Initial Management of MRONJ Stages I and II, a Clinical Trial With Detection of Salivary Biomarkers

NCT04584840 | Unknown

• 1 other identifier: CI-202-17
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication in patients receiving antiresorptive therapies, such as Bisphosphonates and Denosumab. It is defined by the presence of exposed bone or a fistula that probes bone in the jaws for a period greater than 8 weeks in patient with a history of current or past antiresorptive or antiangiogenic treatment, and in the absence of prior radiotherapy or maxillary bone metastases. Depending on the severity of the disease 4 stages are described. On the other hand, although the presence of alterations in the levels of certain biomarkers in saliva has been documented in patients with MRONJ compared to healthy patients, its applicability in clinical practice is still unknown. Until recently, the status quo favored the adoption of a conservative strategy (non-surgical) for the initial management of patients with stage I and II. However, in recent years, this paradigm has been challenged by multiple authors who report better and more predictable outcomes with surgical treatment. Based on the hypothesis that patients with MRONJ stage I and II subjected to initial surgical treatment have better results than those undergoing conservative (non-surgical) treatment, te research group has designed a unicentric, quasi-experimental clinical trial where the clinical and radiological outcome at the third month of 2 groups of patients with stages I and II MRONJ undergoing non-surgical treatment (Group 1 / control) versus initial surgical treatment (Group 2 / intervention) will be compared. Also, the investigators hypothesize that the patients with complete resolution of the disease will also normalize salivary biomarkers levels unlike those with stable or progressive disease, meaning there is a correlation between clinical and biochemical response. Accordingly, the levels of specific salivary biomarkers at baseline and at the third month will be determined and compared with the clinical outcome. After enrollment patients will be instructed and offered both treatment strategies, and assigned to the corresponding group according to their choice. Patients in group 1 (non-surgical) will receive traditional conservative treatment while patients undergoing surgical treatment will receive the same guidelines of conservative treatment plus surgery according to a specific surgical protocol.

Conditions

Osteonecrosis of the Jaw, Bisphosphonate Induced; Osteonecrosis of the Jaw, Bisphosphonate Related

Keywords

Mronj; Dronj; Biomarkers; Saliva; Surgical treatment; Bronj

Outcome Measures

Primary Outcomes (6)

• Complete clinical resolution

  This is the first of the three possible clinical outcome. The patient has achieved complete mucosal healing meaning there is no signs of bone exposure or fistula, the patient is asymptomatic and thus, can be considered cured.

  Third month

• Clinically stable disease

  Second possible clinical outcome. The patient has not been cured but has neither gotten worse meaning that the area of bone exposure (in square centimeters) is equal or not greater than 50 percent of the initial measurement, and has not developed disease up-staging.

  Third month

• Clinical progression or up-staging

  Third possible clinical outcome. The patient has gotten worse meaning that the area of bone exposure (in square centimeters) is greater than 50 percent of the initial measurement, or the patient has progressed to a higher stage.

  Third month

• Level of salivary NTX

  Expressed in nanomoles of bone collagen equivalents

  Third Month

• Level of salivary MMP-9

  Expressed in nanograms/milliliters

  Third Month

• Levels of IL-1a, IL-1b, IL-6, IL-17 and IL-36α.

  Expressed in picograms/milliliters

  Third Month

Secondary Outcomes (3)

• Radiological absence of radiolucent areas or complete ossification.

  Third month

• Radiologically stable disease

  Third Month

• Radiological progression

  Third month

Study Arms (2)

Group 1 (non-surgical treatment)

NO INTERVENTION

* Soft diet. * Suspension of the use of prostheses or intraoral devices. * Oral hygiene guidelines. * Topical antiseptics: in the form of mouthrinses with 0.12% chlorhexidine after every meal and clorhexidine gel over the exposed bone or fistula. * Systemic antibiotics: for patients in stage 2 in which active acute infection is detected with Amoxicillin/Clavulanic Acid 875/125 mg every 8 hours for 2 weeks. Those allergic to penicillin will receive clindamycin 300 mg every 8 hours for 2 weeks or Levofloxacin 500 mg / day for 2 weeks. Systemic antibiotic treatment can be prolonged indefinitely until infection and symptoms are controlled.

