OZONE_EXO: Comparative Analysis of Protocols for Dental Exactions in Patients at Risk of MRONJ: Case-control Study (OZONE_EXO)

Comparative Analysis of Different Protocols for Dental Exactions in Patients at Risk of MRONJ: Case-control Study

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction of antiresorptive and antiangiogenic agents; it is also a potentially painful and debilitating condition. Today, no specific studies have prospectively evaluated the efficacy of its treatment and no robust standard of care has been established.

Among non-invasive procedures to treat MRONJ, the use of medical ozone (O3) arises for its properties and has been deployed and evaluated. O3 has generally proven to play a role in the treatment of chronic, nonhealing, or ischemic wounds, due to its antimicrobial and anti-oxidant properties and to bio-stimulation; it has been extensively used for different medical approaches and purposes. In oral cavity, local applications are carried out by ozonized water (i.e. spray or compress) or gel.

The aim of this study was to carry out a case-control study in order to compare two different protocols of dental extractions in patients at risk of MRONJ, with and without infiltration of a mixture of oxygen-ozone.

All the cases in our study are cancer and oncologic and osteometabolic patients undergoing high-risk therapy for MRONJ (antiresorptive and antiangiogenic drugs) who require dental extractions with a poor prognosis. During the first examination (T0), medical, pharmacological, and dental history of patients are recorded. Data collected are: (1) age; (2) gender; (3) indications for use, type, cumulative dose and duration of MRONJ-related drugs; (4); history of chemotherapy; (5) other medications; (6) other diseases; (7) smoking.

For each patient, an orthopantomography and a cone beam computed tomography of the teeth are performed only if indicated.

Study Overview

• Status: Completed
• Conditions: MEDICATION RELATED OSTEONECROSIS OF THE JAW
• Intervention / Treatment: Biological: OxigenOzone_Insufflation

Detailed Description

The enrolled patients were randomly divided into two groups:

Group A: consisting of 38 patients (undergoing ozone treatment) (OZONE_EXO) intra-tissutal perialveolar injections of a 15-mL mixture of OxigenOzone (O2O3) with a 26Gx1⁄2 - 0.45x13 mm needle and insufflation of the same mixture in the post-extraction site in patients at risk of medication-induced osteonecrosis of the jaw (ONJ).

Group B: comprising 79 controls (not undergoing ozone treatment).(NO_OZONE_EXO) Tooth extraction in patients at risk of medication-induced osteonecrosis of the jaw (ONJ) without the use of ozone application.

Following the same approach as in Group A, patients in Group B underwent additional follow-up visits at T1 (3-5 days), T2 (14 days), and T3 (6 weeks) post-extraction, in accordance with Inflammatory - P roliferative - Remodeling (IPR) Wound Healing Scale.

the IPR scale score, to meticulously monitor surgical wound healing and record pain intensity using the NRS scale, rather than the originally planned VAS scale, for enhanced ease of use [22].

The IPR scale provided a comprehensive assessment of wound healing through distinct subscales, each ranging from 0 to 1, resulting in a total score ranging from 0 to 16. These subscales evaluated the inflammatory response, proliferative response, and remodeling process. At the conclusion of the follow-up period, the total IPR score was computed, with scores spanning from 0 to 16. Scores of 0-4 denoted poor healings, scores of 5-10 indicated acceptable healing, while scores of 11-16 suggested excellent healing.

• Study Type: Interventional
• Enrollment (Actual): 117
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Palermo, Italy, 90127
    • Azienda Ospedaliera Universitaria Policlinico "P. Giaccone" Palermo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• age ≥ 18 yrs
• patients at risk of developing MRONJ for previous or current administration of drugs related
• extraction of teeth with a poor prognosis due to severe decay and/or periodontitis

Exclusion Criteria:

