Risk factors for medication-related osteonecrosis of the : a case-control study in Queensland, Australia

Author McGowan, Kelly

Published 2019-02

Thesis Type Thesis (PhD Doctorate)

School School of Dentistry&Oral Hlth

DOI https://doi.org/10.25904/1912/1807

Copyright Statement The author owns the copyright in this thesis, unless stated otherwise.

Downloaded from http://hdl.handle.net/10072/385549

Griffith Research Online https://research-repository.griffith.edu.au RISK FACTORS FOR MEDICATION-RELATED OSTEONECROSIS OF THE JAWS: A CASE CONTROL STUDY IN QUEENSLAND, AUSTRALIA

Kelly McGowan BOH (Dent Sci), Grad Dip Dent

School of Dentistry & Oral Health Griffith Health Group Griffith University

Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy

February 2019

Abstract

BACKGROUND

Medication-related osteonecrosis of the jaws (MRONJ) is a serious condition that develops in up to 15% of patients who take antiresorptive or antiangiogenic medications. Despite extensive research into MRONJ since it was first reported in 2003, it is not clear why a minority of patients will develop this complication, and no gold standard treatment currently exists. A number of possible risk factors for MRONJ have been reported, but the existing evidence is weak and often contradictory. Preventative dentistry has been shown to reduce the incidence of MRONJ, but current guidelines are based on expert opinion and clinical experience. There is a need to better understand the factors that predispose a patient to MRONJ, and define the role of preventative dental care in reducing the incidence of this disease.

AIMS

The purpose of this research was to investigate the contributing risk factors for MRONJ and identify targets and strategies for MRONJ prevention. The intention was to develop an evidence-base for the dental management of patients taking antiresorptive and antiangiogenic medications.

METHODS

The first stage of this project was to conduct a systematic review of patient populations susceptible to MRONJ and previously reported risk factors. These data were used to define three risk categories for further investigation: dental risk factors, systemic risk factors, and haematological abnormalities as putative risk markers. A survey of patients treated at Royal Brisbane and Women’s Hospital (RBWH) and Gold Coast University Hospital (GCUH) between January 2003 and March 2017 was conducted to identify eligible cases of MRONJ and to determine whether the number of cases had changed over time with increasing awareness and understanding of MRONJ. Three case- control studies were used to compare the presence or absence of dental and systemic risk factors and haematological abnormalities between patients with a clinical diagnosis of MRONJ and disease-free controls. Three controls were individually matched to each case

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia i according to sex, age, primary disease, and antiresorptive type, dose, and duration. Associations between risk factors and MRONJ were investigated using conditional logistic regression.

FINDINGS

The systematic review identified 4106 cases of MRONJ, which included patients being treated for 39 different systemic diseases. There was very low level evidence for 25 possible dental and systemic disease indicators, and haematological risk markers. A clear need for more research into risk factors for MRONJ was identified.

Since the first case of MRONJ was reported in 2003, the number of patients diagnosed with MRONJ at RBWH and GCUH has steadily increased. This suggests that improved awareness of MRONJ and the importance of preventative dental care has not translated into a reduction in disease. A number of were found to be significant risk factors for MRONJ, including diabetes, cardiovascular disease, kidney disease, and tobacco use. The Polypharmacy Score (CPS) was determined to be a valid measure of MRONJ risk, and provides clinicians with a simple method of quantifying the cumulative severity of systemic risk factors.

Two-thirds of all patients did not receive a dental examination in the 12 months prior to starting antiresorptives, and participants averaged less than one dental exam every three years during antiresorptive therapy. Cases averaged approximately one extraction and one filling per year during their antiresorptive therapy, which was significantly higher than treatment rates in the control group. Dental extractions and non-surgical dental care (fillings and dentures) increased the risk of MRONJ eight and six times, respectively.

Cases who developed MRONJ and disease-free controls reported blood test results outside of laboratory reference ranges in similar frequencies. The most commonly reported abnormal results were low haemoglobin, low haematocrit, and low lymphocyte counts. The results of a full blood count do not appear to relate to the risk of MRONJ, but this does not preclude the role of immune function in the development of MRONJ.

MRONJ appears to be a complex multifactorial disease. The underlying pathogenesis remains unclear, but there appears to be a significant opportunity to reduce the incidence of MRONJ by improving access to dental care before starting, and during, antiresorptive therapy. This will require a coordinated and collaborative approach from patients, doctors, and oral health professionals.

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia ii

Statement of Original Authorship

The work contained in this thesis has not been previously submitted to meet requirements for an award at this or any other higher education institution. To the best of my knowledge and belief, the thesis contains no material previously published or written by another person except where due reference is made.

Signed: Date: 16th February, 2019

Student: Kelly McGowan

Acknowledgements

I would like to acknowledge the exceptional support of my supervisory team throughout this project. I am extremely fortunate to have worked with such a high-calibre group of experts, and benefited enormously from the collective experience and expertise of the team. Thank you Professor Ivanovski, Dr Acton, Professor Ware and Professor Johnson for your excellent academic input and also your collegial approach to this project. It made for an overwhelmingly positive experience.

A special thank you to my husband Troy, who provided a steady supply of caffeine and encouragement throughout this project and graciously shouldered more than his share of the parenting duties to give me time to work on this. I would also like to thank my parents for their unwavering support of all my endeavours, and for always providing whatever child-minding or respite services were needed to make this possible. And of course to my boys, Max and Luca, for taking all of this in their stride.

I would like to sincerely thank Mr Alan Castree, my senior science teacher, for the pivotal role he played in enabling my tertiary studies. He may have only taught me for a short period, but his influence has been enduring.

I am also grateful to have received financial support from a Griffith University Postgraduate Scholarship for part of my PhD candidature.

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia iii

Table of Contents

Abstract ...... i Statement of Original Authorship ...... iii Acknowledgements ...... iii Table of Contents ...... iv List of Figures ...... vi List of Tables ...... vii List of Abbreviations ...... viii Acknowledgement of Published Papers ...... x Chapter 1: Introduction ...... 1 1.1 Background ...... 1 1.2 Context ...... 8 1.3 Purposes ...... 14 1.4 Scope and definitions ...... 15 1.5 Ethics and governance ...... 17 1.6 Thesis outline ...... 17 Chapter 2: Literature review ...... 19 2.1 Overview ...... 20 2.2 Abstract ...... 21 2.3 Introduction ...... 21 2.4 Methods ...... 22 2.5 Results ...... 26 2.6 Discussion ...... 32 Chapter 3: Assessing the burden of disease ...... 35 3.1 Overview ...... 36 3.2 Abstract ...... 37 3.3 Introduction ...... 37 3.4 Methods ...... 39 3.5 Results ...... 40 3.6 Discussion ...... 42 Chapter 4: Systemic risk factors for MRONJ ...... 45 4.1 Overview ...... 46 4.2 Abstract ...... 49 4.3 Introduction ...... 49 4.4 Methods ...... 51 4.5 Results ...... 54 4.6 Discussion ...... 58

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia iv

Chapter 5: Dental risk factors for MRONJ ...... 61 5.1 Overview ...... 62 5.2 Abstract ...... 63 5.3 Introduction ...... 64 5.4 Methods ...... 65 5.5 Results ...... 68 5.6 Discussion ...... 74 Chapter 6: Haematological risk markers ...... 77 6.1 Overview ...... 78 6.2 Abstract ...... 79 6.3 Introduction ...... 79 6.4 Methods ...... 81 6.5 Results ...... 83 6.6 Discussion ...... 89 Chapter 7: Discussion ...... 92 7.1 Risk factors for MRONJ ...... 92 7.2 Clinical implications ...... 93 7.3 Recommendations for future research ...... 97 7.4 Conclusions ...... 100 Bibliography ...... 101 Appendices ...... 133 Appendix A : Griffith University HREC approval ...... 133 Appendix B : RBWH HREC approval ...... 134 Appendix C : Public Health Act approval ...... 137 Appendix D : Supplemental Table 1 – NOS modification & interpretation ...... 139 Appendix E : Supplemental Table 2 – Included studies (case series/cohort ≥ 5) ...... 140 Appendix F : Supplemental Table 3 – Included studies (case reports <5) ...... 147 Appendix G : Supplemental Table 4 – Included single predictor studies ...... 150 Appendix H : Supplemental Table – Comorbidities by disease group ...... 153 Appendix I : Supplemental Table - Classification of dental treatment by ADA codes ...... 154 Appendix J : Dental management of patients at risk of MRONJ ...... 156

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia v

List of Figures

Figure 1. Clinical presentation of MRONJ. From Russmueller et al., 2016 (8) ..... 2 Figure 2. Proposed mechanism of the pathogenesis of MRONJ ...... 7 Figure 3. University of Connecticut osteonecrosis numerical scale ...... 9 Figure 4. Australian Therapeutic Guidelines: BRONJ ...... 11 Figure 5. NSW Health BRONJ guideline ...... 12 Figure 6. Scottish NHS clinical guideline ...... 13 Figure 7. Flow chart of identification, screening, eligibility assessment and inclusion of studies in the systematic review ...... 26 Figure 8. Incidence of medical and dental comorbidities reported in the included literature from a total of 4106 cases of ONJ...... 28 Figure 9. Number of patients diagnosed with ORN and MRONJ per year since 2003 ...... 41 Figure 10. Distribution of cases and controls across CPS categories ...... 57 Figure 11. Flow chart of participant selection, exclusion and inclusion based on eligibility for public dental treatment and availability of dental records. 68 Figure 12. Flow chart of participant selection, exclusion and inclusion based on availability of eligible blood test results ...... 84 Figure 13. Rothman’s sufficient component cause model, from Rothman, 2012 (301)...... 94 Figure 14. Proposed multifactorial disease pathway for MRONJ ...... 95 Figure 15. Effect on causal pathways for MRONJ when dental risk factors are addressed ...... 96

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia vi

List of Tables

Table 1. Antiresorptive medications associated with MRONJ ...... 3 Table 2. Antiangiogenic medications associated with MRONJ ...... 3 Table 3. Treatment strategies for MRONJ ...... 4 Table 4. Theories of the pathogenesis of MRONJ ...... 5 Table 5. Preventative strategies for MRONJ ...... 16 Table 6. Demographic and clinical summary of previously published cases of MRONJ ...... 27 Table 7. Diseases with previously reported cases of MRONJ ...... 29 Table 8. Previously reported potential risk factors for MRONJ ...... 30 Table 9. Summary of single predictor studies included in the systematic review . 31 Table 10. Demographic information and clinical diagnoses for patients coded K10.2 ...... 40 Table 11. Primary diseases associated with ONJ at RBWH and GCUH ...... 41 Table 12. Number of patients diagnosed with ORN and MRONJ per year since 2003 ...... 42 Table 13. Summary of published comorbidity measures ...... 46 Table 14. Charlson Comorbidity Index ...... 47 Table 15. CPS severity stratification ...... 48 Table 16. Distribution of demographics and clinical factors (systemic risk factors) ...... 55 Table 17. Association between comorbid conditions and MRONJ disease status 56 Table 18. Association between CPS and risk of MRONJ, with subgroup analysis ...... 57 Table 19. Demographic and clinical characteristics of participants (dental risk factors) ...... 70 Table 20. Dental care of cases and controls prior to and during antiresorptive therapy ...... 71 Table 21. Nature and frequency of dental treatment during antiresorptive therapy ...... 72 Table 22. Subgroup analysis: dental risk factors for oncology vs non-oncology patients ...... 73 Table 23. Distribution of characteristics and demographics between cases and controls ...... 86 Table 24. Frequency (percentage) of patients with results outside of the laboratory-specific reference range ...... 87 Table 25. Results outside laboratory reference ranges for oncology and non- oncology subgroups ...... 88

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia vii

List of Abbreviations

AAOMS American Association of Oral and Maxillofacial Surgeons

ADA Australian Dental Association aOR Adjusted odds ratio

ARONJ Antiresorptive-related osteonecrosis of the jaws

ART Antiresorptive therapy

BAONJ -associated osteonecrosis of the jaws

BMT marrow transplant

BP Bisphosphonate

BRONJ Bisphosphonate-related osteonecrosis of the jaws

CCI Charlson Comorbidity Index

CI Confidence interval

CML Chronic myeloid leukaemia

CPS Comorbidity Polypharmacy Score

CRP C-reactive protein

CTX C-terminal telopeptide

CVD Cardiovascular disease

ESR Erythrocyte sedimentation rate

FBC Full blood count

GCUH Gold Coast University Hospital

GP General practitioner

H&N Head and neck

HbA1c Glycated haemoglobin

HREC Human Research Ethics Committee

ICD International Classification of Disease and Related Health Problems

ITONJ International Task Force on Osteonecrosis of the Jaws

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia viii

MAP Medication action plan

MM Multiple myeloma

MMP

MRONJ Medication-related osteonecrosis of the jaws

NOS Newcastle-Ottawa Scale

NSW New South Wales

ONJ Osteonecrosis of the jaws

OP

OR Odds ratio

ORN

PD Paget’s disease

PHA Public Health Act

PRISMA Preferred reporting items for systematic reviews and meta-analyses

RA Rheumatoid arthritis

RANKL Receptor activator of nuclear factor kappa B ligand

RBCC Red blood cell count

RBWH Royal Brisbane and Women’s Hospital

SCC

SCCM Sufficient component cause model

SCT Stem cell transplant

SD Standard deviation

STROBE Strengthening the reporting of observational studies in epidemiology

TG Therapeutic Guidelines

UCONNS University of Connecticut Osteonecrosis Numerical Scale

VEGF Vascular endothelial growth factor

WBCC White blood cell count

WHO World Health Organisation

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia ix

Acknowledgement of Published Papers

Included in this thesis are papers in Chapters 2, 3, 4, 5 & 6 which are co-authored with other researchers. My contribution to each co-authored paper is outlined at the front of the relevant chapter. The bibliographic details and status for these papers including all authors, are:

Chapter 2: McGowan, K., McGowan, T., & Ivanovski, S. (2018). Risk factors for medication- related osteonecrosis of the jaws: A systematic review. Oral Diseases, 24(4), 527-536.

Chapter 3: McGowan, K., Ivanovski, S., & Acton, C. (2018). Osteonecrosis of the jaws: a 14- year retrospective survey of hospital admissions. Australian Dental Journal, 63(2), 202-207.

Chapter 4: McGowan, K., Acton, C., Ivanovski, S., Johnson, N.W., & Ware, R.S. (2019). Systemic comorbidities are associated with medication-related osteonecrosis of the jaws: case- control study. Oral Diseases, in press.

Chapter 5: McGowan, K., Ware, R.W., Acton, C., Ivanovski, S., & Johnson, N.W. (2019). Both nonsurgical dental treatment and extractions increase the risk of medication-related osteonecrosis of the jaws: case-control study. Clinical Oral Investigations, in press.

Chapter 6: McGowan, K., Ware, R.W., Acton, C., Ivanovski, S., & Johnson, N.W. (2018). Full blood counts are not predictive of the risk of medication-related osteonecrosis of the jaws: a case- control study. Oral Surgery, Oral Medicine, Oral & Oral Radiology, in press.

Appropriate acknowledgements of those who contributed to the research but did not qualify as authors are included in each paper.

Signed: Date: 16th February, 2019

Student: Kelly McGowan

Countersigned: Date: 11th February, 2019

Supervisor: E/Prof Newell W Johnson

Risk factors for medication-related osteonecrosis of the jaws: a case control study in Queensland, Australia x

Chapter 1: Introduction

This chapter provides a background on medication-related osteonecrosis of the (Section 1.1), and outlines the context (Section 1.2), purpose (Section 1.3), and scope (Section 1.4) of this research. Section 1.5 details the ethics and governance requirements for the project, and Section 1.6 outlines the remaining chapters of the thesis.

1.1 BACKGROUND

1.1.1 Terminology Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon but serious complication of antiresorptive and antiangiogenic therapies (1). It was first reported in the literature in 2003 with the introduction of bisphosphonate medications (2), and was originally termed “bisphosphonate-related osteonecrosis of the jaw” (BRONJ). In 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) recommended a change in nomenclature to MRONJ to include cases associated with other antiresorptive agents, namely (1), and new antiangiogenic medications (3-6). It is also referred to in the literature as antiresorptive-related osteonecrosis of the jaw (ARONJ), bisphosphonate-associated osteonecrosis of the jaw (BAONJ), and osteochemonecrosis. The International Task Force on Osteonecrosis of the Jaw (ITONJ) 2015 consensus paper used the term “osteonecrosis of the jaw” (ONJ), however as this could be mistaken to include osteoradionecrosis (ORN) of the jaw, the disease of interest will be referred to as MRONJ for the purposes of this report.

1.1.2 Definition According to the updated 2014 AAOMS definition, a patient is diagnosed with MRONJ when the following criteria are met:

1. Current or previous treatment with antiresorptive or antiangiogenic agents

2. Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for longer than 8 weeks

3. No history of radiation therapy or obvious metastatic disease to the jaws

Chapter 1: Introduction 1

It is important to use the above criteria carefully to differentiate between other types of ONJ and a number of commonly misdiagnosed oral conditions. ONJ can result from radiation, infection or trauma and the causative factor must be correctly identified from careful clinical evaluation and a detailed patient history. Alveolar , sinusitis, , chronic , tumours of the jaw, and metastases of primary tumours must be excluded before a final diagnosis of MRONJ is made (7).

Redacted

Figure 1. Clinical presentation of MRONJ. From Russmueller et al., 2016 (8)

1.1.3 Associated medications Antiresorptives: Two types of antiresorptive medications have been associated with the development of MRONJ; and RANKL inhibitors. Antiresorptives work by interfering with the differentiation and activation of to prevent effective physiological . They are prescribed to increase bone strength in osteoporosis and prevent hypercalcemia and other skeletal-related events in (9-11). The most commonly prescribed antiresorptives are listed in Table 1.

Chapter 1: Introduction 2

Table 1. Antiresorptive medications associated with MRONJ Drug name Trade name Indication Route BISPHOSPHONATES: Alendronate Fosamax® Treatment & prevention of osteoporosis Oral Fosavance® Risendronate Actonel® Treatment & prevention of osteoporosis, treatment Oral of Paget’s disease Actonel Combi® Zoledronate Aclasta® Treatment & prevention of osteoporosis, treatment IV of Paget’s disease and cancer Zometa® Pamidronate Aredia® Treatment of cancer, Paget’s disease, and bone pain IV Ibandronate Bondronat® Treatment and prevention of osteoporosis, treatment Oral or of cancer IV Bonviva® Clodronate Bonefos® Neoplasm-associated hypercalcemia Oral or IV Clasteon® RANKL INHIBITOR: Denosumab Xgeva® Treatment and prevention of osteoporosis, treatment SQ of cancer Prolia®

Abbreviations: IV, intravenous; SQ, subcutaneous

Antiangiogenics: A number of new anticancer strategies using antiangiogenic medications have also reported isolated cases of MRONJ. Angiogenesis inhibitors interfere with the formation of new blood vessels and are used to treat tumours and malignancies (12). A number of different classes of antiangiogenics have been linked to MRONJ, as outlined in Table 2.

Table 2. Antiangiogenic medications associated with MRONJ Drug name Trade name Indication Route H-VEGF ANTIBODY: Bevacizumab Avastin® Metastatic colorectal, renal & non-small cell IV lung carcinomas, glioblastoma TKIs: Sunitinib Sutent® Neuroendocrine tumours, gastro-intestinal Oral stromal tumours, renal cell carcinoma Sorafenib Nexavar® Metastatic hepatic & renal cell carcinoma Oral

Cabozatinib Cometriq® Metastatic medullary thyroid cancer Oral M-TOR INHIBITOR: Everolimus Afinitor® Metastatic renal cell carcinoma, hormone Oral positive breast cancer, organ transplant

Temsirolimus Torisel® Metastatic renal cell carcinoma IV Abbreviations: IV, intravenous; H-VEGF, humanised vascular endothelial growth factor; TKI, tyrosine kinase inhibitor; M-TOR, mammalian target of rapamycin.

Chapter 1: Introduction 3

1.1.4 Epidemiology The prevalence of MRONJ varies with the dose and duration of exposure to antiresorptive medications. Oncology patients are considered to be the most at-risk population for MRONJ, as they receive intravenous bisphosphonates and denosumab at doses 12-15 times higher than those prescribed for patients with post-menopausal osteoporosis (13). The prevalence of MRONJ is reported to be between 1-15% in patients receiving high-dose antiresorptives for malignancy. The risk of MRONJ in osteoporotic patients is estimated to be between 0.004-0.1% (14-16), however this increases to 0.21% after 4 years of antiresorptive therapy (1). While the overall prevalence of MRONJ is low, this still translates to a significant number of affected patients given the high number of individuals prescribed antiresorptive therapies (17).

1.1.5 Treatment Several management options have been proposed for MRONJ, although no agreement on a gold standard of treatment has been reached. Non-surgical, conservative and surgical approaches have been reported with varying success rates, as well as a number of novel and adjunct treatments, as outlined in Table 3. However, MRONJ does not respond predictably to conservative treatment (18-20), and although surgical approaches have reported success rates around 84% (21-23), the risk of refractory disease at the margins of resected bone is a serious potential complication (24), and the general condition of some patients is a contraindication for general anaesthetic (20). Consequently, current recommendations for the clinical management of MRONJ are to individualise treatment to the patient depending on their symptoms, signs of acute infection, the stage of MRONJ, and their life expectancy (1, 17, 25, 26).

Table 3. Treatment strategies for MRONJ References

Non-surgical Oral hygiene, regular dental follow-up, CHX mouthwash, ABs (27-31)

Conservative Sequestrectomy ± superficial debridement of necrotic bone (1, 20, 32) Surgical Calculated removal of all necrotic bone to re-establish normal bone (19, 23, 33-36) margin – may involve marginal, segmental or total resection Adjunct/Novel Low-level laser therapy (37-41) Hyperbaric oxygen therapy (42-44) Teriparatide therapy (45-53) Autologous stem cell transplantation (54, 55) Platelet concentrates (PRP, PRF) (56-64)

Abbreviations: CHX, ; ABs, antibiotics; PRP, platelet-rich plasma; PRF, platelet-rich fibrin

Chapter 1: Introduction 4

1.1.6 Pathogenesis Despite sustained investigation into the underlying pathogenesis of MRONJ since it was first reported in 2003, the exact mechanism of disease remains unclear. Efforts to elucidate the cause of MRONJ are complicated by the low incidence of disease, ethical implications of research involving human subjects, and the difficulty in accurately replicating this complex disease process in animal models. There has been much debate in the literature, but no single theory has yet been able to explain why only certain patients develop MRONJ. The arguments for and against each proposed theory of pathogenesis are summarised in Table 4.

