Abstract
Background: Intravenous bisphosphonates are the primary pharmacological intervention for both primary and secondary paediatric osteoporosis. Following the successful use of bisphosphonates in children with osteogenesis imperfecta (OI), indications have expanded to a broad range of bone pathologies with variable underlying pathophysiology. While bisphosphonate use appears to be safe in children, data on risk factors for acute-phase reaction remain sparse. A prospective characterisation of adverse effects — including baseline musculoskeletal symptoms — has not previously been performed in children. Methods: In this prospective, multicentre observational study, children and adolescents initiating intravenous bisphosphonate therapy at 10 tertiary centres were enrolled. Baseline assessments included diagnosis, fracture history, and patient/proxy-reported pain, fatigue, mobility, and well-being. Acute-phase reactions within days after the first infusion, and symptom scores at 6–8 weeks were obtained by structured telephone interviews and analysed using multivariable models adjusted for age, sex, and diagnostic subgroup. Results: A total of 139 children and adolescents (mean age 9.8 years, 37% female) were included across a spectrum of primary and secondary bone disorders, of whom 83% had a history of fractures. Acute-phase reaction rates varied substantially between diagnostic subgroups: febrile episodes were most frequent in children with inflammatory conditions (71.4%) and OI type III/IV (59.1%) but lowest in OI type I (29.2%), with a comparable pattern for nausea (57.1% vs 22.7% vs 20.8%). Across the cohort, all four symptom domains improved significantly at 6–8 weeks after treatment (p<0.05), with the greatest improvements in patients with inflammatory conditions and those with the highest baseline burden. In zoledronate‑treated children, nausea showed a clear dose relationship and did not occur below 0.02 mg/kg. Conclusions: This prospective, multicentre study demonstrates clinically relevant variability in both acute-phase reactions and treatment response following bisphosphonate treatment initiation in a large cohort of children with bone conditions. Recognition of subgroup‑dependent risk and benefits, and the dose‑dependent occurrence of nausea with zoledronate, supports dose-adapted initiation protocols, particularly for high‑risk groups such as children with inflammatory bone conditions.