THE EFFECTS OF SURGICAL RESECTION AS A METHOD OF MANAGEMENT IN MEDICATION- RELATED OSTEONECROSIS IN THE JAW- A SYSTEMATIC LITERATURE REVIEW.

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Kaunas, 2021

Merlin Jose valiyaparambil

2021, Group 12

THE EFFECTS OF SURGICAL RESECTION AS A

METHOD OF MANAGEMENT IN MEDICATION-

RELATED OSTEONECROSIS IN THE JAW- A

SYSTEMATIC LITERATURE REVIEW.

Master’s Thesis

Supervisor: Gintaras Juodžbalys

Professor, DDS, PhD

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FINAL MASTER ‘S THESIS IS CONDUCTED

AT THE DEPARTMENT OF ORAL AND MAXILLOFACIAL

SURGERY.

STATEMENT OF THESIS ORIGINALITY

I confirm that the submitted Final Master ‘s Thesis. “THE EFFECTS OF SURGICAL

RESECTION AS A METHOD OF MANAGEMENT IN MEDICATION- RELATED OSTEONECROSIS IN THE JAW- A SYSTEMATIC LITERATURE REVIEW”

1. Is done by myself.

2. Has not been used at another university in Lithuania or abroad.

3. I did not used any additional sources that are not listed in the Thesis, and I provide a complete list of references.

I confirm by e-mail, and the work will be signed after the end of the quarantine and emergency situation due to the COVID-19 pandemic in the republic of Lithuania.

(2021.04.23) (Merlin Jose valiyaparambil)

CONCLUSION OF FINAL MASTER ‘S THESIS ACADEMIC SUPERVISORON THE DEFENSE OF THE THESIS.

(2021.04.14)

FINAL MASTER ‘S THESIS IS APPROVED AT THE DEPARTMENT

(date of approval) (name of the Department and full name of the Head of the Department) (signature)

Final Master ‘s Thesis reviewer

(full name) (signature)

Evaluation of Final Master ‘s Thesis Defense Board:

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCE MEDICAL ACADEMY

FACULTY OF ODONTOLOGY CLINIC

ORAL SURGERY DEPARTEMENT

THE EFFECTS OF SURGICAL RESECTION AS A METHOD OF MANAGEMENT IN MEDICATION- RELATED OSTEONECROSIS IN THE JAW- A SYSTEMATIC LITERATURE

REVIEW. Master’s Thesis

The thesis was done

by student Supervisor Gintaras Juodžbalys Professor DDS, PhD 23th April 2021 Merlin Jose Valiyaparambil

5th_Year

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EVALUATION TABLE OF THE MASTER’S THESIS

OF THE TYPE OF SYSTEMIC REVIEW OF SCIENTIFIC LITERATURE

Evaluation: ...

Reviewer: ...

(scientific degree. name and surname)

Reviewing date: ...

No. MT parts MT evaluation aspects

Compliance with MT requirements and evaluation Yes Partially No 1 Summary (0.5 point)

Is summary informative and in compliance with the

thesis content and requirements? 0.3 0.1 0

2 Are keywords

essence?

in compliance with the thesis

0.2 0.1 0

3 Introduction, aim and tasks

(1 point)

Are the novelty, relevance and significance of the

work justified in the introduction of the thesis? 0.4 0.2 0 4 Are the problem, hypothesis, aim and tasks formed

clearly and properly? 0.4 0.2 0

5 Are the aim and tasks interrelated? 0.2 0.1 0

6 Selection criteria of the studies, search methods and strategy (3.4 points)

Is the protocol of systemic review present? 0.6 0.3 0 7

Were the eligibility criteria of articles for the selected protocol determined (e.g., year, language,

publication condition, etc.)

0.4 0.2 0

8

Are all the information sources (databases with dates of coverage, contact with study authors to identify additional studies) described and is the last search day indicated?

0.2 0.1 0

9

Is the electronic search strategy described in such a way that it could be repeated (year of search, the last search day; keywords and their combinations; number of found and selected articles according to the combinations of keywords)?

0.4 0.1 0

10

Is the selection process of studies (screening, eligibility, included in systemic review or, if applicable, included in the meta-analysis) described?

0.4 0.2 0

11

Is the data extraction method from the articles (types of investigations, participants, interventions, analysed factors, indexes) described?

0.4 0.2 0

12

Are all the variables (for which data were sought and any assumptions and simplifications made) listed and defined?

0.4 0.2 0

13

Are the methods, which were used to evaluate the

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information is to be used in data synthesis, described?

14 Were the principal summary measures (risk ratio,

difference in means) stated? 0.4 0.2 0

15

Systemization and analysis of data

(2.2 points)

Is the number of studies screened: included upon assessment for eligibility and excluded upon giving the reasons in each stage of exclusion presented?

0.6 0.3 0

16

Are the characteristics of studies presented in the included articles, according to which the data were extracted (e.g., study size, follow-up period, type of respondents) presented?

0.6 0.3 0

17

Are the evaluations of beneficial or harmful outcomes for each study presented? (a) simple summary data for each intervention group; b) effect estimates and confidence intervals)

0.4 0.2 0

18

Are the extracted and systemized data from studies presented in the tables according to individual asks?