Group 2 (surgical treatment)

EXPERIMENTAL

Same guidelines of conservative treatment plus surgical treatment according to the following protocol: Specific protocol for surgical treatment: * Wide mucoperiosteal flaps and complete surgical excision of necrotic bone together with a mucosa margin of at least 2 mm. * Removal of dental pieces included in the diseased area and regularization of bony margins avoiding leaving sharp edges or spicules. * Secure a two layered waterproof closure without tension (simple or with local flaps). * Samples will be sent for Pathological and microbiological analysis. * Stitches removal after two weeks * Postoperative systemic antibiotic following the mentioned protocol until stitches removal.

Procedure: Surgical treatment

Interventions

Surgical treatment PROCEDURE

Same guidelines as group 1 (non-surgical) plus surgical treatment according to the following protocol: Specific protocol for surgical treatment * Wide mucoperiosteal flaps and complete surgical excision of necrotic bone together with a mucosa margin of at least 2 mm. * Removal of dental pieces included in the diseased area and regularization of bony margins avoiding leaving sharp edges or spicules. * Secure a two layered waterproof closure without tension (simple or with local flaps). * Samples will be sent for Pathological and microbiological analysis. * Stitches removal after two weeks * Postoperative systemic antibiotic following the mentioned protocol until stitches removal.

Group 2 (surgical treatment)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- Diagnosis of stage I or stage II medication related osteonecrosis of the jaws (MRONJ) according to the 2014 AAOMS position paper.

You may not qualify if:

• Coexistence of any medical or social condition that prevents proper adherence to treatment or follow-ups (dependent patients without adequate socio-familiar support, drug addiction, severe psychiatric illness, terminal disease with life expectancy less than 3 months).
• Coexistence of Brown's Tumor, Paget's Disease or other bone diseases with the exception of Osteoporosis or bone metastases.

Sponsors & Collaborators

• Fundació d'investigació Sanitària de les Illes Balears: lead

Study Sites (1)

Hospital Universitario Son Espases

Palma de Mallorca, Balearic Islands, 07120, Spain

RECRUITING

Related Publications (23)

• Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F; American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. 2014 Oct;72(10):1938-56. doi: 10.1016/j.joms.2014.04.031. Epub 2014 May 5.

  PMID: 25234529 BACKGROUND

• Bedogni A, Fusco V, Agrillo A, Campisi G. Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ). Oral Dis. 2012 Sep;18(6):621-3. doi: 10.1111/j.1601-0825.2012.01903.x. Epub 2012 Feb 22. No abstract available.

  PMID: 22353421 BACKGROUND

• Schiodt M, Reibel J, Oturai P, Kofod T. Comparison of nonexposed and exposed bisphosphonate-induced osteonecrosis of the jaws: a retrospective analysis from the Copenhagen cohort and a proposal for an updated classification system. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014 Feb;117(2):204-13. doi: 10.1016/j.oooo.2013.10.010. Epub 2013 Nov 15.

  PMID: 24332520 BACKGROUND

• Kolokythas A, Karras M, Collins E, Flick W, Miloro M, Adami G. Salivary Biomarkers Associated With Bone Deterioration in Patients With Medication-Related Osteonecrosis of the Jaws. J Oral Maxillofac Surg. 2015 Sep;73(9):1741-7. doi: 10.1016/j.joms.2015.03.034. Epub 2015 Mar 19.

  PMID: 25889372 BACKGROUND

• Thumbigere-Math V, Michalowicz BS, de Jong EP, Griffin TJ, Basi DL, Hughes PJ, Tsai ML, Swenson KK, Rockwell L, Gopalakrishnan R. Salivary proteomics in bisphosphonate-related osteonecrosis of the jaw. Oral Dis. 2015 Jan;21(1):46-56. doi: 10.1111/odi.12204. Epub 2013 Nov 29.

  PMID: 24286378 BACKGROUND

• Bagan J, Sheth CC, Soria JM, Margaix M, Bagan L. Bisphosphonates-related osteonecrosis of the jaws: a preliminary study of salivary interleukins. J Oral Pathol Med. 2013 May;42(5):405-8. doi: 10.1111/jop.12021. Epub 2012 Nov 15.

