Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory bone disease that primarily affects children and/or adolescents at a median age of 10 years. Until now, there is no consensus regarding the treatment of CRMO. Non-steroidal anti-inflammatory drugs (NSAIDs) are considered the first line of therapy with remission in approximately 30% of cases. If unsuccessful, several treatments are tried in addition to NSAIDs, including bisphosphonates and anti-TNFs.
The effectiveness of bisphosphonates (including zoledronate) has been reported in clinical cases and/or retrospective series. They are said to be particularly effective in multifocal forms, mandibular and/or vertebral involvement, but no controlled trials have been conducted. Bisphosphonates have even been proposed as first-line therapy in spinal involvement. The only prospective study, is a phase II trial currently underway in Denmark to study the efficacy of zoledronate (NCT02594878) versus placebo in SAPHO (acronym, standing for Synovitis - Acne - Pustulosis - Hyperostosis - Osteitis) patients considered to be a very similar form of CRMO occurring in adults.
In this context, this study proposes evaluate the efficacy of zoledronate compared to placebo in reducing pain at week 12 in children aged ≥4 and \<17 years with NSAID-resistant CRMO. Zoledronate will be administered in three escalating doses: 0.025 mg/kg at baseline (W0), 0.05 mg/kg at week 12 (W12), and 0.05 mg/kg at week 24 (W24). In addition to pain reduction, improvements in MRI findings will be observed, biological markers of inflammation, and quality of life in the zoledronate group. Although subjective, pain reduction remains the most widely used criterion in clinical practice to assess therapeutic efficacy. Zoledronate efficacy will therefore be assessed by the change in standardized pain score (0-10 scale) from baseline to week 12 as the primary endpoint, with additional pain assessments at weeks 4, 24, and 36 as secondary endpoints.
Physician-confirmed diagnosis of CRMO according to Jansson's criteria, with compatible MRI findings. Having lesions on MRI within 12 weeks prior to inclusion and clinically active disease defined by at least one of 2 criteria: patient/parent VAS (pain) superior or equal to 30/100 and/or physician VAS superior or equal to 30/100 after failure of at least 4 weeks of NSAIDs at a stable dose
Written informed consent signed by the parents (the child may sign the consent if they wish, but their signature is not mandatory)
Having had a dental review within 3 months prior to inclusion, with completion of any necessary invasive dental work before the first dose of zoledronate.
History of malignancy or current tumour
History of seizure
Current infectious osteomyelitis
Contraindication to the study drug
Parallel
Zoledronic Acid / Zoledronate 4 MG/100 ML Intravenous Solution
DrugBaseline : 0.025 mg/kg ; Week 4 : 0.05 mg/kg ; Week 6 : 0.05 mg/kg
NaCL 0.9% Intravenous Solution
Other interventionBaseline, Week 4 \& Week 6
Change in pain score from baseline to week 12
Change in standardized pain score (0-10 scale) from baseline to week 12, using Visual Analog Scale VAS 0-10/ 0 = no pain ; 10 = worst imaginable pain
Compare pain score (0-10 scale) evolution between groups at Weeks 4, 24 and 36
Change in standardized pain score (0-10 scale) from baseline to week 4,24 \&36, using Visual Analog Scale VAS 0-10/ 0 = no pain ; 10 = worst imaginable pain
Use of NSAIDs, other analgesics and corticosteroids between the two groups during follow-up.
compare the use of NSAIDs, other analgesics and corticosteroids between the two groups during follow-up.
Clinical signs (Number of participants presenting clinical manifestations of CRMO (pain on palpation, arthritis, spinal deformity, extra-osseous manifestations, growth impairment and pubertal delay) between the two groups at baseline and follow-up visits
Clinical manifestations will be assessed by physical examination at baseline and at weeks 12, 24 and 36. The proportion of participants presenting each manifestation (pain on palpation, arthritis, spinal deformity, dermatological manifestations, inflammatory bowel disease, growth impairment and pubertal delay) will be compared between groups.
Biological inflammatory markers between the two groups at baseline and follow-up visits.
compare biological inflammatory markers between the two groups at baseline and follow-up visits.
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