Table 4. Theories of the pathogenesis of MRONJ Theory Arguments for Arguments against

Apoptosis of BPs have high affinity for bone mineral and have Very low prevalence of disease suggests been shown to accumulate in the bone, even patient-specific factors influence onset of within the lacunae (65, 66) MRONJ rather than general physiologic actions of the medications (72) Histological evidence of empty lacunae and focal matrix in MRONJ-affected bone (67) Theory is specific to actions of BP and does not explain MRONJ in patients taking Accumulation of nonviable osteocytes evident in denosumab or antiangiogenics animal models with BP use (68) Suggests that nonviable bone would occur May explain why are considered throughout the skeleton, which has not been an additive risk factor, as they are also associated proven (73) with increased osteocyte (69, 70) Viable osteocytes are seen histologically in In vitro results show osteocyte apoptosis samples of MRONJ-affected bone (67) increases with BP concentration, which may explain increasing risk of MRONJ relative to duration of drug therapy (71)

Suppression of MRONJ primarily affects patients taking Very low overall prevalence of MRONJ in osteoclastic antiresorptive medications (1, 17) patients taking antiresorptives (1, 17) bone activity Daily alendronate administration in dogs was Antiangiogenic medications that have no shown to significantly suppress turnover of the direct action on bone cells are also jawbone (although did not establish a clear associated with MRONJ (75-77) cause-effect relationship with MRONJ) (68) No reported cases of MRONJ in children Teraparatide, a recombinant human parathyroid taking high doses of BPs for osteogenesis hormone that stimulates bone remodelling, has imperfecta (78, 79) been used to successfully resolve MRONJ Markers of bone turnover are not lesions (46, 48, 74) suppressed in many patients with MRONJ (80-82)

Inhibition of Other types of osteonecrosis (i.e. avascular There is no evidence that denosumab exerts angiogenesis & necrosis of the hip and osteoradionecrosis of the any antiangiogenic effects, yet is associated obstruction of jaw) are caused by iatrogenic disruption of the with the same risk of MRONJ as BPs (17) vasculature vasculature (83-86) shows vasculature still present in BPs decrease micro-vessel density of bone in necrotic regions of MRONJ (92) vivo, and may inhibit new blood vessel formation (87-90) Zolendronate has been shown to decrease levels of circulating VEGF, which is a marker for angiogenesis (91), and antiangiogenic medications are associated with MRONJ (4, 75)

Chapter 1: Introduction 5

Suppression of In vitro studies demonstrate BPs affinity to Denosumab is not associated with any epithelial cells epithelial tissue, and suppressive or cytotoxic adverse soft tissue effects & soft tissue effects on oral epithelial cells (93, 94) Trauma to the mucosa alone is not healing BPs have been shown to inhibit soft tissue sufficient to cause MRONJ, and the proliferation and wound healing in murine majority of at-risk patients heal without model (95, 96) complications after or oral surgery (97)

Genetic risk MMP-2 and polymorphisms of cytochrome Other research has failed to demonstrate factors P450 have been proposed as possible risk factors any link between therapeutic doses of BPs (98, 99) and MMP expression or MMP-2 activity (101) Suggested that MRONJ occurs due to post- translational modification in osteoclasts that results in impaired cell morphology and adhesion (100)

Suppression of Multiple myeloma patients, who are immune- Only approximately 11% of patients with natural deficient as a result of both myeloma-related multiple myeloma develop MRONJ, immunity effects on the immune system and the effects of therefore immune suppression alone is their chemotherapy, have the highest incidence unlikely to be the causative factor (105) of MRONJ (102, 103) Risk of MRONJ increases in patients taking long-term steroids or undergoing chemotherapy (13) After osteoclasts, monocytes and are the cells most affected by BPs, denosumab, and sunitinib (104)

Oral biofilms Numerous strains of have been Not every sample of MRONJ-affected bone causing identified in MRONJ lesions (106) showed evidence of infection (although & some techniques such as swabs or light infection Bacteria are capable of inducing pathologic microscopy may not detect bacteria in a resorption and may explain why resorptive pits biofilm) (115) are visible histologically in MRONJ-affected bone where no osteocytes are present and the No data has been able to prove if infection patient has been taking potent antiresorptives is a primary initiating factor or a secondary (107, 108) consequence of exposed bone in the mouth 60% of MRONJ cases are preceded by dental Most at-risk patients heal normally after surgery, and most of the remaining 40% are extraction of infected teeth (97) precipitated by denture trauma, periodontal disease, or other physical trauma that would Spontaneous cases of MRONJ are reported allow oral bacteria to breach the mucosa (109) where no infective or inflammatory event was recorded (116, 117) Preoperative antibiotics have been shown to decrease the risk of MRONJ after dental extractions in rats (110) BPs have been shown to increase bacterial adhesion to bone (96) Proper dental treatment and maintenance significantly reduces the incidence of MRONJ (111-114)

Abbreviations: BPs, bisphosphonates; VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase

With consideration of the available evidence, patient susceptibility appears to be critical in the pathogenesis of MRONJ. The low incidence of disease suggests that the direct effects of antiresorptive medications (inhibition of osteoclasts, osteocyte apoptosis, inhibition of angiogenesis, and soft tissue toxicity) are insufficient to initiate MRONJ otherwise more patients would be affected. While oral micro-organisms, predominantly bacteria, are likely to be implicated, it is evident that neither dental infection nor exposure

Chapter 1: Introduction 6 of the alveolar bone to oral pathogens are the sole determinants of MRONJ development, as the majority of at-risk patients heal normally after extraction of infected teeth where standard precautions are taken (118-120). Immune function is likely to play a contributory role, as patients susceptible to MRONJ are in the unfortunate position where all three lines of defence (the and mucoperiosteum; resident host immune and inflammatory cells – perhaps critically cells of the monocyte/ lineage; and circulating leucocytes) that protect the underlying soft and hard tissues from oral microbes can be simultaneously compromised. Specifically, the oral mucosa is subject to mechanical irritation from dentures, routine mastication, and oral hygiene practices. It can also be surgically breached during dental treatment, and is susceptible to ulceration with chemotherapy (121) and other common medications (122). The macrophage population can be compromised by denosumab, bisphosphonates, and antiangiogenics (104, 123-125), and leucopoenia is induced by a number of comorbidities often present in patients taking antiresorptives including chemotherapy and corticosteroids, having poorly controlled diabetes, and by smoking (17).

It therefore seems most likely that a combination of multiple compromising factors produces a “perfect storm” where oral pathogens breach the mucosa of a susceptible patient, whose immune defence mechanisms are not able to adequately respond and the healing capacity of the soft and hard tissues is impaired by antiresorptive and/or antiangiogenic medications. This concept is illustrated in Figure 2.

Figure 2. Proposed mechanism of the pathogenesis of MRONJ

Chapter 1: Introduction 7

The only finding in the literature that is not consistent with this theory of disease development is the reported cases of “spontaneous” MRONJ where no initiating dental factor is evident. However, the possibility of oral ulceration as an initiator is rarely presented in the literature, even when medications known to cause oral ulceration are recorded in the patient’s medication history. This is likely due to the inherent difficulty of clinically diagnosing an ulcer where MRONJ had subsequently developed at the site. Of particular relevance to patients at risk of MRONJ, chemotherapy (126), alendronate (127, 128), sunitinib (129), and nicorandil (130, 131) have been reported to cause severe oral ulceration, as well as a significant number of other medications and diseases (132). Oral ulceration could offer an explanation for these “spontaneous” cases that do not otherwise fit in the proposed model of disease development.

1.1.7 Prevention of MRONJ The literature advocates strongly for the prevention of MRONJ through careful dental examination and treatment as required before patients commence antiresorptive or antiangiogenic medications (26, 111, 133-143). Medical practitioners are encouraged to liaise closely with dental professionals to ensure that every patient has received a comprehensive dental examination with intraoral radiographs and orthopantogram (OPG) to identify areas of existing infection or the presence of compromised teeth. Treatment should be performed as indicated, and the commencement of antiresorptive or antiangiogenic therapy delayed until six weeks after any invasive treatment. Ill-fitting dentures must be identified and corrected, and high risk areas such as tori should be noted for ongoing monitoring. Patients should receive thorough oral hygiene instruction and education regarding the possible risk of MRONJ, and both fluoride applications and chlorhexidine rinses should be considered. A reduction in the occurrence of MRONJ is consistently reported where preventative dental care is given (111, 112, 138, 142, 144).

1.2 CONTEXT

The results of preventative studies suggest that dental professionals have an opportunity to reduce the incidence of MRONJ, if not prevent it entirely, with diligent and proactive preventative care. Given that the treatment of MRONJ is complex and unpredictable once established, it seems prudent to focus future research efforts on strategies for prevention and not treatment. However, effective preventative strategies

Chapter 1: Introduction 8 rely on both the identification of high-risk individuals and ability to provide targeted interventions to reduce or eliminate causes of the disease. More research is needed to understand why MRONJ develops, who is most likely to develop it, and how the risk of MRONJ can be reduced.

1.2.1 Guidelines for the dental management of patients at risk of MRONJ There are a number of guidelines available that provide recommendations for the dental management of patients taking antiresorptive medications, but these are based predominantly on expert opinion due to the lack of evidence on the causal mechanisms of MRONJ. The limitations of currently available guidelines make it difficult to manage the oral health of patients taking antiresorptive medications. Anecdotally, many clinicians report feeling confused and anxious when patients on antiresorptives present requesting treatment. Clear, evidence-based guidelines are needed so that clinicians can confidently and effectively manage the oral health of patients on antiresorptives to reduce the risk of MRONJ.

University of Connecticut Osteonecrosis numerical scale (145) There has been one published attempt to develop an instrument to assess individual patient risk of MRONJ, which is the University of Connecticut Osteonecrosis Numerical Scale (UCONNS). UCONNS was presented as a method of standardising risk reporting and assessment of patients between institutions, and although it was never validated, it was a commendable effort considering the lack of scientifically validated data pertaining to risk factors. The scale is presented in Figure 3.

Redacted

Figure 3. UCONNS osteonecrosis numerical scale. From Landesberg et al, 2011 (145)

Chapter 1: Introduction 9

A significant body of research has been published in the field of MRONJ since UCONNS was proposed in 2011 – most significantly, the results of large clinical trials of denosumab and antiangiogenic agents were released and these medications were subsequently associated with MRONJ. Neither of these medications, nor seven other bisphosphonates with recorded cases of MRONJ (146-149), are considered in the UCONNS calculation of risk, which only accounts for pamidronate and zoledronate. It also does not take into consideration a number of potentially significant comorbidities, and does not provide any preventative care recommendations for each of the three risk levels it identifies. No attempts to validate the scale were able to be located in the literature, and due to the considerable limitations of the model, it is not suitable for clinical use.

Australian Therapeutic Guidelines: Oral & Dental (150) The Oral & Dental Therapeutic Guidelines (TG) provide limited direction for clinicians regarding the safe treatment of patients. The guidelines on MRONJ (the TG use the term “BRONJ”) are available in Figure 4. Clinicians are advised to “monitor the patient’s oral health regularly…”, however there is no recommendation to tailor this care depending on the patient’s individual level of risk. The use of C-terminal telopeptide (CTX) testing is advocated as the sole method of determining a patient’s risk of MRONJ prior to tooth extraction or bone surgery, despite international recommendations that this is not an accurate measure (1, 17, 151). It is unfortunate that the current guidelines do not clearly outline the critical role of dentists and auxiliary staff in preventing MRONJ, as this is a primary reference tool for most of the dental profession in Australia. The failure of the TG to adequately address MRONJ prevention was a primary driver of this research.

From personal experience supervising undergraduate dental students, there is a concerning emphasis on extractions as the sole treatment modality for dental problems. A significant proportion of patients are referred to oral and maxillofacial surgeons to address the patient’s presenting complaint without any consideration of ongoing preventative care to reduce the likelihood of future dental problems.

While the missed opportunity for preventative dental care is unfortunate, the TG recommendation for drug holidays could be potentially catastrophic if used for patients receiving denosumab. There are multiple reports of rebound spinal fractures where denosumab was ceased for dental extractions (152, 153), and the TG does not differentiate between bisphosphonates and denosumab. There is an urgent need to develop an

Chapter 1: Introduction 10 evidence-based guideline for the dental management of patients taking antiresorptives in Australia to replace the current TG.

Redacted

Figure 4. Australian TG for BRONJ. From Therapeutic Guidelines, 2015 (150)

New South Wales Health guideline on BRONJ prevention (154) In Australia, many clinicians also refer to New South Wales (NSW) Health guideline for patients at risk of MRONJ. This 24-page document relates specifically to dental and oral surgical treatment in patients receiving bisphosphonate therapies only, and has been adopted by Queensland Health facilities and Griffith University to support clinical practices. On page 14, a series of tables are provided (see Figure 5) to determine the risk level of both the patient and the proposed treatment, and these are combined to give an overall risk level for the procedure.

The model is simple to use and provides useful support for clinical decision making where extraction or oral surgery is required, but this highlights a critical issue in MRONJ management: the intervention point for preventative treatment needs to occur ideally before antiresorptive therapy begins, but at least before dental infection requiring an extraction develops. Providing “preventative” care for an extraction is not where risk assessment and risk reduction activities should be focussed. Patients at risk of MRONJ

Chapter 1: Introduction 11 need to be identified early and managed effectively to avoid the need for any surgical dental procedures, which are consistently reported as the most common initiating event for MRONJ development (1, 109, 155). This document was never proposed as a general guideline for MRONJ management and therefore no reference to regular recall appointments or preventative dentistry are made. It also does not include any recommendations for denosumab, and for these reasons is not an appropriate guideline for MRONJ prevention.

Redacted

Figure 5. NSW Health BRONJ guideline. From New South Wales Health, 2008 (154).

Scottish NHS: Oral Health Management of Patients at Risk of MRONJ (156) In March 2017, the Scottish Dental Clinical Effectiveness Programme published an updated clinical guideline for the management of patients at risk of MRONJ. This comprehensive document is the best attempt to date to convert the available evidence into a clinical recommendation.

The guideline recommends securing oral health before starting drug therapy, and to maintain this through “personalised preventative advice”, although no suggestion as to what constitutes appropriately personalised preventative care is given. Patients are stratified into low or higher risk categories based on a very simple model, as outlined in Figure 6. The determinates of a higher risk patient are: treatment with an antiresorptive or anti-angiogenic drug for the management of cancer, duration of bisphosphonate therapy >5 years, concurrent treatment with a systemic , or a previous

Chapter 1: Introduction 12 diagnosis of MRONJ. The document also provides specific advice for extractions in low and higher risk patients.

Critically, the authors of the guideline identify that the document is to be considered best practice advice based on clinical experience and expert opinion, and identify the need for high quality research to improve the evidence base for MRONJ. In particular, the authors identify the epidemiology of MRONJ, risk factors, incidence following tooth extraction, incidence with implant therapy, efficacy of prevention protocols for oral surgery, and efficacy of proposed treatment strategies as serious knowledge gaps (156).

Redacted

Figure 6. Scottish NHS clinical guideline. From Scottish Dental Clinical Effectiveness Programme, 2017 (156)

1.2.2 Statement of need To date, no evidence-based method for determining the most appropriate dental care for an individual patient at risk of MRONJ can be located. There is a clear need for high-quality research to guide the dental management of patients taking antiresorptive and antiangiogenic medications.

Chapter 1: Introduction 13

1.3 PURPOSES

The purpose of this research is to develop an evidence base to support the clinical care of patients at risk of MRONJ. Causation is very difficult to establish for any disease (157), but this is further complicated for MRONJ by a very low incidence of disease and a long latency period. For these reasons, this project does not aim to establish the causative factors for MRONJ. Instead, this project will investigate the contributing risk factors for MRONJ and identify targets and strategies for prevention of MRONJ. It is intended that the findings of this project can be used to develop an evidence-based guideline for the dental management of patients taking antiresorptive and antiangiogenic medications. Previous research has established that antiresorptive dose and duration increases the risk of MRONJ, but this project is interested in the role of systemic disease, oral health, and immune function as patient-specific risk factors for MRONJ.

1.3.1 Research questions 1. How does a patient’s systemic health influence their risk of MRONJ?

2. How does a patient’s dental health influence their risk of MRONJ?

3. Do the results of routine blood tests correlate with the risk of MRONJ?

4. How can oral health professionals identify and manage high-risk patients to reduce the likelihood of developing MRONJ?

1.3.2 Research aims 1. Understand how systemic health influences the risk of MRONJ, and identify factors that can be used to stratify high-risk patients

2. Understand how oral health influences the risk of MRONJ, and identify factors that can be used to stratify high-risk patients

3. Investigate whether blood cell counts correlate with the risk of MRONJ, and identify haematological markers that can be used to stratify high-risk patients

4. Identify which risk factors are the most feasible targets for MRONJ prevention

5. Provide an evidence base for the dental management of patients at risk of MRONJ

Chapter 1: Introduction 14

1.4 SCOPE AND DEFINITIONS

1.4.1 Definition of preventative care This research is concerned with the prevention of MRONJ. Methods of diagnosing and imaging MRONJ, as well as the clinical management and treatment strategies for established MRONJ will not be covered by this thesis.

There are a number of published definitions of preventative dentistry, including:

1. “Dentistry concerned with maintenance of a normal masticating mechanism by fortifying the oral cavity against damage and disease.” (158)

2. “A philosophy and method of dental practice that seeks to prevent the initiation, progression, and recurrence of dental disease.” (159)

3. “The science of the care required to prevent disease of the teeth and supporting structures.” (160)

Prevention can be targeted at a primary, secondary or tertiary level (161). Primary prevention aims to reduce the number of new cases of a disease, while secondary prevention aims to reduce the severity and morbidity of disease once it has developed, and the goal of tertiary prevention is to limit disease progression and reduce complications (161). The scope of this project will be limited to primary prevention that seeks to reduce the incidence of new cases of disease.

Clinically, there are two distinct elements of primary prevention of MRONJ: the first incorporates all efforts to establish and maintain optimal oral health of patients at risk of MRONJ, and the second involves specific precautions prior to dental extractions and oral surgery. For the purposes of this research, primary prevention will not include peri-operative preventative measures, as per Table 5. If clinicians are able to provide targeted and diligent primary prevention for their patients, the need for peri-operative prevention should be minimised or eliminated. For the remainder of this paper, the term “prevention” will refer specifically to the primary prevention of MRONJ. Peri-operative prevention is outside the scope of this research.

Chapter 1: Introduction 15

Table 5. Preventative strategies for MRONJ Primary prevention strategies Peri-operative prevention

Prior to commencing antiresorptive therapy: Antibiotics • comprehensive extra- and intra- oral exam Antimicrobial mouth rinses • radiographic evaluation (OPG, PA/s) Platelet rich concentrates (PRP, PRF) • treatment as required to optimise oral health Low-level laser therapy assisted extractions (see Error! Reference source not found.) Primary wound closure During antiresorptive/antiangiogenic therapy: CTX test • maintenance of good oral hygiene Drug holiday • antimicrobial mouth rinses Minimally traumatic extraction technique • periodic dental check-ups with professional Smoothing of interseptal bone post-extraction cleaning & radiographic re-evaluation

• treatment as required to maintain oral health

• avoidance of procedures that involve direct osseous injury • regular examination of prostheses

Abbreviations: OPG, orthopantogram; PA, periapical; CTX, C-terminal telopeptide; PRP, platelet-rich plasma; PRF, platelet-rich fibrin

1.4.2 Definition of MRONJ & non-exposed variants There is some contention in the literature regarding exposed and non-exposed variants of MRONJ. Initially, the 2009 AAOMS definition of MRONJ specified “exposed bone” (7), however this was redefined as “exposed bone or bone that can be probed through an intraoral or extraoral fistula” in 2014 (1). This was in response to a number of studies which showed that limiting the clinical definition of MRONJ to patients with exposed bone was underrepresenting the frequency of disease and excluding up to 25% of cases (162-169). However, the international consensus paper released in 2015 did not include non-exposed variants in their clinical definition of MRONJ (170), and received a sharp reply from a number of prominent oral surgeons who felt this was incorrect (171).

As the literature supports the inclusion of non-exposed variants of MRONJ, the 2014 AAOMS definition was adopted for this research. As such, patients with non- exposed MRONJ were eligible for inclusion, however all cases identified in the search strategy had the exposed variant of MRONJ. Resultantly, patients diagnosed with MRONJ in this study meet both the 2014 AAOMS and 2015 ITFONJ diagnostic criteria, and any controversy over the inclusion of non-exposed variants has been avoided.

Chapter 1: Introduction 16

1.5 ETHICS AND GOVERNANCE

In order to access patient records for this project, ethical approval specifying a waiver of consent was required to support a Public Health Act (PHA) application. Gold Coast University Hospital (GCUH) and the Royal Brisbane and Women’s Hospital (RBWH) had different requirements for data access, and therefore two separate ethics applications were submitted. Firstly, approval was granted from the Griffith University Human Research Ethics Committee (HREC) for access to GCUH, then RBWH HREC approval was granted for access to RBWH.

Evidence of ethics approval is attached as Appendix A (Griffith University HREC) and Appendix B (RBWH HREC). Once ethical approval and a waiver of consent was received, a PHA application was submitted and approved (Appendix C).

1.6 THESIS OUTLINE

The next five chapters of this thesis are presented as published or submitted papers. Chapter 2 presents the results of a systemic review that collated all published cohort studies, case series, and case reports on MRONJ to assess the available evidence on risk factors and determine which patient populations are susceptible to MRONJ. This chapter highlights the low-quality and often contradictory data currently available on risk factors for MRONJ, and that MRONJ is not limited to patients with multiple myeloma, breast cancer, prostate cancer, and osteoporosis.

Chapter 3 reports the findings of a 14-year retrospective survey of patients treated in the two study hospitals for osteonecrosis of the jaws. The primary aim of this research was to identify eligible cases for the case-control study, and determine whether the number of cases of MRONJ had decreased over time with improved awareness and understanding of the condition. The results showed an upward trend in the number of cases of MRONJ, which suggests that more work is needed to improve awareness and prevention of MRONJ. This study also compared the ratio of cases of MRONJ to osteoradionecrosis (ORN), and found that ORN occurred much more frequently than MRONJ. This was unexpected, given that patients undergoing radiation to the head and neck region receive dental screening and preventative care through a multi-disciplinary care team. However, this formal care pathway does not cover post-radiation treatment, and it will be important to ensure that the preventative recommendations of this study are also extended to patients at risk of ORN.

Chapter 1: Introduction 17

Chapter 4 presents the findings of the first case-control study that investigated the association between systemic comorbidities and MRONJ. This study used the Comorbidity Polypharmacy Score (CPS) as a simple assessment of both a patient’s disease burden and pharmacological profile. The CPS has been validated in a number of other patient populations, but has not previously been applied to patients at risk of MRONJ. The results show that patients who developed MRONJ reported significantly higher CPSs, and this offers clinicians a useful tool for relating the cumulative severity of disease in an individual patient to their risk of developing MRONJ.

Chapter 5 reports the second case-control study which aimed to determine how a patient’s oral health influenced their risk of developing MRONJ, and whether patients were receiving adequate dental treatment before and during antiresorptive therapy. The results showed that only a minority of patients received a dental examination in the 12 months prior to commencing their antiresorptive, and patients averaged less than one dental exam every three years during antiresorptive therapy. Cases required significantly more dental treatment than controls, and this increased their risk of developing MRONJ. This chapter highlights an important opportunity to reduce the incidence of MRONJ by improving the oral health of patients undergoing antiresorptive therapy.

Chapter 6 outlines the third case-control study which investigated whether a patient’s immune status was associated with their risk of MRONJ. This study found that patients taking antiresorptive medications frequently returned blood tests results outside of the standard laboratory reference range. Altered blood counts were not limited to cases who developed MRONJ and do not appear to be clinically useful in identify high-risk patients. This does not preclude immune function as an important factor in MRONJ pathogenesis, but suggests routine blood tests are not able to infer information about the risk status of an individual patient.

Chapter 7 discusses the key findings and clinical relevance of the thesis, and makes recommendations for future research.

Chapter 1: Introduction 18

Chapter 2: Literature review

STATEMENT OF CONTRIBUTION TO CO-AUTHORED PUBLISHED PAPER

This chapter includes a co-authored paper. The bibliographic details of the co-authored paper, including all authors, are:

McGowan, K., McGowan, T., & Ivanovski, S. (2018). Risk factors for medication-related osteonecrosis of the jaws: A systematic review. Oral Diseases, 24(4), 527-536.

My contribution to the paper involved: developing and registering the protocol for the systemic review, consulting with the health librarians to develop and review the search strategy, performing the search, assessing and screening the articles (as one of two independent reviewers), collecting and analyzing the data, and writing the manuscript. I am the corresponding author for the article, and was also responsible for submitting and revising the manuscript.

Signed: Date: 16th February, 2019

Student: Kelly McGowan

Countersigned: Date: 11th February, 2019

Supervisor: E/Prof Newell W Johnson

Chapter 2: Literature review 19

2.1 OVERVIEW

The purpose of this research was to better understand the factors that increase individual susceptibility to MRONJ, and develop an evidence-base for improving the preventative dental care of patients taking antiresorptive medication. The first stage of this project was to determine which medical and dental comorbidities have been previously reported as potential risk factors for MRONJ, and whether there is sufficient existing data to quantitatively analyse the relative significance of each.

This chapter also aimed to define the target population for preventative dental care. Most reported cases of MRONJ are associated with antiresorptive treatment for osteoporosis, multiple myeloma, breast cancer, and prostate cancer but there are an increasing number of reports of MRONJ in other patient populations (111, 113, 172-175). This review sought to comprehensively determine which patient groups are at risk of MRONJ.

A systematic review protocol was developed as per the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) statement (176), and registered in the International Prospective Register of Systematic Review (PROSPERO, registration number CRD42016053225, registered 23/12/2016). The full protocol is available on the PROSPERO website: https://www.crd.york.ac.uk/prospero/index.php. The review aimed to answer:

1. Which patient populations are susceptible to MRONJ?

2. What medical and dental comorbidities are risk factors for MRONJ in human subjects?

The review concluded that there is currently insufficient data to determine which medical and dental comorbidities are significant risk factors for MRONJ. There is very little data available that compares patients with MRONJ to a control group. More research is needed to determine which factors increase the risk of developing MRONJ, and how these can be targeted to reduce the incidence of this disease.

The online supplementary appendixes are attached as Appendix D (Modified Newcastle Ottawa Scale), Appendix E (Included articles: cohort & case series), Appendix F (Included articles: case studies), and Appendix G (Included articles: single predictors).

Chapter 2: Literature review 20

2.2 ABSTRACT

Objective: The purpose of this study was to identify the patient populations at risk of medication related osteonecrosis of the jaw (MRONJ) and determine which medical and dental comorbidities are significant risk factors for this disease.

