Researchers have been working towards practical approaches to inhibiting RUNX2 activity as a way to slow age-related loss of bone mineral density. Bone extracellular matrix is constantly remodeled throughout life, created by osteoblast cells and destroyed by osteoclast cells. In youth these activities are balanced, but with advancing age osteoclast activity comes to dominate. Many drugs have been deployed in attempts to improve osteoblast activity or suppress osteoclast activity, but researchers continue to try to create incrementally better approaches. RUNX2 inhibition acts by increasing osteoblast activity. Here, a novel RUNX2 inhibitor emerging from the cancer research community is demonstrated to slow loss of bone mineral density in mice.
Osteoporosis is a metabolic bone disorder characterised by low bone mass, structural deterioration, and increased fracture risk. Current therapies are limited. Antiresorptives such as bisphosphonates and denosumab reduce fracture risk but long-term use carries risks of atypical femoral fractures and osteonecrosis of the jaw. Anabolic agents, including parathyroid hormone (PTH) derivatives and analogues, namely teriparatide and abaloparatide, are effective but require daily injection. Romosozumab offers monthly dosing but has cardiovascular safety concerns. Hormone replacement therapy also reduces fracture risk but its association with breast, ovarian, and uterine cancer risk limits patient uptake. Thus, new treatments with few side effects and broader applicability remain a clinical priority.
We recently evaluated the small molecule RUNX2 antagonist CADD522 in several preclinical cancer models. RUNX2 is critical for in utero skeletogenesis and cancer metastasis. Unexpectedly, CADD522 reduced cancer-induced bone disease, suggesting potential utility in osteoporosis. 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.
Link: https://doi.org/10.1038/s44386-026-00076-z
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