0.6 0.3 0

19

Discussion (1.4 points)

Are the main findings summarized and is their

relevance indicated? 0.4 0.2 0

20 Are the limitations of the performed systemic

review discussed? 0.4 0.2 0

21 Does author present the interpretation of the

results? 0.4 0.2 0

22

Conclusions (0.5 points)

Do the conclusions reflect the topic, aim and

tasks of the Master’s thesis? 0.2 0.1 0

23 Are the conclusions based on the analysed material?

0.2 0.1 0

24 Are the conclusions clear and laconic? 0.1 0.1 0

25

References (1 point)

Is the references list formed according to the

requirements? 0.4 0.2 0

26

Are the links of the references to the text correct? Are the literature sources cited correctly and precisely?

0.2 0.1 0

27 Is the scientific level of references suitable for _{Master’s thesis?} 0.2 0.1 0

28

Do the cited sources not older than 10 years old form at least 70% of sources, and the not older than 5 years – at least 40%?

0.2 0.1 0

Additional sections, which may increase the collected number of points

29 Annexes Do the presented annexes help to understand the

analysed topic? +0.2 +0.1 0

30

Practical

recommendations Are the practical recommendations suggested

and are they related to the received results? +0.4 +0.2 0

31

Were additional methods of data analysis and their results used and described (sensitivity analyses ,meta-regression)?

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32

Was meta-analysis applied? Are The selected statistical methods indicated? Are the results of each meta-analysis presented?

+2 +1 0

General requirements, non-compliance with which reduce the number of points

33

General requirements

Is the thesis volume sufficient (excluding annexes)?

15-20 pages (-2 points)

<15 pages (-5 points) 34 Is the thesis volume increased

artificially? -2 points -1 point

35 Does the thesis structure satisfy the _{requirements of Master’s thesis?} -1 point -2 points 36 Is the thesis written in correct language,

scientifically, logically and laconically? -0.5 point -1 points 37 Are there any grammatical, style or

computer literacy-related mistakes? -2 points -1 points 38 Is text consistent, integral, and are the

volumes of its structural parts balanced? -0.2 point -0.5 points

39 Amount of plagiarism in the thesis. >20%

(not evaluated)

40

Is the content (names of sections and sub- sections and enumeration of pages) in compliance with the thesis structure an aims?

-0.2 point -0.5 points

41

Are the names of the thesis parts in compliance with the text? Are the titles of sections and sub-sections

distinguished logically and correctly?

42 Are there explanations of the key terms

and abbreviations (if needed)? -0.2 point -0.5 points 43

Is the quality of the thesis typography (quality of printing, visual aids, binding) good?

*In total (maximum 10 points):

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ABBREVIATIONS

ONJ- Osteonecrosis in jaw

BP- Bisphosphonate

BRONJ- Bisphosphonate related osteonecrosis in jaw MRONJ- Medication-related osteonecrosis in jaw ECOG-PS- ECOG performance status.

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ABSTRACT

Objective: The purpose of this study is to evaluate the effects of surgical resection as a

method of management, in patients with medication-related osteonecrosis in the jaw by using a systematic literature review.

Method: The data research was performed on PubMed and Cochrane library on English

studies dated from 2011 until 2020. The keywords used for the search is as followed: bisphosphate, surgical resection, osteonecrosis, which resulted in 70 studies. Screening of titles, abstracts, and full texts was done. Seven articles matched up to the criteria and used for data extraction.

Results: Seven articles were used in the study which had met the inclusion criteria. The

stages of MRONJ, location of the affected area, the procedure conducted on the patient, BP usage and outcomes were evaluated. Along with the recurrence rate and post-operative complication was analysed. A significant positive outcome was identified with patients who underwent surgical resection. This method of management was most effective in patients with stage 3 MRONJ. The recurrence rate was low and most post-operative complications were treatable. These complications could be managed with conservative treatments. The best outcome was reached with a combination of surgical and conservative management.

Conclusion: Based on studies, it is understood that surgical resection has a positive

outcome on patients with advanced MRONJ. However, further studies need to be conducted in order to come to a clear conclusion with regards to the reliability of surgical intervention as a method of management. Also, taking into consideration the influence of drug therapy leading to MRONJ.

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INTRODUCTION

Osteonecrosis is a condition which results in necrotic bone cells. It can be described as avascular necrosis (APV), ischemic bone necrosis or aseptic necrosis. Over time, this condition has been discovered to be related to intravenous administrations of bisphosphonates, zoledronate, pamidronate and antiresorptive medications. These medications are used during the management of metastatic breast cancer and multiple myeloma [8].

Bisphosphonate (BP’s) are unstable equivalents of inorganic pyrophosphate which contributes towards inhibition of bone resorption. This mechanism causes indifferences in osteoclasts metabolic activity. The function of osteoclasts is to inhibit differentiation of precursor cells, maturation of osteoclasts and apoptosis. BP’s also influence the anti- angiogenic activity. The interaction between BP’s and angiogenic activity cause hypercalcemia levels to reduce. This does not help the fact that tumor’s and/or bone metastases also contribute a reduction in hypercalcemia levels [9].

There are many great benefits in using BP on patients with malignancy and benign conditions. There is a possible low-grade risk of ONJ which can be associated with oral BP used in the treatment of osteopenia, osteoporosis and Paget's disease. On the other hand, there is a higher-grade risk associated with intravenous (IV) administration for the treatment of multiple myeloma and bone metastases [13].

There are two types of BP’s: nitrogenous and non- nitrogenous. In previous studies, there has been conclusions made that only nitrogenous BP is associated in BRONJ [11].

