The SIK2/SIK3 inhibitor GLPG3970 increases bone formation and trabecular bone mass in hypogonadal female mice and rats

Currently, there are no orally available bone anabolic therapies to treat osteoporosis. Intermittent parathyroid hormone injections stimulate bone formation through a signaling pathway that inhibits the actions of salt inducible kinase (SIK) isoforms 2 and 3. Therefore, direct small molecule SIK2/SIK3 inhibitors represent a promising treatment strategy to mimic PTH actions. Here we tested GLPG3970, a potent and selective SIK2/SIK3 inhibitor developed for clinical use in inflammatory diseases, in rodent models of post-menopausal osteoporosis. In bone cells, GLPG3970 reduces phosphorylation levels of SIK substrates and regulates gene expression patterns, as assessed by RNA-sequencing, in a PTH-like manner. GLPG3970 was administered to female mice and rats rendered hypogonadal via surgical oophorectomy (OVX) via twice daily oral gavage. In parallel, separate groups of rodents were treated with once daily subcutaneous PTH injections. Skeletal endpoints, serum bone turnover markers, micro-CT, histomorphometry, and mechanical testing, were assessed after study termination. In both OVX-operated mice and rats, GLPG3970 treatment increased markers of bone formation and cancellous bone mass, and increased rat vertebral body bone strength. These results provide strong justification for further development of orally available SIK2/SIK3 inhibitors to treat post-menopausal osteoporosis.