Hutchinson-Gilford Progeria Syndrome (HGPS) is a uniformly fatal condition that is especially prevalent in skin, cardiovascular and the musculoskeletal systems (1, 2). A wide gap exists between our knowledge of the disease and a promising treatment or cure. The aim of this study was to first characterize the musculoskeletal phenotype of the homozygous G608G BAC-transgenic progeria mouse model, and to determine the phenotype changes of HGPS mice after a five-arm preclinical trial of different treatment combinations with lonafarnib, pravastatin, and zoledronic acid. Micro computed tomography (µCT) and CT based rigidity analysis (CTRA) were performed to assess cortical and trabecular bone structure, density, and rigidity. Bones were loaded to failure with three-point bending to assess mechanical properties. Contrast-enhanced µCT (CECT) imaging of mouse femurs was performed to measure glycosaminoglycan (GAG) content, thickness, and volume of the femoral head articular cartilage. Advanced glycation end products (AGEs) were assessed with a fluorometric assay. The changes demonstrated in the cortical bone structure, rigidity, stiffness and flexural modulus of the HGPS G608G mouse model may increase the risk for bending and deformation of bones, which could result in the skeletal dysplasia characteristic of HGPS. Cartilage abnormalities seen in this HGPS model resemble the changes observed in the age-matched wild type controls, including early loss of GAGs, decreased cartilage thickness and volume. Such changes might mimic prevalent degenerative joint diseases in the elderly population. Lonafarnib monotherapy did not improve bone or cartilage parameters; but treatment combinations with pravastatin and zoledronic acid significantly improved bone structure and mechanical properties and cartilage structural parameters, which aid to ameliorate the musculoskeletal phenotype of the disease.