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    Topic review

    Medication-Related Osteonecrosis of Jaw (MRONJ)

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    Submitted by: olga di fede
    (This entry belongs to Entry Collection "Immunotherapy in Solid Tumors ")

    Definition

    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.

    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], (b) invasive techniques (i.e., conservative or aggressive surgical approaches) [3] and (c) a combination of (a) and (b) (i.e., surgery plus one of the aforementioned non-invasive procedures) [4]. Non-invasive procedures include: medical treatment, intraoral vacuum-assisted treatment [5], the use of pentoxifylline (associated or not with tocopherol [6][7]), Er:YAG laser ablation, and Nd: YAG/diode laser biostimulation [8][9][10] and teriparatide [11][12][13][14]. 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].

    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].

    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]. 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.

    2. Studies

    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 1 and Table 2 summarize the eligible studies.

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

    Treatment Study Study Type Pts Intervention Outcome Follow-Up
    Conservative Surgery De Souza Povoa et al., 2016 Case report N = 1
    Onc
    Stage 1
    Removal of the exposed necrotic bone and primary wound closure Complete healing and new bone formation in the surgical site 26 months
    Ribeiro et al., 2015 Case report N = 1
    Ost
    Stage unspecified
    Surgical removal of whole necrotic bone, extraction of all compromised teeth Complete healing 12 months
    De Souza Faloni et al., 2011 Case report N = 1
    Ost
    Stage 2
    Conservative debridement of the necrotic bone and of part of the surrounding healthy bone, as a margin of safety Complete healing 8 months
    Pechalova et al., 2011 Case series N = 3
    Onc
    Stage unspecified
    Conservative surgical debridement Complete healing Average of 4 months
    Martins et al., 2012 Retrospective clinical study N = 5
    Onc
    Stage 1,2
    Sequestrectomy and/or ostectomy and/or osteoplasty until bone marrow bleeding 60% patients completely healed 6 months
    Jung et al., 2017 Case series N = 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 site 3 months
    Atalay et al., 2011 Retrospective clinical study N = 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 appeared 40% patients completely healed 6 months
    Vescovi et al., 2012 Retrospective clinical study N = 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 bone 53% patients completely healed 9 months
    Vescovi et al., 2011 Prospective clinical study N = 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 bone 65% patients completely healed 12 months
    Freiberger et al., 20125 Randomized control trial N = 19
    Onc + Ost
    Stage 1,2,3
    Surgical debridement of the necrotic bone 33% patients completely healed 24 months
    Fortuna et al., 2012 Single-center prospective open-label clinical trial N = 26
    Onc
    Stage 2,3
    Systemic and topical antibiotic therapy following by sequestrectomy 73% patients completely healed Average of 10 months
    Lee et al., 2014 Case series N = 30
    Ost + Onc
    Stage 1,2,3
    Minor surgical debridement was performed after irrigation, in which the necrotic bone fragments were removed Complete healing Average of 16 months
    Schubert et al., 2012 Prospective study N = 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 healed 6 months (72%)
    Graziani et al., 2012 Retrospective cohort multicenter study N = 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 margins 49% patients completely
    healed
    6 months
    Conservative Surgery with Buccal Fat Pad Closure Duarte et al., 2015 Case report N = 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 defect Complete healing 3 months
    Gallego et al., 2012 Case series N = 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 healing Average of 12 months
    Berrone et al., 2015 Case series N = 5
    Onc
    Stage 3
    Removal of the necrotic bone and primary closure of the oroantral communication using a buccal fat pad flap. Complete healing Average of 12 months
    Lopes et al., 2015 Retrospective observational cohort study N = 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., 2017 Multicenter retrospective study N = 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 Surgery Hewson et al., 2012 Case report N = 1
    Onc
    Stage 3
    Radical surgical excision of all diseased bone and nasio-labial flap reconstruction. Complete healing 6 months
    Ghazali et al., 2013 Case report N = 1
    Ost
    Stage 3
    Hemimandibulectomy and an osteocutaneous fibula flap reconstruction Complete healing 24 months
    Shintani et al., 2015 Cohort study N = 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., 2014 Case report N = 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 healing Average of 8 months
    Hanasono et al., 2013 Case series N = 13
    Onc
    Stage2, 3
    Segmental mandibulectomy and microvascular free flap reconstruction. Complete healing Average of 15 months
    Graziani et al., 2012 Retrospective cohort multicenter study N = 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., 2017 Multicenter retrospective study N = 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.

