One of the most feared complications of modern osteoporosis and cancer therapy may carry its warning signal in the bloodstream. Medication-related osteonecrosis of the jaw, or MRONJ, is a devastating condition in which sections of jawbone die and become exposed, sometimes for months, in patients taking powerful antiresorptive drugs such as bisphosphonates and denosumab. Now, a large multicentre study from South Korea, published in Experimental & Molecular Medicine, reports that patients who develop the condition have markedly lower circulating levels of dopamine β-hydroxylase, an enzyme long known as a chemical workhorse of the sympathetic nervous system. The finding, validated across independent patient cohorts and echoed in the vast UK Biobank, points to an unexpected culprit in the disease: dysregulation of the body’s fight-or-flight machinery.
The clinical stakes are considerable. MRONJ is defined clinically as exposed bone, or bone that can be probed through a fistula, in the maxillofacial region persisting for more than eight weeks in patients without prior radiation therapy or metastatic disease. Although incidence among osteoporosis patients on antiresorptives is typically below 0.2 percent, it rises to several percent or more among cancer patients receiving high-dose intravenous bisphosphonates. The consequences include chronic bone exposure, pain and impaired chewing, and the fear of the condition often forces clinicians to pause antiresorptive therapy around dental procedures, potentially undermining treatment of the underlying bone disease. Despite decades of investigation, no circulating biomarker has achieved reliable clinical adoption for identifying who is at risk.
Previous candidate markers have repeatedly disappointed. C-terminal telopeptide of type I collagen, tartrate-resistant acid phosphatase 5b, dickkopf-related protein 1, and the RANKL-to-osteoprotegerin ratio were all proposed over the years, but meta-analyses and guideline committees have largely rejected them, citing small, heterogeneous, single-centre studies and a hypothesis-driven focus on a narrow set of bone-turnover proteins. The Korean team, led by researchers at Seoul National University and Ewha Womans University, took a deliberately different route: an unbiased, high-resolution survey of the entire serum proteome, followed by validation in separate cohorts and population-scale data.
In the discovery phase, the researchers applied tandem mass tag-based quantitative proteomics to serum from 25 MRONJ patients and 16 medication-exposed controls, depleting the fourteen most abundant serum proteins to reveal the deeper proteome. The workflow quantified 1,481 proteins with high technical reproducibility, with median coefficients of variation between internal standard channels of roughly four percent. Among all of these, one protein stood out: dopamine β-hydroxylase, or DBH, was significantly less abundant in the MRONJ group, with an adjusted P value of 0.037 after Benjamini–Hochberg correction for multiple testing.
DBH is the enzyme that converts dopamine into norepinephrine inside sympathetic neurons and adrenal chromaffin cells, and it is co-released with norepinephrine during sympathetic activation. Because it circulates more stably than norepinephrine itself, it has long been proposed as a surrogate window onto sympathetic tone, though earlier small studies produced inconsistent results. To confirm the proteomic signal, the team measured DBH by enzyme-linked immunosorbent assay and found excellent agreement with the mass spectrometry data, with a Pearson correlation coefficient of 0.962. Median serum DBH in MRONJ patients was 915.1 picograms per millilitre, compared with 1,317 picograms per millilitre in controls, a difference that was highly statistically significant.
The association survived rigorous statistical scrutiny. In multivariable logistic regression adjusted for age and sex, each one-standard-deviation decrease in DBH was associated with nearly twelve-fold higher odds of MRONJ in the discovery cohort, with a receiver operating characteristic area under the curve of 0.848 and an optimal cut-off of 1,082 picograms per millilitre yielding 84 percent sensitivity and 81.3 percent specificity. Crucially, an independent validation cohort of 55 additional participants reproduced the direction of the effect, with lower DBH again significantly associated with MRONJ after adjustment. Sensitivity analyses excluding cancer patients, anti-angiogenic drug users, beta-blocker users, and users of any sympathetically active medication all preserved the association, arguing against confounding by concurrent drugs or comorbidities.
