This study identifies transcriptional reprogramming during human osteoclast differentiation and highlights regulators of osteoclast activity. Osteoclasts are key cells in bone remodeling, and their overactivity contributes to osteoporosis. The research used RNA sequencing to analyze gene expression changes in CD14-negative monocytes from eight female donors as they differentiated into osteoclasts. The results revealed 8,980 differentially expressed genes grouped into eight temporal expression patterns, which were associated with postmenopausal osteoporosis susceptibility genes. Network analysis showed mutual dependencies between these patterns and provided insights into subtype-specific transcriptional networks. The study identified genes such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1) as predictive of mature osteoclast resorption activity. G-protein coupled receptors (GPCRs) were found to be strongly expressed during osteoclast differentiation and were linked to bone mineral density SNPs, suggesting their role in osteoclast activity. The study tested the effects of three GPCRs—C5AR1, SSTR2, and FFAR4—on osteoclast differentiation and activity. Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 and FFAR4 decreased resorptive activity. The findings suggest that SSTR2 and FFAR4 are antiresorptive GPCRs, and FLNB and LOX-1 are potential molecular markers of osteoclast activity. These results provide insights into the molecular regulators of osteoclast differentiation and activity, offering potential targets for new antiosteoporotic therapies. The study also highlights the importance of transcriptional reprogramming during osteoclast differentiation and its implications for bone development, fracture repair, and the genetics of osteoporosis.This study identifies transcriptional reprogramming during human osteoclast differentiation and highlights regulators of osteoclast activity. Osteoclasts are key cells in bone remodeling, and their overactivity contributes to osteoporosis. The research used RNA sequencing to analyze gene expression changes in CD14-negative monocytes from eight female donors as they differentiated into osteoclasts. The results revealed 8,980 differentially expressed genes grouped into eight temporal expression patterns, which were associated with postmenopausal osteoporosis susceptibility genes. Network analysis showed mutual dependencies between these patterns and provided insights into subtype-specific transcriptional networks. The study identified genes such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1) as predictive of mature osteoclast resorption activity. G-protein coupled receptors (GPCRs) were found to be strongly expressed during osteoclast differentiation and were linked to bone mineral density SNPs, suggesting their role in osteoclast activity. The study tested the effects of three GPCRs—C5AR1, SSTR2, and FFAR4—on osteoclast differentiation and activity. Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 and FFAR4 decreased resorptive activity. The findings suggest that SSTR2 and FFAR4 are antiresorptive GPCRs, and FLNB and LOX-1 are potential molecular markers of osteoclast activity. These results provide insights into the molecular regulators of osteoclast differentiation and activity, offering potential targets for new antiosteoporotic therapies. The study also highlights the importance of transcriptional reprogramming during osteoclast differentiation and its implications for bone development, fracture repair, and the genetics of osteoporosis.