In 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) recommended changing the nomenclature BRONJ to medication-related osteonecrosis of the jaw (MRONJ) because other anti-resorptive drugs such as denosunab are also related to the onset of this disease [10]. The classification of stages of MRONJ were reconsidered previously, as it was not reflection accurate stages of the disease and to allow possible stratification of patients [10] (Table 1).

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Stage 0 requires systematic management. This includes the use of antibiotics and pain medication. Stage 1 requires the use of antibacterial mouth rinse and a clinical follow up to review the indication for continued bisphosphonate therapy. Stage 2 requires debridement to relieve soft tissue irritation and infection control along with symptomatic treatment. Lastly, stage 3 requires surgical debridement or resection for longer term palliation of infection and pain [10] (Table 8).

Surgical resection can be defined as the partial removal of an organ or tissue. Therefore, a Mandiblelectomy or mandible resection is described as a partial removal of the mandible.

Surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is considered controversial. Current recommendations contraindicate aggressive surgery as post-operative results are unpredictable and may lead to the advancement of the disease. Which may result in the recurrence of the disease [12].

The aim of the study is to evaluate the outcomes of surgical treatment on patients with advanced MRONJ. The primary outcome is to assess the reliability of surgical resection as method of management. The secondary outcome includes an analysis of post-operative complications and the reliability of surgical resection. The hypothesis is that surgical resection will have a positive outcome on patients with advanced MRONJ presented in the study.

The tasks of this review are:

1. To analyse the outcomes of surgical resection on patients with advanced MRONJ.

2. To evaluate the reliability of surgical resection as a method of management.

3. To assess post-operative complication.

Disease definition

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Table 1: Classification according to AAMOS 2014 [10].

Staging of Medication-related osteonecrosis of the jaw.

Description

At risk

Patients who have been treated with intravenous or oral bisphosphonate and with no significant clinical evaluation of bone necrosis.

Stage 0 No clinical evidence of necrotic bone but

nonspecific clinical findings, radiographic changes, and symptoms.

Stage 1

Exposed and necrotic bone or fistulas attached to the bone. can be identified. In patients who are asymptomatic and have no evidence of infection.

Stage 2 Exposed and necrotic bone or fistulas attached to the bone. that is associated with infection which is prevalent through pain and erythema in the region effected. Can be present with or without purulent drainage.

Stage 3

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1.SELECTION CRITERIA FOR STUDY, SERACH METHOD

AND STRATEGY

Bioethics approval code-BEC-OF-83 (Annex 4)

1.1 Protocol and registration

Documentation of the protocol for systematic review was specified prior to the analysis and the inclusion criteria method has been presented according to PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols). (Refer to Annex 1)

1.2 Focus Question

The clinical question was presented according to the population, intervention,

comparison and outcome (PICO) study design.

Table 2: PICO study design.

Focus question:

How can surgical resection have an impact on patients with advanced MRONJ and to evaluate effectiveness of this method of management?

1.3 Types of publications

The studies used in this systematic review is performed on humans and is reviewed in

Component Description

Population (P) Patients who has been diagnosed with advanced ONJ, underwent bisphosphate therapy also used surgical resection as method of management.

Intervention (I) Clinical evaluation regards to outcomes of surgical resection.

Comparison (C) Comparison has been made between patients with different stages of MRONJ and has underwent surgical resection.

Outcomes (O) To evaluate the clinical significance of surgical resection on advanced of MRONJ.

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the English language.

1.4 Types of studies

The systematic review included all human studies published between January 2011-January 2021. These studies involve surgical resection as a method of management on patients with medication related ONJ.

1.5 Population

Male and female patients from a variety of ages, who have been diagnosed with ONJ. Who have underwent bisphosphonate therapy and had chosen surgical resection as a method of management.

1.6 Information source

Information sources were chosen from PubMed and Cochrane library databases.

1.7 Article search strategy

A search on the online literature was conducted. Databases that were chosen by the author included PubMed and Cochrane library. Medical subjects' headings [MesH] terms were used to increase the precision of the search and find articles. The search was conducted using the following keywords: bisphosphate, surgical resection, osteonecrosis. The keywords were presented in the search engine as ‘bisphosphonate associated osteonecrosis of the jaw [MeSH Terms]) AND (surgical resection [Text word] which resulted in 57 articles. Whereas using ((bisphosphonate) [text word] AND (osteonecrosis)) [text word] AND (surgical resection) [Text word] resulted in 70 articles. The articles used in this study was repeated in both searches. Therefore, usage of keywords bisphosphonate, osteonecrosis and surgical resection allowed for a better understanding of the study conducted. The search was limited to English language and

performed on humans. Articles published from 1st January 2011 - 31st December 2020

were extracted.

1.8 Inclusion and exclusion criteria Inclusion criteria

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-Classification of stages in MRONJ according to AAOMS

-Studies which used surgical resection as a method of management for MRONJ

-Studies published between 2011-2021

-Studies conducted on humans

-Full-text articles

-Retrospective studies and prospective studies

-Clinical trails

Exclusion criteria

- Case reports and literature reviews

-Non-English articles

-Duplicate articles

-Studies conducted before 2011

-Studies on animals

-Studies with usage of other surgical intervention as well as resection -In vitro and laboratory studies

1.9 Sequential search strategy

Articles were selected according to relevancy to the topic of this study. All exclusion criteria were considered. The following articles were excluded due to irrelevant data which cannot be applicable to the conducted study. Articles were screened by reading full-texts and confirming each article is based on inclusion and exclusion criteria. The initial search of two databases were carried out which resulted in 70 articles. The extraction of data was implemented by the use of filters such as: full-text, clinical trials and year of publication between 2011-2021. 45 articles were ruled out with 25 articles remaining. The remaining articles were assessed for edibility in response to the goals and themes of the current review.

1.10 Critical appraisal

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articles being used, with regards to the study conducted. The critical appraisal is conducted through 28 questions which attempts to determine the validity and applicability the articles. The checklist questions are divided into four main sections (population, data collection, study design and results). All articles included in the study have met the inclusion criteria [20]. (Refer to the Annex 2)

Table 3: EBL checklist results.

Section A Section B Section C Section D Overall validity Bedogni et al. 2011 Y/T=6/6 =100% valid Y/T=8/8 =100% valid Y/T=5/5 =100% valid Y/T=5/6 =83.3% valid Y/T=24/27 =88.8% valid Eckardt et al. 2011 Y/T=6/6 =100% valid Y/T=7/8 =87.5% valid Y/T=5/5 =100% valid Y/T=5/6 =83.3% valid Y/T=23/27 =85.2% valid Graziani et al. 2011 Y/T= 5/6 =83.3% valid Y/T=7/8 =87.5% valid Y/T=4/5 =80% valid Y/T=5/6 =83.3% valid Y/T=21/27 =77.7% valid Giuseppe et al. 2014 Y/T=6/6 =100% valid Y/T=8/8 =100% valid Y/T=5/5 =100% valid Y/T=5/6 =83.3% valid Y/T= 24/27 =88.8% valid Klingelhöffer et al. 2016 Y/T=5/6 =83.3% valid Y/T=8/8 =100% valid Y/T=5/5 =100% valid Y/T=5/6 =83.3% valid Y/T= 23/27 =85.2% valid Caldroney et al. 2017 Y/T=5/6 =83.3% valid Y/T=7/8 =87.5% valid Y/T=4/5 =80% valid Y/T=4/5 =83.3% valid Y/T=21/27 =77.7 % valid

Altay et al. 2018 Y/T=5/6

=83.3% valid Y/T= 7/8 =87.5% valid Y/T=4/5 =80% valid Y/T= 5/6 =83.3% valid Y/T= 21/27 =77.5% valid

Total Calculation for overall validity: (Y+N+U=T)

If Y/T ≥75% or if N+U/T ≤ 25% then you can safely conclude that the study is valid

1.11 Data extraction

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1.12 Data items

1 “Author” -Described author of publication 2 “Year” – Indicated the year of study

3 “Type of study”- Revealed the type of study

4 “Groups”- indicated the type of disease (MRONJ or BRONJ)

5 “Sample size”- revealed the number of patients involved in the study.

6 “Methods”- described the type of treatment (surgical resection) and sample size (patients affected by advanced MRONJ)

7 “Indication of drug therapy”- Revealed the reason in which the drug was administrated to the patients which contributed to the occurrence of MRONJ. 8 “Stages of MRONJ”- described patient’s status while the study was conducted

according to AAOMS.

9 “Location”- revealed the most common location in which the disease had occurred in the affected patients.

10 “BP history”- Revealed pervious administration of BP due to other diseases. 11 “Outcomes”- Outlined the possible outcomes of the procedure (positive or

negative outcome)

12 “Recurrence rate”- describes the possibility of recurrence (After surgical resection)

13 “Post-operative complication)- indicated the complication which was present after the procedure.

1.13 Synthesis of results

Relevant data of interest on the previously stated variables were collected and organised into 3 tables. They were then divided accordingly to the selected parameters such as sample size, surgical procedure, location, BP history, outcome, recurrence rate and post-operative complication. Additionally, a pie chart indicating the reason for drug therapy is also presented in this study. All of which contribute to different possible outcomes of the study.

1.14 Statistical analysis.

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2.SYSTEMISATION AND DATA ANALYSIS

2.1 Study selection

Inclusion and exclusion criteria were considered. Therefore, duplication and irrelevant topics to the primary outcome were excluded. A total number of 70 articles was reviewed and analyzed using the inclusion criteria, out of which only 7 articles met the criteria and was used for data extraction. In the data extraction, outcomes of surgical intervention on patients with advanced MRONJ, recurrence rate and post-operative complications were considered. The flow diagram of study selection according to PRISMA guidelines is presented below (Figure 1).

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2.2 Exclusion criteria

The exclusion criteria were used to assess 18 full-text [21-38] articles in which primary outcomes was not achieved. Therefore, excluded from the present study.

2.3 Study characteristics

The studies revealed that most common indications for drug therapy is for patients with multiple myeloma, prostate cancer and breast cancer. Also, there are other carcinomas contributing to the requirement of drug therapy. A common disease which is also recognised to have the demand of such treatment is osteoporosis. MRONJ is commonly presented at the site of the mandible. Furthermore, all patients underwent surgical intervention (Figure 2) [1-7].

In the study conducted by S.Caldroney et al., 11 patients selected were classified with stage 3 MRONJ. The majority of patients (90%) were treated with bisphosphonates and followed by denosumab. These patients underwent ablative surgery or resection with microvascular free flap reconstruction. With follow-up at 8 weeks.

complete bone reunion was observed in all the patients, this was proven with radiographic evidence which in evaluation revealed bone to bone contact. There was no recurrence of MRONJ reported [1].

The recurrence rate (9.5%) was recognised within the study conducted by Alberto bedogni et. Al. Detection of Osteomyelitis in the resection margins post-surgery can contribute to BRONJ recurrence. The cumulative recurrence rate of BRONJ in resected jaws is 3.1% and 9.4% at 3 and 6 months [2] [Table 5].

The overall conclusion of the results from the articles revealed a positive outcome on patients who underwent surgical resection [Table 4].

Postoperative complications mentioned in S.Caldroney et al. include wound infection, wound dehiscence and plate exposure (27%). ECOG-PS preoperative score ranged from 0-2 and the post-operative score was not effected negatively [Table 6] [1].

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All patients underwent or are currently undergoing treatment with bisphosphonate. Indication for drug therapy was mostly related to patients with metastatic breast cancer (36%) on A.M Eckardt et al and multiple myeloma on Filippo Graziani et al. (Figure 2). Surgical treatment comprised mandibular resection and immediate microvascular bone reconstruction.

A different outcome was identified in the study conducted by Filippo Graziani et al, in which resective surgery resulted in a statistically significant difference (P = .002) as there was an improvement observed in 68%, with no improvement in 27% and a worse clinical condition in 5%. It was compared to stage II patients in which there was a significant improvement. Whereas, no clinical improvement was observed in stage III patients [5]. Therefore, patients in this particular study with advanced MRONJ had a negative or no significant improvement after the surgical resection.

There was an overall positive outcome evaluated with surgical resection with low chances of recurrence. Post complication varied between the individuals and was managed accordingly.

Figure 2: Characteristics of included studies

Others include: Plasmocytoma. Renal cell carcinoma. non-hodgkin lymphoma, acute

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Table 4: Outcomes of surgical treatment on patients with advanced MRONJ.

Table 5: Reliability of surgical intervention on patients with advanced MRONJ

Author Recurrence rate (%)

Bedogni et al. 2011 9.4 within 3 to 6 months

Giuseppe et al. 2014 0 Caldroney et al. 2017 0 Author Study design Sample size Stage of MRONJ Location (most common site) Procedure BP History Outcomes variables Eckardt et al, 2011 Prospective 143 Advanced (23) Mandible (82) Maxilla (39) Marginal bone resection Y Positive outcome Graziani et al, 2011 Prospective 347 Advanced (27) Mandible (154) Maxilla (59) Both (14) Resective intervention Y Negative outcome or no signs of improvement Klingelhöffer et al, 2016

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Table 6: Post-operative complications.

3. DISCUSSION

MRONJ is a challenging yet well discussed condition which will greatly influence a patient’s quality of life. The best form management is still unclear and is under discussion. Treatment recommendations are subjective to each individual and is in accordance with the stage of disease that is present. Some antiresorptive drugs have had a positive impact on patients with breast cancer, prostate cancer and multiple myeloma. In other literature, it is mentioned that antiresorptive drugs also has an influence on patients with bone metastasis, osteoporosis, osteopenia, and Paget disease. However, patients who are administered higher doses over a 2-year period are at an increased risk of developing MRONJ. [15].

In recent studies, it has been observed that oral administration has a mean incidence of 0.1% to 0.06% whereas intravenous administration has 7% chances of being affected by MRONJ [16].

Surgical debridement or sequestrectomy with primary mucosal closure is effective for patients with exposed necrotic bone. If a recurrence is observed, conservative treatment is recommended to be carried out on the affected area of the bone [14]. The authors in this study discussed the possible outcomes of surgical resection on the individuals who has been suffering with advanced MRONJ.

There have been many publications in the recent years which have focused on the surgical outcomes of BRONJ and how surgical intervention is an effective form of management. Van der Wyngaert et al.[18] concluded in their analysis over a 2 year period that 73% of patients showed residual BRONJ after conservative or surgical

Author Post-operative complications

Bedogni et al. 2011 Free flap loss, Salivary gland fistula, Neck hematoma, Multiple fracture and Partial wound dehiscence.

Caldroney et al. 2017

Wound infection, Wound dehiscence and Plate exposure

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therapy. There are many studies which support the idea that conservative therapy resolved BRONJ. 23% of 4,019 patients had been treated fully with conservative treatment in the study presented [17].

Abu-Id et al. reported that healing rates are better with radical treatment compared to conservative therapy. marginal or segmental bone resection was effective in 86% of patients. Whereas, 46% of patients were fully treated with conservative therapy [19]. Some authors presented a success rate of 80-90% with surgical treatment. Whereas, 10-62% with conservative therapy respectively [12]. According to treatment guidelines [18] after symptoms are closely analysed by clinicians. The required treatment is advocated to the patient with their best interest

Table 7: Treatment at different stages of MRONJ.

In this study, surgical resection was analyzed as a method of management. Results indicate that patients with advanced MRONJ can be treated with positive outcomes and show signs of improvement. Case reports with small sample groups have described successful immediate reconstruction of bone and its revascularization. This was assessed through radiographic examination and follow ups. Stage 0 and stage 1 are better resolved with conservative treatments. Whereas, treatment for stage 3 is mainly focused on surgical intervention or a combination of both conservative treatment and surgical intervention.

Stages Treatment

At risk No need for treatment, only the patient needs to be informed

about the possible outcomes for the drug therapy

0 Systemic management e.g.- pain medication and antibiotics

1 Antibacterial mouth rinse and ensure the patient is aware if the

possible outcomes of continuing the drug therapy

2 Symptomatic treatment with antibiotics with pain control

debridement to relieve soft tissue irritation and infection control

3 All conservative treatments with surgical debridement or

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4. CONCLUSION

1. The outcomes and effectiveness of surgical resection varies in different stages of MRONJ. In the presented study, patients with advanced MRONJ had a positive outcome to surgical resection.

2. At present, there is no specific verdict on the reliability of surgical resection on patients with MRONJ.

3. The post-operative complication aforementioned within the study allows to address possible outcomes of the surgical resection. This in turn can lead to a discussion of possible methods of management towards patients. This is to ensure better surgical practices and a successful surgical procedure.

We can conclude that the type of treatment and its effectiveness varies between individuals. Furthermore, it is important that further studies are to be conducted to focus more on other methods of surgical intervention and different ways to reduce the influence of drug therapy which may potentially lead to MRONJ.

5. ACKNOWLEDGMENT

I would like to express my deepest appreciation to Professor Gintaras Juodžbalys and Dr Sherly George for all the expert guidance and relentless support.

6. PRACTICAL RECOMMENDATIONS

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7. REFERENCE

1. Caldroney S, Ghazali N, Dyalram D, Lubek JE. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw. Int J Oral Maxillofac Surg. 2017 Jul;46(7):871-876. doi: 10.1016/j.ijom.2017.01.023. Epub 2017 Feb 21. PMID: 28233647.

2. Bedogni A, Saia G, Bettini G, Tronchet A, Totola A, Bedogni G, Ferronato G, Nocini PF, Blandamura S. Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis. Oral Oncol. 2011 May;47(5):420- 4. doi: 10.1016/j.oraloncology.2011.02.024. Epub 2011 Mar 24. PMID: 21439892.

3. Eckardt AM, Lemound J, Lindhorst D, Rana M, Gellrich NC. Surgical management of bisphosphonate-related osteonecrosis of the jaw in oncologic patients: a challenging problem. Anticancer Res. 2011 Jun;31(6):2313-8. PMID: 21737657.

4. Klingelhöffer C, Zeman F, Meier J, Reichert TE, Ettl T. Evaluation of surgical outcome and influencing risk factors in patients with medication-related osteonecrosis of the

jaws. J Craniomaxillofac Surg. 2016 Oct;44(10):1694-1699. doi:

10.1016/j.jcms.2016.08.001. Epub 2016 Aug 9. PMID: 27591091.

5. Graziani F, Vescovi P, Campisi G, Favia G, Gabriele M, Gaeta GM, Gennai S, Goia F, Miccoli M, Peluso F, Scoletta M, Solazzo L, Colella G. Resective surgical approach shows a high performance in the management of advanced cases of

bisphosphonate-related osteonecrosis of the jaws: a retrospective survey of 347 cases. J Oral Maxillofac Surg. 2012 Nov;70(11):2501-7. doi: 10.1016/j.joms.2012.05.019. Epub 2012 Aug 9. PMID: 22883322.

6. Altay MA DDS, PhD, Radu A DMD, Pack SE DDS, MD, Yıldırımyan N DDS, Flores-Hidalgo A DDS, Baur DA DDS, MD, Quereshy FA MD, DDS, FACS. Medication-related osteonecrosis of the jaw: An institution's experience. Cranio. 2020 Sep;38(5):333-341. doi: 10.1080/08869634.2018.1528711. Epub 2018 Oct 9. PMID: 30296919.

7. Spinelli G, Torresetti M, Lazzeri D, Zhang YX, Arcuri F, Agostini T, Grassetti L. Microsurgical reconstruction after bisphosphonate-related osteonecrosis of the jaw: our experience with fibula free flap. J Craniofac Surg. 2014 May;25(3):788-92. doi: 10.1097/SCS.0000000000000833. PMID: 24820708.

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9. Russell RG (2011) Bisphosphonates: the first 40 years. Bone 49(1):2–19

10. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F (2014) 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 72(10):1938–1956

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14. Mücke T, Haarmann S, Wolff KD, Hölzle F. Bisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstruction. J Craniomaxillofacial Surg. 2009;37:291–297.

15. Saad F., Brown J. E., Van Poznak C., et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Annals of Oncology. 2012;23(5):1341–1347. doi: 10.1093/annonc/mdr435

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18. Van den Wyngaert T, Huizing MT, Vermorken JB. Osteonecrosis of the jaw related to the use of bisphosphonates. Curr Opin Oncol. 2007 Jul;19(4):315-22. doi: 10.1097/CCO.0b013e32819f820b. PMID: 17545793.

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Kreusch T. "Bis-phossy jaws" - high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J Craniomaxillofac Surg. 2008 Mar;36(2):95-103. doi: 10.1016/j.jcms.2007.06.008. Epub 2008 Jan 30. PMID: 182345

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27. 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.

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8. ANNEX

Annex 1-

Protocol for systematic review according to PRISMA-P

Title The effects of surgical resection as a method of management in medication- related osteonecrosis in the jaw.

Introduction

Aim The aim of the study is to evaluate the outcomes of surgical

treatment on patients with advanced MRONJ.

Tasks 1. To analyse the outcomes of surgical resection on patients with

advanced MRONJ.

2. To evaluate the reliability of surgical resection as a method of management.

3. To assess post-operative complications.

Methods

Eligibility criteria

P- Patients who has been diagnosed with advanced ONJ, underwent

bisphosphate therapy also used surgical resection as method of management.

