This study investigates the transcriptional reprogramming during human osteoclast differentiation to identify regulators of osteoclast activity. RNA sequencing of osteoclasts differentiated from CD14+ monocytes from eight female donors revealed 8,980 differentially expressed genes grouped into eight temporal patterns. These patterns were associated with distinct molecular functions and postmenopausal osteoporosis susceptibility genes. Network analyses identified mutual dependencies between temporal expression patterns and provided insights into subtype-specific transcriptional networks. Key findings include the identification of filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1) as potential molecular markers of osteoclast activity, and the discovery of G-protein coupled receptors (GPCRs) such as complement 5A receptor 1 (CSART), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFARA/GPR120) as novel molecular targets for modulating osteoclast differentiation and activity. In vitro pharmacological modulation of these receptors demonstrated that activating CSART enhanced osteoclast formation, activating SSTR2 decreased resorptive activity, and activating FFARA reduced both the number and resorptive activity of mature osteoclasts. These results provide a genetic overview of transcriptional reprogramming during human osteoclast differentiation and highlight potential therapeutic targets for osteoporosis.This study investigates the transcriptional reprogramming during human osteoclast differentiation to identify regulators of osteoclast activity. RNA sequencing of osteoclasts differentiated from CD14+ monocytes from eight female donors revealed 8,980 differentially expressed genes grouped into eight temporal patterns. These patterns were associated with distinct molecular functions and postmenopausal osteoporosis susceptibility genes. Network analyses identified mutual dependencies between temporal expression patterns and provided insights into subtype-specific transcriptional networks. Key findings include the identification of filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1) as potential molecular markers of osteoclast activity, and the discovery of G-protein coupled receptors (GPCRs) such as complement 5A receptor 1 (CSART), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFARA/GPR120) as novel molecular targets for modulating osteoclast differentiation and activity. In vitro pharmacological modulation of these receptors demonstrated that activating CSART enhanced osteoclast formation, activating SSTR2 decreased resorptive activity, and activating FFARA reduced both the number and resorptive activity of mature osteoclasts. These results provide a genetic overview of transcriptional reprogramming during human osteoclast differentiation and highlight potential therapeutic targets for osteoporosis.