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

2. 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

3. 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

4. Introduction – OI VI 1 4

5. 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): 1 5

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

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

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

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

10. Results – First experiences:

11. Results – osteoclastic activity Urinary DesoxyPyriDinoline (DPD)

12. Results - DPDs
Denosumab Treatment
Normal range
Unpublished data

13. 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
Z-score
Z-score
Start
Denosumab
Start
Denosumab 1 -1 -2 -3 -4
Age (Years)
Unpublished data

14. 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.

15. 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.