Suppression of Bone Resorption in OI VI using the RANKL Antibody Denosumab Heike Hoyer-Kuhn Oliver Semler / Eckhard Schoenau ICCBH, Rotterdam, June 24th 2013

Introduction – OI VI Characterization based on clinical / histological findings: No fractures at birth Fractures more frequent Typical histomorphometric findings with mineralization defect and elevated osteoid volume 1 2

Introduction – OI VI Patients with OI type VI showed a reduced treatment response to pamidronate compared to OI type I/III/IV: Fractures more frequent despite bisphosphonate treatment Reduced growth velocity No reduction of vertebral compressions 1 3

Introduction – OI VI 1 4

Introduction – SERPINF1 Member of the serpin gene family coding for PEDF (pigment epithel derived factor). SERPINF1 mutations lead to reduced PEDF expression. PEDF is involved in angiogenesis and neuronal differentiation. In PEDF knockout mice (-/-) bone abnormalities are comparable to those seen in patients with OI VI. Type I collagen production is normal and seems not to be affected in these patients. Bogan et al., JBMR Jul 2013;28(7):1531-1536. 1 5

Introduction – Role of PEDF RANKL OPG SERPINF1 Modified from Boyle WJ, et al. Nature. 2003;423:337-342

Introduction - Mutation in SERPINF1 PEDF RANKL OPG SERPINF1 Modified from Boyle WJ, et al. Nature. 2003;423:337-342

Introduction - Denosumab PEDF RANKL OPG OPG Denosumab SERPINF1 Modified from Boyle WJ, et al. Nature. 2003;423:337-342

Research question: Is there a suppression of bone resorption in children with OI type VI treated with the RANKL antibody denosumab ?

Results – First experiences:

Results – osteoclastic activity Urinary DesoxyPyriDinoline (DPD)

Results - DPDs Denosumab Treatment Normal range Unpublished data

Results – areal Bone Mineral Density (DXA) aBMD L2-L4 I.B., male, 10.5 years aBMD L2-L4 K.M., male, 8.5 years Age (Years) 1 -1 -2 -3 -4 6 7 8 9 10 11 Z-score Z-score Start Denosumab Start Denosumab 1 -1 -2 -3 -4 6 7 8 9 10 11 Age (Years) Unpublished data

Summary / Conclusion The first applications of denosumab in children with OI VI were well tolerated and showed no severe side effects. DPD levels and BMD measurement provided evidence that treatment with denosumab reduced bone resorption in OI VI. The antiresorptive treatment with denosumab should be evaluated in clinical trials to optimize intervals and to analyze its efficacy in a larger cohort of OI type VI children.

Acknowledgements: Children`s hospital Rehabilitation Human Genetics Funded by Köhler Award 2012 HHK and OS declare no conflicts of interest. ES received speakers fee from Amgen.