Fig 1.
Open boxes represent datasets. In the screening cohort, nine patients with MRONJ stage ≥1 and nine patients before treatment with BMAs were compared by metabolomic analysis. In the validation cohort, eight patients with MRONJ stage ≥1 and nine patients without MRONJ after treatment with BMAs were compared in order to confirm the validity of findings in the screening cohort in a more clinically relevant setting.
Fig 2.
Patients provided a saliva sample following overnight fasting (~0.5 mL; minimum: 0.1 mL), transferred the sample to a cold-storage bag, and transported to the hospital within 4 h of collection, where it was stored at −80°C until use.
Fig 3.
Heat map of salivary metabolomic profiles.
Nine saliva samples from patients before BMA and nine from patients with MRONJ were analyzed by CE-MS. Of the 232 metabolites analyzed, 118 were detected in ≥50% of samples and used for supervised cluster analysis to separate the two groups. Color codes: red, high; blue, low; and white, average.
Fig 4.
Candidate metabolites in the two cohorts.
Five metabolites, including histamine, 3-(4-hydroxyphenyl)propionate, malonate, carnosine, and hypotaurine, showed the highest concentrations in the MRONJ group in the (A) screening cohort. In the (B) validation cohort, hypotaurine [MRONJ(−) vs MRONJ(+), 9.4 ± 11.2 × 10−4 vs. 26.6 ± 14.2 × 10−4; p = 0.017] and malonate (8.9 ± 5.6 × 10−4 vs. 21.3 ± 45.8 × 10−4; p = 0.472) showed consistently higher concentrations in MRONJ patients, although only hypotaurine was significantly higher. *p < 0.05.
Table 1.
Patient characteristics.
Fig 5.
Relationships between hypotaurine concentration and MRONJ stage.
Hypotaurine concentrations were analyzed in specimens from the screening and validation patient cohorts. The graph shows data representing the mean ± SD. The open and filled bar graphs show MRONJ(−) and MORONJ(+), respectively. There was a significant difference in hypotaurine concentration between the control (n = 18) and stage 2 groups (n = 9) but not with the stage 1 group (n = 6) or stage 3 group (n = 2). *p < 0.05.