I- Clinical evaluation of outcomes of surgical resection. C- Comparison has been made between patients with different

stages of MRONJ and has underwent surgical resection.

O- To evaluate the clinical significance of surgical resection on

advanced of MRONJ.

Inclusion criteria

-Studies including patients with MRONJ and underwent bisphosphonate therapy

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-Studies which used surgical resection as a method of management for MRONJ

-Studies published between 2011-2021 -Studies conducted on humans

-Full-text articles

-Retrospective studies and prospective studies -Clinical trails

Exclusion criteria

- Case reports and literature reviews -Non-English articles

-Duplicate articles

-Studies conducted before 2010 -Studies on animals

-Studies with usage of other surgical intervention as well as resection

Information source

Electronic database: PubMed, Cochrane library, science direct Keywords: bisphosphonate, osteonecrosis and surgical resection Time period: January 2011- January 2021

Study selection Including data which is suitable for the inclusion criteria. Screening for duplicates

exclusion studies by assessing eligibility and exclusion criteria.

Outcomes and prioritization

The secondary outcome included analysis of the post-operative complications and reliability of

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Annex 2-

S.Caldroney et al, 2017

EBL Critical Appraisal Checklist _{Yes (Y) No (N) Unclear (U) N/A}

Sect io n A: P o pu la tio n

Is the study population representative of all users, actual and eligible, who might be included in the

study? √

Are inclusion and exclusion criteria definitively outlined? √

Is the sample size large enough for sufficiently precise estimates? √ Is the response rate large enough for sufficiently precise estimates? √

Is the choice of population bias-free? √

If a comparative study:

Were participants randomized into groups? Were the groups comparable at baseline?

If groups were not comparable at baseline, was incomparability addressed by the authors in the analysis?

√

Was informed consent obtained? √

Sect io n B : Da ta Co llect io n

Are data collection methods clearly described? √

If a face-to-face survey, were inter-observer and intra-observer bias reduced? √ Is the data collection instrument validated? _√

If based on regularly collected statistics, are the statistics free from subjectivity? √ Does the study measure the outcome at a time appropriate for capturing the intervention’s effect? _√ Is the instrument included in the publication? √ Are questions posed clearly enough to be able to elicit precise answers? √ Were those involved in data collection not involved in delivering a service to the target population? √

Sect io n C: Study Desig n

Is the study type / methodology utilized appropriate? √

Is there face validity? √

Is the research methodology clearly stated at a level of detail that would allow its replication? √

Was ethics approval obtained? √

Are the outcomes clearly stated and discussed in relation to the data collection? √

Sect

io

n D:

Resul

ts

Are all the results clearly outlined? √

Are confounding variables accounted for? √

Do the conclusions accurately reflect the analysis? √ Is subset analysis a minor, rather than a major, focus of the article? √ Are suggestions provided for further areas to research? √

Is there external validity? √

Calculation for section validity: (Y+N+U=T)

If Y/T <75% or if N+U/T > 25% then you can safely conclude that the section identifies significant omissions and that the study’s validity is questionable. It is important to look at the overall validity as well as section validity.

Calculation for overall validity: (Y+N+U=T)

If Y/T ≥75% or if N+U/T ≤ 25% then you can safely conclude that the study is valid.

Section A validity calculation: 5/6= 83.3% valid Section B validity calculation: 7/8= 87.5 % valid Section C validity calculation: 4/5= 80% valid Section D validity calculation: 5/6= 83.3% valid

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Mehmet Ali Altay et al, 2018

study? √

Are inclusion and exclusion criteria definitively outlined? √ Is the sample size large enough for sufficiently precise estimates? √ Is the response rate large enough for sufficiently precise estimates? √

√

Sect io n B : Da ta Co llect io

n Are data collection methods clearly described? √

If a face-to-face survey, were inter-observer and intra-observer bias reduced? √ Is the data collection instrument validated? √

If based on regularly collected statistics, are the statistics free from subjectivity? √ Does the study measure the outcome at a time appropriate for capturing the intervention’s effect? √

Is the instrument included in the publication? √ Are questions posed clearly enough to be able to elicit precise answers? √ Were those involved in data collection not involved in delivering a service to the target population? √

Sect

io

n D:

Resul

ts

If Y/T <75% or if N+U/T > 25% then you can safely conclude that the section identifies significant omissions and that the study’s validity is

questionable. It is important to look at the overall validity as well as section validity.

Section A validity calculation: 5/6= 83.3% valid Section B validity calculation: 7/8= 87.5% valid

Section C validity calculation: 4/5= 80% valid Section D validity calculation:5/6= 83.3% valid

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Filippo Graziani et al, 2011

study? √

Is the sample size large enough for sufficiently precise estimates? √ Is the response rate large enough for sufficiently precise estimates? √

√

If based on regularly collected statistics, are the statistics free from subjectivity? _√ Does the study measure the outcome at a time appropriate for capturing the intervention’s effect? √ Is the instrument included in the publication? √ Are questions posed clearly enough to be able to elicit precise answers? √ Were those involved in data collection not involved in delivering a service to the target population? √

Sect

io

n D:

Resul

ts

Section A validity calculation: 5/6= 83.3% valid Section B validity calculation: 7/8= 87.5% valid Section C validity calculation: 4/5= 80% valid Section D validity calculation:5/6= 83.3% valid

