Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption

Osteoclasts are responsible for bone erosion in osteoporosis and rheumatoid arthritis (RA). Both Btk and Tec kinases have essential functions in osteoclast differentiation. Tirabrutinib is a highly potent and dual oral Btk/Tec inhibitor with an IC50 in the nmol/L range and significantly inhibits the M-CSF and RANKL-driven osteoclast differentiation. It was hypothesized that the in vitro activity of tirabrutinib could be demonstrated in mice bone resorption model. The RANKL model studies show that tirabrutinib significantly suppressed bone loss with the inhibition of serum TRAPCP5b and urinary CTX-1. Bone Mineral Density (BMD) loss in tirabrutinib-treated mice was 55% (P < .05), 87% (P < .001) and 88% (P < .001) for the 3, 10 and 30 mg/kg dose groups respectively. Btk and Tec are required for osteoclast differentiation and activation based on the genetic evidence obtained from Btk and Tec double deficient mice. Tirabrutinib may be a novel therapeutic target for bone diseases, such as osteoporosis and RA.