The study investigates the role of the serine synthesis pathway (SSP) in osteoclast differentiation and bone metabolism. Key findings include: 1. ** transient activation of SSP is essential for osteoclastogenesis**: Deletion of the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH) in osteoclast progenitors impairs their differentiation and increases bone mass. 2. **Pharmacological inhibition of SSP blocks bone loss**: In a mouse model of postmenopausal osteoporosis, inhibiting PHGDH abrogates bone loss by blocking bone resorption. 3. **Mechanism of action**: SSP-derived α-ketoglutarate (αKG) is necessary for histone demethylases to remove repressive histone methylation marks at the *Nfatc1* gene locus, thereby inducing *Nfatc1* expression and osteoclast maturation. 4. **Transcriptomic and proteomic analysis**: The SSP is transiently upregulated during early osteoclast differentiation, and its activation precedes the peak in *Nfatc1* expression. 5. **Clinical implications**: Pharmacological inhibition of PHGDH completely prevents estrogen deficiency-induced bone loss without affecting osteoblast parameters, suggesting that the SSP is a promising therapeutic target for osteoporosis. Overall, the study reveals a metabolic-epigenetic coupling mechanism that drives osteoclast differentiation and highlights the potential of targeting the SSP to prevent osteoporotic bone loss.The study investigates the role of the serine synthesis pathway (SSP) in osteoclast differentiation and bone metabolism. Key findings include: 1. ** transient activation of SSP is essential for osteoclastogenesis**: Deletion of the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH) in osteoclast progenitors impairs their differentiation and increases bone mass. 2. **Pharmacological inhibition of SSP blocks bone loss**: In a mouse model of postmenopausal osteoporosis, inhibiting PHGDH abrogates bone loss by blocking bone resorption. 3. **Mechanism of action**: SSP-derived α-ketoglutarate (αKG) is necessary for histone demethylases to remove repressive histone methylation marks at the *Nfatc1* gene locus, thereby inducing *Nfatc1* expression and osteoclast maturation. 4. **Transcriptomic and proteomic analysis**: The SSP is transiently upregulated during early osteoclast differentiation, and its activation precedes the peak in *Nfatc1* expression. 5. **Clinical implications**: Pharmacological inhibition of PHGDH completely prevents estrogen deficiency-induced bone loss without affecting osteoblast parameters, suggesting that the SSP is a promising therapeutic target for osteoporosis. Overall, the study reveals a metabolic-epigenetic coupling mechanism that drives osteoclast differentiation and highlights the potential of targeting the SSP to prevent osteoporotic bone loss.