Medication-Related Osteonecrosis of Jaw (MRONJ): Comparison
Please note this is a comparison between Version 1 by olga di fede and Version 5 by Conner Chen.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction of antiresorptive and antiangiogenic agents, and it is also a potentially painful and debilitating condition.

  • ONJ
  • osteonecrosis
  • treatment
  • therapy
  • surgery
  • staging

1. Introduction

Whilst different treatments (therapeutic or palliative) have been described for MRONJ management, it is still a matter of controversy in the oral and maxillofacial communities that a gold standard has not yet been defined. In brief, this standard would involve the three main categories of MRONJ: (a) non-invasive procedures (ranging from pharmacological to laser treatment) [1][2][8,9], (b) invasive techniques (i.e., conservative or aggressive surgical approaches) [3][10] and (c) a combination of (a) and (b) (i.e., surgery plus one of the aforementioned non-invasive procedures) [4][11]. Non-invasive procedures include: medical treatment, intraoral vacuum-assisted treatment [5][12], the use of pentoxifylline (associated or not with tocopherol [6][7][13,14]), Er:YAG laser ablation, and Nd: YAG/diode laser biostimulation [8][9][10][15,16,17] and teriparatide [11][12][13][14][18,19,20,21]. Only partial and delayed healing has been reported with non-invasive techniques, to the exclusion of low-level laser treatment (LLLT) and, in certain cases, teriparatide. Furthermore, there is a paucity of high-impact studies in the literature, which would demonstrate effective positive outcomes [15][22].

Surgical treatments comprise: (i) conservative approaches, such as bone debridement, and sequestrectomy, and (ii) invasive, more aggressive procedures, such as re-sectioning the affected bone and jawbone reconstruction, where indicated. Several studies have yielded very positive results for surgical treatment in MRONJ treatment, especially if performed in the early stages of the disease [16][17][18][19][23,24,25,26].

Many in the field consider that the term ‘treatment’ is often used inappropriately, in that it is not possible for the disease to heal completely or for the majority of MRONJ patients to arrive at a state of remission. Thus, and as documented in the MRONJ literature, treatment goals are mainly concerned with managing pain, controlling for any infection of the soft and hard tissues and reducing the progression or occurrence of bone necrosis [4][11]. Over and above every consideration, the authors of this paper hold that maximizing a patient’s quality of life has to be a key feature of every protocol requiring MRONJ treatment.

The aim of this systematic review with a pooled analysis is to examine and compare the main categories of MRONJ treatment: surgical techniques (conservative or aggressive) versus combined procedures (surgery plus non-invasive procedures), by focusing on their therapeutic effectiveness. The recommendations outlined by the Prisma-P 2015 checklist systematic review protocol were followed in order to formulate the methodology for this systematic review.

2. SMatudieerials and Methods

In order to be included in the systematic review outlined in this paper, studies had to include results from: prospective, non-randomized and randomized clinical trials, retrospective cohort studies and case series ( n ≥ 10), which investigated the role of surgical (conservative or aggressive) techniques with or without combined procedures (surgery plus a non-invasive one) and with a follow-up ≥ 6 months. Studies were excluded if they constituted a Commentary, Review, Editorial or Protocol. Case series ( n < 10) or case reports were excluded from the pooled analysis, and the studies were limited to research regarding human beings.

Furthermore, other data sources (from international meetings and indexed dentistry journals such as Journal of Dentistry, Journal of Oral Maxillofacial Surgery, Journal of Dental Research) were scanned as a source of grey literature.

Screening and eligibility were assessed independently by two reviewers (F.C. and O.D.F.), who were in agreement regarding the results. The Titles of papers and Abstracts were initially screened for relevance and possible eligible results, and thereafter full texts were retrieved. Finally, the reviewers combined their results to create a corpus of selected papers to assess for final eligibility. According to the aim of this review, the resulting papers were allocated to four experimental categories: (1) conservative surgery, (2) aggressive surgery, (3) a conservative plus non-invasive procedure and (4) aggressive surgery plus non-invasive protocols. Table 12 and Table 23 summarize the eligible studies.

Table 1. Summary of the characteristics and the results of the studies concerning MRONJ surgical therapies.

