Corticosteroids, the only treatment with proven efficacy in Duchenne muscular dystrophy (DMD) are associated with severe side effects. Here, in a proof of concept study nano-sterically stabilized liposomes (NSSL), remote loaded with methylprednisolone (MPS), were selectively targeted to the diaphragm, the mdx affected muscle at the early stage of the disease. The bioactivity of NSSL-MPS was evidenced by significant decreased serum TGF-β level and reduced diaphragm macrophage infiltration similar to free-MPS. Free-MPS (5 mg/kg) and two doses of NSSL-MPS (2 and 5 mg/kg) were tested for long-term treatment (58 weeks). All MPS treated groups had significantly lower CPK levels compared with control mdx mice. 2 mg/kg NSSL-MPS treatment resulted in significantly improved fore-limb muscle strength compared to free-MPS and control mdx mice. 5 mg/kg NSSL-MPS significantly improved animal mobility compared to control mdx mice. Treatment with the free-MPS has a clear bone catabolic effect; decrease in trabecular bone-volume density (BV/TV), deterioration in the trabecular number (Tb.N), as well as a significant decrease in the trabecular connectivity density (Conn.D) of the tibia bone. These were mitigated by both NSSL-MPS doses. Treatment with both doses produced a significant increase in BV/TV values compared with the mdx free-MPS group. 2 mg/kg NSSL-MPS treatment resulted in significantly increased Tb.N and Conn.D compared to free-MPS mice, indicating increase in micro-architectural structure's strength. Treatment with both NSSL-MPS doses significantly increased Conn.D, Tb.N and decreased trabecular spacing in comparison with the control and the free-MPS group, but had no effect on the BV/TV of lumbar vertebra 3 (L3), indicating an increase in the micro-architectural structure's strength also in mdx L3 bone. The results of this study suggest that NSSL-MPS is superior to free-MPS in treatment efficacy and reduced osteoporosis in the mdx mouse model of DMD.