• previous radiation in the head and neck area
• neoplastic involvement of the jaw
• previous MRONJ diagnosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (OZONE_EXO); intra-tissutal perialveolar injections of a 15-mL mixture of OxigenOzone (O2O3) with a 26Gx1⁄2 - 0.45x13 mm needle and insufflation of the same mixture in the post-extraction site in patients at risk of medication-induced osteonecrosis of the jaw (ONJ).	Biological: OxigenOzone_Insufflation; intra-tissutal perialveolar injections of a 15-mL mixture of OxigenOzone (O2O3) with a 26Gx 1⁄2 - 0.45x13 mm needle and insufflation of the same mixture in the post-extraction site for at least 1 minute, hemostasis, and suture.
No Intervention: Group B (NO_OZONE_EXO); Tooth extraction in patients at risk of medication-induced osteonecrosis of the jaw (ONJ) without the use of ozone application.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Healing Evaluation Using Inflammatory-Proliferative-Remodelling Scale (IPR Scale): Inflammatory Phase	The inflammatory phase is evaluated 3-5 days after tissue injury on the basis of eight parameters, measured on a 9-point scale (0-8): bleeding (spontaneously or on palpation), granulation tissue, hematoma, tissue color, incision margins, suppuration, edema, and pain. A score of 5-8 indicates a successful inflammatory phase	3-5 days after the intervention
Healing Evaluation Using Inflammatory-Proliferative-Remodelling Scale (IPR Scale): Proliferative Phase:	The proliferative phase is evaluated 14 days after tissue injury on the basis of five parameters, measured on a 6-point scale (0-5): re-epithelialization, tissue color, scar, suppuration, and pain. A score of 3-5 score indicates successful healing.	14 days after the intervention
Healing Evaluation Using Inflammatory-Proliferative-Remodelling Scale (IPR Scale): Remodelling Phase	The remodeling phase is evaluated 6 weeks after tissue injury on the basis of three parameters, measured on a 4-point scale (0-3): scar, tissue color, and pain. A score of 2-3 indicates successful healing	6 weeks after the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Healing Evaluation Using IPR Scale: Total Process	The total score of the IPR scale ranges from 0 to 16:0-4 indicates poor healing; 5-10, acceptable healing; and 11-16, excellent healing The inflammatory phase carries the greatest weight in the final score because its impairment can jeopardize the entire series of biologic events leading to early wound healing.	6 week

Collaborators and Investigators

• Sponsor: University of Palermo
• Investigators: Principal Investigator: Olga Di Fede, Professor, University of Palermo

Publications and helpful links

General Publications

• Campisi G, Mauceri R, Bertoldo F, Bettini G, Biasotto M, Colella G, Consolo U, Di Fede O, Favia G, Fusco V, Gabriele M, Lo Casto A, Lo Muzio L, Marciano A, Mascitti M, Meleti M, Mignogna MD, Oteri G, Panzarella V, Romeo U, Santarelli A, Vescovi P, Marchetti C, Bedogni A. Medication-Related Osteonecrosis of Jaws (MRONJ) Prevention and Diagnosis: Italian Consensus Update 2020. Int J Environ Res Public Health. 2020 Aug 18;17(16):5998. doi: 10.3390/ijerph17165998.
• Oldoini G, Frabattista GR, Saragoni M, Cosola S, Giammarinaro E, Genovesi AM, Marconcini S. Ozone Therapy for Oral Palatal Ulcer in a Leukaemic Patient. Eur J Case Rep Intern Med. 2020 Jan 14;7(2):001406. doi: 10.12890/2020_001406. eCollection 2020.
• Palma LF, Joia C, Chambrone L. Effects of ozone therapy on periodontal and peri-implant surgical wound healing: a systematic review. Quintessence Int. 2023 Feb 10;54(2):100-110. doi: 10.3290/j.qi.b3512007.
• Agrillo A, Ungari C, Filiaci F, Priore P, Iannetti G. Ozone therapy in the treatment of avascular bisphosphonate-related jaw osteonecrosis. J Craniofac Surg. 2007 Sep;18(5):1071-5. doi: 10.1097/scs.0b013e31857261f.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2018
• Primary Completion (Actual): March 30, 2020
• Study Completion (Actual): March 30, 2020

Study Registration Dates

• First Submitted: September 27, 2023
• First Submitted That Met QC Criteria: October 4, 2023
• First Posted (Actual): October 10, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 17, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Adverse event; Osteonecrosis; MRONJ; Ozone therapy; Jaw; Antiresorptive; Antiangiogenic drugs
• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Pathologic Processes; Necrosis; Osteonecrosis
• Other Study ID Numbers: OZONE_EXO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes