Enhancing Wnt signaling lowers fracture incidence in a severe mouse model of Osteogenesis Imperfecta.

Increased risk of fracture is a hallmark feature in the skeletal disorder Osteogenesis Imperfecta (OI). One therapy in clinical trials for OI is an antibody that neutralizes sclerostin (a Wnt signaling inhibitor) that is already FDA approved for patients with osteoporosis. In addition to increasing bone mass and lowering incident fractures in patients with osteoporosis, anti-sclerostin antibody increased bone mass and skeletal strength (measured ex vivo) in several preclinical models of OI. Because in vivo fracture incidence is the primary outcome measure in human OI trials, we examined the effect of enhancing Wnt signaling in a preclinical mouse model of moderate-severe, autosomal dominant OI (the Col1a1Aga2/+ mouse). We genetically enhanced Wnt signaling using the Lrp5A214V allele, which makes the Wnt co-receptor LRP5 resistant to inhibition by sclerostin. By crossing Col1a1Aga2/+ sires with Lrp5A214V/+ dams, we generated pups with OI alone and OI with enhanced Wnt signaling. We radiographically examined these animals for fracture at 5, 9, and 13 weeks of age. We observed that enhanced Wnt signaling significantly reduced the number of fractures in this model by 30% at all 3 ages (e.g., 5.4 +/- 1.7 fractures compared to 7.8 +/- 1.8 fractures at 5-weeks-old, p < 0.001). These data indicate enhancing Wnt signaling lowers incident fractures in a pre-clinical model of OI and suggest lower fracture incidence should achieved by giving anti-sclerostin antibody to patients with OI. These data also suggest that bone mass could be used as a surrogate marker for lowering fracture risk in patients with OI.