Decreased circulating dopamine β-hydroxylase is associated with medication-related osteonecrosis of the jaw and implicates sympathetic dysregulation.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of antiresorptive therapy, yet no reliable circulating biomarker exists for risk stratification. Using an unbiased serum proteomics approach in a multicentre framework, we identified dopamine β-hydroxylase (DBH) as a differentially expressed protein with significantly lower levels in patients with MRONJ. This finding was validated in an independent clinical cohort and further supported in the UK Biobank population. Circulating DBH levels were positively associated with blood-pressure traits, consistent with its role as a surrogate marker of sympathetic nervous system activity, and suggesting that reduced DBH levels in MRONJ may reflect altered sympathetic regulation. In a mouse model, pharmacological sympathetic inhibition with propranolol exacerbated jaw osteonecrosis and further suppressed osteoclast activity in the presence of zoledronic acid. Osteoblast-osteoclast co-culture experiments demonstrated additive inhibitory effects on osteoclast differentiation under β-adrenergic blockade. Together, these findings support an association between reduced circulating DBH levels and MRONJ and suggest that sympathetic dysregulation may contribute to disease pathogenesis. Circulating DBH may serve as a candidate biomarker for risk assessment and disease monitoring in patients receiving antiresorptive therapy.