Background:　Endoplasmic　reticulum　stress　(ERS)　and　mitochondrial　dysfunction　(MD)　involved　in　bone　metabolism　disorders.　However,　the　particular　mechanisms　of　ERS　and　MD　related　genes　(ERS&MDRGs)　in　osteoporosis　(OP)　have　not　been　elucidated.　In　present　study,　biomarkers　related　to　ERS　and　MD　in　OP　were　identified.　Methods:　Differentially　expressed　genes　(DEGs)　were　obtained　based　on　GEO　dataset.　ERS&MDRGs　were　derived　from　Genecard　database.　Initially,　ERS&MD　related　DEGs　(ERS&MDRDEGs)　were　obtained　by　overlapping　DEGs　and　ERS&MDRGs.　The　key　module　was　screened　by　WGCNA.　The　intersection　of　ERS&MDRDEGs　and　key　module　was　screened　by　machine　learning　to　obtain　key　genes.　Then,　receiver　operating　characteristic　curve　(ROC)　was　drawn　to　calculated　diagnostic　accuracy　of　key　genes.　The　ssGSEA　and　Cibersort　algorithms　were　performed　to　analyze　immune　cell　infiltration.　The　miRNA-mRNA-TF　network　were　draw　by　cytoscape　software.　Moleculaer　docking　and　DGIdb　database　were　employed　for　screening　potential　drugs.　Finally,　the　expression　of　key　genes　was　verified　by　qRT-PCR.　Results:　The　122　ERS&MDRDEGs　were　obtained　by　preliminary　screening.　ERS&MDRDEGs　were　mainly　enriched　in　lipid　metabolism,　calcium　ion　transport,　and　ossification.　The　5　key　genes　were　identified,　including　AAAS,　ESR1,　SLC12A2,　TAF15,　and　VAMP2.　Immune　infiltration　analysis　showed　monocyte　and　macrophage　were　different　between　OP　and　control　groups.　The　miRNA-mRNA-TF　regulatory　network　indicated　has-miR-625-5p,　has-miR-296-3p,　CTCT　and　EP300　as　potential　regulatory　targets.　The　2　potential　small　molecule　drugs,　namely　bumetanide　and　elacestrant　were　screened.　The　expression　of　AAAS,　ESR1,　VAMP2　were　higher,　and　SLC12A2　and　TAF15　were　lower　in　OP　than　control　group.　Conclusion:　This　research　identified　5　key　genes　AAAS,　ESR1,　SLC12A2,　TAF15　and　VAMP2.　Bumetanide　and　elacestrant　were　potential　drugs.　These　findings　provided　valuable　insights　into　the　pathophysiology　of　OP　and　the　development　of　new　therapeutic　strategies.