GL-0001, a first-in-class dual GIP/GLP-2 analogue, reduces bone fragility by enhancing bone material properties in a murine model of type III osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a severe heritable skeletal disorder characterized by bone fragility, short stature, and increased fracture risk. Currently, no pharmacological treatment has been approved for OI, and bisphosphonates are commonly used off label. While bisphosphonates increase bone mass, their effects on bone quality and fracture reduction remain limited. GL-0001, a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-2 (GLP-2) compound that targets bone material properties, may offer alternative skeletal benefits. We evaluated the effects of 9 weeks of GL-0001 treatment in the oim/oim murine model of severe OI, a well-established model carrying a homozygous Col1a2 mutation resulting in abnormal type I collagen formation and compared outcomes with zoledronic acid (100 g/kg) or saline. Analyses included longitudinal growth, fracture incidence, bone biomechanics, microarchitecture, turnover markers, and bone material properties. OI mice exhibited reduced body weight, impaired femoral growth, severe trabecular and cortical deficits, altered bone turnover, and compromised biomechanical properties compared with WT controls. GL-0001 increased femur length by 5% (p=0.015) and reduced spontaneous fracture incidence by 90% (p=0.004), whereas zoledronic acid had no significant effect on fracture burden. Bone microarchitecture was not significantly altered by GL-0001, whereas zoledronic acid improved trabecular and cortical parameters. At the tissue level, GL-0001 improved bone strength, increasing ultimate stress (+26%, p=0.022) and yield stress (+30%, p=0.014), and reducing brittleness (-32%, p=0.002). These changes were associated with increased collagen maturity (+12%, p<0.001). In contrast, zoledronic acid had limited effects on bone material properties. These findings demonstrate that GL-0001 improves skeletal fragility in the oim/oim murine model of severe OI through mechanisms primarily involving enhancement of bone material properties and longitudinal growth, rather than changes in bone mass or microarchitecture. GL-0001 may therefore represent a novel therapeutic strategy targeting bone quality in OI.