TreatmentStudyStudy TypePtsInterventionOutcomeFollow-Up
Conservative SurgeryDe Souza Povoa et al., 2016Case reportN = 1

Onc

Stage 1
Removal of the exposed necrotic bone and primary wound closureComplete healing and new bone formation in the surgical site26 months
Ribeiro et al., 2015Case reportN = 1

Ost

Stage unspecified
Surgical removal of whole necrotic bone, extraction of all compromised teethComplete healing12 months
De Souza Faloni et al., 2011Case reportN = 1

Ost

Stage 2
Conservative debridement of the necrotic bone and of part of the surrounding healthy bone, as a margin of safetyComplete healing8 months
Pechalova et al., 2011Case seriesN = 3

Onc

Stage unspecified
Conservative surgical debridementComplete healingAverage of 4 months
Martins et al., 2012Retrospective clinical studyN = 5

Onc

Stage 1,2
Sequestrectomy and/or ostectomy and/or osteoplasty until bone marrow bleeding60% patients completely healed6 months
Jung et al., 2017Case seriesN = 7

Ost

Stage 2,3
Patient underwent conventional surgery, and the bone defects were filled with absorbable collagen plugs.Complete healing and new bone formation in the surgical site3 months
Atalay et al., 2011Retrospective clinical studyN = 10

Onc

Stage
The affected bony tissues were curetted from the surface of the bone using bone curettes and round tungsten carbide burs. The necrotic bone was completely removed until the vital bone tissues and vessel spots appeared40% patients completely healed6 months
Vescovi et al., 2012Retrospective clinical studyN = 17

Onc + Ost

Stage 1,2,3
Conservative surgical treatments consisted of sequestrectomy of necrotic bone, superficial debridement/curettage, or corticotomy/surgical removal of alveolar and/or cortical bone53% patients completely healed9 months
Vescovi et al., 2011Prospective clinical studyN = 17

Onc + Ost

Stage 1,2,3
Conservative surgical treatments included sequestrectomies, superficial debridement/curettage and corticotomies/surgical removal of surrounding alveolar and/or cortical bone65% patients completely healed12 months
Freiberger et al., 20125Randomized control trialN = 19

Onc + Ost

Stage 1,2,3
Surgical debridement of the necrotic bone33% patients completely healed24 months
Fortuna et al., 2012Single-center prospective open-label clinical trialN = 26

Onc

Stage 2,3
Systemic and topical antibiotic therapy following by sequestrectomy73% patients completely healedAverage of 10 months
Lee et al., 2014Case seriesN = 30

Ost + Onc

Stage 1,2,3
Minor surgical debridement was performed after irrigation, in which the necrotic bone fragments were removedComplete healingAverage of 16 months
Schubert et al., 2012Prospective studyN = 54

Onc + Ost

Stage 1,2,3
Complete electrical or manual removal of the osteonecrosis until points of bleeding from the bone can be macroscopically detected.88.8% patients completely healed6 months (72%)
Graziani et al., 2012Retrospective cohort multicenter studyN = 227

Ost + Onc

Stage 1,2,3
Local debridement was comprised of all surgical interventions, such as sequestrectomy, soft tissue debridement and curettage, that did not require bone surgery beyond the regular margins49% patients completely

healed
6 months
Conservative Surgery with Buccal Fat Pad ClosureDuarte et al., 2015Case reportN = 1

Onc

Stage 2
The extensive necrotic bone area was surgically removed, resulting in oral sinus communication. A buccal fat pad was used to cover the defectComplete healing3 months
Gallego et al., 2012Case seriesN = 3

Onc + Ost

Stage 1,2,3
Sequestrectomy and bone debridement. The overlying mucosa was sutured over the defect with reconstruction with buccal fat pad.Complete healingAverage of 12 months
Berrone et al., 2015Case seriesN = 5

Onc

Stage 3
Removal of the necrotic bone and primary closure of the oroantral communication using a buccal fat pad flap.Complete healingAverage of 12 months
Lopes et al., 2015Retrospective observational cohort studyN = 46

Onc + Ost

Stage 2,3
Removal of all necrotic bone until bleeding was obtaining at the bony margins, conscious smoothing of all sharp bone edges and primary closure of the wound.87% patients

completely healed
10 months
Hayashida et al., 2017Multicenter retrospective studyN = 38

Onc + Ost

Stage 1,2,3
One group received conservative surgery, removal of only the necrotic bone and extensive surgery, defined as removal of the necrotic and surrounding bone (marginal mandibulectomy or partial maxillectomy).76.7% patients

completely healed
Average of 15 months
Aggressive SurgeryHewson et al., 2012Case reportN = 1

Onc

Stage 3
Radical surgical excision of all diseased bone and nasio-labial flap reconstruction.Complete healing6 months
Ghazali et al., 2013Case reportN = 1

Ost

Stage 3
Hemimandibulectomy and an osteocutaneous fibula flap reconstructionComplete healing24 months
Shintani et al., 2015Cohort studyN = 4

