The Bisphosphonate Accumulation Index (BAI): A Quantitative Metric for Cumulative Antiresorptive Exposure in...

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication of bisphosphonate therapy, whose risk is currently assessed through qualitative staging systems that do not integrate pharmacological determinants of cumulative drug exposure. The aim of this study is to present the Bisphosphonate Accumulation Index (BAI), a pharmacologically derived, dimensionless scalar quantifying cumulative exposure to bone-targeted antiresorptive agents by integrating relative potency, administered dose, dosing frequency, route-specific bioavailability, and treatment duration, for use as a pre-procedural assessment tool in patients receiving bisphosphonates. Methods: The BAI combines five pharmacologically grounded parameters from peer-reviewed literature: (1) relative antiresorptive potency referenced to etidronate; (2) dose per administration (mg); (3) monthly dosing frequency; (4) bioavailability route; and (5) years of treatment within the preceding 10-year window. The model includes nine bisphosphonates registered in Italy. Results: The BAI spans approximately five orders of magnitude (from <1000 for short-term oral therapy to >120,000 for monthly intravenous zoledronic acid). Four analyses support the model: sensitivity analysis identifies relative potency as the main source of variance; ecological calibration against nine MRONJ incidence data points yielded r = 0.911 (p = 0.0006, R² = 0.829), indicating that the BAI accounts for approximately 83% of the population-level variance in published incidence rates across heterogeneous regimens (ecological correlation; this does not establish individual-level predictive validity); Monte Carlo simulation on 10,000 patients generated a plausible exposure-strata distribution (6.1% low, 66.6% moderate, 27.3% high); and concordance analysis with a DDD-based metric showed discordance in 7/8 regimens. Conclusions: The BAI is a transparent, reproducible, pharmacologically grounded metric of cumulative antiresorptive exposure addressing the quantitative gap identified in the AAOMS 2022 Position Paper. The BAI measures pharmacological exposure, which is a necessary but insufficient component of MRONJ risk; clinical modifiers such as corticosteroid co-administration, diabetes, renal function, and procedure type are not integrated and must be evaluated independently. The provisional exposure strata reported here (<1000, 1000-10,000, >10,000) are hypothesis-generating and intended solely to guide the design of validation studies; they should not be used as clinical decision rules until prospective patient-level validation has been completed.