Methods: An electronic search of Embase, MEDLINE, Cochrane Central Register of Controlled Trials, WHO International Clinical Trials Registry Platform and ProQuest Dissertations and Theses Global was conducted to identify all human studies that reported risk factors for MRONJ. Only a qualitative analysis was performed due to significant heterogeneity in the collected data.

Results: The search strategy identified 2872 records, of which 219 studies were eligible for inclusion. 4106 patients with MRONJ were identified, 39 different systemic diseases were implicated, and 14 medical and 11 dental risk factors were reported, although no statistical analysis of the significance of each of these factors was possible.

Conclusions: The clinical reach of MRONJ may be wider than anticipated, and more data on the significance of each potential risk factor is needed to guide the identification and management of at-risk patients.

2.3 INTRODUCTION

Medication-related osteonecrosis of the jaws (MRONJ) is an uncommon but serious disease that presents as areas of necrotic bone in the or (177), and often results in a significant reduction in quality of life for the patient (178). Despite sustained investigation into the underlying pathogenesis of MRONJ since it was first reported in 2003 (2), the exact mechanism of the disease remains unclear and there is no universally accepted protocol for MRONJ treatment (170).

Although considerable gaps in the collective knowledge of this disease persist, the literature consistently reports a reduction in the incidence of MRONJ where preventative dental measures are applied (141, 142, 179-181) and therefore it is critical that dental professionals are able to identify patients at risk of disease so that appropriate preventative

Chapter 2: Literature review 21 dental care can be provided. Previously, identifying at-risk patients was relatively simple as MRONJ was thought to be limited only to patients taking bisphosphonates. With the introduction of denosumab and new antiangiogenic medications, this has become increasingly complex. In particular, the association between MRONJ and antiangiogenics remains unclear and this uncertainty is reflected in the diagnostic criteria available to clinicians. Notably, the 2009 American Association of Oral and Maxillofacial Surgeons (AAOMS) criteria (182) were expanded to include all antiresorptives and antiangiogenics in 2014 (177), but the 2015 International Taskforce on Osteonecrosis of the Jaw (ITONJ) consensus paper again removed antiangiogenics due to a lack of evidence (170). As reports of osteonecrosis of the jaw in patients receiving antiangiogenics or chemotherapy without a prior history of antiresorptive therapy gradually accumulate (75, 77, 183-185) (186-189), a comprehensive review of the literature is necessary to establish which patients are at risk of MRONJ.

In addition to identifying susceptible patient populations, the dental team must also be able to tailor the nature and frequency of preventative dental care according to the individual patient, with consideration of additional medical and dental risk factors that may place that patient at increased risk of MRONJ. As the overall incidence of MRONJ is very low (17), individual patient susceptibility is likely be a critical factor in disease development. Therefore, the aims of this systematic review are to examine the cases of MRONJ reported in the literature and determine: 1) Which patient populations are susceptible to MRONJ and 2) What medical and dental comorbidities are risk factors for MRONJ in human subjects?

2.4 METHODS

Study registration This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42016053225) on 23/12/2016. The results of the systematic review are reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines (190).

Chapter 2: Literature review 22

Eligibility criteria This review aimed to capture as many reported cases of MRONJ as possible and therefore all study designs were eligible for inclusion, including single case reports, where medical and dental comorbidities were reported. Studies that reported only on prevalence, pharmacological parameters (such as duration of antiresorptive therapy or antiresorptive dosing details only), diagnostic techniques, or treatment of established lesions were excluded as these have been comprehensively reviewed elsewhere (17, 191). Reviews were excluded, but their reference lists were manually searched to ensure all relevant articles were included.

Inclusion criteria 1. Human studies.

2. Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has not healed within 8 weeks after identification by a health care provider.

No inclusion criteria were set for previous exposure to pharmacological agents or primary disease, nor were age limits imposed, to ensure that atypical presentations of MRONJ would not be excluded.

Exclusion Criteria:

3. History of radiation therapy to the craniofacial region

4. Metastatic disease of the jaws

5. Reports from large adverse event or medical claim databases where the risk of duplicate data was very high

6. Publication language other than English, French or Arabic.

Information Sources:

An electronic search of Embase (via embase.com, holdings 1947 to present) and MEDLINE (via OvidSP, holdings 1946 to present) databases was conducted on the 16th of December 2016. The Cochrane Central Register of Controlled Trials, the WHO International Clinical Trials Registry Platform and ProQuest Dissertations and Theses

Chapter 2: Literature review 23

Global were also searched. The reference lists of all included studies were manually cross-referenced to ensure comprehensive data collection.

Search Strategy:

The following search strategy was used for the Embase database and adapted appropriately for the MEDLINE search. The search strategy was reviewed by two specialist Health Librarians as per the PRESS guideline recommendations (192)

#1: “jaw osteonecrosis OR osteonecro*NEAR/4 jaw”; #2: #1 AND ‘human’/de; #3: ‘epidemiology’/exp; #4 ‘risk’/exp; #5: #3 OR #4; #6: #2 AND #5

Study Selection:

The search results were downloaded into an Endnote X7 library and duplicates were removed. The library was then uploaded to Rayyan (193) and one reviewer (KM) screened all titles and available abstracts to determine if they were potentially relevant. Full text articles were obtained for all records that appeared to meet the inclusion criteria, or could not be confidently excluded. Two independent reviewers (KM and TM) assessed each article against the inclusion and exclusion criteria and reasons for exclusion were recorded. Any disagreements were resolved by discussion. The inclusion and exclusion criteria were piloted on a small subset of studies prior to formal screening to ensure a high degree of reliability. Cohen’s Kappa coefficient was calculated to be 0.98, indicating a high degree of inter-rater reliability.

Data Collection Process:

Data was collected from each included article by KM into a piloted Numbers spreadsheet (Version 3.6.2, Apple Inc. 2008-2015). This review is unconventional as it does not compare interventions and outcomes. It was designed from a clinical perspective to allow dental professionals to identify which patients are susceptible to MRONJ. In order to meet both aims of this review, different data sets were required. Studies reporting on six or more cases of confirmed MRONJ were filed separately for quantitative analysis of medical and dental risk factors. Case reports of five or fewer patients were filed into another category to qualitatively examine the primary diseases and risk factors reported. This category was specifically designed to capture the atypical cases of MRONJ and

Chapter 2: Literature review 24 provide descriptive information on the uncommon patient groups affected by MRONJ. Articles that reported on single risk factors, for example genetic factors or biomarkers, were allocated to a third category for qualitative assessment of other potentially relevant risk factors.

Data Items, Summary Measures & Synthesis of Results:

Data items collected for each category were as follows:

7. Case Series or Cohorts (>5 cases MRONJ): funding, research design, time frame, setting, participant types, number of MRONJ cases, case demographics, MRONJ location, antiresorptive history, primary disease, medical comorbidities, and dental comorbidities. Quantitative analysis of this data was planned to provide risk ratios for each of the reported medical and dental factors where sufficient data was available.

8. Case Studies (≤5 cases MRONJ): case demographics, primary disease, medication/s implicated in MRONJ development, medical comorbidities, and dental comorbidities. Qualitative analysis of this data was planned to determine if there were any atypical cases of MRONJ reported that may have been excluded from the larger studies, and to identify new risk factors.

9. Single Risk Factor Studies: predictor/risk factor examined and outcome of study. This category was included to capture possible risk factors that may be of clinical significance but are not generally reported in larger studies (for example systemic and salivary biomarkers).

Risk of Bias:

The majority of included studies were not randomized and did not include a control group, and therefore were assessed using the Newcastle-Ottawa Scale (NOS) (194) This scale allocates a total of nine stars across three criteria (selection, comparability, outcomes) and was modified for the purposes of this review. It allowed for the assessment of case series and case studies included in the review, however according to the NOS guidelines, these were not able to score more than six stars. The modified NOS scale and guidelines for what constitutes a good, fair or poor quality rating are included as a supplemental appendix (Appendix D).

Chapter 2: Literature review 25

2.5 RESULTS

Search Results: The search strategy identified 2,872 records, with 219 meeting the inclusion criteria. These were sorted into three categories depending on the type of data reported, as outlined in Figure 7. Due to the large number of included articles, the reference list for each category is provided as a supplemental appendix (Appendix E, Appendix F, and Appendix G)

Figure 7. Flow chart of identification, screening, eligibility assessment and inclusion of studies in the systematic review

The planned quantitative analysis was not possible due to significant heterogeneity in the reported data. Only a narrative synthesis was performed, and findings from each category were summarized into tables and figures to demonstrate the clinical reach of MRONJ and the wide variation in risk factors reported.

Patient demographics and characteristics: 102 studies reporting on 6 or more cases of MRONJ were included, which captured 4106 individual cases of MRONJ. A summary of findings is presented in Table 6. Of the 4106 reported cases of MRONJ, 61.5% were female patients, 31.5% male, and gender was not provided in 7%. 30% of patients had multiple myeloma, 24% breast cancer, 24%

Chapter 2: Literature review 26 osteoporosis, and 8% prostate cancer. 8% of patients had unspecified malignant diseases, 4% had other and 1% had other non-malignant systemic diseases. A comprehensive list of the other types of cancers and systemic diseases with reported cases of MRONJ is outlined in Table 7. The mean age of patients at time of MRONJ diagnosis was 65.3 years (range 29-99). Location of MRONJ was only specified in 2973 studies and affected the mandible in 65% of cases, the maxilla in 28% and both jaws in 7%.

Table 6. Demographic and clinical summary of previously published cases of MRONJ Case series/cohorts included N = 102 % Antiresorptives reported* 76 75 76 75 Pamidronate 64 63 Alendronate 53 52 Ibandronate 34 33 Risendronate 24 24 Other BP** 15 15 Denosumab 5 5

Reported cases of MRONJ N = 4106 % Gender Female 2525 61.5 Male 1294 31.5 Not reported 287 7 Location Mandible 1923 47 Maxilla 828 20 Both 222 5.5 Not reported 287 7 Primary Disease Multiple myeloma 1220 30.3 Breast cancer 979 24.3 Prostate cancer 336 8.3 Unspecified cancer 336 8.3 Renal cancer 66 1.6 Lung cancer 39 1.0 Other cancer**** 55 1.4 Osteoporosis/ 973 24.2 Other systemic disease 24 0.6 * Reflects prominence of each antiresorptive in the published literature, with figures depicting how many times each bisphosphonate was reported in association with MRONJ out of 102 possible articles. Most articles reported on more than one antiresorptive, therefore the percentages calculated do not equal 100%. ** Other BPs include minodronate, clodronate, incadronate, and etidronate. *** Cases of MRONJ reported in the maxilla include two cases of MRONJ located on the **** Comprehensive list of other cancers and systemic diseases provided in Table 8

There was very little consistency in the risk factors reported, with some studies focusing only on dental risk factors and not reporting any medical comorbidities (23 studies) while others reported only medical histories and did not provide any relevant

Chapter 2: Literature review 27 dental data (10 studies). The other 69 included articles reported on widely varying data points, with many reporting on only the most well-known risk factors such as corticosteroids, chemotherapy, diabetes and dental extractions. This heterogeneity in the collected data prevented calculation of odds ratios or more rigorous statistical analysis, but does demonstrate the trends in reporting of risk factors associated with MRONJ, as outlined in Figure 8. Extractions were the most commonly reported dental risk factor, while chemotherapy (including hormone therapy and immunosuppressive therapy) was the most prominent medical risk factor. Periodontal disease and corticosteroids were the second most common dental and medical risk factors, respectively.

Figure 8. Incidence of medical and dental comorbidities reported in the included literature from a total of 4106 cases of ONJ.

Abbreviations: Mets, metastases; RT, radiation therapy; BMT/SCT, transplant/stem cell transplant; TBI/HDC, total body irradiation/high dose chemotherapy; CVD, cardiovascular disease. *“Other Systemic Diseases” included gastro-oesophageal reflux disease, Crohn’s disease, gastritis, Sjögren's syndrome, sarcoidosis, chronic obstructive pulmonary disease, kidney transplant, renal failure/insufficiency, Parkinson’s disease, dementia, thrombotic event, liver disease, asthma, angina, Lupus, obesity, , cerebral , hypothyroidism, osteoarthritis and pulmonary embolism. **“Other Dental Factor/Treatment” included fixed partial denture, crown preparation, trauma from impression tray or intubation, mylohyoid ridge, and knife-edge ridge.

Chapter 2: Literature review 28

In order to capture which patient groups are susceptible to MRONJ, the primary disease data from the larger studies were combined with the data collected from the case reports. A comprehensive list of primary diseases with reported cases of MRONJ is presented in Table 7. The diseases in bold font are traditionally associated with MRONJ, and were the most commonly reported as per Table 6, however it is evident that MRONJ is not strictly limited to patients with these diseases.

Table 7. Diseases with previously reported cases of MRONJ Cancer patients with reported MRONJ Systemic diseases with reported MRONJ Multiple myeloma 1-2*, 4-8*, 10-12*, 14-15*, 17-18*, 21*, 23*, 26*, 28-32*, Osteoporosis 1-2*, 4*, 10-11*, 16*, 18-22*, 24-25*, 31*, 33*, 35*, 34-37*, 39-44*, 47*, 54-55*, 57-59*, 61-64*, 69-71*, 73*, 41-44*, 48*, 50-53*, 55-62*, 64*, 67-71*, 76-77*, 76-78*, 80-81*, 83-88*, 90-91*, 93*, 95-98*, 101-103* 80-82*, 85*, 91*, 93*, 99-101*

Breast 1-2*, 4*, 7-8*, 12*, 14-15*, 18*, 21*, 25-32*, 35*, 38*, 40- Fibrous dysplasia 64*, 93*, 34^ 43*, 45*, 47*, 49*, 54-55*, 57-58*, 61*, 63-65*, 67*, 69*, 71*, 74-78*, 80*, 84-89*, 92-93*, 96-98*, 101-102* Prostate 1-4*, 8-12*, 14-15*, 18*, 25-26*, 28-31*, 35*, 38*, 41-43*, Paget’s disease 1*, 59*, 61*, 71*, 4^ 47*, 49*, 54*, 57-58*, 61-65*, 67*, 69*, 71*, 74-78*, 82*, 84-89*, 92-94*, 96-97*, 101*

Renal 4*, 29-30*, 35*, 43*, 47*, 49*, 58*, 61-62*, 67*, 71*, 74- Histocytosis X 98* 76*, 79*, 82*, 84-86*, 88*, 92-93*, 96-97*, 102*, 3^, 26^ 15*, 18*, 28*, 35*, 67*, 73-76*, 78*, 93*, 2^, 18^ Artificial joint 93* Liver 34* Kidney transplant 46^ Lung 93*, 12^, 39^, 44^ Osteopenia 56* Ovarian 93*, 96* Osteogenesis imperfecta 40^ Bladder 21*, 35*, 74* Autoimmune hepatitis 16^ Bronchial 15*, 9^ Fibromyalgia 2^ Nasopharyngeal 15*, 64*, 69* Rheumatoid arthritis 20*, 24*, 51*, 82*, 100*, 2^, 20^, 33^, 41^ Stomach 67*, 74* Sarcoidosis 28* Cervical 47*, 93* Gastrointestinal 67*, 74* Mastocytoma 69*, 93* Rectal 15*, 58* Herpes zoster** 51^ Urethral 15* Thalassemia major** 13^ Thyroid 12*, 35*, 96* Factor V Leiden 45^ Laryngeal 69* Heterozygosity** Colon 30*, 69*, 76* Endometrial 74* Neurogenic 47* Leukaemia 12*, 62*, 93*, 96*, 54^ Melanoma 35* Sarcoidosis 28* Myelodysplastic syn. 66*, 73*, 93* 39^ * Reference from Appendix E: Supplemental Table 2 – Included case series and cohort studies ^ Reference from Appendix F: Supplemental Table 3 – Included case studies ** Reported cases of MRONJ that did not strictly meet the inclusion criteria (Thalassemia Major patients presented with non-exposed variant, and exposed necrotic bone was not stated to be present for at least 8 weeks in Herpes Zoster patients or the Factor 5 Leiden Heterozygosity case). For this reason, they have not been listed as primary diseases associated with MRONJ but have been included as possible risk factors in Table 3 given that these are capable of producing areas of necrotic jaw bone.

Chapter 2: Literature review 29

The medical and dental risk factors reported in all three study categories are summarized in Table 8. There was insufficient data to determine the relative significance of each individual factor, but the data is presented as a comprehensive list of possible risk factors to be considered by both clinicians and researchers.

Table 8. Previously reported potential risk factors for MRONJ

Medical Comorbidities References Dental Comorbidities References Stage of cancer 3*, 80* Extraction 1*, 3-17*, 20-25*, 27*, 29*, 31-36*, 39-43*, 45*, 47-48*, 50*, 52-60*, 63-66*, 68-72*, 74-78*, 80*, 1*, 3-11*, 13-15*, 17-19*, 22-24*, 26-31*, 34- Chemotherapy 84-87*, 89-95*, 98*, 100-103* Alkylating Agents 39*, 41*, 42*, 44*, 46-48*, 50-59*, 61-71*, Antimetabolites 73*, 75*, 76*, 78*, 81-86*, 88*, 90-94*, 96- Periodontal disease 3*, 9-12*, 20*, 22*, 25-27*, 32*, 34-36*, 38-39*, Anti-tumor Antibiotics 103*, 8^, 6- 12^, 1-3^, 6-12^, 14-18^, 20^, 22- 43*, 47-48*, 54*, 57*, 63-64*, 67*, 72*, 76*, 78*, Topoisomerase Inhibitors 23^, 26^, 28^, 31-36^, 39-50^, 52^, 54-55^, 58- 89*, 93*, 96* Mitotic Inhibitors 59^, 61-65^ Differentiating Agents Acute dental infection 2-3*, 9*, 26*, 36*, 38*, 40*, 43*, 54*, 57*, 63*, 72*, Hormone Therapy 76*, 89*, 93*, 102* Immunotherapy Corticosteroids Dental implant or related 4*, 9-12*, 16*, 20*, 23-25*, 31-33*, 35*, 40-42*, Implantation 47-48*, 51-52*, 56-57*, 63*, 68*, 71-72*, 74*, 86*, 3*, 30*, 49*, 59*, 79*, 96*, 10^, 26^, 6-7`, 13`, Targeted therapy Augmentation 91*, 93*, 100*, 17`, 18` Monoclonal antibodies 17`, 42`, 46` Peri-implantitis Small molecules Explantation 13*, 27*, 46*, 55*, 63*, 69*, 83* Radiation therapy (excl. H&N) Other oral surgery 2*, 4*, 9-11*, 21*, 34*, 36*, 40-42*, 47*, 52*, 56- 57*, 69*, 72*, 79*, 83*, 93*, 95-96*, 101* Bone marrow/stem cell transplant 5*, 6*, 15*, 41*, 42*, 73*, 83*, 58^, 61^ Endodontic treatment 9-11*, 21*, 35*, 71*, 85-87*, 93* Diabetes 4*, 5*, 16*, 19-20*, 24-25*, 30-31*, 34*, 38- Prosthesis 8*, 23-24*, 45*, 48*, 74*, 80*, 87*, 92*, 94-95*, 39*, 44*, 46*, 48*, 52*, 54*, 58*, 59*, 62-63*, Removable dentures 103*, 39` 66-67*, 69-70*, 76-77*, 82*, 84-86*, 91*, 94- Fixed partial denture/s 95*, 99*, 21` Tobacco use 1*, 6*, 9-11*, 30*, 39*, 45*, 52*, 53*, 57-58*, Trauma 2*, 12*, 21-22*, 27*, 29*, 31-33*, 40-43*, 50*, 54*, 70- 71*, 73*, 76-78*, 85*, 87*, 91* Removable prosthesis 59*, 63*, 65-66*, 71-72*, 74*, 79*, 89*, 91*, 93- Iatrogenic 94*, 96*, 100-102* 1*, 41*, 53*, 85*, 92* Alcohol intake Other

Pathology results 10*, 11*, 19*, 26*, 34*, 38*, 41*, 58*, 59*, Anatomical 9*, 32*, 35-36*, 50*, 54*, 56-57*, 66*, 71-72*, 93*, Anaemia, SCA, TM 73*, 84*, 94*, 3`, 21`, 24-26`, 29`, 33-34`, 40` Tori 95* CRP ESR Knife-edge ridge WBC/neutropenia Mylohyoid ridge

Blood Glucose/HbA1c 10-11*, 26*, 34*, 38*, 57*, 67-68*, 79*, 89*, 94-96* CTX Oral condition/s Caries Cardiovascular disease 22*, 24*, 25*, 41*, 44*, 48*, 51-53*, 58*, 59*, Poor Oral Hygiene Hypertension 63*, 67*, 69*, 73*, 84*, 85*, 91*, 94*, 96*, Xerostomia Other Hyperlipidemia 99*, 100* Angina Other 3^, 5^, 18^, 23^, 26^, 52^, 54^

Systemic inflammatory disease 19*, 26*, 44*, 48*, 50*, 52*, 53*, 66*, 67*, Rheumatoid Arthritis 71*, 80*, 2^, 14^, 65^ Sjögren’s Syndrome Sarcoidosis Other

19*, 24*, 44*, 58*, 84*, 19^, 41^, 49^, 62^ Renal disease Failure Insufficiency Transplant

Gastrointestinal disease 52*, 2^, 26^, 27^, 31^, 49^, 65^ Crohn’s Disease Gastritis Inflammatory Bowel Disease Gastro-Oesophageal Reflux Disease Other

Other systemic disease/s 19*, 52*, 63*, 73*, 84*, 91*, 1^, 7^, 13^, 31^, 34^, 42^, 61^

Abbreviations: SCA, sickle cell anaemia; TM, thalassemia major; H&N, head and neck; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; WBC, white blood cells; HbA1c, glycated haemoglobin; CTX, C-terminal telopeptide. * Reference from Appendix E: Supplemental Table 2 – Included case series and cohort studies ^ Reference from Appendix F: Supplemental Table 3 – Included case studies ` Reference from Appendix G: Supplemental Table 4 – Included single predictor studies

Chapter 2: Literature review 30

The data from the single predictor studies was collected to determine if there were new risk factors that should be considered when determining an individual patient’s risk of MRONJ. A number of genetic factors and serum biomarkers showed a possible association with MRONJ, but further research is required before conclusions can be confidently drawn. The outcomes of the single predictor studies are presented in Table 9.

Table 9. Summary of single predictor studies included in the systematic review

Possible Association with MRONJ Unlikely Association with MRONJ

Genetic Factors: DNA methylation by BP treatment 43` CYP2C8 22`, 23`, 32`, 48` VEGF polymorphisms 1`, 9` Biomarkers: 38` NTX 20` RBMS3 gene, rs17024608 20` 47` BAP MHC class II polymorphisms 20` 32` OC PPAR-γ 20` 27` DPD Aromatase g.132810TT 3`, 20`, 24`, 29`, 40` 31` CTX Drug & bone gene SNPs PTH 20`

Biomarkers: nadir WBC <1000/uL 33-34` Treg/Th17 ratio 30` GCF IL-1B 50` Serum IG against P Gingivalis 50` Serum VEGF 51` Serum ESR 10` Serum CRP 10` Serum CTX 25`, 26`, 28`

Increased BMD values 49` Baseline osteomyelitis 45` 4` Oestrogen deficiency (anti-oestrogen therapy) 52` PDL widening 12` UBPI score (quantitative ultrasound) 41`

Sunitinib 7` Trastusumab 42` Bevacizumab 46` Anthracycline 5` Targeted therapy (TKI & ZA) 6`, 13`, 16`, Abbreviations: MHC, major histocompatibility complex; SNPs, single nucleotide polymorphisms; WBC, white blood cell; BMD, bone mineral density; PDL, periodontal ligament; UBPI, ultrasound bone profile index; TKI, tyrosine- kinase inhibitor; ZA, zoledronic acid; NTX, N-terminal telopeptide; BAP, bone alkaline phosphatase; OC, osteocalcin; DPD, deoxypyridinoline; C-terminal telopeptide; PTH, parathyroid hormone. ` Reference from Appendix G: Supplemental Table 4 – Included single predictor studies

Level of evidence: The NOS was used to assess the methodological quality of the large (>5 MRONJ cases) studies, which scored well for representativeness of the exposed cohort, ascertainment of exposure, and demonstration that the outcome of interest was not present at the start of the study. Assessment of MRONJ, follow-up times and adequacy of follow- up were also consistently well reported in the included studies. The NOS score for each included article is listed in Appendix E.

Chapter 2: Literature review 31

The quality of evidence was low as no randomized trials were included, although it should be noted that randomized trials on risk factors for MRONJ would not be ethical and therefore it is expected that only lower “quality” evidence will be available on this topic. Study methods and execution were generally of a high standard, and there was good consistency in the clinical definition of MRONJ.