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A.M Eckardt et al. 2011

EBL Critical Appraisal Checklist _Yes

(Y) No (N) Unclear (U) N/A S ec ti on A : P o pu la ti on

Is the study population representative of all users, actual and eligible, who might be included in the study? √ Are inclusion and exclusion criteria definitively outlined? _√ Is the sample size large enough for sufficiently precise estimates? √ Is the response rate large enough for sufficiently precise estimates? _√

√

If based on regularly collected statistics, are the statistics free from subjectivity? _√ Does the study measure the outcome at a time appropriate for capturing the intervention’s effect? √

Is the instrument included in the publication? √ Are questions posed clearly enough to be able to elicit precise answers? √ Were those involved in data collection not involved in delivering a service to the target population? √

Sect

io

n D:

Resul

ts

Section A validity calculation: 6/6= 100% valid Section B validity calculation: 7/8= 87.5 valid Section C validity calculation: 5/5= 100% valid Section D validity calculation: 5/6= 83.3% valid

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Alberto bedogni et. al, 2011

(Y) No (N) Unclear (U) N/A Sect io n A: P o pu la tio n

study? √

Are inclusion and exclusion criteria definitively outlined? √ Is the sample size large enough for sufficiently precise estimates? _√ Is the response rate large enough for sufficiently precise estimates? _√

Is the choice of population bias-free? _√

√

Was informed consent obtained? _√

If based on regularly collected statistics, are the statistics free from subjectivity? √ Does the study measure the outcome at a time appropriate for capturing the intervention’s effect? √ Is the instrument included in the publication? √ Are questions posed clearly enough to be able to elicit precise answers? √ Were those involved in data collection not involved in delivering a service to the target population? √

Sect

io

n D:

Resul

ts

If Y/T <75% or if N+U/T > 25% then you can safely conclude that the section identifies significant omissions and that the study’s validity is questionable. It is important to look at the overall validity as well as

section validity.

Section A validity calculation: 6/6= 100% valid Section B validity calculation: 8/8= 100%valid Section C validity calculation: 5/5= 100% valid Section D validity calculation:5/6= 83.3% valid

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Christoph Klingelhöffer et al, 2016

(Y) No (N) Unclear (U) N/A Sect io n A: P o pu la tio n

study? √

Is the sample size large enough for sufficiently precise estimates? _√ Is the response rate large enough for sufficiently precise estimates? _√

Is the choice of population bias-free? _√

√

If based on regularly collected statistics, are the statistics free from subjectivity? √ Does the study measure the outcome at a time appropriate for capturing the intervention’s effect? √ Is the instrument included in the publication? √ Are questions posed clearly enough to be able to elicit precise answers? √ Were those involved in data collection not involved in delivering a service to the target population? √

Sect

io

n D:

Resul

ts

If Y/T <75% or if N+U/T > 25% then you can safely conclude that the section identifies significant omissions and that the study’s validity is questionable. It is important to look at the overall validity as well as

section validity.

Section A validity calculation: 5/6= 83.3% valid Section B validity calculation: 8/8= 100%valid Section C validity calculation: 5/5= 100% valid Section D validity calculation:5/6= 83.3% valid

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Spinelli Giuseppe et. al, 2014

study? √

Are inclusion and exclusion criteria definitively outlined? _√ Is the sample size large enough for sufficiently precise estimates? √ Is the response rate large enough for sufficiently precise estimates? √

√

Sect io n B : Da ta Co llect io n

If based on regularly collected statistics, are the statistics free from subjectivity? _√ Does the study measure the outcome at a time appropriate for capturing the intervention’s effect? √ Is the instrument included in the publication? √ Are questions posed clearly enough to be able to elicit precise answers? √ Were those involved in data collection not involved in delivering a service to the target population? √

Sect io n C: Study Desig n

Sect

io

n D:

Resul

ts

If Y/T <75% or if N+U/T > 25% then you can safely conclude that the section identifies significant omissions and that the study’s validity is questionable. It is important to look at the overall validity as well as section validity.

Section A validity calculation: 6/6= 100% valid Section B validity calculation: 8/8= 100%valid Section C validity calculation: 5/5= 100% valid Section D validity calculation:5/6= 83.3% valid

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THE EFFECTS OF SURGICAL RESECTION AS A METHOD OF MANAGEMENT IN MEDICATION- RELATED OSTEONECROSIS IN THE JAW- A SYSTEMATIC LITERATURE REVIEW.

THE EFFECTS OF SURGICAL RESECTION AS A

METHOD OF MANAGEMENT IN MEDICATION-

RELATED OSTEONECROSIS IN THE JAW- A

SYSTEMATIC LITERATURE REVIEW.

FINAL MASTER ‘S THESIS IS CONDUCTED

AT THE DEPARTMENT OF ORAL AND MAXILLOFACIAL

SURGERY.

STATEMENT OF THESIS ORIGINALITY

LITHUANIAN UNIVERSITY OF HEALTH SCIENCE MEDICAL ACADEMY

FACULTY OF ODONTOLOGY CLINIC

ORAL SURGERY DEPARTEMENT

TABLE OF CONTENTS

ABBREVIATIONS

ABSTRACT

INTRODUCTION

1.SELECTION CRITERIA FOR STUDY, SERACH METHOD

AND STRATEGY

2.SYSTEMISATION AND DATA ANALYSIS

3. DISCUSSION

4. CONCLUSION

5. ACKNOWLEDGMENT

6. PRACTICAL RECOMMENDATIONS

7. REFERENCE

8. ANNEX