Introduction/background
Postoperative delirium (POD) is common after hip fracture surgery in older adults. We investigated whether osteoporosis is associated with POD and whether the bone-derived hormone undercarboxylated osteocalcin (ucOCN) protects hippocampal synapses after surgery.

Methods
We prospectively enrolled 186 adults aged 65 years or older undergoing hip fracture surgery and assessed delirium using the 3D-CAM. For the case-control analysis, 29 patients with POD were matched to 145 without POD by age, sex, and body mass index. Preoperative cerebrospinal fluid (CSF) ucOCN was measured by ELISA. We assessed behavior and hippocampal synaptic function after femoral fracture surgery in ovariectomized and osteocalcin-deficient (Bglap1-null) mice. To investigate the mechanism, we knocked down hippocampal GPR158 in mice and inhibited MEK in HT22 cells exposed to inflammatory conditioned medium.

Results
POD occurred in 29 of 186 patients (15.6%). Osteoporosis was associated with higher odds of POD (adjusted odds ratio 4.85, 95% CI 1.30–18.10). Median preoperative CSF ucOCN was lower in patients with POD (11.8 vs 14.0 ng/mL, P < 0.001). Preoperative plasma ucOCN did not differ significantly between groups. Preoperative intracerebroventricular ucOCN improved delirium-like behavior, preserved hippocampal synaptic structure, and restored long-term potentiation in both mouse models. Intraperitoneal ucOCN also improved behavioral and synaptic outcomes in Bglap1-null mice. Hippocampal GPR158 knockdown abolished the behavioral and synaptic benefits of intracerebroventricular ucOCN in Bglap1-null mice. In HT22 cells, ucOCN activated Raf/MEK/ERK signaling. MEK inhibition attenuated the ability of ucOCN to preserve brain-derived neurotrophic factor (BDNF) and synaptic protein levels.

Conclusion
Osteoporosis and lower preoperative CSF ucOCN were associated with POD after hip fracture surgery. The experimental findings implicate GPR158–Raf/MEK/ERK–BDNF signaling in hippocampal synaptic protection and support further investigation of ucOCN for POD prevention.