2.6 DISCUSSION

Patient Groups with Reported Cases of MRONJ

This review demonstrates that MRONJ affects a wide range of patient groups. While multiple myeloma, breast cancer and prostate cancer accounted for 63% of reported cases, MRONJ was documented in 24 other types of cancer. Of these, renal cancer had the highest number of reported cases which may be due to an increased risk of MRONJ resulting from the use of targeted therapies incorporating a combination of bisphosphonates and antiangiogenics (195, 196). Osteoporosis was the most commonly reported non-malignant disease, accounting for 24% of cases, however 5 other systemic diseases were associated with MRONJ. The mean age of patients at the time of MRONJ diagnosis was 65.2 years, although the minimum reported age was 25, and 10 of the articles reported MRONJ in one or more patients under the age of 40. This is important as an effective preventative strategy must be able to accurately identify all at-risk patients and therefore should not limit for disease type or age groups.

Medications Associated with MRONJ

There were only 8 (out of 4106) cases of atypical MRONJ reported where no history of antiresorptive therapy was recorded, which confirms that bisphosphonates and denosumab are the medications primarily associated with MRONJ. It is interesting to note that 50% of included case series or cohorts specified a history of bisphosphonate therapy in their inclusion criteria, and an additional 30% specified patients with either multiple myeloma, breast cancer, prostate cancer or osteoporosis, which raises the possibility of reporting bias. It was for this reason that a separate category was planned to capture case reports of atypical presentations however even with this provision, only 0.2% of patients with MRONJ did not have a prior history of antiresorptive therapy.

Chapter 2: Literature review 32

Risk Factors for MRONJ

The most reported dental risk factor was tooth extraction (45%), followed by periodontal disease (10%), and therefore it is reasonable to suggest that optimizing the health of the oral cavity by reducing inflammation and treating infection to prevent the need for future invasive treatment should be the overarching aim of preventative dental care in at-risk patients. Chemotherapy, corticosteroids, and smoking were the most frequently reported medical risk factors, which suggests that assessing the patient’s systemic and immunological health may be important in determining which patients are at the highest risk of MRONJ.

While clear trends were evident in the collected data, these must be carefully interpreted in the context of highly varied reporting and significant voids in the available information pertaining to risk factors. Out of 102 included case series and cohort studies, 62 reported on use, 51 on chemotherapy, 38 on diabetes, 27 on smoking and 21 on cardiovascular disease. Of the dental comorbidities, extraction history was reported in 78 studies and periodontal disease in 30, while oral hygiene status was only provided in 9. The other medical and dental comorbidities listed in Table 3 were only reported sporadically. The significant heterogeneity in reported data prevented any quantitative analysis, which is unfortunate as the low incidence of MRONJ means that combining results is required to obtain a sufficiently large data set for identifying trends and risk factors. It is recommended that the complete list of potentially relevant risk factors outlined in Table 3 is used as a guide for future MRONJ research, in order to ensure that comprehensive risk assessment of patients is conducted. This would improve the homogeneity of the resulting data and allow for more rigorous systematic review and meta-analysis of risk factors in the future.

Clinical Relevance of Findings

It is important to consider MRONJ in the context of the patient’s primary disease - antiresorptive medications have been consistently shown to be of benefit to both oncologic and osteoporotic patients with significant reduction in skeletal-related events, improved pain control and increased survival rates (10, 11, 197, 198). Accordingly, providing effective preventative dental care to reduce the risk of MRONJ should be the highest priority for dental practitioners involved in the care of at-risk patients so that they can benefit from antiresorptive therapy without enduring further reduction in their quality of life as a result of MRONJ.

Chapter 2: Literature review 33

Previously reported preventative dental guidelines report consistent themes (181, 199, 200), however it is likely that both the type and frequency of care may vary depending on how many concurrent risk factors an individual patient presents with. While MRONJ is still primarily a disease of patients being treated for multiple myeloma, breast cancer, prostate cancer and osteoporosis, the list of patient groups affected by this disease is growing. Clinicians should consider any patient receiving antiresorptive or antiangiogenic therapy as being at risk of MRONJ, especially if these medications are prescribed in combination. It seems likely that both the patients’ general systemic health as well as their overall dental health may contribute to their individual susceptibility, and their preventative dental management should be modified accordingly.

Conclusions

MRONJ was reported to occur most frequently in multiple myeloma, breast cancer, prostate cancer and osteoporosis, however patients with renal cancer appear to be another particularly vulnerable population for this disease. Isolated cases were also reported in association with 24 other malignant diseases and 11 other systemic conditions, which suggests that preventative efforts should aim to capture all patients prescribed antiresorptive agents. 25 potential risk factors were identified, and future research efforts should ensure that these are comprehensively reported to improve consistency in the resulting data and facilitate quantitative analysis in future reviews.

Acknowledgements

The authors thank Dr Caroline Acton, Oral & Maxillofacial Surgeon, who kindly provided clinical advice and guidance. Professor Robert Ware, Menzies Health Institute Queensland, Griffith University, planned the quantitative statistical analysis in the review protocol and provided statistical advice. Bonnie Dixon, Griffith University Health Librarian, assisted in the development of the search strategy and was the primary reviewer of the final search strategy as per the PRESS guideline. Katrina Henderson, Griffith University Health Librarian, was the second reviewer of the final search strategy.

Chapter 2: Literature review 34

Chapter 3: Assessing the burden of disease

STATEMENT OF CONTRIBUTION TO CO-AUTHORED PUBLISHED PAPER

This chapter includes a co-authored paper. The bibliographic details of the co-authored paper, including all authors, are:

McGowan, K., Ivanovski, S., & Acton, C. (2018). Osteonecrosis of the jaws: a 14-year retrospective survey of hospital admissions. Australian Dental Journal, 63(2), 202-207.

My contribution to the paper involved: developing the protocol for the study, submitting and obtaining ethical approval, submitting a site-specific assessment for both hospitals, submitting a Public Health Act application to access patient data, collecting and analyzing the data, and writing the manuscript. I am the corresponding author for the article, and was also responsible for submitting and revising the manuscript.

Signed: Date: 16th February, 2019

Student: Kelly McGowan

Countersigned: Date: 11th February, 2019

Supervisor: E/Prof Newell W Johnson

Chapter 3: Assessing the burden of disease 35

3.1 OVERVIEW

The second stage of this project was to conduct an audit of patients presenting to tertiary facilities in South East Queensland with MRONJ. The primary aim was to identify the cases for Chapters 4, 5 & 6, and the secondary aim was to determine whether the number of cases of MRONJ were decreasing over time with improved awareness and preventative measures.

The audit produced three unexpected findings that were highly relevant to clinical practice. Firstly, over half of the patients who were diagnosed with MRONJ were receiving low-dose antiresorptives for osteoporosis, rheumatoid arthritis or Paget’s disease. The very low prevalence of MRONJ in this patient group (estimated to be 0.0- 0.04% (17)) translated into a substantial burden of disease due to the large numbers of patients who are treated for osteoporosis. The literature suggests that oncology patients receiving high-dose antiresorptives constitute the majority of MRONJ cases, but clinicians should not dismiss the risk of MRONJ for patients who are treated with low- dose antiresorptives.

The second important finding was that there were substantially fewer cases of MRONJ than osteoradionecrosis (ORN) of the jaws, which is a complication of radiation to the head and neck region. We had anticipated that MRONJ would present in higher frequencies than ORN because patients at each hospital receive dental screening and preventative care prior to their radiation therapy, whereas there is no formal preventative dental program for patients prior to commencing antiresorptive therapy. Unfortunately, deleterious patient behaviours such as poor oral hygiene, tobacco use, and alcohol appeared to be counteracting the benefits of preventative dental care in many of the ORN patients. This highlights the importance of extending the preventative recommendations of this study to both patients at risk of MRONJ and ORN.

Finally, the data showed an upward trend in the number of cases of MRONJ and ORN since MRONJ was first reported in the literature 14 years ago. This suggests that improved awareness of MRONJ and ORN and the importance of preventative dental care was not resulted in fewer cases. More work is needed to integrate targeted and ongoing dental care into the medical management of patients who require antiresorptives or radiation therapy to the head and neck.

Chapter 3: Assessing the burden of disease 36

3.2 ABSTRACT

Background: Osteonecrosis of the jaw (ONJ) is a serious complication of both radiation and antiresorptive therapies. This study aimed to determine how many patients have been treated for medication-related osteonecrosis of the jaws (MRONJ) and osteoradionecrosis (ORN), and whether the number of diagnoses has decreased over time with improved awareness and preventative measures.

Methods: Medical records at the Royal Brisbane & Women’s Hospital and Gold Coast University Hospital were reviewed to identify patients diagnosed with MRONJ and ORN between January 2003 – May 2017. Data on patient demographics, year of admission, and primary disease were analysed.

Results: 238 patients were diagnosed with ONJ, of which 74.4% were ORN and 25.6% were MRONJ. Tongue (24.6%), floor of mouth (17.3%), and tonsillar (15.1%) squamous cell carcinomas were the most common primary diseases associated with ORN, with a strong male predominance (80%). 52.5% of patients diagnosed with MRONJ were taking low-dose antiresorptives for osteoporosis (44.2%), rheumatoid arthritis (4.6%) or Paget’s disease (3.3%), while 47.5% were oncology patients receiving high-dose antiresorptives.

Conclusions: The number of patients diagnosed with MRONJ and ORN has trended upwards since 2003. ORN affected three times more patients than MRONJ, and patients on low- dose antiresorptives accounted for over half of the MRONJ cases.

3.3 INTRODUCTION

Osteonecrosis of the jaw is a rare complication of both radiation and medical therapies for systemic diseases. Osteoradionecrosis (ORN) is defined as the presence of an area of exposed, devitalised irradiated bone that fails to heal within 3-6 months, in the absence of local neoplastic disease (85, 201), and has been reported in the literature from as early as 1922 (202). Medication related osteonecrosis of the jaws (MRONJ) was first reported in 2003 with the introduction of bisphosphonate medications (2). It is defined as

Chapter 3: Assessing the burden of disease 37 an area of exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a health care provider, in a patient who has received antiresorptive or antiangiogenic agents with no history of radiation or metastatic disease to the jaws (1). The exact pathogenesis of both diseases remains controversial despite extensive research (17, 203-205), although a number of treatment-related and patient-specific risk factors have been implicated as possible contributors (13, 206-208).

The reported prevalence of ORN and MRONJ varies widely in the literature, which makes it difficult for clinicians to estimate the risk of these serious sequelae for their patients. The risk of MRONJ varies depending on the dose and duration of exposure to antiresorptive medications, and is reported to be rare (0.0-0.04%) in patients receiving low-dose antiresorptives for osteoporosis and between 1-15% for oncology patients receiving high dose bisphosphonates (17). Similarly, the number of patients who are reportedly affected by ORN varies between 2-18% (201), with post-radiation dental extractions and a radiation dose of more than 60 Gy associated with a higher risk of disease (209-211).

Patients who are irradiated for head and neck cancers are known to be a high risk group for dental disease (212). While ORN is considered the most severe complication of radiation treatment to the head and neck (201), other consequences for the oral cavity include mucositis, hyposalivation, loss of taste, radiation caries, and (213). As bony trauma, and in particular post-radiation extractions are a critical risk factor for ORN development (206, 207, 214), preserving the patients’ remaining dentition is a priority for both physicians and dentists (133, 215). Prior to radiation therapy involving the jaws, it is recommended that patients are sent for oral screening and treatment as required to remove infectious foci and stabilise the patient’s oral health (212, 216). It is more difficult to implement targeted preventative dental care prior to the initiation of antiresorptive therapies as these medications are prescribed to a wider range of patients, however the same basic recommendations for oral screening, treatment and prevention apply (1, 17, 142).

There is considerable evidence to suggest that the occurrence of both ORN and MRONJ can be significantly reduced or even completely prevented with meticulous dental prophylactic care (112, 144, 215). Therefore, it is important to determine whether preventative efforts are effectively translating into a decreased prevalence of ONJ. The aims of this study were to: (i) determine how many patients have been admitted for treatment of ONJ in three public hospitals in South East Queensland since MRONJ was

Chapter 3: Assessing the burden of disease 38 first diagnosed in 2003, (ii) describe and compare the demographics of the patients affected by ORN and MRONJ, and (iii) determine if the rates of ONJ have decreased over time as a result of improved awareness and preventative measures.

3.4 METHODS

Ethical approval for the project was obtained from the Royal Brisbane and Women’s Hospital (RBWH) Human Research Ethics Committee (ID: EC00172, HREC/17/QRBW/242). A retrospective chart review was conducted of patients admitted to either the RBWH or Gold Coast University Hospital in the 14 years between January 2003 and March 2017.

Patients were identified using the ICD code K10.2, which represents inflammatory conditions of the jaw. As this code covers a number of different conditions, including osteitis (acute, chronic and suppurative), osteomyelitis, osteonecrosis (drug induced, radiation induced), osteoradionecrosis, , and of jaw bone (acute, chronic and suppurative), patient records were manually reviewed to determine which clinical diagnosis had been made. All patient records were assigned codes and de- identified to preserve anonymity during the study. Clinical diagnosis, gender, age, year of admission, and length of stay were recorded for every patient with a K10.2 diagnosis. For patients whose clinical records confirmed a diagnosis of either ORN or MRONJ, the primary disease for which medical or radiation therapy was prescribed was also recorded. The collected data was entered into Excel spreadsheets (Version 15.27, © Microsoft 2016, Redmond, WA, USA) for analysis.

The statistical analyses were conducted using IBM SPSS Statistics, Version 24.0.0 (IBM Corporation 2012 ©, Aarmonk, NY, USA). Descriptive statistics were run for demographic data and are summarised as means and standard deviations for age and as median and range for length of stay. The demographic characteristics of patients diagnosed with MRONJ and ONJ were compared using Chi-square analysis for gender, independent samples t-test for age, and Mann-Whitney U-test for length of stay.

Chapter 3: Assessing the burden of disease 39

3.5 RESULTS

Between January 1st 2003 and March 1st 2017, 477 patients were admitted to RBWH (77.4%) and GCUH (22.6%) for inflammatory conditions of the jaw. The most common clinical diagnosis was ORN (37.0%), followed by MRONJ (12.8%), and abscess or infection (10.3%), although a number of other conditions were captured by this code as outlined in Table 10.

Table 10. Demographic information and clinical diagnoses for patients coded K10.2 N (%) Characteristic (N = 477)

Hospital Royal Brisbane & Women’s Hospital 369 (77.4) Gold Coast Health Service District 108 (22.6) Sex Male 317 (66.5) Female 160 (33.5) Clinical Diagnosis ORN 177 (37.0) MRONJ 61 (12.8) Abscess/infection 49 (10.3) Extraction/s 44 (9.2) Osteomyelitis 18 (3.8) Resection/surgery for OC 17 (3.6) Fracture 16 (3.3) Cyst 9 (1.9) Implant related 6 (1.2) 3 (0.6) Tori removal 2 (0.4) Other † 19 (4.0) Unclear/unable to locate chart 56 (11.7) Abbreviations: MRONJ, medication related osteonecrosis of the jaw; ORN, osteoradionecrosis; OC, . †Other clinical diagnoses included facial reconstructions for congenital abnormalities, sodium hypochlorite injuries, cleft palate surgery, sialadentitis, tracheostomies, removal of infected plates, ear infections, dental exams prior to radiation therapy, and orthognathic surgery.

Of the 238 patients admitted for ONJ, 74.4% were diagnosed with ORN and 25.6% with MRONJ. Patients with ORN had been diagnosed with and irradiated for various head and neck cancers, but most commonly tongue (24.6%), floor of mouth (17.3%), and tonsillar (15.1%) squamous cell carcinomas (SCC).

Of the 61 cases identified as MRONJ, 44.2% were associated with antiresorptive treatment for osteoporosis. 24.6% occurred in patients being treated for multiple myeloma, 11.5% in patients with metastatic breast cancer, and 9.8% in patients with prostate cancer. A complete list of primary diseases associated with ORN and MRONJ is presented in Table 11.

Chapter 3: Assessing the burden of disease 40

Table 11. Primary diseases associated with ONJ at RBWH and GCUH N (%) MRONJ (N=61) Osteoporosis 27 (44.2) Multiple myeloma 15 (24.6) Breast cancer 7 (11.5) Prostate cancer 6 (9.8) Rheumatoid arthritis 3 (4.9) Paget’s disease 2 (3.3) Chronic myeloid leukaemia 1 (1.6)

ORN (N=177) Tongue SCC 44 (24.6) Floor of mouth SCC 31 (17.3) Tonsillar SCC 27 (15.1) Oropharyngeal SCC 11 (6.1) Alveolar SCC 8 (4.5) Retromolar trigone SCC 6 (3.4) Buccal SCC 6 (3.4) Adenocarcinoma 6 (3.4) Metastatic SCC 5 (2.8) SCC 4 (2.2) Skin cancer 4 (2.2) Other ‡ 21 (11.7) Abbreviations: MRONJ, medication related osteonecrosis of the jaw; ORN, osteoradionecrosis; SCC, squamous cell carcinoma. ‡Other diseases associated with ORN included SCC of the pyriform fossa, oral commissure, soft palate, lateral canthus, neck, larynx, nasopharynx and antrum, as well as synovial sarcoma of the parapharyngeal space, Merkel cell carcinoma, fibrous histocytoma, small cell cancer of the neck, rhabdomyosarcoma, angiosarcoma, and glioblastoma.

The number of cases of ORN and MRONJ increased over time as demonstrated in Figure 9, with the highest number of diagnoses for both conditions in 2015 (2017 data was not included as only clinical coding to March was available at the time of data extraction).

Figure 9. Number of patients diagnosed with ORN and MRONJ per year since 2003

Chapter 3: Assessing the burden of disease 41

2 There was a significant difference in the distribution of ONJ between sexes (c 32.16, p<0.001) as per Table 12, with ORN affecting significantly more males (80%) than females (20%). More females (59%) than males (41%) were diagnosed with MRONJ, however the disparity between sexes was not as pronounced.

Table 12. Number of patients diagnosed with ORN and MRONJ per year since 2003 ORN (n = 177) MRONJ (n=61) 2 p c N (%) N (%)

Sex Male 141 (80) 25 (41) 32.16 <0.001 Female 36 (20) 36 (59) Abbreviations: MRONJ, medication related osteonecrosis of the jaw; ORN, osteoradionecrosis

The mean age of patients diagnosed with ORN was 62.67 (±11.18) years, compared to 66.86 (±13.35) for MRONJ, which was found to be statistically significant (t = 2.20, p=0.030). The median length of stay for patients with ORN was 4 days (1, 75), compared to 3 days (1, 93) for MRONJ, however this difference was not significant (Z=- 0.607, p=0.544).

3.6 DISCUSSION

Between January 2003 and March 2017, 238 patients were admitted to Royal Brisbane & Women’s Hospital and Gold Coast University Hospital with osteonecrosis of the jaw. ORN was diagnosed more commonly than MRONJ at a ratio of 3:1, and 80% of the patients who developed ORN were male. This strong male predominance is consistent with the findings of other epidemiological studies of ORN (206, 217-219). The mean age of patients diagnosed with ORN was 62.7 years, compared to 66.9 for MRONJ.

Osteoporosis patients taking low dose antiresorptives had the most reported cases of MRONJ (44.2%), which suggests that although the overall prevalence of MRONJ in this patient group is low (estimated to be 0.0-0.04% (17)), this still translates into a substantial burden of disease due to the high number of patients treated for osteoporosis. This is an important finding, as the purpose of this study was to determine how the prevalence data reported in the literature translates into clinical practice. The findings suggest that the number of osteoporosis patients affected by MRONJ should not be underestimated. Of the 61 cases of MRONJ identified, 32 were taking low dose antiresorptives for either osteoporosis (27 patients), rheumatoid arthritis (3 patients), or

Chapter 3: Assessing the burden of disease 42

Paget’s disease (2 patients). In comparison, 29 oncology patients receiving high dose antiresorptives developed MRONJ, with multiple myeloma patients most commonly affected (15 patients), followed by breast cancer (7 patients), prostate cancer (6 patients), and one patient with chronic myeloid leukaemia.

Patients with squamous cell carcinomas of the tongue (44 patients) and floor of the mouth (31 patients) reported the highest number of ORN diagnoses, which is expected considering that the mandible was in the field of radiation. There were more cases of ORN than anticipated, given that head and neck cancer patients at each hospital received dental screening and prophylactic treatment prior to their radiation therapy. It was expected that MRONJ would be more prevalent due to the difficulties associated with providing preventative dental care to a more diverse group of patients. However, a number of patient behaviours such as poor oral hygiene (214, 219), tobacco use (207), and alcohol (219) may be counteracting the benefits of preventative dental care in many of the ORN patients.

While there were fluctuations in the number of diagnoses of ORN and MRONJ over the 14 years of the study, there was a general upward trend for both diseases with the number of diagnoses peaking in 2015. There are a number of potential confounders that may have influenced this finding, however it suggests that more needs to be done to prevent these diseases. As the management of ONJ is complex (26, 203, 205), it is unfortunate that preventative efforts have not been more successful.

There were a number of limitations of this study that must be considered when interpreting the results. As the data were collected retrospectively from patient medical records, it is subject to inherent inaccuracies including missing data, coding errors, inaccessible patient records, and the inability to control potential confounders. It was also not possible to calculate the prevalence of MRONJ or ORN, as the size of the population from which the patients were sourced is unknown. Therefore, the data can only be interpreted as a survey of patients with each disease. However, as it can be difficult to use reported prevalence data to determine the burden of a disease in a particular population, reporting a simple count of affected patients provides a clinical perspective on the distribution of disease.

Due to the retrospective nature of the study, it was not possible to accurately determine the stage of ONJ for each patient. However, it is likely that only the more severe cases of disease were captured, as earlier stages of ORN and MRONJ may not

Chapter 3: Assessing the burden of disease 43 have required hospital admission. Therefore, the number of affected patients identified in this study may be a serious underestimate of the prevalence of ONJ.

Although ORN and MRONJ are two separate disease entities, the basic recommendations for their prevention are similar: identification and education of at-risk patients, treatment of infectious foci prior to the start of radiation or medical therapy, establishment of an adequate standard of oral hygiene, maintenance of a stable oral environment, and securing patient compliance for both at-home oral care and an appropriate schedule of dental follow-up (1, 111, 212, 213, 220). However, patients at risk of ONJ are being treated for life-threatening systemic diseases and therefore it is understandable that the potential oral consequences of their life-extending treatments might be considered a low priority (221). This is further complicated by many barriers to dental treatment including cost, fear, health literacy, access to dental services, and general perceptions that oral disease is of low importance (222, 223). The findings of this study suggest that despite a considerable body of evidence reporting the efficacy of preventative measures in the reduction of both ORN and MRONJ (112, 144, 215), this has not translated into a reduced number of patients presenting with these treatment complications.

Conclusion: There were 177 patients diagnosed with ORN and 61 with MRONJ at the Royal Brisbane & Women’s Hospital, Gold Coast University Hospital, and Robina Hospital between January 2003 and May 2017. Osteoporosis patients had the highest number of MRONJ diagnoses, while ORN most commonly affected patients irradiated for squamous cell carcinomas of the tongue and floor of mouth. The number of patients admitted for MRONJ and ORN has trended upwards since 2003, suggesting that collaborations within the health care system are needed to reduce the number of patients who develop MRONJ or ORN. This must include sustained preventative dental care.

Chapter 3: Assessing the burden of disease 44

Chapter 4: Systemic risk factors for MRONJ

STATEMENT OF CONTRIBUTION TO CO-AUTHORED PUBLISHED PAPER

This chapter includes a co-authored paper. The bibliographic details of the co-authored paper, including all authors, are:

McGowan, K., Acton, C., Ivanovski, S., Johnson, N.W., & Ware, R.S. (2019). Systemic comorbidities are associated with medication-related osteonecrosis of the jaws: case-control study. Oral Diseases, in press.

My contribution to the paper involved: developing the protocol for the study, submitting and obtaining ethical approval, submitting a site-specific assessment for both hospitals, submitting a Public Health Act application to access patient data, collecting and analyzing the data, and writing the manuscript. I am the corresponding author for the article, and was also responsible for submitting and revising the manuscript.

