Bone Protective Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in an Animal Model

Severe weight loss is often associated with reduction of bone mineral density (BMD) and an imbalance between bone formation and reabsorption in obese people. As a consequence, there can be an increased risk of bone fractures with body weight loss. Several studies have proposed that the gut hormones, GIP and GLP-1, might be modulators of bone growth and remodeling. HM15211 is a novel long-acting GLP-1/GIP/Glucagon agonist that is being developed for the treatment of obesity. In this study, we investigated whether treatment with HM15211 prevents bone loss under a severe weight loss condition, and the underlying mechanism of action. First, the bone protective effect of HM15211 was evaluated using diet induced obesity ovariectomized osteoporosis rat model. After 4 weeks subcutaneous treatment of HM15211 (120 µg/kg/Q3D), lower levels of serum decarboxylated osteocalcin (42.2 ng/mL) and higher serum P1NP (procollagen type I pro-peptide, 53.2 ng/mL) were observed compared with those of vehicle- (156.4 ng/mL for osteocalcin, 28.6 ng/mL for PINP) and liraglutide-treated groups (94 µg/kg/BID, 120.6 ng/mL for osteocalcin, 29.4 ng/mL for PINP). Furthermore, HM15211 showed comparable BMD of femur bones and lumbar spine with vehicle group while weight loss was greater (-26.0% vs. vehicle) compared to liraglutide (-11.5% vs. vehicle). These results suggest that treatment with HM15211 effectively prevents bone loss even after potent body weight loss in high fat dieted ovariectomized obese rats. Second, to elucidate the underlying molecular mechanism, related marker gene expression was investigated using the SaOS2 cell, human osteogenic cell. In line with the bone protective effect in vivo , HM15211 led to significant increases in type 1 collagen-α1, -α2, and carboxylated osteocalcin expression, which were blunted by inhibition of GIPR-mediated signaling. In conclusion, these results suggest that HM15211 might provide potent weight loss without the otherwise inevitable bone loss. Disclosure S. Lee: Employee; Self; Hanmi Pharmaceutical. Y. Kim: None. J. Lee: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. Y. Kim: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. S. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical.