Bisphosphonate treatment for secondary osteoporosis in children, youth, and young adults: a systematic review and meta-analysis

Chronic illnesses and their treatments in childhood pose significant risks of bone fragility due to osteoporosis. Bisphosphonates (BP) are commonly used for treatment, yet evidence remains limited and heterogeneous. This systematic review aims to consolidate current empirical evidence on BP efficacy and safety in children, youth and young adults aged ≤ 21 years with secondary osteoporosis. Ovid MEDLINE and EMBASE, PubMed, Web of Science, Cumulative Index to Nursing and Allied Health, and Cochrane Central Register of Controlled Trials were searched by May 29th, 2025. This review followed the PRISMA guidelines the GRADE approach. This review was registered at PROSPERO (CRD42021242156). Seventeen studies were included (fifteen randomized controlled trials (RCTs), two quasi-RCTs) evaluating BP. Meta-analysis indicated that BP improved lumbar spine bone mineral density (BMD) z-score (mean difference (MD): 0.67; 95% confidence interval (CI): 0.37, 0.97) and lumbar spine bone mineral content (BMC) (MD: 2.90 g; 95% CI: 0.91, 4.90). There were no studies adequately powered to assess vertebral and non-vertebral fractures. Patient-reported outcomes showed no consistent results. Adverse events (AEs) were comparable between treatment and control groups (relative risk (RR): 1.08; 95% CI: 0.94, 1.23). When limited to short-term periods after the first infusion, AEs were more likely in the treatment group (RR: 2.24; 95% CI: 1.22, 4.11). BP treatment benefits pediatric secondary osteoporosis by improving lumbar spine BMD and BMC. However, small sample sizes and heterogeneity among the study methods continue to challenge the reliability of results, and larger RCTs are needed to assess fracture rates.