Signed: Date: 16th February, 2019

Student: Kelly McGowan

Countersigned: Date: 11th February, 2019

Supervisor: E/Prof Newell W Johnson

Chapter 4: Systemic risk factors for MRONJ 45

4.1 OVERVIEW

The third stage of this project was to determine how a patient’s systemic health influenced their risk of developing MRONJ, and identify factors that can be used to stratify high-risk patients. There are long lists of diseases, conditions, and medications that have been reported as possible risk factors for MRONJ (13), but it is difficult to determine how these relate to a particular patient’s risk of MRONJ, especially when multiple risk factors are present. This chapter investigated whether previously validated comorbidity measures were able to quantify a patient’s risk of MRONJ. A number of attempts to standardise the “weight” or value of comorbidities exist in the literature, as outlined in Table 13. There are varying levels of evidence to support each approach, however there is currently no gold standard method to measure comorbidity due to the varying strengths and weaknesses of each scoring system. The selection of the most appropriate method depends largely on the research question, the patient population of interest, and the type of data available (224).

Table 13. Summary of published comorbidity measures

Method, abbreviation & reference Purpose

Adult Comorbidity Evaluation-27 (ACE-27) (225) Assess comorbidity among cancer patients Adjusted Clinical Groups (ACG) (226) Predict resource use American Society of Anaesthesiologists (ASA) (227) Assess acute operative risk Alcohol-Tobacco Related Comorbidities Index (ATRCI) (228) Assess comorbidity in patients with HNCA Charlson Comorbidity Index (CCI) (229) Develop prognostic taxonomy Chronic Disease Score (CDS) (230) Predict resource use Cumulative Illness Rating Scale (CIRS) (231) Measure of physical impairment Comprehensive Prognostic Index (CPI) (232) Measure comorbidity in BCA, PCA Comorbidity Polypharmacy Score (CPS) (233) Quantify magnitude of comorbid conditions Diagnostic Cost Group (DC) (234) Predict resource use Elixhauser approach (235) Measure comorbidity using administrative data Index of Coexistent Disease (ICED) (236) Measure impact on physical functioning Kaplan-Feinstein Index (KFI) (237) Comorbidity measure in diabetic patients Multipurpose Australian Comorbidity Scoring System (MACSS) (238) Develop a generalised measure of comorbidity National Institute on Aging/NCI Collaborative Study (239) Assess comorbidity burden in cancer patients National Cancer Institute Comorbidity Index (NCI) (240) Comorbidity in cancer using administrative data Satariano approach (241) Assess comorbidity in BCA Simplified Comorbidity Index (SCI) (242) Assess comorbidity in patients with LCA Tammamagi approach (243, 244) Assess comorbidity among BCA, LCA Total Illness Burden Index (TIIBI) (245) Measure total burden of disease Washington University Head & Neck Comorbidity Index (WUHNCI) (246) Assess comorbidity in patients with HNCA

Adapted from Sarfati, 2012 (247). Abbreviations: HNCA, head and neck cancer; BCA, breast cancer; PCA, prostate cancer; LCA, lung cancer

Chapter 4: Systemic risk factors for MRONJ 46

Comorbidity measures are not widely used in MRONJ research to date, and no method has been validated in patients at risk of MRONJ. Three previous studies have used the Elixhauser index (248) or the Charlson Comorbidity Index (249, 250), however neither of these methods are well suited to everyday use in dental practice.

Elixhauser index as a summary measure of comorbidities (235) The Elixhauser index uses ICD coding to estimate in-hospital mortality, and these codes are not readily available to oral health practitioners in Australia. Coding-based measures also do not account for pharmacological risk factors, which are important for MRONJ.

Charlson Comorbidity Index as a summary measure of comorbidities (229) The Charlson Comorbidity Index (CCI) predicts the one-year mortality rate for patients based of a list of 21 diseases. A weighted score of 1-6 is assigned to each condition, and these are totalled to give an overall score. However, as per Table 14, the application of the CCI requires an advanced medical knowledge, beyond that of the average dental professional, as well as access to a detailed patient history and laboratory results. For example, the criteria for chronic pulmonary disease includes: “patients who are dyspneic with slight activity, with or without treatment and those who are dyspneic with moderate activity despite treatment, as well as patients who are dyspneic at rest, despite treatment, those who require constant oxygen, those with CO2 retention and those with a baseline PO2 below 50 torr…” (229).

Table 14. Charlson Comorbidity Index Weight Clinical condition

1 Myocardial infarct; Congestive heart failure; Peripheral vascular disease or bypass; Dementia or Alzheimer’s disease; Cerebrovascular disease or transient ischemic disease; Chronic pulmonary disease or asthma; Conjunctive tissue disease; Diabetes, no end organ damage; Gastric or peptic ulcer 2 Hemiplegia; Diabetes with end organ damage; Renal disease; Mild liver disease; Cancer 3 Moderate or severe liver disease 6 Metastatic solid tumour; AIDS

Adapted from Charlson & Foley, 1987 (229). Abbreviations: AIDS, acquired immune deficiency syndrome

The CCI was trialled in this project, but due to the complexity and time taken to apply the model, it was deemed unsuitable as a routine measure of systemic health in the context of this project. It would not be feasible to recommend that oral health professionals use the CCI to quantify systemic risk factors for MRONJ in everyday practice.

Chapter 4: Systemic risk factors for MRONJ 47

Comorbidity Polypharmacy Score as a summary measure of comorbidities (233) The Comorbidity Polypharmacy Score (CPS) attempts to better quantify the magnitude of comorbid conditions by incorporating the number of co-administered medications into the assessment of disease burden (233). The CPS is the sum of the number of pre-injury medications (prescription and over-the-counter) and all known comorbidities (including medical, psychiatric, and substance abuse). Each comorbidity or medication is assigned one point, and the total is used to determine the patient’s overall severity using the stratification outlined in Table 15 . It was originally developed in a population of trauma patients (233, 251), and has since been validated in a number of other settings (252-258). It has been suggested that the CPS may act as a surrogate marker for a patient’s physiologic age by providing a measure of the “cumulative severity” of all comorbid conditions.

Table 15. CPS severity stratification Severity Score

Minor 0-7 Moderate 8-15 Severe 15-21 Morbid >22

Adapted from Stawicki et al, 2015 (256)

For the purposed of this research, the CPS was the most suitable comorbidity assessment available. It incorporates the large number of systemic diseases that have previously been suggested as possible contributors to MRONJ susceptibility, accounts for pharmaceutical risk factors, and is very simple and fast to administer.

This chapter compared the CPSs for cases who developed MRONJ with their individually matched controls and found that patients with multiple systemic comorbidities and high levels of polypharmacy were significantly more likely to develop MRONJ. This is an important finding for clinical practice, as it offers oral health professionals a simple tool that has been previously validated in a number of different patient populations to identify patients at increased risk of MRONJ. However, the CPS does not incorporate dental risk factors, and therefore the findings of Chapter 5 also need to be considered in conjunction with the CPS when assessing a patient’s overall risk of MRONJ.

The supplementary table for this article is provided in Appendix H (Comorbidities by disease group)

Chapter 4: Systemic risk factors for MRONJ 48

4.2 ABSTRACT

Objectives: Medication-related osteonecrosis of the jaws (MRONJ) is a serious condition developed in up to 15% of patients who take antiresorptive medications. Its underlying pathogenesis remains unclear. The association between systemic comorbidities and MRONJ was investigated.

Subjects & methods: A case-control study was conducted in Brisbane, Australia. Hospital records were used to identify 68 cases of MRONJ between January 2003- March 2017. Each case was individually matched to 3 controls (204 in total) according to sex, age, primary disease, and type and duration of antiresorptive therapy. Data on patient demographic, social, and clinical characteristics were collected. Systemic comorbidities and medications were quantified as a Comorbidity Polypharmacy Score (CPS). Associations were investigated using conditional logistic regression.

Results: The CPS calculated for patients who developed MRONJ (mean±SD = 20.2±5.1) was significantly higher than for controls (12.9±4.6). Multivariable analysis determined a significant relationship between CPS and the presence of MRONJ (OR=1.5; 95%CI=1.3, 1.8, p<0.001).

Conclusions: Patients with multiple systemic comorbidities and high levels of polypharmacy were more likely to develop MRONJ. The CPS is a simple and effective tool to quantify the risk of MRONJ attributed to a patient’s systemic condition, and should be considered in conjunction with the patient’s oral health to assess the overall risk of MRONJ.

4.3 INTRODUCTION

Medication-related osteonecrosis of the jaws (MRONJ) has remained a largely enigmatic condition despite considerable research into its underlying pathogenesis since the first case series was published in 2003 (2). The prevalence of MRONJ is estimated to be between 0.001%-0.01% for osteoporotic patients, and 1%-15% for oncology patients (13). Medications associated with reported cases of MRONJ include bisphosphonates, denosumab, sunitinib, and bevacizumab, and possibly azacitidine, imatinib, everlimus, ipilimumab, and ziv-aflibercept (259). It remains unclear why a small minority of patients

Chapter 4: Systemic risk factors for MRONJ 49 will develop areas of jawbone necrosis during antiresorptive or antiangiogenic therapy, with therapy dose, duration and potency likely to influence the risk of MRONJ (1). Importantly, however, high or sustained doses of implicated medications are not necessary for this disease to develop (260).

There are a number of theories regarding the pathogenesis of MRONJ, with varying levels of evidence to support the following as contributing factors: osteocyte apoptosis (261); suppression (68); inhibition of blood vessel formation (91); obstruction of the vasculature (87); suppression of soft tissue healing (94), impaired immunity (104), genetic risk factors (262); and infection or inflammation as a result of oral biofilms (106). The role of oral health, and in particular dental extractions, has been extensively reported. While removal of a tooth in a patient on antiresorptive therapy is the most commonly reported initiator of MRONJ (263), most patients on antiresorptives will heal normally after a dental extraction (120). The pattern of disease suggests that patient susceptibility is key, with two constituent parts to a patient’s risk profile: 1) their overall dental health, and 2) their overall systemic health. This study is specifically interested in systemic risk indicators, some of which may be true risk factors, for MRONJ.

A number of potential systemic risk factors for MRONJ have been previously reported, including chemotherapy, diabetes, glucocorticoid therapy, anemia, renal disease and smoking (13, 263), however there is currently no evidence-based method to assimilate these potential risk factors into a clinically relevant format. In medicine, a number of comorbidity indices are used to predict which patients are likely to experience poor outcomes. The Comorbidity Polypharmacy Score (CPS) was developed in a population of trauma patients in 2011 (233, 251), and has been validated in a number of other settings (252-254, 264). The CPS is the sum of the number of pre-MRONJ medications plus all known comorbidities, with the total score indicating the patient’s cumulative severity. The incorporation of both the patient’s medical and pharmacological history makes it a good candidate for use in MRONJ populations. The ease of administration makes it a feasible approach for the routine clinical dental setting.

The aim of this study was to investigate whether CPS was associated with the risk of MRONJ in patients taking antiresorptive medications. It was hypothesized that systemically unwell patients were at a higher risk of MRONJ, and therefore a higher CPS will be associated with an increased risk of MRONJ.

Chapter 4: Systemic risk factors for MRONJ 50

4.4 METHODS

Study Design A case-control study was conducted in Brisbane, Australia, to compare the presence or absence of putative medical risk factors, as risk indicators, between cases with a clinical diagnosis of MRONJ and controls. Patients who were treated between 1 January 2003 and 30 March 2017 were eligible for inclusion. Patient records were reviewed at the Royal Brisbane & Women’s Hospital (RBWH), and at the Gold Coast University Hospital. Ethical approval for the study was obtained from the RBWH Human Research Ethics Committee (ID: EC00172, HREC/17/QRBW/242) and Griffith University Human Research Ethics Committee (Ref 2016/927). All patient information was de-identified to protect anonymity. The reporting of this study conforms to the STROBE statement (265).

Case Selection Potential cases were identified from hospital records using International Classification of Disease and Related Health Problems (ICD-10-AM 9th Edition) code K10.2, which represents inflammatory conditions of the jaw. As K10.2 includes a number of diseases (osteitis, osteomyelitis, osteonecrosis, osteoradionecrosis, periostitis, and sequestrum of jaw bone), each chart was manually reviewed to confirm the clinical diagnosis. The following criteria were used to determine case eligibility: 1. Taking antiresorptive or antiangiogenic medications 2. Exposed bone in the oral cavity that did not heal within 8 weeks after identification by a health care provider 3. No history of radiation therapy to the craniofacial region 4. No history of malignant or metastatic disease of the jaws 5. Aged 18 years or older 6. Not pregnant or breastfeeding

Control Selection Three controls were individually matched to each case on age, sex, primary disease, and antiresorptive therapy and duration. Controls were identified from hospital records using ICD-10-AM codes for breast cancer, prostate cancer, multiple myeloma, osteoporosis, Paget’s disease, and rheumatoid arthritis. Age and sex were matched to eliminate possible confounding due to age-related decline in immune function, or any

Chapter 4: Systemic risk factors for MRONJ 51 hormonal variation in risk. The type of antiresorptive drug prescribed and its dosage and duration were matched as closely as possible, as these variables are known to increase the risk of MRONJ (1). Where it was not possible to match the antiresorptive regimen exactly, the selected controls were required to have more potent or longer duration antiresorptive therapy in order to ensure that pharmaceutical factors were not reducing the risk of MRONJ in controls relative to their cases. Sex and age (to within 5 years) were matched to eliminate hormonal variations or age-related factors as potential confounders. Two potential controls who had received teriparatide (Forteo) for osteoporotic fractures were replaced, as teriparatide has been used in the treatment of MRONJ (46) and may have offered some protection against MRONJ in these patients.

Variables & Data Collection The primary exposures of interest were co-existing chronic diseases, and pharmacological therapies. For cases, all data were collected from the most recent time point available prior to their MRONJ diagnosis, while the most current data were recorded for controls. The primary data source was clinical notes, but all available sources were used to limit potential information bias due to incomplete notes when possible. Comorbidities were determined from computer-generated GP referrals or specialist outpatient clinic letters. Medications were recorded from the patient’s Medical Action Plan (MAP) provided by the hospital pharmacist or an outpatient medication list. Data on domestic living arrangements, tobacco and alcohol use were collected using the Patient Risk Assessment form or pre-anesthetic record. Patients were defined as cohabiting if they were married or in a de facto relationship. Alcohol abuse was determined from the hospital risk assessment form as either daily alcohol use or >6 drinks/session. Tobacco use was recorded as one of four categories: never, quit within the past five years, quit more than five years previously, or current user. Each patient’s postcode and marital status was collected from their admission data. Postcodes were used to calculate the Index of Relative Socio-Economic Disadvantage and Advantage for each subject, using the Socio-Economic Indexes for Areas Index (266).

Antiresorptive therapy was recorded from the MAP, outpatient medication lists, chemotherapy orders, or infusion records. Systolic and diastolic blood pressure, pulse rate, and anthropometric variables were collected from general observation charts, chemotherapy orders, or pre-anesthetic assessments. Body Mass Index was calculated

Chapter 4: Systemic risk factors for MRONJ 52 using standard formula and categorized as: <18.5 = below healthy weight range, 18.5-25 = healthy weight range, and >25 = above healthy weight range.

Each patient’s comorbidities were converted into the “C” component of the CPS by adding all identified comorbidities together. Identified comorbidities are listed in Supplemental Appendix 1. Data on polypharmacy were collected as a list of medications, and converted into the “P” component of the CPS by adding all identified medications together. As supplementary medications were sometimes prescribed as individual supplements (calcium, magnesium, glucosamine, iron) and sometimes as combinations or multi-vitamins, patients scored one point if they were prescribed any supplementary medication. Regular pain medications were scored similarly, excluding morphine or oxycodone that were scored individually. Each comorbidity or medication was assigned one point, and the “C” and “P” scores were added together to give an overall CPS. CPS scores were then grouped according to previously identified categories: mild (0-7 points), moderate (8-15 points), severe (15-21 points) or morbid (>21 points) (233, 251).

Statistical methods: Sample size calculations were based on the assumption of a binary exposure variable (categorised as high or low risk). To calculate the detectable difference in MRONJ cases by risk status we assumed 60 MRONJ cases would be identified, with three matched controls per case. Prior data indicated the average probability of a control being classified as high risk was 0.5, and the correlation coefficient for being high risk between matched cases and controls was 0.3. With 80% power and alpha = 0.05 we would be able to detect a significant difference in risk groups if the odds ratio observed was 2.2 or greater.

Statistics were summarised as frequencies (percentage). Demographic, social, and clinical characteristics of cases and controls were compared using the chi-square test. Conditional logistic regression was used to identify factors associated with MRONJ. Models were conditioned on their individually-matched case-control groups. Unadjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated where the exposure was CPS score and the outcome was MRONJ. Adjusted odds ratios (aOR) were calculated using multivariable conditional logistic regression.

Potentially confounding variables included in multivariable analysis were smoking and duration of antiresorptive therapy as these variables were identified during the univariable analysis. Disease groups that were significant in the univariable analysis

Chapter 4: Systemic risk factors for MRONJ 53 but were captured in the CPS were not adjusted for in the multivariable models. A pre- specified stratified analysis of oncologic and non-oncologic subgroups was conducted. Statistical analyses were conducted using IBM SPSS Statistics, Version 25 (IBM Corporation 2017 ©, Aarmonk, NY, USA).

4.5 RESULTS Study Design Overall, 68 cases of MRONJ were identified. Three controls were individually matched to each case (204 controls), with a total sample size of 272. The age of patients ranged from 43 to 94 years, with a mean ±SD age of 69.4 ± 12.2 years, and 60% of participants were female. Demographic, social, and clinical characteristics of cases and controls are compared in Table 16, and show that the matching process was effective at preventing any significant differences in sex, age, primary disease, or type of antiresorptive therapy. There was no significant difference between socioeconomic position or living arrangements for cases and controls. There was a significant difference in the duration of antiresorptive therapy with controls tending to have received longer courses of antiresorptive than cases, reflecting the decision making process in the matching protocol. Consequently, duration of antiresorptive therapy was included as a co-variable in multivariable analyses.

The systemic health of cases and controls were compared and results are presented in Table 17. Patients with non-insulin dependent diabetes mellitus, respiratory disease, cardiovascular disease, chronic kidney disease, blood disorders, mental illness, or who were current smokers had significantly greater odds of developing MRONJ. The distribution of chemotherapy was very similar between cases and controls, likely reflecting the standardised treatment recommendations for the matched primary diseases. Only 1 case and 3 controls were prescribed antiangiogenics, and therefore it was not possible to perform any meaningful analysis on the relative risk of MRONJ with antiangiogenic medications in this cohort.

Associations between the comorbidity and polypharmacy components of the CPS, as well as the combined CPS, and disease status are presented in Table 18. There was a highly statistically significant difference in both the individual components and the overall CPS. The mean CPS score for cases was 20.2 ± 5.1 compared to 12.9 ± 4.6 for controls. The model showed that the odds of developing MRONJ increased by 1.5 for every 1 unit increase in CPS (95%CI=1.6, 2.y; p<0.001), after adjusting for the potentially

Chapter 4: Systemic risk factors for MRONJ 54 confounding variables of tobacco use and duration of antiresorptive therapy. Oncology cases and controls reported a mean CPS of 19.1 ± 4.5 and 12.4 ± 4.5 respectively, which was similar to the mean CPS of 20.9 ± 5.7 and 13.3 ± 4.7 calculated for the non-oncology cases and controls. When CPSs were grouped into severity categories, the odds of a morbid patient developing MRONJ were 12.7 times greater (p=<0.001) than that of a severe patient. The odds of a patient with a moderate CPS score developing MRONJ was 10 times lower than patients classified as severe (p<0.001). The distribution of cases and controls between CPS stratifications is shown in Figure 10.

Table 16. Distribution of demographics and clinical factors (systemic risk factors) Characteristics Case (N=68) Control (N=204) p N (%) N (%) Sex 1.00 Male 28 (41.2) 84 (41.2) Female 40 (58.8) 120 (58.8) Age (years) 0.60 41-60 20 (29.4) 48 (23.5) 61-80 34 (50.0) 107 (52.5) 81-100 14 (20.6) 49 (24.0) Socioeconomic status (thirds) 0.71 Low 22 (34.4) 55 (27.1) Medium 18 (26.5) 59 (29.1) High 28 (41.2) 89 (43.8) Domestic living arrangements 0.40 Cohabiting 31 (45.6) 105 (51.5) Not cohabiting 37 (54.4) 99 (48.5) Primary disease 0.97 Osteoporosis 28 (41.2) 86 (42.2) Multiple myeloma 17 (25.0) 53 (26.0) Breast cancer 8 (11.8) 24 (11.8) Prostate cancer 10 (14.7) 30 (14.7) Other^ 5 (7.4) 11 (5.4) Antiresorptive therapy 0.63 Alendronate (Fosamax) 14 (20.6) 35 (17.2) Zoledronic acid (Aclasta) 5 (7.4) 16 (7.8) Zoledronic acid (Zometa) 16 (23.5) 43 (21.1) Pamidronate (Aredia) 7 (10.3) 21 (10.3) Risendronate (Actonel) 7 (10.3) 21 (10.3) Denosumab (Prolia) 3 (4.4) 13 (6.4) Denosumab (Xgeva) 8 (11.8) 35 (17.2) Other^^ 2 (3.0) 0 (0.0) Combination 4 (5.9) 15 (7.4) Duration antiresorptive therapy 0.013 1-2 years 26 (38.2) 42 (20.6) 3-4 years 23 (33.8) 95 (46.6) 5+ years 19 (28.0) 67 (32.8) Abbreviations; CML, chronic myeloid leukaemia; OR, odds ratio; aOR, adjusted odds ratio ^Other included rheumatoid arthritis, Paget’s disease and chronic myeloid leukaemia ^^Other included one case each of clodronate and ibandronate

Chapter 4: Systemic risk factors for MRONJ 55

Table 17. Association between comorbid conditions and MRONJ disease status Characteristics Case (N=68) Control (N=204) Unadjusted Adjusted

N, % N, % OR (95% CI) aOR (95% CI) Antiangiogenics 1 (1.5) 3 (1.5) 1.0 (0.1, 7.2) 1.5 (0.1, 24.5)

Chemotherapy

No 31 (45.6) 88 (43.1) Reference Reference

Non-cancer 2 (2.9) 8 (3.9) 0.8 (0.2, 3.2) 0.54 (0.1, 3.3)

Cancer 35 (51.5) 108 (52.9) 0.9 (0.6, 1.5) -

Corticosteroids

No 27 (40.3) 96 (47.1) Reference Reference

Inhaled 7 (10.4) 16 (7.8) 1.4 (0.6, 3.2) 1.6 (0.6, 4.4)

Systemic 33 (49.3) 92 (45.1) 1.2 (0.7, 2.0) 1.6 (0.7, 3.6)

Diabetes mellitus 19 (27.9) 26 (12.7) 2.0 (1.2, 3.3)** 3.0 (1.4, 6.6)**

Hypertension 33 (48.5) 83 (40.7) 1.3 (0.8, 2.0) 2.3 (1.1, 5.0)*

Dyslipidaemia 20 (29.4) 50 (24.5) 1.2 (0.7, 2.0) 1.1 (0.6, 2.3)

Other cardiovascular disease 34 (50.0) 60 (29.4) 1.9 (1.2, 3.1)*** 4.2 (1.9, 9.5)***

Gastrointestinal disease 24 (35.3) 49 (24.0) 1.5 (0.9, 2.5) 3.1 (1.5, 6.2)*

Respiratory disease 27 (39.7) 47 (23.0) 1.8 (1.1, 2.9)* 1.7 (0.9, 3.3)

Kidney disease 15 (22.1) 14 (6.9) 2.4 (1.4, 4.2)** 5.2 (1.9, 13.9)**

PTA diseases 9 (13.2) 17 (8.3) 1.5 (0.7, 2.9) 2.1 (0.8, 5.5)

Blood disorders 14 (20.6) 8 (3.9) 3.0 (1.7, 5.4)** 5.5 (1.8, 16.9)**

Autoimmune/Inflammatory 17 (25.0) 50 (24.5) 1.0 (0.6, 1.8) 1.1 (0.7, 1.6)

Mental health 16 (23.5) 33 (16.2) 1.4 (0.8, 2.5) 2.1 (1.0, 4.4)*

Tobacco use

Not current user 45 (70.3) 169 (87.6) Reference Reference

Current user 19 (29.7) 24 (12.4) 3.1 (1.5, 6.8)** 3.3 (1.5, 7.3)**

Alcohol dependency 18 (26.5) 38 (18.6) 1.5 (0.9, 2.6) 1.1 (0.5, 2.4)

Body mass index Underweight <18.5 2 (5.7) 5 (4.1) 1.8 (0.2, 13.8) 1.5 (0.1, 21.9) Normal 18.5-24.9 12 (34.3) 33 (27.0) 1.0 (0.3, 2.8) 0.5 (0.1, 2.1) Overweight 25-29.9 7 (20.0) 44 (36.1) 0.3 (0.1, 1.1) 0.1 (0.0, 0.7)*

Obese ≥30 14 (40.0) 40 (32.8) Reference Reference Systolic blood pressure

≤130 35 (57.4) 115 (56.7) Reference Reference

>130 26 (42.6) 88 (43.3) 1.0 (0.6, 1.6) 1.1 (0.6, 2.2)

Diastolic blood pressure

≤90 57 (93.4) 190 (93.6) Reference Reference >90 4 (6.6) 13 (6.4) 1.0 (0.4, 2.8) 0.6 (0.1, 2.3) Abbreviations: SD, standard deviation; OR, odds ratio; aOR, adjusted odds ratio; PTA, parathyroid, thyroid and adrenal. Multivariable analyses adjusted for current smoking status and duration of AR therapy. * indicates result is significant at p<0.05, ** p<0.01, *** p<0.001

Chapter 4: Systemic risk factors for MRONJ 56

Table 18. Association between CPS and risk of MRONJ, with subgroup analysis Characteristics Case (N=68) Control (N=204) Univarible Multivariable p Mean ± SD Mean ±SD OR (95% CI) aOR (95% CI) All patients: Comorbidity Score 7.2 ± 3.0 3.9 ± 1.9 1.3 (1.2, 1.34) 2.1 (1.6, 2.7) <0.001 Polypharmacy Score 13.1 ± 4.0 8.9 ± 3.4 1.2 (1.1, 1.3) 1.5 (1.3, 1.7) <0.001 Combined CPS 20.2 ± 5.1 12.9 ± 4.6 1.2 (1.1, 1.2) 1.5 (1.3, 1.8) <0.001

Oncology subgroup: (n=36) (n=108) Comorbidity Score 5.8 ± 2.5 3.3 ± 1.8 1.3 (1.2, 1.5) 2.3 (1.5, 3.6) <0.001 Polypharmacy Score 13.8 ± 3.7 9.1 ± 3.4 1.2 (1.1, 1.3) 1.7 (1.3, 2.2) <0.001 Combined CPS 19.1 ± 4.5 12.4 ± 4.5 1.2 (1.1, 1.3) 1.8 (1.3, 2.7) 0.001

Non-oncology subgroup: (n=32) (n=96) Comorbidity Score 8.7 ± 2.8 4.7 ± 1.7 1.4 (1.2, 1.5) 2.0 (1.4, 2.8) <0.001 Polypharmacy Score 12.3 ± 4.1 8.7 ± 3.4 1.2 (1.1, 1.3) 1.4 (1.2, 1.7) 0.001 Combined CPS 20.9 ± 5.7 13.3 ± 4.7 1.2 (1.1, 1.2) 1.5 (1.2, 2.0) 0.002

Case (N=68) Control (N=204) Univariable Multivariable p N (%) N (%) OR (95% CI) aOR (95% CI) All patients: Minor (0-7) 0 (0.0) 31 (15.4) - - - Moderate (8-14) 4 (6.1) 96 (47.8) 0.1 (0.0, 0.3) 0.1 (0.0, 0.8) <0.001 Severe (15-21) 37 (56.1) 67 (33.3) Reference - Morbid (>22) 25 (37.9) 7 (3.5) 2.26 (1.36, 3.76) 12.7 (3.2, 50.0) <0.001 Abbreviations: SD, standard deviation; OR, odds ratio; CPS, Comorbidity Polypharmacy Score Multivariable analyses adjusted for current smoking status and duration of antiresporptive therapy.

Figure 10. Distribution of cases and controls across CPS categories

Chapter 4: Systemic risk factors for MRONJ 57

4.6 DISCUSSION

The CPS is a simple and effective tool to quantify how the cumulative severity of disease in an individual patient relates to their risk of developing MRONJ. While individual diseases are separately associated with the development of MRONJ, an obvious advantage of the CPS is the ease of clinical application and interpretation.

The CPS offers a number of advantages over other comorbidity measures for MRONJ. Two other comorbidity indices have been used in previous MRONJ research and support the association between multiple comorbid conditions and increasing MRONJ risk. Lapi et al. used the Charlson Comorbidity Index (CCI) as a measure of chronic severity and found that MRONJ cases reported significantly higher CCIs compared to controls (249). Kwon et al. used individual components of the CCI to adjust for confounding and reported that cases more frequently recorded CCI conditions but no formal analysis of this difference was conducted (250). Based on these published reports, the use of the CCI was piloted in this project but was deemed unsuitable due to the complexity of the criteria (229) and the time taken to accurately calculate a result. Baillargeon et al. used a modified version of the Elixhauser method (235) to quantify comorbidities and also found that MRONJ cases had significantly more comorbidities than controls (248). The Elixhauser method uses International Classification of Disease (ICD) codes which dental practitioners do not routinely access, and for this reason it was also not suitable for this project.

Within the CPS, the inclusion of the patient’s pharmacology profile in addition to their comorbid conditions better reflects previously reported risk factors for MRONJ (13, 263). The simplicity of the system makes it a feasible approach for routine use in dental practice. This study found that the association between CPS and MRONJ was similar between oncology and non-oncology patients and therefore it could be applied to all patients without the need for complicated weightings for different patient groups. It is a validated predictor of outcomes (233, 251), readmissions (254), in-hospital complications (264), and mortality (252) in older trauma patients, as well as hospital mortality and readmissions for surgical patients (258). It was also shown to be a more accurate prognostic tool than the CCI or chronologic age for overall survival in elderly patients with cancer of the oropharynx (267). The authors suggested the superiority of the CPS over the CCI may be due to the inclusion of polypharmacy, which better reflected the mortality risk than assessment of comorbidities alone (267).

Chapter 4: Systemic risk factors for MRONJ 58

The ability of the CPS to identifying high-risk patients has important clinical implications for the dental management of patients on antiresorptive therapies. It is well established that preventative dental measures significantly reduce the incidence of MRONJ (112, 142, 144, 180), and the CPS could be used to identify patients at the highest risk of MRONJ so that more frequent and intensive preventative care can be provided. Current guidelines state that dental implants can be considered for osteoporotic patients on antiresorptive therapy (17) but there is no validated method for determining which patients are suitable candidates. Similarly, a number of modifications to techniques for exodontia have been described to minimise the risk of MRONJ (268), but it is important for surgical planning to understand which patients are at increased risk of developing MRONJ. C-terminal telopeptide (CTX) scans have been previously investigated as a possible predictor of MRONJ risk (269) but have been subsequently shown to have no predictive value (151). The clinical utility of the CPS should be further investigated as a rapid and non-invasive alternative to laboratory testing to assist clinicians in managing patients on antiresorptive therapies.

The careful matching of cases to controls on the basis of their primary disease and antiresorptive therapy was an important strength of this study. Eliminating the type and duration of antiresorptive therapy as confounding factors allowed this study to focus on the role of comorbidities and polypharmacy in determining MRONJ risk. Although the intention was to match for duration of antiresorptive therapy, it was not possible to achieve this in every instance. Where necessary, controls with longer durations of antiresorptive therapy were used. This unbalanced distribution of duration was reflected in the univariable analysis, where the odds ratios were biased downwards (i.e. towards the null). The use of retrospective hospital data was an important limitation and must be considered when interpreting the results. Errors within individual clinical records and missing data may have influenced the outcome, and it was not possible to collect data on the timing and duration of chemotherapy and corticosteroid use. Although the sample size was calculated using a binary exposure variable, during data collection it was decided to treat CPS as an interval variable. Given that continuous exposure variables have higher power against fixed alternative hypotheses than binary exposure variables, we did not recalculate the sample size, and the highly significant results demonstrate that a sufficient number of participants were identified.

In this study, cases and controls received chemotherapy and corticosteroids in equal frequencies and the risk of MRONJ was not significantly associated with either

Chapter 4: Systemic risk factors for MRONJ 59 medication type. This may reflect that medical treatment in Australia is regulated through clinical and therapeutic guidelines, and therefore matching patients by primary disease may have incidentally matched for certain systemic treatments. However, most of the data that supports a significant association between chemotherapy, corticosteroids and MRONJ comes from cohort studies (McGowan et al., 2018), and without a control group it is possible that this relationship has been overestimated. Our study suggests that chemotherapy and corticosteroids are common treatments in patients who receive antiresorptive therapy, and that the cumulative burden of disease and pharmacotherapy are more predictive of MRONJ risk than individual medications.

It is important to note that the CPS does not measure dental risk factors, which are a critical consideration when assessing the likelihood of an individual patient developing MRONJ. Australia has universal health coverage under Medicare but this does not extend to dental treatment. Almost half of the participants in this study did not have an available public dental record, and therefore the association between oral disease, dental treatment and MRONJ could not be determined within the present data set. Dental risk factors will be investigated in a future report utilizing the available dental data.

The use of hospital controls is often associated with the recruitment of a generally sicker population, and therefore the CPSs calculated in this study may be higher than those of patients taking antiresorptive therapies that are managed in general practice clinics. This may explain the large number of osteoporotic cases, as patients managed in hospital-based endocrinology clinics would have more complicated medical histories and therefore be at an increased risk of MRONJ. It is also important to note that the CPS does not provide any measure of dental risk factors, which must be considered when assessing the likelihood of an individual patient developing MRONJ. The generalizability of these results to other patient populations is currently unknown, and it will be important to determine if the association between CPS results and MRONJ risks persists in other populations of patients taking antiresorptive therapies, such as patients managed outside of the hospital setting as well as populations from different countries and with different ethnicities. Future research should also investigate whether CPS is a predictor of MRONJ treatment outcomes.

Results of this study suggest that a patient’s risk of MRONJ increases significantly with systemic comorbidities and polypharmacy. The CPS offers a simple and effective method of quantifying this risk. Clinical assessment of the patient’s dental risk factors should be used in conjunction with the CPS to estimate the overall risk of MRONJ.

Chapter 4: Systemic risk factors for MRONJ 60

Chapter 5: Dental risk factors for MRONJ

STATEMENT OF CONTRIBUTION TO CO-AUTHORED PUBLISHED PAPER

This chapter includes a co-authored paper. The bibliographic details of the co-authored paper, including all authors, are:

McGowan, K., Ware, R.W., Acton, C., Ivanovski, S., & Johnson, N.W. (2019). Both non-surgical dental treatment and extractions increase the risk of medication- related osteonecrosis of the jaws: case-control study. Clinical Oral Investigations, in press.

My contribution to the paper involved: developing the protocol for the study, submitting and obtaining ethical approval, submitting a site-specific assessment for both hospitals, submitting a Public Health Act application to access patient data, collecting and analyzing the data, and writing the manuscript. I am the corresponding author for the article, and was also responsible for submitting and revising the manuscript.

Signed: Date: 16th February, 2019

Student: Kelly McGowan

Countersigned: Date: 11th February, 2019

Supervisor: E/Prof Newell W Johnson

Chapter 5: Dental risk factors for MRONJ 61

5.1 OVERVIEW

This chapter reports the results of the second case-control study which investigated the relationship between a patient’s oral health and their risk of developing MRONJ. Dental disease and treatment were identified as common risk factors in the earlier systematic review (Chapter 2), with extraction of a tooth the most frequently reported initiator of MRONJ. Periodontal disease, implants, denture trauma, odontogenic infection, and tori were also commonly implicated in the development of MRONJ (263). This chapter also sought to determine how many patients received a dental check-up in the 12 months prior to starting their medication, and whether patients were receiving ongoing dental care throughout antiresorptive therapy in line with current recommendations (156).

Australia has universal health coverage under Medicare but this does not extend to dental care, which prevented the combined analysis of dental and systemic risk factors. For logistical reasons, the data for this chapter were collected from public dental clinics as this could be requested from a central database. Only 44 of the 68 cases and 113 of the 204 controls in the previous chapter had dental records accessible, so available data was audited and cases and controls were re-matched.

The findings of this chapter highlight the current deficiencies in preventative oral care provided both before commencing antiresorptive medications, and during antiresorptive therapy. The majority of patients did not receive a dental examination in the 12 months prior to starting their antiresorptive, and both cases and controls averaged less than one exam every three years of antiresorptive therapy. Cases required significantly more extractions and fillings than controls, and this increased their risk of developing MRONJ. Despite the recommendations of a number of international clinical guidelines, most patients are not receiving a comprehensive dental examination and treatment to optimise the oral cavity prior to starting antiresorptive medications. Patients are also not receiving diligent preventative dental care on a regular basis throughout antiresorptive therapy. These findings suggest that there is a significant opportunity to reduce the incidence of MRONJ by improving the dental care and oral health of patients who require antiresorptive therapy.

The supplementary table for this article is provided in Appendix I (Classification of dental treatment based on ADA codes).

Chapter 5: Dental risk factors for MRONJ 62

5.2 ABSTRACT

Objectives: Medication-related osteonecrosis of the jaws (MRONJ) is a serious condition whose risk factors remain unclear. The aim of this study is to investigate the role of oral health and of dental treatment in the development of MRONJ.

Materials & Methods: A case-control study was conducted in Brisbane, Australia. Hospital records were used to identify incident cases of MRONJ between January 2010 and March 2017. Cases were individually matched to up to 3 controls according to age, sex, primary disease, and type of antiresorptive therapy. Demographic information, medical history, and public dental records were collected. Associations between oral health, dental treatment and MRONJ were investigated using conditional logistic regression.

Results: Overall, 44 cases were identified and matched to 115 controls (total sample = 159). 27% of cases and 34% of controls received a dental examination in the 12 months prior to starting antiresorptive therapy. After adjusting for potentially confounding variables, non-surgical dental treatment (OR=6.3; 95%CI=2.1, 19.1; p=0.001) and dental extractions (OR=8.0; 95%CI=3.0, 21.0, p<0.001) were significantly associated with development of MRONJ.

Conclusions: Two-thirds of patients did not receive a dental examination in the year prior to commencing antiresorptive therapy. Preventative dental care was insufficient to eliminate the need for dental treatment and extractions during antiresorptive therapy, which increased the risk of MRONJ.

Clinical Relevance: Optimising the health of the oral cavity and ongoing preventative dental care must be a priority for patients prior to the initiation of antiresorptive medications.

Chapter 5: Dental risk factors for MRONJ 63

5.3 INTRODUCTION

Objectives: The dental profession plays a central role in the prevention, diagnosis and management of medication-related osteonecrosis of the jaws (MRONJ). MRONJ presents as an area of necrotic jawbone in a small percentage of patients who take antiresorptive and antiangiogenic medications (1). The prevalence of MRONJ is estimated to be between 0.001%-0.01% for osteoporotic patients, and 1%-15% for oncology patients (17).

MRONJ presents almost exclusively in the mandible and maxilla, and this is likely due to the unique anatomical characteristics and functional environment of the oral cavity (270). The mandible and maxilla support the teeth, which can develop dental decay and periodontal diseases that are a potential source of infection and inflammation to the surrounding bone. The mucosa that covers the jawbones is thin and can be damaged during normal physiological function, allowing oral microbes access to the underlying osseous structures (270). Mucosal trauma from dentures has also been associated with the subsequent development of MRONJ (271). The unique relationship between the teeth and the jaws creates a situation where areas of bone are directly exposed to the oral cavity after removal of a tooth. These exposed surfaces are vulnerable to colonization by microbial biofilms (106), which contain complex and organized communities of microbes that are difficult to control once established. Dental extractions are the most commonly reported initiator of MRONJ (263), however it is not clear whether biofilms are directly involved in the pathogenesis of MRONJ or whether they simply form on exposed bone surfaces secondary to the development of MRONJ.

It is inherently difficult to investigate a rare condition like MRONJ prospectively, and as a result, the existing literature on dental risk factors is limited and often contradictory. Various reports have implicated dentures (272), extractions (273-275), periodontal disease (274, 276), exostoses (274), local suppuration (277), dental caries (278), apical lesions (279), and poor oral hygiene (278) as factors that increase the risk of MRONJ, while others have suggested that periodontal disease (272) and total number of decayed, missing and filled teeth (DMFT) (276) are not associated with an increased risk of MRONJ.

Establishing the role of dental disease in the pathogenesis of MRONJ is important, as management of dental disease potentially offers the most feasible strategy for

Chapter 5: Dental risk factors for MRONJ 64 prevention. While the type, dose and duration of antiresorptive medication has been reported to influence susceptibility to MRONJ, these elements are difficult to modify, as they are optimized to manage serious underlying systemic disease. The aim of this study was to investigate the role of oral health and of dental treatment in the development of MRONJ. It was hypothesized that patients who had dental examinations and appropriate dental treatment prior to their antiresorptive therapy were at a lower risk of MRONJ, while patients who developed dental disease and received dental interventions whilst on antiresorptive therapy were at increased risk of MRONJ.

5.4 METHODS

Study design A case-control study was conducted in Brisbane, Australia, to investigate the association between oral health and dental treatment and development of MRONJ. Patients treated at the Royal Brisbane & Women’s Hospital (RBWH) and the Gold Coast University Hospital (GCUH) between 1 January 2010 and 31 March 2017 were eligible for inclusion. Both hospitals are tertiary level facilities with specialist oral and maxillofacial surgery departments. Ethical approval for the study was obtained from the RBWH Human Research Ethics Committee and Griffith University Human Research Ethics Committee. The reporting of this study conforms to STROBE guidelines (265).

Case selection RBWH and GCUH patient databases were searched to identify patients with a clinical condition diagnosed using International Classification of Disease and Related Health Problems (ICD-10-AM 9th Edition) code K10.2 (“Inflammatory conditions of the jaw”). Patient records were manually reviewed to confirm a clinical diagnosis of MRONJ according to the American Association of Oral and Maxillofacial Surgeon’s (AAOMS) 2014 diagnostic criteria (1). Cases over the age of 18 were eligible for inclusion if they had previously received v or antiangiogenic medications: these were incident cases of MRONJ, had no prior history of radiation or metastatic disease to the jaws, and had an area of exposed bone in the oral cavity that did not heal within 8 weeks after identification by a health care provider. When cases were diagnosed with more than one instance of MRONJ, only data for the first incident case were included. As this study relied on public dental records, only patients who held a current health care card or pension card (i.e. were entitled to free public dental care in Australia) were eligible for inclusion. Patients who

Chapter 5: Dental risk factors for MRONJ 65 were not eligible for public dental treatment were excluded, as their dental records were not available.

Control selection Controls were selected from the same treating hospital according to the primary disease for which antiresorptive therapy was indicated. ICD-10-AM codes for multiple myeloma, breast cancer, prostate cancer, osteoporosis, and rheumatoid arthritis were used to search patient databases, and up to three controls with the same primary disease were individually matched on age, sex, and antiresorptive therapy and duration. Care was taken to match the type, dose and duration of antiresorptive treatment as these variables are known to influence the risk of developing MRONJ (1). Where it was not possible to match the antiresorptive regimen exactly, controls that had received longer duration antiresorptive therapy were selected to ensure that controls did not have a lower pharmaceutical risk profile relative to their matched cases. Age (to within 7 years) and sex were matched to eliminate age-related factors and hormonal variations as potential confounding variables.

Variables & data collection A case-control The main explanatory variables were pre- antiresorptive dental examination and dental treatment during antiresorptive therapy. Demographic information and the history of antiresorptive therapy were recorded from hospital records. Data extractors were masked to the case/control status of individual patients. Dental treatment was grouped into three categories:

1. Preventative care: oral examination, removal of plaque or calculus, application of remineralisation or cariostatic agents, desensitizing procedures, dietary analysis, oral hygiene instruction, and tobacco counselling. 2. Non-surgical dental treatment: periodontics, endodontics, restorations, fixed prosthodontics, and removable prosthodontics. 3. Extractions: simple, sectional, and surgical removal of a tooth or part(s) thereof, with or without removal of bone. More information on the classification of treatment is provided in Online Resource 1.

Dental treatment during antiresorptive therapy was recorded as both the number of treatments provided and the dichotomous assessment of any preventative treatment, non- surgical treatment, or extraction. For cases, any dental treatment from the date of antiresorptive commencement to the date of first MRONJ diagnosis was included. For

Chapter 5: Dental risk factors for MRONJ 66 controls, all treatment from the date of antiresorptive commencement until 31st March 2017 was included. As the duration of antiresorptive therapy varied between patients, treatment type per year of antiresorptive therapy was also calculated.

Pre-antiresorptive dental examination was determined using Australian Dental Association (ADA) treatment codes and appointment dates. These data were obtained from the Information System for Oral Health through the Office of the Chief Dental Officer in Queensland Health. Patients were considered to have received a pre- antiresorptive dental examination if an 011 (comprehensive oral exam), 012 (periodic oral exam) or 013 (limited oral exam) was recorded within the 12 months prior to their first dose of antiresorptive. Chemotherapy order forms, medication action plans, and outpatient medication lists were used to determine the commencement date for antiresorptive therapy. July 1st was used as the index date for nine patients where the year but not the month of antiresorptive commencement could be determined. Radiographs (intraoral and panoramic), professional cleans, oral hygiene instruction, tobacco counselling, and dietary analysis and advice were recorded, as was any other treatment provided. ADA codes were grouped into treatment categories as per Appendix 1.

Tobacco use, diabetes, and socio-economic status were considered to be possible confounding variables, and were extracted from hospital records. Socio-economic status was calculated at the postcode level using the Australian Bureau of Statistics Index of Relative Socio-Economic Disadvantage and Advantage (266), before being categorised into thirds.

Statistical methods Sample size calculations were based on a binary exposure variable (received any dental treatment or did not receive any dental treatment during antiresorptive therapy). An audit of available data was undertaken which revealed there were 44 cases of MRONJ. We assumed there would be 3 matched controls for each case, that the probability of a control receiving treatment was 0.4, and the correlation coefficient for treatment between matched cases and controls was 0.3. With 80% power we were able to detect an odds ratio (OR) of 2.4 or greater (alpha=0.05).

Statistics were summarized as frequencies, and demographic and clinical characteristics of cases and controls were compared using the chi-square test. Conditional logistic regression was used to calculate unadjusted odds ratios (OR) and 95% confidence intervals (CI) where the exposure was dental treatment and the outcome was MRONJ.

Chapter 5: Dental risk factors for MRONJ 67

Models were conditioned on their individually-matched case-control groups. Adjusted odds ratios (aOR) were calculated using multivariable conditional logistic regression. Potentially confounding variables were identified via univariable analysis, and variables significant at p<0.05 were included in the multivariable model. A pre-specified subgroup analysis was conducted to determine if there were any differences between the clinical management of oncology and non-oncology (endocrinology and ) patients. Statistical analyses were conducted using IBM SPSS Statistics, Version 25 (IBM Corporation 2017 ©, Aarmonk, NY, USA).

5.5 RESULTS

The total sample size was 159. Forty-four cases of confirmed MRONJ were eligible for public dental treatment and had dental records available, and four of these developed MRONJ more than once. It was not possible to successfully match 3 controls to every case under our pre-specified criteria, and on 17 occasions, 2 controls were matched (115 controls overall). Participant selection, exclusion and inclusion flow are summarized in Figure 11.

Figure 11. Flow chart of participant selection, exclusion and inclusion based on eligibility for public dental treatment and availability of dental records.

Abbreviations: RBWH, Royal Brisbane and Women’s Hospital; GCUH, Gold Coast University Hospital; MM, multiple myeloma; BC, breast cancer; OP, osteoporosis; RA, rheumatoid arthritis; PD, Paget’s disease.

Chapter 5: Dental risk factors for MRONJ 68

The age of patients ranged from 43 to 94 years, and the mean ± standard deviation (SD) age of cases was 67.8 ± 11.7, compared to 70.4 ± 12.5 for controls. Patients had been on antiresorptive therapies for between 1 and 10 years, with a mean of 3.1 ± 1.6 years for cases and 3.9 ± 1.6 for controls. Demographic and clinical information are presented in Table 19. All cases of MRONJ had received antiresorptive therapy. One received both antiresorptive and antiangiogenic therapy, but no cases were antiresorptive -naïve. Controls had significantly longer durations of antiresorptive therapy, and more cases were smokers or had diabetes. The chi-square analysis for smoking and diabetes as potential confounders did not reach statistical significance (p=0.06 and p=0.08 respectively), but a decision was made to include these factors in the multivariable analyses due to the well-documented effect of smoking and diabetes on oral health.

Of the 44 cases of MRONJ, 28 (64%) were initiated by a dental extraction. 6 (14%) occurred at the site of an acute infection (periodontal and/or endodontic), and 5 (11%) were initiated by denture trauma. Of the remaining 5 cases, one occurred mid- chemotherapy cycle, one after starting antiangiogenic therapy, one after a dental restoration, one after an epileptic seizure, and there was one case where no initiating factor was documented.

