44% of patients (<i>n</i> = 7 of 16; 1 was excluded due to missing data, and 3 were excluded due to NSAID intolerance). The median first-year increase in the LS BMAD (lumbar spine bone mineral apparent density) Z-score was +1.35, and that in the TBLH BMD (total body less head bone mineral density) Z-score was +0.7 (<i>n</i> = 11). Subsequently, median average annual increases in the LS BMAD Z-score of +0.65 and in the TBLH BMD Z-score of +0.45 (<i>n</i> = 5) were recorded. Around 30% of patients (<i>n</i> = 6) required treatment modification (dose reduction, frequency reduction or cessation) due to a rapid escalation in BMD. There were no fractures documented due to raised BMD. Evidence of spine remodelling on DXA vertebral fracture assessment was seen in 38% of patients with spinal lesions (<i>n</i> = 3 of 8). There was no radiological evidence of improvement in any vertebra plana lesion. First-phase reactions (pyrexia) were reported universally in patients who received bisphosphonates, but none were significant requiring hospitalisation. <b>Conclusions:</b> Similar to pamidronate, zoledronate with an advantageous dosing regimen is well tolerated and effective in improving pain and enabling the de-escalation of adjunctive therapy in CRMO. This is the first report tracking changes in BMD and spinal remodelling in response to zoledronate in CRMO patients. Spinal remodelling is minimal in vertebra plana lesions. Bone density monitoring and personalisation of the bisphosphonate dose and regimen are strongly recommended to avoid overtreatment.