Population-scale data provided a third, independent line of evidence. Mining plasma proteomic measurements from 44,740 UK Biobank participants of white British ancestry, the researchers narrowed the analysis to 2,270 people with osteoporosis or bisphosphonate exposure, identifying 10 MRONJ cases and 2,224 controls. Using Firth’s penalized likelihood logistic regression to handle the rare outcome, they found that each standard-deviation decrease in plasma DBH was associated with 1.57-fold higher odds of MRONJ after adjusting for age, sex, body mass index, bisphosphonate use and genetic ancestry. The prevalence of MRONJ in this subset, 0.45 percent, matched expectations for antiresorptive-exposed populations, lending credibility to the case definitions.
To establish that circulating DBH genuinely tracks sympathetic activity, the team turned to blood pressure, a classic downstream readout of sympathetic tone. Across 34,948 UK Biobank participants, plasma DBH was positively associated with both systolic and diastolic blood pressure after adjustment for age, sex, body mass index, smoking, drinking and genetic principal components. Spline and quantile regression analyses showed the relationship strengthening at higher blood pressures, and participants in the top 30 percent of DBH levels had significantly elevated odds of hypertension. These data rehabilitate DBH as a population-level marker of sympathetic tone and suggest that the low DBH seen in MRONJ patients reflects genuinely altered sympathetic regulation rather than a mere biochemical curiosity.
The mechanistic twist came from the laboratory. In a mouse model in which repeated zoledronic acid administration combined with maxillary molar extraction reliably produces jawbone necrosis, the researchers added propranolol, a non-selective beta-adrenergic blocker, to pharmacologically suppress sympathetic signalling. Propranolol did not change bone structure beyond what zoledronic acid achieved, but it dramatically worsened the disease itself: histology revealed significantly larger necrotic bone areas in the combination group than with zoledronic acid alone. Tartrate-resistant acid phosphatase staining showed that propranolol further reduced the number of giant, dysfunctional osteoclasts that zoledronic acid induces, particularly at non-extraction sites, indicating an additive suppression of bone resorption on top of an already profound antiresorptive state.
Co-culture experiments fleshed out the cellular logic. When primary mouse osteoblasts were stimulated with the beta-adrenergic agonist isoproterenol, the ratio of RANKL to osteoprotegerin, the key osteoblast-derived signals that drive osteoclast differentiation, rose sharply, and propranolol abolished this effect. Zoledronic acid left the RANKL-to-osteoprotegerin ratio untouched, yet in functional osteoblast–osteoclast co-cultures the two drugs acted through distinct pathways to inhibit osteoclast formation additively. Since excessive suppression of bone resorption is widely regarded as the central mechanism of MRONJ, the authors propose that reduced sympathetic signalling, as reflected by low circulating DBH, may push osteoclast activity below the threshold needed for jawbone maintenance, particularly in the high-turnover alveolar bone of the jaw. The team is careful to note limitations: DBH was measured after disease onset, so prospective studies are needed to confirm predictive value, and the UK Biobank case definitions carry some classification uncertainty. Even so, the convergence of clinical proteomics, population genetics-scale validation and animal experimentation makes circulating DBH the most credible candidate biomarker for MRONJ risk stratification to date, and opens an entirely new chapter in the neuro-skeletal biology of the jaw.
Subject of Research: Circulating dopamine β-hydroxylase as a biomarker and sympathetic dysregulation mechanism in medication-related osteonecrosis of the jaw
Article Title: Decreased circulating dopamine β-hydroxylase is associated with medication-related osteonecrosis of the jaw and implicates sympathetic dysregulation
Article References: Decreased circulating dopamine β-hydroxylase is associated with medication-related osteonecrosis of the jaw and implicates sympathetic dysregulation. (n.d.). https://doi.org/10.1038/s12276-026-01868-z
Image Credits: AI Generated
DOI: 10.1038/s12276-026-01868-z
Keywords: medication-related osteonecrosis of the jaw, dopamine beta-hydroxylase, sympathetic nervous system, bisphosphonates, antiresorptive therapy, serum proteomics, UK Biobank, osteoclasts, biomarker, propranolol, bone remodeling, norepinephrine
News Source: Nathaniel Bowman. (October 14, 2026). Blood enzyme linked to jawbone destruction reveals surprise role for stress hormones in bone disease. Scienmag.