Ost + Onc

Stage 1,2,3
Segmental resection and immediate reconstruction with a reconstruction plate were performed.3/4 patients

completely healed
12 months
Lee et al., 2014Case reportN = 10

Ost + Onc

Stage 1,2,3
Large necrotic bone segment was removed by an ultrasonic bone saw. A bone file or rongeur was used for rounding the sharp bone edge. Then, the bone defect was closed by sutures or COE pack.Complete healingAverage of 8 months
Hanasono et al., 2013Case seriesN = 13

Onc

Stage2, 3
Segmental mandibulectomy and microvascular free flap reconstruction.Complete healingAverage of 15 months
Graziani et al., 2012Retrospective cohort multicenter studyN = 120

Ost + Onc

Stage 1,2,3
Re-sective procedures were defined as corticotomy, surgical removal of the lesion and extended bone removal without prejudice for the continuity of the mandible/maxilla.68% patients

completely healed
6 months
Hayashida et al., 2017Multicenter retrospective studyN = 121

Onc + Ost

Stage 1,2,3
Extensive surgery, defined as removal of the necrotic and surrounding bone (marginal mandibulectomy or partial maxillectomy).86.8% patients

completely healed
Average of 15 months

Table 2. Summary of the characteristics and the results of the studies on MRONJ surgery plus non-invasive procedures.

StudyStudy TypePopulationInterventionOutcomeFollow-Up
Conservative surgery plus (+) non-invasive procedures
1. Surgery + Blood ComponentGönen et al., 2017Case reportN = 1

Onc

Stage 3
Sequestrectomy + PRFComplete resolution18 months
Soydan et al., 2014Case reportN = 1

Onc

Stage unspecified
Curettage + PRFComplete resolution6 months
Maluf et al., 2016Case seriesN = 2

Onc

Stage 2
Resection of the necrotic tissues, curettage and osteotomy + L-PRFPartial healing6 months
Dincă et al., 2014Retrospective clinical studyN = 10

Onc

Stage 2
Sequestrectomy or curettage + PRFComplete resolution1 month
Nørholt et al., 2016Prospective studyN = 15

Onc + Ost

Stage 2,3
Curettage + L-PRF93.3% patients completely healed20 months
Anitua et al., 2013Case reportN = 1

Onc

Stage unspecified
Curettage + PRGFComplete resolution12 months
Bocanegra-Pérez et al., 2012Prospective descriptive studyN = 8

Onc + Ost

Stage 2
Curettage + PRPComplete resolution14 months
Mozzati et al., 2012Retrospective clinical studyN = 32

Onc

Stage 2
Conservative surgery + PRFGComplete resolutionFrom 48 to 50 months
Tsai et al., 2016Case reportN = 1

Ost

Stage 3
Surgical debridement, sequestrectomy + PRFComplete resolution10 months
Pelaz et al., 2014Cohort studyN = 5

Ost

Stage 3
Sequestrectomy and curettage + PRFComplete resolutionAn average of 20 months
Park et al., 2017Prospective studyN = 25

Onc + Ost

Stage 1,2,3
Conservative surgery + L-PRF36% patients completely healed4 months
Fernando de Almeida Barros Mourao C et al., 2020Case seriesN = 11

Ost

Stage 2
Surgical removal of necrotic bone + PRF membranesComplete healing24 months
Giudice A et al., 2020Case reportN = 1

Ost

Stage 3
Surgical removal of necrotic bone + PRF membranesComplete healing60 months
Bouland C et al., 2020Case reportN = 2

Ost + Onc

Stage 2 and 3
Surgical removal of necrotic bone + SVF and L-PRF membranesComplete healing18 months
2. Surgery + Blood Component + Photodynamic TherapyDe Castro et al., 2016Case seriesN = 2

Ost

Stage 2,3
Surgical debridement + PDT + PRFComplete resolutionAn average of 12 months
3. Surgery + Blood Component +

Bone Morphogenetic Protein
Park et al., 2017Prospective studyN = 30

Onc + Ost

Stage 1,2,3
Conservative surgery + combined L-PRF and recombinant human BMP-2 (rhBMP-2)60% patients completely healed4 months
4. Surgery + TeriparatideLee et al., 2010Case reportN = 1

Ost

Stage 2
Sequestrectomy + teriparatideComplete resolution6 months
5. Surgery + Teriparatide + Bone Morphogenetic ProteinJung et al., 2017Cohort studyN = 6