The number of patients who received dental treatment before and during antiresorptive therapy is presented in Table 20. 27% of cases and 34% of controls received a dental examination in the 12 months prior to starting antiresorptive therapy, with 9% and 16% receiving oral hygiene instructions respectively. Of the patients with remaining natural dentition, 11% of cases and 24% of controls received a professional clean. After adjusting for duration of antiresorptive, diabetes and smoking status, the model showed that receiving non-surgical dental treatment while on antiresorptive therapy increased the odds of developing MRONJ five times (OR=5.0; 95%CI=1.8, 14.0, p<0.05). Having a tooth extracted resulted in an eight-fold increase in the odds of MRONJ (OR=8.0; 95%CI=3.0, 21.0, p<0.001). Preventative care was not associated with the odds of developing MRONJ (OR=1.8; 95%CI=0.66, 4.8; p=0.25).

The total number of appointments, extractions and fillings during antiresorptive therapy as well as the average number of treatments performed per year of antiresorptive therapy are presented in Table 21. Cases and controls both received an average of 0.3 examinations per year of treatment. 64% of cases and 18% of controls had one or more tooth extracted while on antiresorptive therapy. Cases averaged nearly one tooth removed per year of antiresorptive treatment (0.9 ± 1.4), compared to 0.2 ± 0.4 extractions per year

Chapter 5: Dental risk factors for MRONJ 69 for controls. The odds of developing MRONJ increased three times with every additional extraction (OR=2.9; 95%CI=1.2, 7.9; p=0.03). Cases had twice as many teeth filled per year, and attended more dental appointments overall, both of which significantly increased the odds of developing MRONJ.

Table 19. Demographic and clinical characteristics of participants (dental risk factors) Characteristics Case (N=44) Control (N=113) p N (%) N (%) Sex 0.59 Male 20 (45.5) 46 (40.7) Female 24 (54.4) 67 (59.3) Age (years) 0.26 41-60 14 (31.8) 25 (22.1) 61-80 23 (52.3) 58 (51.3) 81-100 7 (15.9) 30 (26.5) Socioeconomic status (thirds) 0.71 Low 15 (34.1) 32 (28.3) Medium 16 (36.4) 41 (36.3) High 13 (29.5) 40 (35.4) Primary disease 0.81 Osteoporosis 16 (36.4) 49 (43.4) Multiple myeloma 13 (29.5) 31 (27.4) Breast cancer 5 (11.4) 15(13.3) Prostate cancer 7 (15.9) 11 (9.7) Rheumatoid arthritis 3 (6.9) 7 (6.2) Antiresorptive therapy 0.91 Alendronate (Fosamax) 10 (22.7) 28 (24.8) Zoledronic acid (Aclasta) 3 (6.8) 7 (6.2) Zoledronic acid (Zometa) 14 (31.8) 31 (27.4) Pamidronate (Aredia) 5 (11.4) 14 (12.4) Risendronate (Actonel) 5 (11.4) 15 (13.2) Denosumab (Prolia) 2 (4.5) 6 (5.3) Denosumab (Xgeva) 5 (11.4) 12 (10.6)

Duration antiresorptive therapy <0.001 1-3 years 31 (70.5) 39 (36.4) 4+ years 13 (29.5) 68 (63.6) Diabetes mellitus 13 (29.5) 19 (16.8) 0.08 Current smoker 11 (26.2) 14 (13.2) 0.06 Dentures 0.62 None 16 (40.0) 29 (32.6) 1 or more partial dentures 11 (27.5) 20 (22.5) Full/partial dentures 8 (20.0) 22 (24.7) Full/full dentures 5 (12.5) 18 (20.0)

Chapter 5: Dental risk factors for MRONJ 70

Table 20. Dental care of cases and controls prior to and during antiresorptive therapy

Characteristics Case Control Univariate Multivariate (N=44) (N=113) N, % N, % OR (95% CI) aOR (95% CI)

Received pre-ART dental examination: 12 (27.3) 38 (33.6) 0.8 (0.3, 1.7) 1.0 (0.5, 2.7)

Radiographic examination 5 (11.4) 19 (16.8) 0.7 (0.3, 1.8) 0.7 (0.3, 1.9)

Professional clean 5 (11.4) 27 (23.9) 0.5 (0.2, 1.3) 0.5 (0.2, 1.3)

Oral hygiene instruction 4 (9.1) 18 (15.9) 0.6 (0.2, 1.7) 0.8 (0.3, 2.1)

Denture remake/reline/adjustment 1 (2.3) 1 (0.9) 1.8 (0.3, 13.0) 1.4 (0.2, 10.9)

Fillings 7 (15.9) 20 (17.7) 0.9 (0.4, 2.0) 1.1 (0.5, 2.5)

Extractions 2 (4.5) 7 (6.2) 0.8 (0.2, 3.2) 0.7 (0.2, 3.1)

Periodontal debridement 1 (2.3) 2 (1.8) 1.2 (0.2, 8.7) 0.7 (0.1, 5.0)

Received any dental treatment during ART: 32 (72.7) 54 (47.8) 3.3 (1.5, 7.6)* 4.2 (1.5, 11.8)*

Dental examination 16 (36.4) 37 (32.7) 1.3 (0.6, 2.7) 1.7 (0.7, 4.4)

Radiographic examination 24 (54.5) 34 (30.1) 3.5 (1.6, 8.1)** 5.1 (1.9, 13.7)***

Professional clean 11 (27.5) 30 (30.6) 1.1 (0.5, 1.9) 1.8 (0.6, 5.0)

Oral hygiene instruction 11 (19.5) 22 (19.5) 1.3 (0.6, 3.1) 1.4 (0.5, 4.0)

Periodontal treatment 3 (6.8) 4 (3.5) 1.9 (0.5, 8.5) 1.6 (0.3, 8.6)

Endodontic therapy (completed obturation) 5 (11.4) 6 (5.3) 2.2 (0.6, 7.7) 2.2 (0.5, 9.1)

Restorative treatment 18 (40.9) 35 (31.0) 1.6 (0.8, 3.6) 2.6 (1.0, 7.1)*

Denture issued/adjusted/relined 11 (25.0) 23 (20.4) 1.4 (0.6, 3.0) 1.3 (0.5, 3.1)

Treatment of acute periodontal infection 4 (9.1) 3 (2.7) 7.8 (0.8, 74.0) 9.0 (0.8, 97.1)

Extirpation of 6 (13.6) 7 (6.2) 2.2 (0.7, 6.9) 2.0 (0.5, 8.0)

Received preventative care during ART: 17 (38.6) 39 (34.5) 1.2 (0.6, 2.6) 1.8 (0.7, 4.8)

Received non-surgical treatment during ART: 32 (72.7) 48 (42.5) 3.9 (1.8, 8.9)** 6.3 (2.1, 19.1)**

Had one or more tooth extracted during ART: 28 (63.6) 20 (17.7) 6.8 (3.0, 15.2)*** 8.0 (3.0, 21.0)***

Abbreviations: OR, odds ratio; aOR, adjusted odds ratio, ART, antiresorptive therapy. Dental treatment includes categories outlined in Supplemental Table 1. Extractions were treated as their own category. * indicates result is significant at p<0.05, ** p<0.01, *** p<0.001. Adjusted for smoking status, diabetes and duration of antiresorptive therapy.

Chapter 5: Dental risk factors for MRONJ 71

Table 21. Nature and frequency of dental treatment during antiresorptive therapy

Characteristics Case (N=44) Control (N=113) Univariate Multivariate

Mean ± SD Mean ±SD OR (95% CI) aOR (95% CI)

Received any dental treatment during AR therapy: N = 32 (73%) N = 54 (48%)

No. of appointments for preventative care 1.2 ± 1.6 2.1 ± 2.2 1.0 (0.8, 1.2) 1.1 (0.8, 1.5)

No. of appointments for non-surgical treatment 7.2 ± 8.3 6.9 10.1 1.0 (1.0, 1.1) 1.1 (1.0, 1.2)**

No. of teeth extracted 2.1 ± 4.6 1.0 ± 2.2 1.3 (1.0, 1.5)* 1.3 (1.1, 1.7)*

No. of teeth filled 3.6 ± 7.8 3.5 ± 4.6 1.0 (1.0, 1.1) 1.1 (1.0, 1.2)*

Examinations/year of AR therapy 0.3 ± 0.4 0.3 ± 0.3 2.4 (0.6, 9.2) 3.5 (0.8, 16.0)

Cleans/year of AR therapy 0.3 ± 0.6 0.4 ± 0.6 2.0 (0.7, 5.4) 2.6 (0.9, 7.8)

Extractions/year of AR therapy 0.9 ± 1.4 0.2 ± 0.4 3.3 (1.3, 8.1)** 2.9 (1.2, 7.9)*

Fillings/year of AR therapy 1.2 ± 2.0 0.6 ± 0.8 1.5 (1.1, 2.1)* 1.8 (1.2, 2.6)*

Appts/year of AR therapy 2.8 ±2.6 1.9 ± 1.8 1.3 (1.1, 1.6)** 1.6 (1.2, 2.1)**

Abbreviations: SD, standard deviation; OR, odds ratio; aOR, adjusted odds ratio; AR, antiresorptive; No., number * indicates result is significant at p<0.05, ** p<0.01, *** p<0.001 Adjusted for smoking status, diabetes and duration of antiresorptive therapy.

Comparison of oncologic and non-oncologic subgroups is presented in Table 22 and shows that while extractions significantly increased the odds of developing MRONJ in both groups, the risk was substantially higher in cancer patients. Cancer patients who received any interventional dental treatment were also more likely to develop MRONJ than their counterparts on lower doses of antiresorptives.

Chapter 5: Dental risk factors for MRONJ 72

Table 22. Subgroup analysis: dental risk factors for oncology vs non-oncology patients

Characteristics Case (N=44) Control (N=113) Univariate Multivariate

N, % N, % OR (95% CI) aOR (95% CI)

ONCOLOGY PATIENTS N = 25 (56.8) N = 57 (50.4)

Pre-ART dental examination: 8 (32.0) 24 (42.1) 0.7 (0.3, 2.1) 1.3 (0.3, 4.6)

Pre-ART clean 3 (12.0) 16 (28.1) 0.4 (0.1, 1.7) 0.6 (0.1, 3.4)

Pre-ART fillings 4 (16.0) 13 (22.8) 0.9 (0.6, 1.3) 1.6 (0.4, 7.6)

Pre-ART extraction/s 2 (8.0) 5 (8.8) 1.2 (0.9, 1.6) 1.8 (0.2, 14.4)

Preventative care during ART: 9 (36.0) 19 (33.3) 1.1 (0.4, 3.0) 2.6 (0.6, 11.8)

Examination during ART 9 (36.0) 18 (31.6) 1.2 (0.5, 3.6) 2.1 (0.6, 8.1)

Clean during ART 4 (16.0) 15 (26.3) 1.3 (0.5, 3.6) 1.3 (0.3, 6.0)

Non-surgical treatment during ART: 19 (76.0) 20 (35.1) 6.7 (1.9, 23.5)** 19.5 (2.2, 171.5)**

Filling during ART 12 (48.0) 15 (26.3) 2.7 (1.0, 7.1)* 12.4 (1.5, 100.3)*

Denture^ during ART 7 (36.8) 9 (15.8) 1.3 (0.4, 4.4) 1.2 (0.3, 5.0)

Extraction/s during ART: 15 (60.0) 7 (12.3) 13.8 (3.1, 61.3)*** 3.5 (1.5, 8.1)**

NON-ONCOLOGY PATIENTS N = 19 (43.2) N = 56 (49.6)

Pre-ART dental examination: 4 (21.1) 14 (25.0) 0.8 (0.2, 2.7) 0.4 (0.1, 2.3)

Pre-ART clean 2 (10.5) 11 (19.6) 0.5 (0.1, 2.7) 0.1 (0.1, 1.8)

Pre-ART fillings 3 (15.8) 7 (12.5) 0.9 (0.5, 1.5) 1.4 (0.2, 7.9)

Pre-ART extraction/s 0 (0.0) 2 (3.6) - -

Preventative care during ART: 8 (42.1) 20 (35.7) 1.4 (0.4, 4.7) 1.4 (0.3, 5.7)

Examination during ART 7 (36.8) 19 (33.9) 1.2 (0.4, 4.4) 1.2 (0.3, 5.4)

Clean during ART 8 (42.1) 18 (28.6) 2.2 (0.6, 7.9) 2.4 (0.6, 10.1)

Non-surgical treatment during ART: 12 (63.2) 28 (50.0) 2.3 (0.7, 7.1) 4.2 (0.9, 21.7)

Filling during ART 6 (31.6) 20 (35.7) 0.8 (0.3, 2.6) 0.9 (0.2, 3.2)

Denture^ during ART 6 (31.6) 14 (25.0) 1.4 (0.5, 4.0) 1.4 (0.8, 2.6)

Extraction/s during ART: 13 (68.4) 13 (23.2) 4.5 (1.6, 12.1)** 7.0 (1.9, 26.3)**

Abbreviations: OR, odds ratio; aOR, adjusted odds ratio; ART, antiresorptive therapy ^Denture included issue of new dentures or relining of existing full dentures. * indicates result is significant at p<0.05, ** p<0.01, *** p<0.001 Adjusted for smoking status, diabetes and duration of antiresorptive therapy.

Chapter 5: Dental risk factors for MRONJ 73

5.6 DISCUSSION

Non-surgical dental treatment and dental extractions were associated with an increased risk of developing MRONJ. Cases attended the dentist more often during antiresorptive treatment than controls, and averaged twice as many fillings per year and more than four times as many extractions. Based on the frequency and nature of dental treatment required, cases experienced more dental disease than controls during antiresorptive treatment and this appears to play an important role in determining MRONJ susceptibility. This is consistent with the results of a number of studies that have implemented targeted preventative dental care for patients prior to commencing antiresorptive therapy and found a significant reduction in the subsequent development of MRONJ (138, 144). Most patients in this study did not receive a dental examination and only 6% had infected teeth removed prior to commencing antiresorptive treatment. During antiresorptive therapy, both cases and controls received a dental examination less than once every three years. There appears to be a serious deficiency in preventative dental care both prior to and during antiresorptive therapy. Optimising and maintaining the oral health of patients who require antiresorptive therapy must be a clinical priority to avoid the need for subsequent treatment that increases the risk of MRONJ.

Nearly half of the included cases were treated with lower doses of antiresorptives for osteoporosis or rheumatoid arthritis, which has important clinical implications. Currently, the incidence of MRONJ in patients with osteoporosis is estimated to be between 0.0 to 0.04%, which implies only a very small risk compared to the general public (17). While the absolute risk of MRONJ is very small, millions of patients receive antiresorptive therapies for osteoporosis, and therefore cases of MRONJ in osteoporotic patients presented in similar frequencies to oncology patients at these tertiary hospitals. Dental practitioners should be aware of the risk of MRONJ in this population, but be careful not to overstate it in their discussions with patients. Alarmist messages about MRONJ may result in patients ceasing their antiresorptive against the advice of their doctor (280). A reply from orthopaedic associates to a recent article reporting MRONJ prevention and management guidelines for osteoporotic patients in Singapore (281) raised concerns that “sending all patients for dental clearance may frighten and deter some patients from taking the medications that they need to prevent a fracture and even premature death as a result of the fracture” (282). It is deeply concerning that some medical professionals would prefer that their patients specifically do not attend for pre- dental examinations before starting antiresorptive therapy. Preventative dental care

Chapter 5: Dental risk factors for MRONJ 74 should be seen as an important factor in ensuring patients can safely take their antiresorptive medications, not as a possible impediment to patient compliance. It is a reminder for our profession that our concerns about MRONJ pale in comparison to the potentially catastrophic skeletal complications that patients risk by refusing or stopping their antiresorptive medications. Dental practitioners must be careful to explain that the very small risk of MRONJ associated with osteoporotic antiresorptive medications can be significantly reduced by keeping the mouth healthy. The professional must position itself as a partner and not an adversary in caring for patients on antiresorptives.

In this study, efforts from endocrinologists and oncologists to direct their patients to dentists prior to starting antiresorptives were well documented in the medical records. Unfortunately, antiresorptive treatment was delayed in a number of cases due to evident poor oral health where the patient did not or could not access dental treatment. In Australia, this is complicated by a number of factors. Private dental treatment comes with significant out-of-pocket expenses, and there are waiting lists for treatment in the public dental system. Patients can call a triage phone number for an emergency appointment, but are seen based on the urgency of their presenting complaint. Our results suggest that various barriers to treatment prevented over two-thirds of eligible patients from receiving a publicly-funded dental check-up prior to commencing their antiresorptive, however it is possible that some patients may have sought private dental treatment that was not captured. The data collected in this study suggest that the current public access arrangement is insufficient to prevent MRONJ in at risk patients.

Four cases developed MRONJ more than once, and each instance was initiated by a dental extraction (although only clinical data prior to the first diagnosis was included in this study). In each of these four cases, there was confusion as to whether the antiresorptive could be safely continued during and after treatment for MRONJ. Two of these patients took themselves off their medications and refused to restart them. Both subsequently suffered skeletal fractures, which highlights the serious potential consequences for patients where adequate oral health is not established and maintained.

An important strength of this study is the careful matching of cases and controls by primary disease, antiresorptive type, and antiresorptive duration to eliminate significant confounders. Based on population-level measures, the social position of both groups was comparable and therefore important social determinants of oral health are assumed to have affected both groups evenly. However, the retrospective nature of the study does limit the interpretation of results. Coding errors and omissions may have influenced the

Chapter 5: Dental risk factors for MRONJ 75 findings, and hospital controls usually represent populations with poorer general health. Only six controls had orthopantograms available, which prevented radiographic estimation of the number of decayed, missing, and filled teeth and the level of periodontal bone loss. The very low incidence of MRONJ creates a reliance on case-control studies to investigate risk factors, and this limits the ability to study the temporal relationship between dental disease, dental interventions, and MRONJ. It is possible that non-surgical dental treatment, and in particular restorations, act as a surrogate marker for poor oral health and the increased risk of MRONJ attributed to these dental treatments is due to the higher likelihood of surgical treatment and/or dentures in the future and not the treatment itself.

These results suggest that dental disease and the interventions required to treat it are both associated with an increased risk of MRONJ. There must be good communication and clear referral pathways between health professionals to increase the rate of pre-dental screening for patients who require antiresorptive medications. Furthermore, it is important to improve awareness of and access to preventative dental care throughout antiresorptive treatment. The priority for dental professionals should be addressing the broad risk factors for dental disease that necessitate high-risk interventional treatments. Optimising the health of the oral cavity and ongoing preventative dental care is critical for patients who require antiresorptive medications.

Chapter 5: Dental risk factors for MRONJ 76

Chapter 6: Haematological risk markers

STATEMENT OF CONTRIBUTION TO CO-AUTHORED PUBLISHED PAPER

This chapter includes a co-authored paper. The bibliographic details of the co-authored paper, including all authors, are:

McGowan, K., Ware, R.W., Acton, C., Ivanovski, S., & Johnson, N.W. (2019). Full blood counts are not predictive of the risk of medication-related osteonecrosis of the jaws: a case-control study. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, in press.

My contribution to the paper involved: developing the protocol for the study, submitting and obtaining ethical approval, submitting a site-specific assessment for both hospitals, submitting a Public Health Act application to access patient data, collecting and analyzing the data, and writing the manuscript. I am the corresponding author for the article, and was responsible for submitting and revising the manuscript.

Signed: Date: 16th February, 2019

Student: Kelly McGowan

Countersigned: Date: 11th February, 2019

Supervisor: E/Prof Newell W Johnson

Chapter 6: Haematological risk markers 77

6.1 OVERVIEW

This chapter aims to determine whether certain parameters from routine blood testing can be used to identify patients at high risk of developing MRONJ. As per the proposed mechanism of MRONJ development outlined earlier in Figure 2, it is hypothesised that immune function plays a role in determining individual susceptibility to MRONJ, especially where dental infection or injury is present.

Previous cohort studies have suggested that leukopenia and anaemia may be risk factors for MRONJ, and inflammatory markers have been associated with treatment outcomes. This chapter compared the blood test results of patients who developed MRONJ with those who did not to determine if there were any significant differences. Cases were eligible for inclusion in this study if they had a full blood count report available within the 3-12 months prior to their MRONJ diagnosis. Controls were eligible if they had an available full blood count within the 12 months prior to their index date. As for the previous chapter, cases and controls were audited and re-matched according to the specified criteria.

This study found that patients who take antiresorptive medications often show blood results with one or more parameters outside the standard laboratory reference range, but this does not correlate with their risk of developing MRONJ and cannot be used to identify high-risk patients. However, standard laboratory tests of circulating blood cells and serum chemistry may not be representative of the complex interactions between bone and immune systems in the jawbones and the findings of this study do not preclude immunological dysfunction as an important factor in MRONJ pathogenesis.

Chapter 6: Haematological risk markers 78

6.2 ABSTRACT

Objectives: The role of immune function in susceptibility to medication-related osteonecrosis of the jaws (MRONJ) remains unclear. This study investigated whether full blood counts, as a measure of systemic health and immune function, predict the development of MRONJ.

Materials & Methods: A case-control study was conducted in Brisbane, Australia. 57 cases diagnosed with MRONJ from January 2010 to March 2017 were identified from hospital records and individually matched with up to 4 controls using primary disease, sex, age and antiresorptive therapy (total sample = 249). Demographic and clinical data were extracted and associations were investigated using conditional logistic regression.

Results: 67% of cases and 65% of controls reported at least one result outside of the laboratory reference range (OR=0.7; 95%CI: 0.3, 1.5; p=0.29). The most commonly reported abnormal results were low haemoglobin (53% of cases, 48% of controls) and low haematocrit (33% of cases, 25% of controls). There were no significant differences between groups in any of the reported parameters.

Conclusions: Patients taking antiresorptive medications frequently return blood test results outside the standard laboratory reference range. Altered blood counts were not limited to patients who developed MRONJ and do not appear to be clinically useful in identifying patients at high risk for this condition.

6.3 INTRODUCTION

Suppression and dysfunction of the natural immune response has been implicated in the development of medication-related osteonecrosis of the jaws (MRONJ) (1, 17). It is widely reported that higher doses of antiresorptives, an extended duration of antiresorptive therapy, and dental extractions are associated with an increased risk of this rare complication (1, 17). However not every patient who develops MRONJ will report these risk factors (283) and not all patients with these risk factors will develop MRONJ

Chapter 6: Haematological risk markers 79

(97). Other patient-specific factors appear to play a critical role in determining susceptibility, and immune dysfunction is a possible candidate.

The innate and adaptive immune systems may both play a role in the pathogenesis of MRONJ. Chemotherapy and prolonged corticosteroids have been associated with an increased risk of MRONJ (273). Multiple myeloma patients, who are primarily immunosuppressed as a result of their aberrant plasma cells but are further compromised by the corticosteroids and chemotherapies used to treat their cancer, are reported to experience the highest rate of MRONJ (263). There is in vivo and in vitro evidence to suggest bisphosphonates are taken up by neutrophils (284) resulting in decreased survival and function of this cell population (285). In addition, clinical results show that nitrogen- containing bisphosphonates decrease subsets of innate T cells (286), and patients who developed MRONJ lacked immune resiliency and normal function (287). Macrophages also appear to be susceptible to medications associated with MRONJ, with evidence to suggest they are inhibited by denosumab, BPs, and antiangiogenics (104, 125). Given that medical and dental histories of patients who develop MRONJ vary significantly, it seems likely that immune function would be one of a number of causal components in a multi- factorial disease pathway in MRONJ. The high microbial load in the mouth and the relative ease with which routine function and dental procedures can breach the integrity of the oral mucosa are likely to compound the effects of impaired immunity in a small subset of patients and result in MRONJ.

Most clinical research concerning laboratory parameters associated with MRONJ has focused on C-terminal telopeptide (CTX) tests, which have been subsequently shown not to correlate with the risk of developing MRONJ (151, 288). Minimal data are available on the complete blood counts of patients who develop MRONJ and consequently it is difficult to determine the role of systemic immune function in susceptibility to MRONJ. Leukopenia (289) and anaemia (273, 290) have previously been reported as possible risk factors, and lower C-reactive protein (CRP) levels have been associated with successful treatment of MRONJ (279). White blood cell counts (WBCC) were shown to not be associated with treatment outcomes (291, 292), but leukopenia has been identified as an important prognostic factor for recurrence (293). No significant difference was found in the laboratory parameters of patients with osteoradionecrosis and MRONJ (294), but this was not referenced to a control group. The aim of this study is to investigate whether common laboratory test results, as markers of systemic health and immune function, are associated with an increased risk of developing MRONJ. It was

Chapter 6: Haematological risk markers 80 hypothesized that patients with an impaired immune response and/or results outside of the laboratory reference range would be more likely to develop MRONJ.