  PMID: 23157469 BACKGROUND

• Bagan J, Saez GT, Tormos MC, Hens E, Terol MJ, Bagan L, Diaz-Fernandez JM, Lluch A, Camps C. Interleukin-6 concentration changes in plasma and saliva in bisphosphonate-related osteonecrosis of the jaws. Oral Dis. 2014 Jul;20(5):446-52. doi: 10.1111/odi.12150. Epub 2013 Jul 10.

  PMID: 23837828 BACKGROUND

• Zhang Q, Atsuta I, Liu S, Chen C, Shi S, Shi S, Le AD. IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws. Clin Cancer Res. 2013 Jun 15;19(12):3176-88. doi: 10.1158/1078-0432.CCR-13-0042. Epub 2013 Apr 24.

  PMID: 23616636 BACKGROUND

• Kim S, Williams DW, Lee C, Kim T, Arai A, Shi S, Li X, Shin KH, Kang MK, Park NH, Kim RH. IL-36 Induces Bisphosphonate-Related Osteonecrosis of the Jaw-Like Lesions in Mice by Inhibiting TGF-beta-Mediated Collagen Expression. J Bone Miner Res. 2017 Feb;32(2):309-318. doi: 10.1002/jbmr.2985. Epub 2016 Oct 12.

  PMID: 27567012 BACKGROUND

• Bedogni A, Fedele S, Bedogni G, Scoletta M, Favia G, Colella G, Agrillo A, Bettini G, Di Fede O, Oteri G, Fusco V, Gabriele M, Ottolenghi L, Valsecchi S, Porter S, Petruzzi M, Arduino P, D'Amato S, Ungari C, Fung Polly PL, Saia G, Campisi G. Staging of osteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease. Br J Oral Maxillofac Surg. 2014 Sep;52(7):603-8. doi: 10.1016/j.bjoms.2014.04.009. Epub 2014 May 22.

  PMID: 24856927 BACKGROUND

• Van den Wyngaert T, Claeys T, Huizing MT, Vermorken JB, Fossion E. Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol. 2009 Feb;20(2):331-6. doi: 10.1093/annonc/mdn630. Epub 2008 Oct 26.

  PMID: 18953067 BACKGROUND

• Lerman MA, Xie W, Treister NS, Richardson PG, Weller EA, Woo SB. Conservative management of bisphosphonate-related osteonecrosis of the jaws: staging and treatment outcomes. Oral Oncol. 2013 Sep;49(9):977-983. doi: 10.1016/j.oraloncology.2013.05.012. Epub 2013 Jul 3.

  PMID: 23830962 BACKGROUND

• Norholt SE, Hartlev J. Surgical treatment of osteonecrosis of the jaw with the use of platelet-rich fibrin: a prospective study of 15 patients. Int J Oral Maxillofac Surg. 2016 Oct;45(10):1256-60. doi: 10.1016/j.ijom.2016.04.010. Epub 2016 May 11.

  PMID: 27179556 BACKGROUND

• Mucke T, Koschinski J, Deppe H, Wagenpfeil S, Pautke C, Mitchell DA, Wolff KD, Holzle F. Outcome of treatment and parameters influencing recurrence in patients with bisphosphonate-related osteonecrosis of the jaws. J Cancer Res Clin Oncol. 2011 May;137(5):907-13. doi: 10.1007/s00432-010-0953-1. Epub 2010 Oct 7.

  PMID: 20927569 BACKGROUND

• Lesclous P, Grabar S, Abi Najm S, Carrel JP, Lombardi T, Saffar JL, Samson J. Relevance of surgical management of patients affected by bisphosphonate-associated osteonecrosis of the jaws. A prospective clinical and radiological study. Clin Oral Investig. 2014;18(2):391-9. doi: 10.1007/s00784-013-0979-2. Epub 2013 Apr 19.

  PMID: 23604698 BACKGROUND

• Ruggiero SL, Kohn N. Disease Stage and Mode of Therapy Are Important Determinants of Treatment Outcomes for Medication-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg. 2015 Dec;73(12 Suppl):S94-S100. doi: 10.1016/j.joms.2015.09.024.

