Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta

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Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia, easy susceptibility to fracture, and skeletal deformities. Current treatment options for OI focus on antiresorptive bisphosphonates which have been shown to be effective at increasing vertebral areal bone mineral density and height in clinical trials. However, bisphosphonate effects in long bones are less evident and most pediatric OI trials observe little or no functional benefit. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin is a negative regulator of the Wnt pathway, and a neutralizing sclerostin antibody (Scl-Ab) therapy has proven to be strongly anabolic in other rodent fragility models as well as initial clinical trials. Whether Scl-Ab therapy is capable of stimulating osteoblast activity in animals harboring a typical OI-causing mutation has yet to be demonstrated. The purpose of this project was to evaluate Scl-Ab in a Brtl/+ mouse model of type IV OI with a Gly349Cys mutation on col1a1. We initially sought to determine whether Brtl/+ osteoblasts would respond to short-term Scl-Ab therapy in vivo . Starting with the most well-characterized age in Brtl/+, we treated 8-week old WT and Brtl/+ for 2 weeks with 25mg/kg of Scl-Ab. Scl-Ab proved anabolic and significantly elevated serum osteocalcin levels and also increased periosteal cortical bone-formation rate as measured by dynamic histomorphometry in both WT and Brtl/+ mice. Despite the short-term treatment, Scl-Ab significantly improved cortical bone mass as measured by microCT, which led to greater whole-bone femoral strength as measured by mechanical testing. Fluorescent-guided nanoindentation revealed that Scl-Ab did not change the tissue elastic modulus of the bone formed during the treatment period. These positive results led us to pursue studies of longer term Scl-Ab therapies (5 weeks) at both adult (6 months) and pediatric (3 weeks) ages in Brtl/+. Initial results from these studies in both 6-month and 3-week old Brtl/+ mice indicate that Scl-Ab is strongly anabolic and significantly increases cortical bone mass as well as whole-bone mechanical strength in the femur. In conclusion, Scl-Ab was successfully anabolic in Brtl/+ mice harboring a typical OI-causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in OI.