Background: Osteogenesis imperfecta (OI) is a rare disease leading to an increased bone fragility due to a reduced bone mass. Pathological fractures are the most severe symptom. More than 85% of patients are affected by mutations in COL1A1/A2 impairing quantity and quality of collagen. No approved drugs for OI treatment in childhood are available.
Objective and hypotheses: A prospective pilot study was performed to assess safety and efficacy of an antiresorptive therapy with the RANKL-antibody denosumab in children 510 years with OI caused by mutations in COL1A1/A2.
Method: Ten children (male n=7, mean age 7.48 years) with genetically confirmed OI (COL1A1: seven patients) were included. All children were treated at least 2 years with neridronate before trial entry. Denosumab was applicated after a washout phase of 6 months every 3 months with 1 mg/kg body weight s.c. for 1 year. Weight adjusted vitamin D/calcium substitution was given 4 weeks after each application. Primary efficacy endpoint was change of areal bone mineral density at the lumbar spine assessed by GE lunar iDXA. Mobility was evaluated by gross motor function measurement (GMFM-88) and 1-min walking test if applicable. Bone metabolism markers were evaluated continuously for safety monitoring.
Results: After 40 applications of denosumab no severe side effects were observed. A slight hypocalcemia without clinical relevance was seen in all children after each application. DXA assessment showed a mean increase of lumbar spine Z-scores of +0.9 S.D. (n=10) and total body less head Z-scores of +0.6. Mobility improved in all children (mean percent change of: GMFM-88=3.1% (n=10); 1-min walking distance=20.1% (n=8)).
Conclusion: Denosumab is effective to reduce bone resorption and increase bone mineral density in children with classical OI. Denosumab seems to be safe in the short-term application at least if a close monitoring/substitution of calcium is guaranteed. Finally, long-term observation and a higher sample size are essential to assess risk:benefit ratio more detailed.
Funding: Work was supported by a grant from the Forschungspool University of Cologne 2012 and a grant from Care for brittle bones.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology