Microsurgical Reconstruction of the Jaws Using Vascularised Free Flap Technique in Patients with Medication-Related Osteonecrosis: A Systematic Review

Background Osteonecrosis of the jaw (ONJ) has been reported to be associated with patients receiving primarily bisphosphonate (BP) therapies. However, lately it has been documented that other medications, such as RANK ligand inhibitor (denosumab) and antiangiogenic drug, can cause ONJ. Micro-osseous-vascular reconstruction of the jaws in patients affected by medication-related osteonecrosis of the jaw represents a viable option of treatment for patients affected by stage III of the disease. However, there are still considerable doubts about the success of this procedure in the short, medium, and long term. Material and Methods A multidatabase (PubMed/MEDLINE, EMBASE, and CENTRAL) systematic search was performed. Any type of studies considering human patients treated with antiresorptive and antiangiogenic drugs was considered. The aim of the research is to primarily understand the success rate of micro-osseous-vascular reconstruction in the short, medium, and long period of time. This review has also the goal of better understanding any perioperative and postoperative complications resulting from the use of the reconstruction techniques. Results Eighteen studies resulted eligible for the study. Fibula free flap is the most commonly utilised vascularised free flap reconstruction technique (80.76%). Ten out of eighteen studies reported no complications. Recurrence of osteonecrosis was registered in five cases (6.41%) after free flap reconstruction. The overall free flap success rate was 96.16%. Conclusions Based on the limited data available in literature (Level 4 of the Oxford Evidence-based medicine scale), micro-osseous-vascular reconstruction of the jaws represents a valid treatment in patients with bisphosphonate-related osteonecrosis at stage III of the disease. However, additional data based on a larger cohort of patients are necessary to justify this type of intervention in patient affected by MRONJ.


Introduction
Bisphosphonates (BP) are antiresorptive drugs used in the management of conditions as diverse as osteoporosis and metastatic bone diseases. These drugs are widely administered and generally well tolerated by patients. In 2003, Marx et al. [1] first reported a nonhealing necrosis of the maxillofacial region in some patients taking BPs.
In the last decade researchers have discovered that BPs not exclusively cause osteonecrosis of jaws, as other drugs, such as antiresorptive (bone-targeted) agents like denosumab, but also were found to cause it. In addition, monoclonal antibodies able to bind and selectively inhibit VEGF-A, specifically mTOR inhibitors, can also cause osteonecrosis of the jaw [2][3][4][5][6].
For this reason, in 2014 the bisphosphonate-related osteonecrosis of the jaw (BRONJ) nomenclature was changed by the position paper of the American Association of Oral and Maxillofacial Surgeons (AAOMS) special committee on Medication-Related Osteonecrosis of the Jaws (MRONJ) [7].

BioMed Research International
The term "medication-related osteonecrosis of the jaws" (MRONJ) refers to a complication associated with groups of medications, such as antiangiogenic or antiresorptive drugs [8]. These medications can have different indications depending on their mode of administration (Tables 1 and 2) [9,10].
According to AAOMS, MRONJ is defined as an exposition of necrotic bone in the oral cavity lasting more than 8 weeks, in patients who took antiresorptive or antiangiogenic drugs; these patients have not been exposed to head and neck radiotherapy, nor show signs of bone metastases in the maxillofacial region [7].
A number of systemic risk factors have been associated with increased likelihood of MRONJ; they are summarised in Table 3 [11,12].
Dental extraction or other surgical procedures such as apicectomies or cystectomies have been found in between 52% and 80% of MRONJ patients' medical history [13][14][15].
During the last decade AAOMS has revised and proposed a clinical staging classification system of the disease in an attempt to guide clinicians and surgeons to an appropriate therapeutic approach ( Table 4).
The management of MRONJ is reported to be very challenging and with no current "gold standard". Published studies have reported a number of approaches to treatment, with widely varying success rates, ranging from no or limited to radical surgery. The ideal outcome is total eradication of MRONJ along with an improvement of patients' quality of life through pain release and infection management [16].
Conservative treatment was considered to be partially successful, with resolution reported in only 50% of cases; particular concerns have been reported on MRONJ at clinical stages II and III [17][18][19]. In case conservative treatments fail, surgical approaches like local debridement, osteoplasty, and segmental osteotomy are normally performed [20,21].
However, patients that show evidence of MRONJ stage III with severe pain, infection, pathologic fracture, extra-oral fistula, or osteolysis extending to the inferior border of the mandible require an invasive type of surgery which might result in a disabling outcome [7,16,22].
The absence of a well-established surgical treatment protocol in scientific literature makes it difficult to conduct therapy in advanced cases of the disease.
Up to date, there is no standard treatment for MRONJ associated with antiresorptive and antiangiogenic therapies. Several treatment options have been described since MRONJ was first reported. Although the initial stages of MRONJ seem to respond quite well to conservative treatments or limited bone debridement if conservative treatment fails, the treatment for stage III lesions remains still controversial [23,24].
The objective of this review is to evaluate the outcome of free vascularised osseous tissue transfer and/or osteofasciocutaneous free flap as treatment for patients affected by MRONJ stage III. Systematic reviews have been already published. However, these reviews were not performed in a standardised manner or did not follow strict criteria. Moreover the previous reviews did not consider antiangiogenic drugs in the search criteria. This has resulted in lack of quality assurance, summarised in Table 5 [25][26][27]. This review aims to improve the quality of previous research and expand on the current data available.

Materials and Methods
This systematic review was performed according to PRISMA guidelines [44].
The following the databases were used for the review: PubMed/MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). A three-stage screening approach was used to ensure precision and the quality of the search. The screening of titles and abstracts was carried out independently by three authors (AH, UH, and RS) to eliminate any irrelevant materials (i.e., reviews, animal studies, nonclinical studies, and studies that did not report on patients undergoing to free tissue graft). Disagreements were resolved by discussion.
A data screening and abstraction form was used to (1) verify the study eligibility derived from the above inclusion/exclusion criteria, (2) carry out the methodological quality assessment, (3) extract data on study characteristics and outcomes for the included studies.
The authors of any studies eligible for inclusion in the review, yet without sufficient information, were contacted directly ( Figure 1).     All selected papers were carefully read to identify author(s), year of publication, study design, population and treatment characteristics, and number of patients with recurrent MRONJ.

Criteria for Inclusion in This
In case of missing information, we contacted the authors and gave them 6 weeks to reply. If the information was still missing we then indicated the missing data as "Not Reported (NR)" in the text and in the tables.

Results
Results were expressed in descriptive statistics. No randomised controlled clinical trials or case-controlled studies comparing free flap reconstruction after resection in MRONJ patients were found. A total number of 18 articles we included in the study. All the published dates were described in case report (no. 6) and case series (no. 12) from 2008 to 2017 (  No clinical evidence of necrotic bone, but non-specific clinical findings, radiographic changes and symptoms Stage I Exposed and necrotic bone, or fistulae that probes to bone, in patients who are asymptomatic and have no evidence of infection Stage II Exposed and necrotic bone, or fistulae that probes to bone, associated with infection as evidenced by pain and erythema in the region of the exposed bone with or without purulent drainage Stage III Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone, (i.e., inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) resulting in pathologic fracture, extra-oral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor  The most commonly utilised vascularised free flap reconstruction was fibula free flap (81.92%), followed by iliac crest (12.04%) and scapula (6.02%).
The most frequent type of resection was subtotal (32.53%), followed by segmental (26.50%) and partial (2.40%). However a large percentage of missing data was found regarding the type of resection (NR 38.57%) ( Table 9).
The patients were followed for a period of time ranging from 2 weeks up to 99 months.
Radiographic imaging with CT, cone-beam, and/or orthopantomogram was obtained during follow-up in 95% of the cases.
At follow-up and after free flap reconstruction, recurrence of MRONJ (6.02%) was observed in 5 patients: two of the patients (2.40%) on the contralateral unresected part   (Table 10).

Review Quality Assessment Data.
All the studies and data extraction included in the systematic review were qualitative and the risk of bias assessed independently by the authors. The authors used the CARE Checklist for case report and the Modified Delphi Checklist for the case series studies. In the six case report studies, we identified lack of clarity in many of the thirteen domains, with missing information. We found that the lack of clarity was predominantly on  follow-up and diagnostic procedure at the time of follow-up. Hence we concluded the level of bias to be high for all the included case report studies. In the twelve case series studies, we reported a consistent lack of clarity in some of the seven domains, predominantly regarding the outcome measurement methods. Moreover, we identified some missing information in few other domains; hence we considered the level of bias to be high for all studies We contacted the authors of these clinical cases to clarify this bias; however we were unable to recover the missing information.

