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.

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

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. ReferrDiscussiong 

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.