RUNX2 inhibitor CADD522 improves bone microarchitecture and lipid metabolism in post-menopausal bone loss

Abstract

Osteoporosis is a leading cause of age-related morbidity, yet existing antiresorptive and anabolic therapies remain limited by safety concerns, contraindications and poor long-term adherence. CADD522 is a small molecule inhibitor of the RUNX2 transcription factor currently under development for cancer therapy. Here, we investigated whether RUNX2 inhibition could protect against post-menopausal bone loss. In an ovariectomy-induced mouse model, CADD522 (25 mg/kg, three times weekly for eight weeks) enhanced bone formation, preserved trabecular microarchitecture and reduced marrow and peripheral adiposity. Cross-species pharmacokinetic and toxicological studies demonstrated oral bioavailability, favourable short-term tolerability and target engagement despite rapid systemic clearance, while cellular thermal shift assays confirmed direct engagement of RUNX2. Together, these findings identify RUNX2 inhibition as a therapeutic strategy that simultaneously improves skeletal integrity and metabolic homeostasis, supporting further development of CADD522 for osteoporosis and other RUNX2-driven diseases.