Ost

Stage 2,3
Conservative surgery and absorbable collagen plugs soaked by rhBMP-2 into the bone defect plus daily subcutaneous injection of 20 mg teriparatide for 1–4 months.Complete resolution3 months
6. Surgery + Bone Morphogenetic ProteinJung et al., 2017Cohort studyN = 4

Ost

Stage 2,3
Conservative surgery and absorbable collagen plugs soaked by rhBMP-2 into the bone defect.Complete resolution3 months
7. Surgery + Blood Component + Autolugus Bone Marrow Stem CellsGonzálvez-García et al., 2013Case reportN = 1

Onc

Stage 2
Removal of the necrotic bone+ bone marrow stem cells + beta tricalcium phosphate + demineralized bone matrix + PRPComplete resolution6 months
De Santis et al., 2020Case reportN = 2

Onc

Stage 2
Debridement of the exposed necrotic bone followed by bone marrow stem cells injectionComplete healing and new bone formation in the surgical site.13 months
8. Surgery + LLLTDa Guarda et al., 2012Case reportN = 1

Onc

Stage unspecified
GaAlAs diode laser every 48 h for 10 days + antibiotic therapy + curettageComplete resolution6 months
9. Surgery + Blood Component + Laser PhototherapyAltay et al.,

2014
Retrospective clinical studyN = 11

Onc

Stage2,3
Pre- and post-operative antibiotic administrations + GaA-lAs diode laserComplete resolution12 months
Atalay et al.,

2011
Retrospective clinical studyN = 10

Onc

Stage 1,2
Conservative surgery + low-level laser therapy application (Er:YAG and Nd:YAG)70% patients completely healed12 months
Vescovi et al., 2012Retrospective clinical studyN = 45

Onc + Ost

Stage 1,2,3
Conservative surgery + laser Nd:YAG89% patients completely healed6 months
Vescovi et al.,

2011
Prospective clinical studyN = 62

Onc + Ost

Stage 1,2,3
Conservative surgery + laser LLLT73% patients completely healed17 months.
Martins et al.,

2012
Retrospective clinical studyN = 14

Onc

Stage 1,2,3
Conservative surgery + continuous indium-gallium-aluminum-phosphide diode laser. The LPT treatment started on the first visit and continued daily until mucosal healing was observed.86% patients completely healed12 months
10. Surgery + OzoneAgrillo et al.,

2012
Retrospective studyN = 94

Onc + Ost

Stage unspecified
Curettage or sequestrectomy + Ozone therapy (3 min sessions 2/week) + pharmacological therapy90% patients completely healedAn average of 6 months
11. HBO + Surgery *Fatema et al.,

2013
Case reportN = 1

Onc

Stage 2
Antibiotics therapy, irrigation, pre-operative HBO therapy for 20 sessions, conservative minor surgical debridement and again post-operative HBO therapy for ten sessions.Complete resolutionUnspecified
Al-Zoman et al.,

2013
Case seriesN = 3

Onc

Stage2,3
HBO therapy, oral/parenteral antibiotic, analgesics, conservative surgery (debridement of bone sequestra) and daily rinsing with chlorhexidine mouthwash.Complete resolution12 months
Freiberger et al., 2012Randomized control trialN = 24

Onc + Ost

Stage 1,2,3
40 HBO treatments at 2.0 atm for 2 h twice per day and conservative surgical debridement of the necrotic bone.52% patients completely healed24 months
12. Ozone + Surgery*Ripamonti et al., 2012Case reportN = 1

Onc

Stage unspecified
Antibiotic + antimycotic therapy for 10 days. Local ozone gas (total of 15 applications). Conservative surgery (sequestrectomy).Complete resolution36 months
Brozoski et al., 2020Case seriesN = 2

Onc + Ost

Stage 2
Weekly irrigation with aqueous ozone solution on bone-exposed region + daily mouthwashes of ozone solution. After 3 and 6 months: conservative surgery (debridement and sequestrectomy)Complete resolutionAn average of 24 months
13. Teriparatide + Surgery *Doh et al., 2015Case reportN = 1

Ost

Stage 2
After 4 months of daily teriparatide therapy conservative surgery (sequestrectomy). The TPTD therapy was terminated 6 months after the initial treatment.Complete resolution20 months
Kwon et al., 2012Case seriesN = 6

Ost

Stage 2,3
Daily Teriparatide (20 μg/day) 1–3 months + conservative sequestrectomy/marginal/aggressive segmental resectionComplete resolution3 months
 Kakehashi et al., 2015Case seriesN = 10

