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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

Glucocorticoid-centered drug spectrum of non-jaw osteonecrosis, a FAERS pharmacovigilance study with independent validation in Canada Vigilance and JADER

  • Lisheng Qi1
  • Yu Qiu2
  • Xiaobin Wang1
  • Tao Zhang3
  • Huacai Jiang1
  1. 1Department of Spine Surgery, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University
  2. 2Department of Joint Orthopedics, The First People’s Hospital of Yibin
  3. 3Department of Joint Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University
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Abstract

Objective: To distinguish jaw misclassification and litigation-related reporting from non-jaw osteonecrosis signals and define their reproducible spectrum.

Methods: We analyzed 20,690,895 deduplicated Food and Drug Administration Adverse Event Reporting System (FAERS) reports (2004Q1–2026Q2), using report-level adjudication and four disproportionality criteria. A descriptive jaw-propensity index (JPI) measured the share of each drug’s osteonecrosis reports coded as “jaw.” Reporter restrictions and comparisons with Canada Vigilance and the Japanese Adverse Drug Event Report (JADER) database examined reporting bias. These external databases recorded less solicitation. Additional analyses included glucocorticoid stratification, empirical null calibration with unmasking, indication restriction of every surviving non-glucocorticoid drug, time-to-onset modeling, and machine learning. Estimates are reported with 95% confidence intervals.

Results: Of 47 signals, 27 passed jaw exclusion (JPI < 0.50) and reporter restriction; the final core was unchanged across thresholds of 0.30–0.70. Tenofovir disoproxil’s reporting odds ratio (ROR) fell from 157.9 (153.4–162.6) to 6.33 (5.38–7.45) among health professionals; 84.5% of cases were lawyer-sourced. Canada Vigilance (6.24, 2.00–19.4) and JADER (10.5, 6.60–16.8) were consistent with a litigation-inflated FAERS estimate. Glucocorticoids were replicated in both databases (class RORs 10.3, 54.4). Drug JPI rankings were concordant (r = 0.985, 0.960). All 34 negative controls had ROR < 1 (median 0.16); unmasking rescaled other estimates approximately 2.35-fold. Within-indication analyses detected no residual excess for mycophenolate (0.89) or voxelotor (0.97). Asparaginase combined a within-leukemia residual signal (7.14, 5.10–10.0) with mechanistic evidence and JADER replication (75.7).

Conclusion: The reproducible spectrum is glucocorticoid-centered, with the asparaginase class the best-supported residual and three drugs unresolved. Jaw misclassification, reporting context, and indication explain much of the apparent spectrum. Spontaneous reports cannot establish causation; these adjudications require cohort confirmation. The JPI and cross-jurisdiction comparisons may inform analyses of other misclassification-prone endpoints.

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Cite

BibTeXRIS
BibTeX
@article{qi2026glucocorticoidcentered,
  title = {{Glucocorticoid-centered drug spectrum of non-jaw osteonecrosis, a FAERS pharmacovigilance study with independent validation in Canada Vigilance and JADER}},
  author = {Lisheng Qi and Yu Qiu and Xiaobin Wang and Tao Zhang and Huacai Jiang},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1977191},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1977191/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Glucocorticoid-centered drug spectrum of non-jaw osteonecrosis, a FAERS pharmacovigilance study with independent validation in Canada Vigilance and JADER
AU  - Lisheng Qi
AU  - Yu Qiu
AU  - Xiaobin Wang
AU  - Tao Zhang
AU  - Huacai Jiang
PY  - 2026
DA  - 2026/10/21
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1977191
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1977191/full
AB  - Objective: To distinguish jaw misclassification and litigation-related reporting from non-jaw osteonecrosis signals and define their reproducible spectrum.  Methods: We analyzed 20,690,895 deduplicated Food and Drug Administration Adverse Event Reporting System (FAERS) reports (2004Q1–2026Q2), using report-level adjudication and four disproportionality criteria. A descriptive jaw-propensity index (JPI) measured the share of each drug’s osteonecrosis reports coded as “jaw.” Reporter restrictions and comparisons with Canada Vigilance and the Japanese Adverse Drug Event Report (JADER) database examined reporting bias. These external databases recorded less solicitation. Additional analyses included glucocorticoid stratification, empirical null calibration with unmasking, indication restriction of every surviving non-glucocorticoid drug, time-to-onset modeling, and machine learning. Estimates are reported with 95% confidence intervals.  Results: Of 47 signals, 27 passed jaw exclusion (JPI < 0.50) and reporter restriction; the final core was unchanged across thresholds of 0.30–0.70. Tenofovir disoproxil’s reporting odds ratio (ROR) fell from 157.9 (153.4–162.6) to 6.33 (5.38–7.45) among health professionals; 84.5% of cases were lawyer-sourced. Canada Vigilance (6.24, 2.00–19.4) and JADER (10.5, 6.60–16.8) were consistent with a litigation-inflated FAERS estimate. Glucocorticoids were replicated in both databases (class RORs 10.3, 54.4). Drug JPI rankings were concordant (r = 0.985, 0.960). All 34 negative controls had ROR < 1 (median 0.16); unmasking rescaled other estimates approximately 2.35-fold. Within-indication analyses detected no residual excess for mycophenolate (0.89) or voxelotor (0.97). Asparaginase combined a within-leukemia residual signal (7.14, 5.10–10.0) with mechanistic evidence and JADER replication (75.7).  Conclusion: The reproducible spectrum is glucocorticoid-centered, with the asparaginase class the best-supported residual and three drugs unresolved. Jaw misclassification, reporting context, and indication explain much of the apparent spectrum. Spontaneous reports cannot establish causation; these adjudications require cohort confirmation. The JPI and cross-jurisdiction comparisons may inform analyses of other misclassification-prone endpoints.
SN  - 1663-9812
ER  -