# Pathophysiologic mechanisms during initiation of medication related osteonecrosis of the jaws

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $357,646

## Abstract

Antiresorptive medications, particularly bisphosphonates (BPs) and denosumab are potent inhibitors of
osteoclast function and are used to manage skeletal diseases such as bone malignancy or osteoporosis.
Although clinically important, these medications are associated with medication related osteonecrosis of the
jaw (MRONJ), a rare but serious side effect, that can cause debilitating pain and morbidity. Moreover, the fear
of developing MRONJ has contributed to a progressive decline in patient compliance with antiresorptive use,
and a looming crisis in osteoporosis. Improving MRONJ prevention, diagnosis and treatment would have a
great impact in health care of patients with skeletal diseases. From studies supported by the parent grant, our
well-established, interdisciplinary team of clinician-scientists has made important contributions to the
pathophysiology, diagnosis and management of MRONJ. Collectively, our studies have provided significant
insight into MRONJ pathogenesis. In control animals with dental disease, bone resorbs away from the
inflammatory nidus. In contrast, osteoclast inhibition leads to bone being exposed to inflammation, and to
osteonecrosis adjacent to inflammatory foci. Epithelial migration occurs in both control and antiresorptive
treated animals. However, with inhibition of bone resorption, the epithelium descends towards the alveolar
crest, and eventually rims the necrotic bone, resulting in bone exposure. Extraction of teeth with dental
disease, results in conspicuous MRONJ. In contrast, after extraction of healthy teeth in animals on
antiresorptives mucosal and socket healing is achieved. Through our studies, we have developed and
characterized animal models of MRONJ by inducing experimental periodontal or periapical disease and
treating with high-dose antiresorptives, in the absence of tooth extraction. These models capture early tissue
changes during MRONJ initiation. Based on our published and preliminary findings, we hypothesize that
initiation of the pathophysiologic framework that eventually leads to clinically exposed bone involves an
interplay among dying osteocytes, challenged soft tissue homeostasis, and a distorted immune response. Our
objective is to determine the early pathophysiologic mechanisms of MRONJ initiation and progression and to
pursue effective therapeutic interventions. To meet our objective and test our hypothesis, we propose three
Specific Aims. Aim 1: Determine the extent to which HMGB1 released from necrosing osteocytes contributes to
MRONJ initiation and progression Aim 2: Delineate macrophage involvement in MRONJ initiation and
progression. Aim 3: Define the role of macrophage and osteocyte heme-oxygenase-1 (HO-1) in MRONJ
initiation and progression.

## Key facts

- **NIH application ID:** 10466925
- **Project number:** 5R01DE019465-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** SOTIRIOS TETRADIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $357,646
- **Award type:** 5
- **Project period:** 2009-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466925

## Citation

> US National Institutes of Health, RePORTER application 10466925, Pathophysiologic mechanisms during initiation of medication related osteonecrosis of the jaws (5R01DE019465-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10466925. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*