Association between oral frailty and cystatin C-related indices—A questionnaire (OFI-8) study in general internal medicine practice

**Background:** Oral frailty is an age-related decline in oral function linked to systemic frailty, sarcopenia, and adverse outcomes including mortality and disability. Cystatin C-related indices—specifically the creatinine-to-cystatin C ratio (Cr/CysC) and the ratio of eGFRcys to eGFRcre (eGFRcys/eGFRcre)—have been shown to reflect muscle mass and strength and may serve as blood-based markers of sarcopenia. The Oral Frailty Index-8 (OFI-8) is an 8-item questionnaire designed for easy screening of oral frailty risk without specialized dental equipment. This study aimed to determine whether cystatin C-related indices differ between patients at low-to-moderate versus high risk of oral frailty in a general internal medicine outpatient setting.

**Methods:** This cross-sectional study enrolled 251 patients (128 men, mean age 77.1±7.3 years; 123 women, mean age 78.4±5.7 years) attending outpatient clinics at Osaka Dental University Hospital and the National Cerebral and Cardiovascular Center between April and December 2022. All participants completed the OFI-8 questionnaire, underwent blood tests (including creatinine and cystatin C), physical measurements (height, weight), and grip strength testing. Participants were divided by sex into low-to-moderate risk (OFI-8 ≤3) and high-risk (OFI-8 ≥4) groups. eGFRcre and eGFRcys were calculated using Japanese Society of Nephrology equations. Intergroup comparisons used Student's t-test and Fisher's exact test; ROC analysis assessed diagnostic efficacy of Cr/CysC and eGFRcys/eGFRcre for OFI-8 ≥4.

**Key Results:** The mean OFI-8 score was significantly higher in women than men (3.8±2.0 vs. 2.8±2.0, p<0.001), with 48.8% of women and 28.9% of men classified as high risk (OFI-8 ≥4). In men, the high-risk group showed significantly lower height (162.5±7.3 vs. 165.8±6.9 cm, p=0.018), grip strength (27.0±8.5 vs. 30.7±7.6 kg, p=0.018), Cr/CysC (0.81±0.15 vs. 0.87±0.15, p=0.042), eGFRcys/eGFRcre (0.95±0.20 vs. 1.04±0.21, p=0.031), red blood cell count (418±53 vs. 443×10⁴/μL, p=0.015), hemoglobin (13.4±1.4 vs. 13.9±1.3 g/dL, p=0.036), and albumin (4.0±0.3 vs. 4.2±0.3 g/dL, p<0.001). In women, the high-risk group had significantly lower grip strength (15.3±4.2 vs. 17.7±4.5 kg, p=0.002), Cr/CysC (0.65±0.13 vs. 0.70±0.13, p=0.022), and eGFRcys/eGFRcre (0.93±0.21 vs. 1.03±0.22, p=0.012). ROC analysis confirmed that both Cr/CysC and eGFRcys/eGFRcre were significantly associated with OFI-8 ≥4 in both sexes.

**Clinical Implications:** Cystatin C-related indices, which are routinely available from blood tests in medical practice, are significantly lower in patients at high risk for oral frailty. These indices may serve as practical screening tools to identify patients who could benefit from dental referral and oral function evaluation. The association between low Cr/CysC/eGFRcys/eGFRcre and high OFI-8 scores supports the concept that oral frailty and systemic sarcopenia are interconnected. The findings also suggest that anemia (in men) and hypoalbuminemia (in men) may accompany high-risk oral frailty, indicating potential underlying nutritional deficiencies or systemic disease. The study promotes a bidirectional medical-dental collaboration model: low cystatin C-related indices should prompt OFI-8 screening, and high OFI-8 scores should prompt precise dental evaluation. Limitations include the cross-sectional design (precluding causal inference), lack of objective oral function assessment using the seven-item dental standard, potential OFI-8 item limitations, and a small sample from only two institutions.