    Study Study Type Population Intervention Outcome Follow-Up
    Conservative surgery plus (+) non-invasive procedures
    1. Surgery + Blood Component Gönen et al., 2017 Case report N = 1
    Onc
    Stage 3
    Sequestrectomy + PRF Complete resolution 18 months
    Soydan et al., 2014 Case report N = 1
    Onc
    Stage unspecified
    Curettage + PRF Complete resolution 6 months
    Maluf et al., 2016 Case series N = 2
    Onc
    Stage 2
    Resection of the necrotic tissues, curettage and osteotomy + L-PRF Partial healing 6 months
    Dincă et al., 2014 Retrospective clinical study N = 10
    Onc
    Stage 2
    Sequestrectomy or curettage + PRF Complete resolution 1 month
    Nørholt et al., 2016 Prospective study N = 15
    Onc + Ost
    Stage 2,3
    Curettage + L-PRF 93.3% patients completely healed 20 months
    Anitua et al., 2013 Case report N = 1
    Onc
    Stage unspecified
    Curettage + PRGF Complete resolution 12 months
    Bocanegra-Pérez et al., 2012 Prospective descriptive study N = 8
    Onc + Ost
    Stage 2
    Curettage + PRP Complete resolution 14 months
    Mozzati et al., 2012 Retrospective clinical study N = 32
    Onc
    Stage 2
    Conservative surgery + PRFG Complete resolution From 48 to 50 months
    Tsai et al., 2016 Case report N = 1
    Ost
    Stage 3
    Surgical debridement, sequestrectomy + PRF Complete resolution 10 months
    Pelaz et al., 2014 Cohort study N = 5
    Ost
    Stage 3
    Sequestrectomy and curettage + PRF Complete resolution An average of 20 months
    Park et al., 2017 Prospective study N = 25
    Onc + Ost
    Stage 1,2,3
    Conservative surgery + L-PRF 36% patients completely healed 4 months
    Fernando de Almeida Barros Mourao C et al., 2020 Case series N = 11
    Ost
    Stage 2
    Surgical removal of necrotic bone + PRF membranes Complete healing 24 months
    Giudice A et al., 2020 Case report N = 1
    Ost
    Stage 3
    Surgical removal of necrotic bone + PRF membranes Complete healing 60 months
    Bouland C et al., 2020 Case report N = 2
    Ost + Onc
    Stage 2 and 3
    Surgical removal of necrotic bone + SVF and L-PRF membranes Complete healing 18 months
    2. Surgery + Blood Component + Photodynamic Therapy De Castro et al., 2016 Case series N = 2
    Ost
    Stage 2,3
    Surgical debridement + PDT + PRF Complete resolution An average of 12 months
    3. Surgery + Blood Component +
    Bone Morphogenetic Protein
    Park et al., 2017 Prospective study N = 30
    Onc + Ost
    Stage 1,2,3
    Conservative surgery + combined L-PRF and recombinant human BMP-2 (rhBMP-2) 60% patients completely healed 4 months
    4. Surgery + Teriparatide Lee et al., 2010 Case report N = 1
    Ost
    Stage 2
    Sequestrectomy + teriparatide Complete resolution 6 months
    5. Surgery + Teriparatide + Bone Morphogenetic Protein Jung et al., 2017 Cohort study N = 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 resolution 3 months
    6. Surgery + Bone Morphogenetic Protein Jung et al., 2017 Cohort study N = 4
    Ost
    Stage 2,3
    Conservative surgery and absorbable collagen plugs soaked by rhBMP-2 into the bone defect. Complete resolution 3 months
    7. Surgery + Blood Component + Autolugus Bone Marrow Stem Cells Gonzálvez-García et al., 2013 Case report N = 1
    Onc
    Stage 2
    Removal of the necrotic bone+ bone marrow stem cells + beta tricalcium phosphate + demineralized bone matrix + PRP Complete resolution 6 months
    De Santis et al., 2020 Case report N = 2
    Onc
    Stage 2
    Debridement of the exposed necrotic bone followed by bone marrow stem cells injection Complete healing and new bone formation in the surgical site. 13 months
    8. Surgery + LLLT Da Guarda et al., 2012 Case report N = 1
    Onc
    Stage unspecified
