Introduction: Bisphosphonate treatment in children with osteogenesis imperfecta reduces bone catabolism and relies on modelling to form new bone. An anabolic treatment, anti-sclerostin antibody (Anti-SOST Ab), is being investigated in clinical trials. We hypothesized that combined treatment may produce superior outcomes in OI.
Methods: Female Col1a2 G610C mice and their wild type littermates (WT) were treated from week 5 to week 9 of life with either saline (control), zoledronic acid (ZA) 0.025 mg/kg s.c. weekly, Anti-SOST Ab given 50 mg/kg i.v. weekly (Anti-SOST), or a combination of both (ZA Anti-SOST). Outcomes included weekly DEXA for areal bone mineral density (BMD) (GE Lunar PIXImus WI, USA), μCT (SkyScan 1174 Kontich, Belgium), mechanical testing of tibiae in four point bending (Instron 5944, MA, USA). Data were analysed with one-way ANOVA (SPSS v11).
Results: Increases in tibial BMD were seen over time in all groups. Anti-SOST treatment alone had no effect on tibial BMD, while ZA (16%) and ZA Anti-SOST (27%) treatments produced significant increases from weeks 1 to 4 (P<0.05). μCT analysis showed increases in tissue mineral density and cortical thickness for combined treatment over respective controls. Tibial four-point bending showed only combined ZA Anti-SOST yielded a significant increase in strength and energy to failure in OI mice, restoring bone strength to that of untreated WT mice. In the spine, all treatments increased compression strength over control, Anti-SOST 30%, ZA 43% and ZA Anti-SOST 91% (P<0.05).
Discussion: Anti-SOST Ab alone had effects on trabecular but not cortical sites in this study in Col1a2 G610C mice. Roschger et al. reported minimal effect in the Col1a1(Jrt)/+ mouse model treated with Anti SOST Ab, whereas large effects were noted with just 2 weeks treatment in 8 week-old Brtl/+ mice, leading to increase in bone size and strength.
Conclusion: A combination of zoledronic acid and anti-sclerostin antibody is superior over either treatment alone in the Col1a2 G610C model of OI. Further studies are required in alternate mouse models of OI to confirm efficacy across different models, and thus to predict possible efficacy across the heterogeneous population of OI patients.
Disclosure:: Michaela Kneissel and Ina Kramer employees of Novartis Pharma, Basel, Switzerland
Craig Munns research funding from Novartis, Amgen
David Little research funding from Novartis, Amgen, Celgene, N8 Medical.
27 - 30 Jun 2015