Combined Romosozumab and Raloxifene treatment targets impaired bone quality in a male murine model of diabetic kidney disease.

Abstract

Comorbid diabetes and chronic kidney disease create a complex disease state with multi-faceted impacts on bone health, primarily reduced bone mass and tissue quality. To reduce fracture risk in this growing population, interventions are needed that target both bone mass and quality. Romosozumab (Romo) is an FDA-approved sclerostin inhibitor that has been shown to increase bone mass and strength in a murine model of combined diabetes and CKD (DKD), while Raloxifene (RAL) is a mild anti-resorptive used to treat osteoporosis that has also been shown to increase bone mechanical properties by increasing bone bound water content. We aimed to test whether combined RAL and Romo treatment could improve bone quality in our murine model of DKD more than either treatment alone. Using a previously established streptozotocin- and adenine-diet-induced model, male, C57BL/6J mice were randomly divided into four treatment groups and given daily subcutaneous injections of 100 μL vehicle (phosphorus buffered saline, PBS) or 0.5 mg/kg RAL. In addition, two groups were also given a weekly dose of Romo (10 mg/kg). Overall, Romo increased whole-bone strength and RAL improved tissue-level mechanical properties. Combined RAL-Romo treatment led to significantly higher cortical and trabecular bone mass compared to untreated controls. These morphological improvements created corresponding improvements in cortical bending strength and vertebral trabecular compression strength. These results suggest that combined RAL-Romo treatment provides both mass and quality improvements to DKD bone.