Ost

Stage 2,3
Daily teriparatide (20 μg/day) ranged from 4 to 24 months. In some cases, surgery was performed to obtain the healing.Partial resolutionFrom 4 to 24 months (duration of teriparatide therapy until mucosal healing)
Aggressive surgery plus non-invasive procedures
1. Surgery + Bone Graft + Bone Morphogenetic ProteinRahim I

2015
Case reportN = 1

Ost

Stage 3
Partial mandibulectomy + bone graft from the iliac crest + rhBMP-7Complete resolution60 months
2. AF-Guided Surgery + LLLTVescovi P

2015
Case reportN = 1

Onc

Stage 3
Osteotomy with Er:YAG laser + AF visualization to guide the osteoplasty. Intraoral irrigations with povidone iodine solution + application of Nd:YAG laser + weekly applications of LLLT for 3 weeks after interventionComplete resolution7 months
* Procedures administered prior to surgery.

Data collection was independently performed by two authors (F.C. and A.G.), and their results were reviewed by a third author (O.D.F.) to check for accuracy.

3. Results

Aggressive surgery plus non-invasive procedures (auxiliary treatment): only two papers (case reports) discussed the results of aggressive surgery protocols with auxiliary treatment [20][21][49,60].

The overall 6-month total resolution rate (a) and the 6-month improvement rate (b) were: 74% (CI 95%; 64–83%) and 87% (CI 95%; 78–94%), respectively. The following was reported for (a): 80% (CI 95%; 68–90%) for invasive surgery alone ( Figure 2 a). 69% (95% CI; 53–84%) for invasive surgery plus non-invasive procedures ( Figure 2 b).

The following was reported for (b): 81% (CI 95%; 67–92%) for invasive surgery alone ( Figure 3 a). 92% (CI 95%; 88–94%) for invasive surgery plus non-invasive procedures ( Figure 3 b).

Figure 2. Forest plot results of pooled results about complete resolution in (a) invasive (conservative/aggressive) treatments, and (b) invasive (conservative/aggressive) treatments + non-invasive treatments.
Figure 3. Forest plot results of pooled results about complete resolution in (a) invasive (conservative/aggressive) treatments, and (b) invasive (conservative/aggressive) plus non-invasive treatments.

Of interest, a significant statistical difference was observed in the 6-month improvement rate, on comparing combined conservative surgery (mean = 91%) versus only surgical (conservative alone and aggressive alone) techniques (mean 77%, p = 0.05). There was no significant difference for any group with respect to the 6-month total resolution rate (82% versus 72%, respectively). No reliable data were available for an analysis of aggressive surgery plus a non-invasive procedure with respect to all the selected indicators.

4. ReferrDiscussion

Referring to the systematic review described herein, the associations between conservative surgery plus blood components, and laser or photodynamic therapy, appear to contribute much to: newly formed bone, the full coverage of bone tissue with healthy mucosa and the absence of symptoms and other signs of necrotic progression. This is due to the analgesic, anti-inflammatory and biomodulatory effects of blood components, and this protocol has been shown to be effective on average over a 6-month follow-up period with a success rate of 86%.

The association of autologous bone marrow stem cells with conservative surgery and blood components has been reported only in one case study, with a success rate of 100% on average over a 6-month follow-up period. The CT scan revealed the diminution of osteolytic lesions with complete bone regeneration of the medial cortex of the lower jaw and a total resolution of symptoms.

The use of surgery has also been associated with teriparatide (TPTD) treatment (prior to or after conventional surgical treatment) for MRONJ in osteoporotic patients. TPTD stimulates trabecular and cortical thickness, and trabecular connectivity and bone size bone formation by increasing osteoblast number and activity. Although successful results using TPTD treatment have been reported in the literature, its safety and efficacy are currently awaiting comprehensive evaluation. The treatment time during which it can be safely administered is strictly limited to less than 2 years in one lifespan [22][23][24][57,58,59]. A success rate of 83% on average over an 11-month follow-up period has been reported for the surgical treatment plus TPTD treatment (or vice versa) of MRONJ: any surgical wound completely healed with X-rays indicating stable alveolar bone. No inflammatory signs and symptoms have been reported to date.

As a pre-surgical treatment, HBO has successfully treated MRONJ lesions, thereby: improving the quality of life of afflicted patients [25][26][27][52,53,54], increasing wound healing, and reducing edema, inflammation and pain. HBO followed by surgical treatment had a success rate of 84% on average over an 18-month follow-up period, with: the complete healing of MRONJ lesion, total mucosal coverage, a cessation in the signs of infection and notable symptomatic relief.