This approach was constructed to appraise the therapeutic effectiveness of a single i.v. dose of osteoblasts generated from co-culturing BM-MSCs with nano-HA, Pt-NPs, or Pt-HA-nanocomposite in osteoporotic rats. MSCs were grown, propagated in culture, and characterized. The effect of the suggested nanoplatforms on the survival, osteogenic differentiation, and mineralization of BM-MSCs was assessed by MTT assay, real-time PCR analysis, and Alizarin red S staining, respectively. Thereafter, the generated osteoblasts were employed for the treatment of ovariectomized rats. Our results revealed that the selected nanoplatforms upregulate the expression of osteogenic differentiation related genes (Runx-2 and BMP-2) significantly and enhance calcium deposition in BM-MSCs after 7 and 21 days, respectively, whereas the in vivo study validated that the infusion of the generated osteoblasts considerably downturn serum BALP, BSP, and SOST levels; upswing OSX level; and regain femur bone mineralization and histoarchitecture. Conclusively, the outcomes of this work provide scientific evidence that transplanting osteoblasts derived from differentiation of BM-MSCs in the presence of nanoplatforms in ovariectomized rats restores bone remodeling balance which constitutes a new hope for the treatment of osteoporosis.