Optimizing bone health with bisphosphonate therapies in pediatric osteogenesis imperfecta: a network meta-analysis of randomized trials

Abstract

This study compares the efficacy of various bisphosphonate treatments for pediatric osteogenesis imperfecta (OI) in terms of lumbar spine areal bone mineral density (LS-aBMD), Z-scores, bone turnover markers (BTMs), fracture rates, and adverse events.

Purpose: The optimal bisphosphonate treatment for pediatric OI remains uncertain. This study aims to analyze the comparative effectiveness of different bisphosphonate therapies for children with OI.

Methods: A network meta-analysis (NMA) was conducted following PRISMA guidelines, screening clinical trials involving oral or intravenous bisphosphonate therapy in pediatric OI. The primary outcomes included changes in LS-aBMD and Z-scores over 1 and 2 years and fracture events. Secondary outcomes included BTM (uNTX/Cr) over 1 and 2 years and adverse event rates.

Results: The NMA included 9 RCTs with 595 children. For LS-aBMD changes, no bisphosphonates showed differences at 1 year; at 2 years, all active treatments improved LS-aBMD compared to placebo, with pamidronate showing greatest improvement (208.73 mg/cm², 95% CI 60.48, 356.98; CoE, moderate). Zoledronic acid demonstrated superior LS Z-scores at both 1 year (1.63 points, 95% CI 0.07, 3.19; CoE, low) and 2 years (1.37 points, 95% CI 0.95, 1.79; CoE, low). In the limited fracture analysis, only olpadronate reduced total fracture numbers compared to placebo (- 1.65, 95% CI - 3.05, - 0.26; CoE, moderate). For BTMs, all treatments reduced 1-year uNTX/Cr versus placebo, with only alendronate maintaining reduction at 2 years (- 182.38 nmol/mmol, 95% CI - 283.67, - 81.09; CoE, moderate). Zoledronic acid showed higher adverse event rates versus placebo (5.49, 95% CI 1.66, 18.19; CoE, low).

Conclusion: Among various bisphosphonates, pamidronate demonstrated superior improvements in LS-aBMD, while zoledronic acid achieved the most substantial Z-score gains but exhibited increased adverse event rates. Evidence gaps, particularly in direct comparative trials, limit definitive conclusions regarding fracture prevention and bone turnover markers. Future large-scale head-to-head trials comparing oral and intravenous formulations are essential to establish evidence-based treatment protocols for pediatric osteogenesis imperfecta.

Trial registration: This research is registered with PROSPERO, registration number CRD42024571408.

Keywords: Bisphosphonate; Bone health; Network meta-analysis; Osteogenesis imperfecta; Pharmacological treatment.