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Aims: This study aims at formulating combined delivery of Risedronate sodium (RIS) and Vitamin D3 (VITD3) for augmented therapeutic outcome against osteoporosis (OP) using deep lung targeted PAMAM-G5-NH 2 dendrimers to minimize RIS gastrointestinal side effects and enhance both drugs bioavailability through absorption from the alveoli directly to the blood., Methods: RIS-PAMAM-G5-NH 2 , VITD3-PAMAM-G5-NH 2 , and RIS/VITD3-PAMAM-G5-NH 2 were prepared and evaluated in vitro for particle size (PS), zeta potential (ZP), %loading efficiency (%LE), morphology and FTIR. The efficacy of the RIS/VITD3-PAMAM-G5-NH 2 compared to oral RIS was evaluated in OP-induced rats by comparing serum calcium, phosphorus, and computed bone mineral density (BMD) pre- and post-treatment. Additionally, a comprehensive metabolomics and molecular pathways approach was applied to find serum potential biomarkers for diagnosis and to evaluate the efficacy of inhaled RIS/VITD3-PAMAM-G5-NH 2 ., Key Findings: RIS/VITD3-PAMAM-G5-NH 2 was successfully prepared with a %LE of 92.4 ± 6.7 % (RIS) and 83.2 ± 4.4 % (VIT-D3) and a PS of 252.8 ± 34.1 adequate deep lung delivery. RIS/VITD3-PAMAM-G5-NH 2 inhalation therapy was able to restore serum calcium, phosphorus, and BMD close to normal levels after 21 days of treatment in OP-induced rats. The WNT-signalling pathway and changes in the metabolite levels recovered to approximately normal levels upon treatment. Moreover, histone acetylation of the WNT-1 gene and miR-148a-3p interference proved to play a role in the regulation of the WNT-signalling pathway during OP progression and treatment., Significance: Pulmonary delivery of RIS/VITD3-PAMAM-G5-NH 2 offers superior treatment for OP treatment compared to the oral route. Molecular and Metabolic pathways represents key indicators for OP diagnosis and progression., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)