    GaAlAs diode laser every 48 h for 10 days + antibiotic therapy + curettage Complete resolution 6 months
    9. Surgery + Blood Component + Laser Phototherapy Altay et al.,
    2014
    Retrospective clinical study N = 11
    Onc
    Stage2,3
    Pre- and post-operative antibiotic administrations + GaA-lAs diode laser Complete resolution 12 months
    Atalay et al.,
    2011
    Retrospective clinical study N = 10
    Onc
    Stage 1,2
    Conservative surgery + low-level laser therapy application (Er:YAG and Nd:YAG) 70% patients completely healed 12 months
    Vescovi et al., 2012 Retrospective clinical study N = 45
    Onc + Ost
    Stage 1,2,3
    Conservative surgery + laser Nd:YAG 89% patients completely healed 6 months
    Vescovi et al.,
    2011
    Prospective clinical study N = 62
    Onc + Ost
    Stage 1,2,3
    Conservative surgery + laser LLLT 73% patients completely healed 17 months.
    Martins et al.,
    2012
    Retrospective clinical study N = 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 healed 12 months
    10. Surgery + Ozone Agrillo et al.,
    2012
    Retrospective study N = 94
    Onc + Ost
    Stage unspecified
    Curettage or sequestrectomy + Ozone therapy (3 min sessions 2/week) + pharmacological therapy 90% patients completely healed An average of 6 months
    11. HBO + Surgery * Fatema et al.,
    2013
    Case report N = 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 resolution Unspecified
    Al-Zoman et al.,
    2013
    Case series N = 3
    Onc
    Stage2,3
    HBO therapy, oral/parenteral antibiotic, analgesics, conservative surgery (debridement of bone sequestra) and daily rinsing with chlorhexidine mouthwash. Complete resolution 12 months
    Freiberger et al., 2012 Randomized control trial N = 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 healed 24 months
    12. Ozone + Surgery* Ripamonti et al., 2012 Case report N = 1
    Onc
    Stage unspecified
    Antibiotic + antimycotic therapy for 10 days. Local ozone gas (total of 15 applications). Conservative surgery (sequestrectomy). Complete resolution 36 months
    Brozoski et al., 2020 Case series N = 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 resolution An average of 24 months
    13. Teriparatide + Surgery * Doh et al., 2015 Case report N = 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 resolution 20 months
    Kwon et al., 2012 Case series N = 6
    Ost
    Stage 2,3
    Daily Teriparatide (20 μg/day) 1–3 months + conservative sequestrectomy/marginal/aggressive segmental resection Complete resolution 3 months
      Kakehashi et al., 2015 Case series N = 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 resolution From 4 to 24 months (duration of teriparatide therapy until mucosal healing)
    Aggressive surgery plus non-invasive procedures
    1. Surgery + Bone Graft + Bone Morphogenetic Protein Rahim I
    2015
    Case report N = 1
    Ost
    Stage 3
    Partial mandibulectomy + bone graft from the iliac crest + rhBMP-7 Complete resolution 60 months
    2. AF-Guided Surgery + LLLT Vescovi P
    2015
    Case report N = 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 intervention Complete resolution 7 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.

    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].

    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 2a). 69% (95% CI; 53–84%) for invasive surgery plus non-invasive procedures ( Figure 2b).

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

    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. Referring 

    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]. 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], 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.

    The entry is from 10.3390/ijerph18168432

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