Linking bone and brain: Dysregulated bone metabolism exacerbates cognitive impairment in bipolar disorder

Based on the "bone-brain axis" hypothesis, this study explored the associations between bone metabolism, bone mineral density (BMD), and cognitive performance in drug-naive patients with bipolar disorder (BD), and explored whether these measures differentiate BD patients from healthy controls (HCs).

A total of 202 drug-naïve BD patients and 161 HCs were enrolled. BMD at the lumbar spine and hip was measured via dual-energy X-ray absorptiometry (DEXA). Serum bone turnover markers (osteocalcin [OC], procollagen type I N-terminal propeptide [PINP], C-terminal telopeptide of type I collagen [CTX-I]) and vitamin D were assessed. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Stroop Color-Word Test. Group comparisons, correlation analyses, binary logistic regression, and elastic net-based classification modeling with cross-validation and SHAP analysis were conducted.

Compared with HCs, BD patients had higher PINP/OC, lower vitamin D and multi-regional BMD, and poorer cognition (especially in attention, memory, and executive function). CTX-I was negatively correlated with cognitive scores, while BMD was positively associated with language functions. In the case-control framework, age (OR = 1.624) and PINP (OR = 1.029) were among the variables significantly associated with differences between BD patients and HCs, whereas CTX-I (OR = 0.153) and semantic fluency showed associations in the opposite direction. The model yielded an AUC of 0.882, with cognitive measures showing the strongest associations with group differences, alongside age and bone metabolism markers.

Drug-naïve BD patients exhibit abnormal bone metabolism and multidimensional cognitive deficits, supporting the potential role of the bone-brain axis in BD-related cognitive impairment.