BONE ANABOLIC EFFECTS OF A NOVEL ORALLY-AVAILABLE SMALL MOLECULE SIK2/SIK3 INHIBITOR
Authors: Cheng-Chia Tang et al.
The purpose of this study was to test a novel, orally-available SIK2/SIK3 inhibitor in preclinical osteoporosis animal models.
A SIK2/SIK3 inhibitor was tested in two models of post-menopausal bone loss in oophorectomized (OVX) mice and rats. Direct comparison was made to treatment with intermittent PTH. OVX mice and rats were treated for 6, resp. 8 weeks with three different doses of the study compound and PTH. Fasting serum was collected at 1, 4, and 8 weeks. Femur and L4 vertebral bodies were collected for µCT, histomorphometry and biomechanical testing.
In the OVX mice SIK2/SIK3i led to dose-dependent increases in the bone formation marker P1NP, increased L5 bone mass and femur cortical thickness (p=0.038) by µCT. Histomorphometry showed that SIK2/SIK3i increased mineralizing surface and bone formation rate.
SIK2/SIK3i increased bone formation rate in a dose-dependent manner to a degree similar to that of PTH.
Orally-available bone anabolic agents represent a major unmet medical need for patients with osteoporosis. Widespread use of parathyroid hormone (PTH)-based osteo-anabolic therapies is limited by the need for daily injections. In this experimental study an oral SIK2/SIK3 inhibitor increased trabecular bone formation and bone mass in OVX mice and rats. Orally-available small molecule SIK2/SIK3 inhibitors may represent a promising new treatment strategy for post-menopausal osteoporosis.