Efficacy and Safety of Zoledronic Acid vs Placebo on Pain Reduction at 12 Weeks in NSAID‑Resistant Pediatric Chronic Recurrent Multifocal Osteomyelitis

The primary objective is to assess the efficacy of zoledronate compared with placebo by measuring the change in standardized pain score (0–10) from baseline to week 12 in children aged 4 to <17 years with NSAID‑resistant Chronic recurrent multifocal osteomyelitis. Secondary objectives include:

• Evaluation of pain trajectory at weeks 4, 24 and 36.
• Comparison of NSAID, additional analgesic, and corticosteroid use during follow‑up.
• Assessment of clinical signs (pain on palpation, arthritis, spinal deformity, extra‑osseous manifestations, growth and puberty) at baseline and subsequent visits.
• Comparison of biological inflammatory markers at baseline and follow‑up.
• Determination of disease activity using the CNO Clinical Disease Activity Score (CNO CDAS) at baseline and follow‑up.
• Evaluation of radiological disease activity on whole‑body MRI using the mRINBO score at baseline and follow‑up.
• Assessment of treatment response with PedCNO30 and PedCNO50 scores.
• Comparison of radiological remission rates at weeks 12, 24 and 36.
• Comparison of clinical and biological remission rates at weeks 12, 24 and 36.
• Evaluation of health‑related quality of life over time.
• Assessment of impact on schooling (children) and parental work absenteeism.
• Evaluation of the safety and tolerability of zoledronate.
• Analysis of the cost‑effectiveness of the treatment strategy.

The trial enrolled pediatric patients with physician‑confirmed Chronic recurrent multifocal osteomyelitis (CRMO) who were refractory to non‑steroidal anti‑inflammatory drugs. Eligible participants were children and adolescents aged 4 to 16 years, inclusive of both females and males. All subjects required active disease demonstrated by recent MRI lesions and a pain score of ≥30 mm on a visual analogue scale after at least four weeks of stable NSAID therapy. Enrollment required a dental evaluation within three months before the first dose and written informed consent from a parent or guardian. The investigational agent, zoledronate, was administered according to a dose‑escalation schedule. The sponsor did not provide the total number of participants. No specific dietary or physical‑activity restrictions were stipulated beyond standard clinical care.

The study is a multicenter, randomized, double‑blind, placebo‑controlled trial evaluating the efficacy and safety of zoledronate versus placebo in pediatric patients with Chronic recurrent multifocal osteomyelitis resistant to non‑steroidal anti‑inflammatory drugs. After an initial screening visit to confirm eligibility, participants receive a baseline visit (day 0) during which the first infusion of zoledronate (0.025 mg/kg, max 4 mg) or matching placebo is administered. Subsequent study visits occur at weeks 4, 12, 24, and 36 for repeated infusions (0.05 mg/kg at weeks 12 and 24), pain assessments, clinical examinations, laboratory tests, and imaging. The primary efficacy endpoint (change in standardized pain score) is measured at the week 12 visit; secondary endpoints are collected through week 36, which serves as the end‑of‑study visit. Participant involvement therefore extends from screening through the final week 36 assessment, encompassing approximately 36 weeks of follow‑up. Early termination may occur if a participant experiences a serious adverse event related to the study drug, withdraws consent, fails to adhere to the protocol schedule, requires prohibited concomitant therapy, or exhibits disease progression necessitating alternative treatment. The overall trial timeline spans recruitment from April 2026 to August 2029, with each enrolled child remaining in the study for the full 36‑week duration unless discontinued earlier for the reasons described.

The investigational product is zoledronic acid supplied as a solution for infusion. The dosing regimen consists of 0.025 mg/kg administered at baseline, followed by 0.05 mg/kg at week 12 and again at week 24, with a maximum of 4 mg per infusion. Infusions are given intravenously according to the specified schedule.

The comparator is a placebo matching the zoledronic acid infusion in appearance and volume. The placebo is administered on the same schedule as the active product (baseline, week 12, and week 24) to maintain blinding.

All infusions are performed in a clinical setting under standard monitoring procedures. Administration times are recorded, and participants are observed for immediate adverse reactions. Compliance is assessed by reviewing infusion logs and confirming that each scheduled dose is delivered according to the protocol.

The primary efficacy assessment is the change in standardized pain score from baseline to week 12, measured with age‑appropriate validated self‑assessment scales: the Faces Pain Scale–Revised for children 4–< 6 years, the pediatric visual analog scale for children ≥6 years who can use it, and the Numerical Rating Scale for children ≥8 years, all on a 0–10 metric.

Secondary efficacy evaluations include pain assessments at baseline and weeks 4, 24, and 36 using the same scales, with a ≥30 % reduction from baseline considered clinically meaningful and a ≥50 % reduction considered substantial; complete pain disappearance (score 0) defines clinical remission at weeks 12, 24, and 36. NSA‑ID and other analgesic use are recorded via patient diaries and quantified as the average number of days of intake over the preceding three months at weeks 12, 24, and 36. Clinical signs such as joint pain, arthritis, spinal deformation, extra‑osseous manifestations, growth, and puberty are documented at baseline and weeks 12, 24, and 36.

Inflammatory activity is monitored by laboratory analyses at baseline and weeks 12, 24, and 36, assessing the proportion of children with elevated white‑blood‑cell count, platelet count, C‑reactive protein, sedimentation rate, and pro‑inflammatory cytokines. Disease activity is quantified with the CNO Clinical Disease Activity Score, a composite of patient (or parent) pain VAS, global disease activity VAS, and clinician‑reported count of active lesions, evaluated at the same time points.

Radiological efficacy is assessed by whole-body MRI at baseline and weeks 12, 24, and 36, recording the number of unequivocal lesions, new lesions since the prior scan, and the mRINBO score. Treatment response is measured using the PedCNO composite score, with PedCNO30 and PedCNO50 defined as ≥30 % and ≥50 % improvement, respectively, in at least three of five core variables without excessive deterioration of any other variable. Radiological remission is defined as MRI normalization at weeks 12, 24, and 36, while clinical and biological remission requires complete pain disappearance and normalization of inflammatory markers at the same visits.

Health‑related quality of life is evaluated with the PedSQL questionnaire at baseline and weeks 12, 24, and 36; children ≥8 years complete a self‑report, and parents provide proxy reports for younger participants. School and parental absenteeism are captured as days absent per 12‑week interval at the same assessments.