PRE-EXTRACTION INTERRUPTION OF BONE-TARGETING AGENTS AND OSTEONECROSIS OF THE JAW IN CANCER PATIENTS WITH BONE METASTASES: A TARGET TRIAL EMULATION WITH DATA-DRIVEN HETEROGENEITY ANALYSIS
Author(s)
Hsiao Ling Chen, Ph.D.1, Chun-Wei Hsu, PhD2, Chen-Han Chueh, PhD3, Wei-ming Huang, PharmD, MD4, Ming-Yu Hong, MS.5, Wen-Liang Lo, PhD6, Chi-Chuan Wang, PhD7, Yu-Wen Wen, PhD8, Ling Chen, PhD9, Yi-Wen Tsai, PhD10.
1Institute of Health and Welfare Policy, National Yang Ming Chiao Tung University, Taipei, Taiwan, 2Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei, Taiwan, 3University of California San Diego, San Diego, CA, USA, 4Institute of Health and Welfare Policy, Taipei, Taiwan, 5Institute of Health and Welfare Policy, National Yang Ming Chiao Tung University, Taiwan, New Taipei City, Taiwan, 6Taipei Veterans General Hospital, Taipei, Taiwan, 7School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan, 8Chang Gung University, Tao-Yuan, Taiwan, 9Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, Taiwan, Taipei, Taiwan, 10National Yang Ming Chiao Tung University, Taipei, Taiwan.
1Institute of Health and Welfare Policy, National Yang Ming Chiao Tung University, Taipei, Taiwan, 2Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei, Taiwan, 3University of California San Diego, San Diego, CA, USA, 4Institute of Health and Welfare Policy, Taipei, Taiwan, 5Institute of Health and Welfare Policy, National Yang Ming Chiao Tung University, Taiwan, New Taipei City, Taiwan, 6Taipei Veterans General Hospital, Taipei, Taiwan, 7School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan, 8Chang Gung University, Tao-Yuan, Taiwan, 9Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, Taiwan, Taipei, Taiwan, 10National Yang Ming Chiao Tung University, Taipei, Taiwan.
OBJECTIVES: Bone-targeting agents (BTAs) are widely used to prevent skeletal-related events in patients with bone metastases but may increase the risk of osteonecrosis of the jaw (ONJ), particularly after tooth extraction. Whether temporary pre-extraction BTA interruption reduces ONJ risk remains uncertain. We evaluated the association between pre-extraction BTA interruption and ONJ risk and explored treatment-response heterogeneity across patient subgroups.
METHODS: Using Taiwan’s National Health Insurance Research Database, we emulated a target trial among patients with bone metastases receiving BTAs who underwent tooth extraction. Temporary interruption was defined as an off-treatment interval exceeding 30 days between the last BTA exposure and tooth extraction. Population-average effects were estimated using doubly robust augmented inverse probability weighting (AIPW), incorporating machine-learning-based propensity score and outcome models. Treatment-response heterogeneity was assessed using permutation-based tests to screen potential effect modifiers and group average treatment effect (GATE) analyses to summarize subgroup variation in estimated interruption effects.
RESULTS: The analytic cohort included 5,427 patients, of whom 2,379 had pre-extraction BTA interruption and 3,048 did not. Temporary interruption was not associated with a statistically significant population-level reduction in ONJ risk (AIPW risk difference, −0.00254; 95% CI, −0.00717 to 0.00209). Longer off-treatment intervals showed consistently more favorable but non-significant estimates, suggesting a possible duration-response pattern. Heterogeneity analyses identified stronger protective patterns among patients with 1-3 years of prior BTA exposure, bisphosphonate use, sequential bisphosphonate-to-denosumab use, and diabetes. Less favorable patterns were observed among patients with exposure exceeding 3 years, denosumab use, anemia, and proton pump inhibitor use.
CONCLUSIONS: Pre-extraction BTA interruption was not associated with a significant population-average reduction in ONJ risk. However, heterogeneous estimated effects suggest that peri-dental BTA management may be individualized according to cumulative BTA exposure, BTA type, and healing-related vulnerability.
METHODS: Using Taiwan’s National Health Insurance Research Database, we emulated a target trial among patients with bone metastases receiving BTAs who underwent tooth extraction. Temporary interruption was defined as an off-treatment interval exceeding 30 days between the last BTA exposure and tooth extraction. Population-average effects were estimated using doubly robust augmented inverse probability weighting (AIPW), incorporating machine-learning-based propensity score and outcome models. Treatment-response heterogeneity was assessed using permutation-based tests to screen potential effect modifiers and group average treatment effect (GATE) analyses to summarize subgroup variation in estimated interruption effects.
RESULTS: The analytic cohort included 5,427 patients, of whom 2,379 had pre-extraction BTA interruption and 3,048 did not. Temporary interruption was not associated with a statistically significant population-level reduction in ONJ risk (AIPW risk difference, −0.00254; 95% CI, −0.00717 to 0.00209). Longer off-treatment intervals showed consistently more favorable but non-significant estimates, suggesting a possible duration-response pattern. Heterogeneity analyses identified stronger protective patterns among patients with 1-3 years of prior BTA exposure, bisphosphonate use, sequential bisphosphonate-to-denosumab use, and diabetes. Less favorable patterns were observed among patients with exposure exceeding 3 years, denosumab use, anemia, and proton pump inhibitor use.
CONCLUSIONS: Pre-extraction BTA interruption was not associated with a significant population-average reduction in ONJ risk. However, heterogeneous estimated effects suggest that peri-dental BTA management may be individualized according to cumulative BTA exposure, BTA type, and healing-related vulnerability.
Conference/Value in Health Info
2026-09, ISPOR Asia Pacific 2026, Bangkok, Thailand
Value in Health, Volume 55, Issue S1
Code
EPH19
Topic
Epidemiology & Public Health
Topic Subcategory
Safety & Pharmacoepidemiology
Disease
SDC: Oncology