Discussion
Some antiresorptive drugs such as BP or denosumab have demonstrated to improve the quality of life in patients affected by bone metastasis, osteoporosis, osteopenia, and Paget disease. Additionally, a new antiangiogenic therapy has been successfully used for specific cancer treatments. However, this has remarkably increased the risk of developing MRONJ. This risk is greater in patients who require a higher administration dosage and an intake period greater than 2 years [14,45,46]. Moreover, literature has reported that demography, corticosteroid therapy, systemic factors, and genetic factors have been associated with MRONJ. A recent review report showed a wide-ranging MRONJ incidence from 0 to 27.5% in individuals exposed to intravenous BPs, with a mean incidence of 7%, whereas it ranges from 0.1% to 0.06% in oral administrations [47][48][49].
Etiopathogenesis of MRONJ is not yet fully understood. Although no gold standard is currently available for the treatment of jaw osteonecrosis, a number of studies debate which MRONJ stage benefits the most from surgical therapy [24,50]. In general, for early stages of the disease (MRONJ 0 and I) conservative treatments might be sufficient; surgical treatment should be restricted to advanced stages (MRONJ II and III) or after failure of conservative treatments [7,50].
The majority of researches as well as AAOMS consider conservative treatments as the treatment of choice of MRONJ.
However, there is not a robust evidence from clinical trials as treatment recommendations mostly come from expert opinions and are, therefore, characterised by a low level of evidence [24,47].
The authors of the 2009 AAOMS position statement recommend reserving resection and immediate reconstruction to patients with stage III of the disease; however, positive outcomes have been noted in patients with stages II and III. Having said that no recommendations were given on which type of reconstruction was to be considered the most predictable [47]. The benefits of surgical management of MRONJ have been extensively debated in literature and radical surgery seems to offer more predictable and curative   [30,43]. Since 2008 microvascular reconstruction of the jaw has been documented as a viable option for MRONJ. This systematic review confirmed that microsurgical reconstruction therapy represents a feasible alternative in case of treatment escalation.
The MRONJ recurrence rate found by this systematic review was 6.02% (5 patients). The predominant recurrence sites were the contralateral unresected part of the jaw (2 cases) and the margin of the resection (2 cases), both bearing an overall recurrence rate of 2.40%. Just one case of recurrence was found on the vascular reconstruction.
Infection was the most frequent complication found with 6.02% incidence. The overall free flap success rate was 96.39%. Three free flaps failed during a follow-up period ranging from 2 weeks up to 99 months.
Amongst all the types of reconstruction, free flap fibula was the most chosen, followed by iliac crest and scapula with success rates, respectively, of 97.60%, 98.80%, and 100%.
Antiresorptive drugs were explicitly discontinued in only three studies out of the eighteen, while no mention was reported in the remaining studies [31,33,41]. It is unclear if the discontinuation strategy leads to a better surgical outcome due to the long skeletal life of some antiresorptive drugs.
In line with the growing body of literature, our findings confirm positive results in treating patients with MRONJ using free flaps microvascular reconstruction. In order to obtain a possible resolution of MRONJ, patients with reasonable life expectancy should be considered for microvascular flap reconstruction after aggressive resection of the diseased bone.

Conclusion
MRONJ is a significant adverse effect amongst patients under antiresorptive agents. Although MRONJ pathogenesis remains unclear, significant progress has been made with respect to the diagnosis and staging of the disease, as well as with risk-reduction strategies and treatments. This systematic review based on multiple-reviewer quality assessment criteria was only able to select articles that meet Level 4 of the Oxford Evidence-based medicine scale. Due to the nature of the MRONJ incidence and the critical condition of the patients affected by the primary disease, it is difficult to improve the quality of evidence unless a common effort is applied. Therefore, the authors believe that additional quality studies, such as control multicentre studies or case-controlled studies, are necessary to support the hypothesis of this study.

Conflicts of Interest
This study was not supported by any company and all the authors have not conflicts of interest.

Authors' Contributions
All the authors of this manuscript have substantial contributions to the conception or design of the work; to the acquisition, analysis, or interpretation of data for the work; to draft of the paper and revising it critically and finally approved the version to be published.