  PMID: 26608159 BACKGROUND

• Carlson ER. Management of antiresorptive osteonecrosis of the jaws with primary surgical resection. J Oral Maxillofac Surg. 2014 Apr;72(4):655-7. doi: 10.1016/j.joms.2013.12.007. Epub 2013 Dec 15. No abstract available.

  PMID: 24480762 BACKGROUND

• El-Rabbany M, Sgro A, Lam DK, Shah PS, Azarpazhooh A. Effectiveness of treatments for medication-related osteonecrosis of the jaw: A systematic review and meta-analysis. J Am Dent Assoc. 2017 Aug;148(8):584-594.e2. doi: 10.1016/j.adaj.2017.04.002. Epub 2017 May 18.

  PMID: 28527518 BACKGROUND

• Hayashida S, Soutome S, Yanamoto S, Fujita S, Hasegawa T, Komori T, Kojima Y, Miyamoto H, Shibuya Y, Ueda N, Kirita T, Nakahara H, Shinohara M, Umeda M. Evaluation of the Treatment Strategies for Medication-Related Osteonecrosis of the Jaws (MRONJ) and the Factors Affecting Treatment Outcome: A Multicenter Retrospective Study with Propensity Score Matching Analysis. J Bone Miner Res. 2017 Oct;32(10):2022-2029. doi: 10.1002/jbmr.3191. Epub 2017 Jul 11.

  PMID: 28585700 BACKGROUND

• Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003 Sep;61(9):1115-7. doi: 10.1016/s0278-2391(03)00720-1. No abstract available.

  PMID: 12966493 BACKGROUND

• Japanese Allied Committee on Osteonecrosis of the Jaw; Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, Taguchi A, Nagata T, Urade M, Shibahara T, Toyosawa S. Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw. J Bone Miner Metab. 2017 Jan;35(1):6-19. doi: 10.1007/s00774-016-0810-7. Epub 2016 Dec 29.

  PMID: 28035494 BACKGROUND

• Ristow O, Ruckschloss T, Muller M, Berger M, Kargus S, Pautke C, Engel M, Hoffmann J, Freudlsperger C. Is the conservative non-surgical management of medication-related osteonecrosis of the jaw an appropriate treatment option for early stages? A long-term single-center cohort study. J Craniomaxillofac Surg. 2019 Mar;47(3):491-499. doi: 10.1016/j.jcms.2018.12.014. Epub 2018 Dec 29.

  PMID: 30642734 BACKGROUND

• Ristow O, Otto S, Troeltzsch M, Hohlweg-Majert B, Pautke C. Treatment perspectives for medication-related osteonecrosis of the jaw (MRONJ). J Craniomaxillofac Surg. 2015 Mar;43(2):290-3. doi: 10.1016/j.jcms.2014.11.014. Epub 2014 Nov 22.

  PMID: 25541255 BACKGROUND

MeSH Terms

Conditions

Bisphosphonate-Associated Osteonecrosis of the Jaw

Interventions

Surgical Procedures, Operative

Condition Hierarchy (Ancestors)

Osteonecrosis; Bone Diseases; Musculoskeletal Diseases; Jaw Diseases; Stomatognathic Diseases; Necrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• MARTA MONJO CABRER, PHD

  Fundació d'investigació Sanitària de les Illes Balears

  STUDY DIRECTOR

• JOANA RAMIS MOREY, PHD

  Fundació d'investigació Sanitària de les Illes Balears

  STUDY DIRECTOR

• VICTOR A LASA MENÉNDEZ, MD

  STUDY CHAIR

• JUAN M ZÁRATE GONZÁLEZ, MD

  Fundació d'investigació Sanitària de les Illes Balears

  PRINCIPAL INVESTIGATOR

Central Study Contacts

JUAN M ZÁRATE GONZÁLEZ, MD

CONTACT

+34636794627; JUANLAK@HOTMAIL.COM

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Unicentric quasi-experimental clinical trial

Study Record Dates

• First Submitted: September 28, 2020
• First Posted: October 14, 2020
• Study Start: November 1, 2020
• Primary Completion: October 1, 2023
• Study Completion: January 15, 2024
• Last Updated: February 16, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: 6 months after publication
• Access Criteria: IPD sharing subjected to prior authorization of the research group

Locations

ES (1)