Due to aging of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone extracellular matrix (ECM) material properties, i.e., the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, that activates simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cyclic adenosine monophosphate-lysyl oxidase pathway to enhance collagen maturity. Furthermore, bilateral ovariectomy was performed in 32 BALB/c mice at 12 weeks of age prior to random allocation to either saline, dual GIP/GLP-2 analogues (GL-0001 or GL-0007) or zoledronic acid groups (n = 8/group). Treatment with dual GIP/GLP-2 analogues was initiated 4 weeks later for 8 weeks. At the organ level, GL-0001 modified biomechanical parameters by increasing ultimate load, postyield displacement, and energy-to-fracture of cortical bone. GL-0001 also prevented excess trabecular bone degradation at the appendicular skeleton and enhanced bone ECM material properties in cortical bone through a reduction of the mineral-to-matrix ratio and augmentation in enzymatic collagen cross-linking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering from bone fragility.