6.4 METHODS

Study design A case-control study was conducted in South East Queensland, Australia, to investigate the association between standard laboratory blood test results and the development of MRONJ. Patients treated at the Royal Brisbane & Women’s Hospital (RBWH) and the Gold Coast University Hospital (GCUH) between 1 January 2010 and 31 March 2017 were eligible for inclusion. Both RBWH and GCUH are tertiary level specialist hospitals with a specialist oral and maxillofacial surgery department. Ethical approval for the study was obtained from the RBWH Human Research Ethics Committee and Griffith University Human Research Ethics Committee. The reporting of this study conforms to the STROBE statement (265).

Case selection Cases were identified by searching RBWH and GCUH patient databases using the International Classification of Disease and Related Health Problems (ICD-10-AM 9th Edition) code K10.2 (“Inflammatory conditions of the jaw”). Medical records were manually reviewed to confirm a clinical diagnosis of MRONJ according to the American Association of Oral and Maxillofacial Surgeon’s 2014 diagnostic criteria (1). Cases were eligible for inclusion if they were aged over 18 years, had previously taken antiresorptive or antiangiogenic medications, presented with exposed bone in the oral cavity that did not heal within 8 weeks, and had no prior history of radiation therapy or metastatic disease of the jaw. Cases were excluded if they did not have a full blood count result available within the 3-12 months prior to their MRONJ diagnosis, or if they were pregnant or breastfeeding. Blood tests within 3 months of a case’s MRONJ diagnosis were excluded to reduce the risk of reverse causality where early inflammation or infection associated with the onset of MRONJ caused alterations in systemic markers.

Control selection Controls with the same primary disease were identified from the same treating hospital using ICD-10 codes for multiple myeloma, breast cancer, prostate cancer, osteoporosis, rheumatoid arthritis, and Paget’s disease. Up to four controls were

Chapter 6: Haematological risk markers 81 individually matched to each case on age, sex, primary disease, and antiresorptive therapy. Sex and age (to within 7 years) were matched to eliminate potential confounding from age-related factors and hormonal variations. The dose and duration of antiresorptive medication is reported to increase the risk of MRONJ(1), and therefore controls with higher doses and/or longer duration treatment histories were selected where exact matching was not possible. Controls were excluded if the results of a full blood count were not available within the 12 months prior to their index date.

Variables & data collection The outcome variable was the presence or absence of clinically diagnosed MRONJ and explanatory variables were the laboratory parameters ascertained from blood tests. Pathology results were provided by the Queensland Health Clinical Information Systems Support Unit, and the data managers who extracted the blood test results were masked to the case/control status of the patients.

As this study aimed to determine whether full blood count results predict MRONJ, it was important to include blood tests that were collected and analysed prior to a clinical diagnosis of MRONJ. The diagnostic criteria for MRONJ specifies lesions that have not healed within 8 weeks (1), and therefore blood tests at least three months but not more than one year prior to MRONJ diagnosis were selected for cases. This was intended to exclude changes in systemic markers that resulted from the inflammatory and infective processes associated with developing or established MRONJ. The most recently available blood tests prior to index date were used for controls. From the FBC, red blood cell count (RBCC), white blood cell count (WBCC), hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular volume, and mean platelet volume were recorded. Neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts and percentages were also recorded. Blood test results came from four different laboratories, and reference ranges varied slightly between laboratories for some parameters. For this reason, results for each category were recorded as within or outside the laboratory-specific reference range. Fasting blood glucose, free thyroxine, thyroid stimulating hormone, Vitamin D, C- reactive protein (CRP), erythrocyte sedimentation rate (ESR), and full blood counts (FBCs) were recorded where available.

Demographic information, history of antiresorptive therapy, and comorbidities and medications were recorded from hospital records. Diabetes mellitus, thyroid disease, chemotherapy, corticosteroids, kidney disease, tobacco use and autoimmune disease were

Chapter 6: Haematological risk markers 82 considered possible confounders. The patient’s first dose of antiresorptive medication was determined from chemotherapy medication orders, hospital medical action plans, or outpatient medication lists. The Australian Bureau of Statistics Index of Relative Socio- Economic Disadvantage and Advantage (266) was used to calculate socio-economic status at the postcode level, and this was categorised into thirds based on Queensland rankings.

Statistical methods Sample size calculations were based on the assumption of a binary exposure variable (categorised as within or outside the laboratory reference range). We assumed 60 MRONJ cases would be identified, with an average of three matched controls per case. Prior data indicated the average probability of a control returning a blood test result outside of the laboratory reference range was 0.5. With 80% power and alpha = 0.05 we would be able to detect a significant difference where the odds ratio observed was 2.2 or greater.

Statistics were summarised as frequencies and the chi-square test was used to compare the clinical and demographic characteristics of cases and controls. Conditional logistic regression determined the unadjusted odds ratios (OR) and 95% confidence intervals (CI) where the exposure was laboratory test results and the outcome was MRONJ. Models were conditioned on their individually-matched case-control groups. Adjusted odds ratios (aOR) were calculated using multivariable conditional logistic regression. Smoking, kidney disease, and duration of antiresorptive therapy were included as potentially confounding variables as these factors differed significantly between groups in the univariable analysis. A pre-specified stratified analysis of oncologic and non-oncologic subgroups was conducted. Statistical analyses were conducted using IBM SPSS Statistics, v25 (IBM Corporation 2017 ©, Aarmonk, NY, USA).

6.5 RESULTS

Fifty-seven confirmed cases of MRONJ had blood test results available in the 3- 12 months prior to diagnosis. It was not possible to match 4 controls to each case, and on 36 occasions 3 controls were matched (192 controls overall) to each case to give a total sample size of 249. Participant screening, inclusion and exclusion are detailed in Figure

Chapter 6: Haematological risk markers 83

12. The majority of controls did not have available results for free thyroxine (67% missing data), thyroid stimulating hormone (65% missing data), vitamin D (77% missing data), CRP (70% missing data) and ESR (82% missing data) so the analyses were limited to the results of full blood counts.

60% of participants were female, and 53% were receiving AR medications for cancer (multiple myeloma, breast cancer or prostate cancer). The age of participants ranged from 43 to 93, and the mean ± standard deviation (SD) age of cases was 68.8 ± 12.6 compared to 70.1 ± 12.1 for controls. The average duration of antiresorptive therapy was 3.1 ± 2.0 years for cases and 4.1 ± 2.3 years for controls. Demographic and clinical information are presented in Table 23. Cases were more likely to be current smokers and have diagnosed diabetes or kidney disease.

Figure 12. Flow chart of participant selection, exclusion and inclusion based on availability of eligible blood test results

Abbreviations: RBWH, Royal Brisbane & Women’s Hospital; GCUH, Gold Coast University Hospital; MM, multiple myeloma; BC, breast cancer; OP, osteoporosis; RA, rheumatoid arthritis; PD, Paget’s disease.

Blood test results are presented in Table 24 as the frequency (percentage) of cases and controls with parameters outside the laboratory-specific reference range, including stratification as ‘below’ or ‘above’ the range. Mean values are not reported as blood tests

Chapter 6: Haematological risk markers 84 were analysed by four different pathology laboratories. 69% of cases and 65% of controls reported at least one out-of-range result. This was not associated with the risk of developing MRONJ in the univariable (OR 1.1; 95% CI=0.6, 2.3; p=0.71) or multivariable (OR=0.7; 95%CI=0.3, 1.5; p=0.29) analyses. Cases were more likely to report white blood cell counts above laboratory reference ranges (16% of cases compared to 7% of controls), and this was significant in the univariable analysis (OR 1.6; 95%CI=1.0, 2.5; p=0.03) but not in the multivariable model once smoking status, kidney disease, and duration of antiresorptive therapy were adjusted for (OR=1.4; 95%CI=0.7, 2.7; p=0.39). The most commonly reported abnormal result for both groups was haemoglobin, with 53% of cases and 48% of controls measuring below the reference range (OR=0.9; 95%CI=0.4,2.3; p=0.86).

Table 25 shows the proportion of oncology and non-oncology patients who returned results outside of the laboratory-specific reference range. The non-oncology subgroup contained 118 patients with osteoporosis (89%), rheumatoid arthritis (9%), or Paget’s disease (2%). The oncology subgroup comprised 131 patients with multiple myeloma (50%), prostate cancer (27%), or breast cancer (23%). In the non-oncology subgroup, 41% of cases reported WBCCs outside of the reference range compared to 14% of controls. The association between WBCCs and the development of MRONJ was significant in the univariable model (OR=2.3; 95%CI=1.3, 3.9; p<0.01) but not in the multivariable model (OR=2.2; 95%CI=0.9, 5.7; p=0.10) once smoking status, kidney disease, and duration of antiresorptive therapy were adjusted for.

In the oncology subgroup, 10% of cases and 17% of controls reported WBCCs outside of the reference range and this difference was not significant in either the univariable or multivariable analyses (OR=0.6; 95%CI=0.2, 2.2; p=0.60). In the non- oncology subgroup, 44% of cases had abnormal neutrophil counts compared to 20.5% of controls. This was associated with increased odds of developing MRONJ (OR=1.9; 95%CI=1.1, 3.3; p=0.018) in the univariate analysis, but was no longer significant once smoking status, kidney disease, and duration of antiresorptive therapy were adjusted for (OR=2.3; 95%CI=0.8, 6.8; p=0.13). In the oncology subgroup, 18.5% of cases and 25.9% of controls reported neutrophil counts outside the laboratory reference range, and this difference was not significant in either the univariable or multivariable analyses (OR=0.3, 95%CI=0.1, 1.4; p=0.13).

Chapter 6: Haematological risk markers 85

Table 23. Distribution of characteristics and demographics between cases and controls

Characteristics Case (N=57) Control (N=192) p N (%) N (%) Sex 0.97 Male 23 (40.4) 78 (40.6) Female 34 (59.6) 114 (59.4) Age 0.61 41-60 16 (28.1) 42 (21.9) 61-80 29 (50.9) 103 (53.6) 81-100 12 (21.1) 47 (24.5) Socioeconomic status 0.67 Low (1-33) 15 (26.3) 42 (21.9) Medium (34-66) 22 (38.6) 73 (38.0) High (67-100) 20 (35.1) 77 (40.1) Primary disease 0.61 Osteoporosis 24 (42.1) 81 (42.2) Multiple myeloma 16 (28.1) 50 (26.0) Breast cancer 7 (12.3) 23 (12.0) Prostate cancer 7 (12.3) 28 (14.6) Rheumatoid arthritis 2 (3.5) 9 (4.7) Paget’s Disease 1 (3.6) 1 (0.5) Antiresorptive therapy 0.71 Alendronate (Fosamax) 12 (21.1) 35 (18.2) Zoledronic acid (Aclasta) 4 (7.0) 13 (6.8) Zoledronic acid (Zometa) 13 (22.8) 39 (20.3) Pamidronate (Aredia) 6 (10.5) 21 (10.9) Risendronate (Actonel) 7 (21.1) 18 (18.2) Denosumab (Prolia) 3 (5.3) 13 (6.8) Denosumab (Xgeva) 6 (10.5) 33 (17.2) Combination 6 (10.5) 20 (10.4) Duration antiresorptive therapy 0.003 1-3 years 35 (67.3) 79 (44.1) 4+ years 17 (32.7) 100 (55.9) Diabetes mellitus 16 (28.1) 25 (13.0) 0.007 Current smoker 15 (27.8) 21 (11.6) 0.004 Thyroid disease 7 (12.3) 17 (8.9) 0.59 Autoimmune/inflammatory disease 15 (26.3) 44 (22.9) 0.60 Chemotherapy 0.95 Oncology 29 (50.9) 102 (53.1) Other systemic disease 2 (3.5) 7 (3.6) Corticosteroids 0.29 Inhaled 5 (8.9) 16 (8.3) Systemic 31 (55.4) 84 (43.8) Kidney disease 15 (26.3) 14 (7.3) <0.000

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Table 24. Frequency (percentage) of patients with results outside of the laboratory- specific reference range Characteristics Case (N=57) Control (N=192) Univariate Multivariate N, % N, % OR (95% CI) aOR (95% CI) ≥1 out-of-range result 38 (69.1) 124 (64.6) 1.1 (0.6, 2.3) 0.7 (0.3, 1.5) Red blood cell count 12 (22.2) 32 (16.8) 1.5 (0.6, 3.4) 0.6 (0.2, 2.1) Below reference range 12 (22.2) 32 (16.8) Above reference range 0 (0) 0 (0) Haematocrit 18 (33.3) 47 (24.6) 1.6 (0.8, 3.4) 0.8 (0.3, 2.4) Below reference range 18 (33.3) 47 (24.6) Above reference range 0 (0) 0 (0) Haemoglobin 29 (52.7) 92 (48.2) 1.1 (0.6, 2.2) 0.9 (0.4, 2.3) Below reference range 29 (52.7) 92 (48.2) Above reference range 0 (0) 0 (0) Mean corpuscular haemoglobin 1 (2.3) 6 (3.8) 0.6 (0.1, 4.7) 0.2 (0.0, 3.7) Below reference range 1 (2.3) 6 (3.8) Above reference range 0 (0) 0 (0) Mean corpuscular volume 0 (0.0) 16 (8.3) 0.6 (0.0, 5.6) - Below reference range 0 (0.0) 10 (5.2) Above reference range 0 (0.0) 6 (3.1) White blood cell count 13 (23.6) 30 (15.7) 1.6 (1.0, 2.5)* 1.4 (0.7, 2.7) Below reference range 4 (7.3) 17 (8.9) Above reference range 9 (16.4) 13 (6.8) Neutrophil count 14 (25.5) 39 (20.5) 1.3 (0.9, 2.0) 1.0 (0.5, 1.9) Below reference range 7 (12.7) 21 (11.1) Above reference range 9 (16.4) 18 (9.5) Lymphocyte count 15 (27.8) 64 (33.5) 0.9 (0.5, 1.7) 0.8 (0.3, 1.9) Below reference range 13 (24.1) 62 (32.5) Above reference range 2 (3.7) 2 (1.0) Monocyte count 10 (17.5) 23 (11.0) 1.4 (0.9, 2.3) 1.2 (0.7, 2.3) Below reference range 2 (3.5) 6 (3.1) Above reference range 8 (14.0) 17 (8.9) Eosinophil count 3 (5.9) 14 (7.3) 0.9 (0.5, 1.8) 0.8 (0.3, 2.6) Below reference range 0 (0.0) 0 (0.0) Above reference range 3 (5.9) 14 (7.3) Basophil count 0 (0.0) 0 (0.0) - - Below reference range 0 (0.0) 0 (0.0) Above reference range 0 (0.0) 0 (0.0) Platelets 14 (24.6) 44 (23.7) 1.4 (0.7, 3.0) 1.3 (0.5, 3.3) Below reference range 11 (19.3) 39 (21.1) Above reference range 3 (5.3) 5 (2.6) Abbreviations: OR, odds ratio; aOR, adjusted odds ratio. *Significant at p<0.05 Adjusted for current smoking status, duration of antiresorptive therapy, and kidney disease.

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Table 25. Results outside laboratory reference ranges for oncology and non-oncology subgroups ONCOLOGY NON-ONCOLOGY Blood test Case Control OR aOR Case Control OR aOR (N=30) (N=101) (95% CI) (95% CI) (N=27) (N=91) (95% CI) (95% CI) N, % N, % N, % N, % ≥1 out of range result 20 (66.7) 67 (65.7) 0.8 (0.3, 2.1) 0.8 (0.3, 2.4) 18 (72.0) 57 (63.3) 1.7 (0.6, 4.7) 0.5 (0.1, 1.9) Red blood cell count 7 (24.1) 23 (22.8) 1.0 (0.3, 2.7) 0.2 (0.0, 1.6) 5 (20.0) 9 (10.1) 3.5 (0.8, 15.2) 3.6 (0.4, 30.2) Below reference range 2 (6.7) 13 (12.9) 2 (8.0) 4 (4.4) Above reference range 1 (3.3) 4 (4.0) 8 (32.0) 9 (10.0) Haematocrit 10 (34.5) 32 (31.7) 1.0 (0.4, 2.7) 0.4 (0.1, 2.1) 8 (32.0) 15 (16.7) 3.0 (0.9, 9.8) 2.2 (0.5, 10.9) Below reference range 2 (6.7) 13 (12.9) 2 (8.0) 4 (4.4) Above reference range 1 (3.3) 4 (4.0) 8 (32.0) 9 (10.0) Haemoglobin 19 (63.3) 54 (53.5) 1.2 (0.5, 3.2) 0.7 (0.2, 2.6) 10 (40.0) 38 (42.2) 1.0 (0.4, 2.6) 1.2 (0.3, 4.5) Below reference range 2 (6.7) 13 (12.9) 2 (8.0) 4 (4.4) Above reference range 1 (3.3) 4 (4.0) 8 (32.0) 9 (10.0) Mean corpuscular haem. 0 (0.0) 2 (2.6) - - 1 (4.8) 4 (5.1) 0.7 (0.1, 6.1) 0.5 (0.0, 7.0) Below reference range 2 (6.7) 13 (12.9) 2 (8.0) 4 (4.4) Above reference range 1 (3.3) 4 (4.0) 8 (32.0) 9 (10.0) Mean corpuscular volume 0 (0.0) 5 (5.0) 0.1 (0.0, 77.9) - 0 (0.0) 11 (12.1) 0.1 (0.0, 23.1) - Below reference range 2 (6.7) 13 (12.9) 2 (8.0) 4 (4.4) Above reference range 1 (3.3) 4 (4.0) 8 (32.0) 9 (10.0) White blood cell count 3 (10.0) 17 (16.8) 0.7 (0.2, 1.9) 0.6 (0.2, 2.2) 10 (41.0) 13 (14.4) 2.3 (1.3, 3.9)** 2.2 (0.9, 5.7) Below reference range 2 (6.7) 13 (12.9) 2 (8.0) 4 (4.4) Above reference range 1 (3.3) 4 (4.0) 8 (32.0) 9 (10.0) Neutrophil count 5 (18.5) 21 (25.9) 0.6 (0.3, 1.5) 0.3 (0.1, 1.4) 11 (44.0) 18 (20.5) 1.9 (1.1, 3.3)* 2.3 (0.8, 6.8) Below reference range 5 (18.5) 16 (15.7) 2 (8.0) 5 (5.7) Above reference range 0 (0.0) 5 (4.9) 9 (36.0) 13 (14.8) Lymphocyte count 8 (27.2) 35 (34.7) 0.7 (0.3, 1.9) 0.8 (0.2, 2.7) 7 (28.0) 29 (32.2) 1.0 (0.4, 2.5) 1.0 (0.3, 3.9) Below reference range 7 (24.1) 34 (33.7) 6 (24.0) 28 (31.1) Above reference range 1 (3.4) 1 (1.0) 1 (4.0) 1 (1.1) Monocyte count 3 (10.3) 10 (9.9) 1.1 (0.5, 2.4) 1.1 (0.4, 2.9) 7 (28.0) 13 (14.4) 1.7 (0.9, 3.1) 1.8 (0.8, 4.2) Below reference range 0 (0.0) 4 (4.0) 2 (8.0) 2 (2.2) Above reference range 3 (10.3) 6 (5.9) 5 (20.0) 11 (12.2) Eosinophil count 0 (0.0) 11 (10.9) 0.2 (0.0, 6.2) - 3 (12.5) 3 (3.3) 1.7 (0.8, 3.7) 2.0 (0.5, 9.0) Below reference range 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Above reference range 0 (0.0) 11 (10.9) 3 (12.5) 3 (3.3) Basophil count 0 (0.0) 0 (0.0) - - 0 (0.0) 0 (0.0) - - Below reference range 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Above reference range 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Platelets 9 (31.0) 21 (21.4) 1.4 (0.5, 3.5) 1.8 (0.4, 7.3) 5 (23.8) 23 (26.1) 1.5 (0.7, 3.1) 0.9 (0.2, 3.9) Below reference range 9 (31.0) 19 (19.4) 2 (9.5) 20 (22.7) Above reference range 0 (0.0) 2 (2.0) 3 (14.3) 3 (3.4) Adjusted for current smoking status, duration of antiresorptive therapy, and kidney disease. Abbreviations: haem, haemoglobin. * Significant at p<0.05; ** significant at p<0.01

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6.6 DISCUSSION

Patients who receive antiresorptive medications for the treatment of cancer, osteoporosis and rheumatoid arthritis frequently return blood tests with parameters outside of standard laboratory reference ranges. The proportion of abnormal results was similar for patients who developed MRONJ and those who did not, and low haemoglobin was the most common out-of-range result. This highlights the importance of a control group when interpreting clinical parameters. One quarter of patients had been diagnosed with an autoimmune disease and over half of all patients had received chemotherapy and/or corticosteroids. Diabetes, smoking, kidney disease, and thyroid disease were commonly reported by both cases and controls, although more frequently by cases. With the additional effects of cancer therapies and antiresorptive medications, there are too many confounders and effect modifiers to identify any clinically relevant risk markers for MRONJ from a full blood count.

These findings agree with previous reports that anaemia and blood cell count alterations are common findings in patients with MRONJ (295). The proportion of patients with WBCCs above and below the reference range were similar to those reported in a previous study of 212 patients with MRONJ (293). One prior study that compared the nadir WBCC of 8 prostate cancer patients with MRONJ to 48 controls found that a nadir WBCC <1000/uL was a significant predictive factor for MRONJ (289). Although nadir counts were not available for all patients in this study, the subgroup analysis of oncology patients found that nearly twice as many controls reported WBCCs below the reference range.

There was more pronounced variation between cases and controls in the subgroup of patients who were prescribed antiresorptive medications for diseases other than cancer. One third of cases in the non-oncology subgroup reported total WBC and neutrophil counts above the reference range, which suggests that their immune systems were responding to infection, inflammation or acute stress in the body. It is not possible to infer what role oral disease and inflammation played in producing these high cell counts, but a previous study determined that 89% of this subgroup developed MRONJ as the result of a known dental precipitator (263). These included extractions, acute periodontal infections, and denture trauma. Future studies should prospectively evaluate whether the presence of oral disease alters full blood count results, and whether this correlates with the risk of MRONJ. This may assist in better understanding the underlying pathogenesis of MRONJ.

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An important strength of this study was the carefully matched control group, which minimized the influence of key confounders on the relationship between blood test results and MRONJ. Matching by primary disease produced an almost identical proportion of cases and controls who received chemotherapy and corticosteroids, and this was particularly important for the interpretation of white blood cell counts. However, a critical limitation of this study is that the number and functionality of macrophages cannot be measured via blood tests and this immune cell population may play an important role in MRONJ pathogenesis. Macrophages form the second line of defense against microbes from the oral cavity when the mucosa (the first line of defense) is breached. Macrophages and osteoclasts are derived from the same myeloid precursor cell, and macrophages can fuse to form osteoclasts when stimulated by macrophage colony-stimulating factor (M- CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) (296). This intimate relationship with osteoclasts renders macrophages susceptible to the effects of antiresorptive medications (104).

There is a growing body of evidence to suggest that bone and immune systems share mechanisms, niches, cytokines and receptors (297), although the relevance of this to MRONJ remains unclear. Even at a basic level, many of the cellular components of the immune system are derived from haematopoiesis which occurs predominantly in the bone marrow (297) and therefore it is biologically plausible that antiresorptive therapies would have some effect on immune function. This is supported by limited evidence that shows denosumab (298), bisphosphonates (124, 125), and antiangiogenics (123, 299) interfere with immune and inflammatory responses, and this may have some clinical relevance to MRONJ that could not be detected from standard laboratory blood tests.

In this study, blood tests from four different laboratories were included and this prevented any analysis of the numerical values returned in the pathology reports. Each laboratory had small variations in their standard references ranges, which mandated the use of below, within or above categories for each test. Even though laboratory accreditation and regular on-site audits are mandatory in Australia, there will still be some variation in the accuracy of test results from each laboratory and this may have influenced the findings. The use of hospital controls also results in a patient population that is systemically unwell, and this limits the generalizability of these results.

Patients taking antiresorptive medications for oncologic and systemic diseases frequently return blood test results outside of the standard laboratory reference range.

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Abnormal blood test results were not limited to patients who developed MRONJ and do not appear to be clinically useful in identifying high-risk patients. Standard laboratory tests of circulating blood cells may not be representative of the complex interactions between bone and immune systems in the jawbones and the findings of this study do not preclude immunological dysfunction as an important factor in MRONJ pathogenesis. Future research should be aimed at better understanding the innate immune response and in particular the role of macrophages in the development of MRONJ.

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Chapter 7: Discussion

7.1 RISK FACTORS FOR MRONJ

7.1.1 Systemic risk factors A patient’s systemic health appears to play in important role in determining their susceptibility to MRONJ. A key finding of this study was that systemic health should be considered in terms of cumulative severity, and not as a checklist of specific high-risk diseases and medications. Currently, most clinical guidelines specify chemotherapy and corticosteroids use as key systemic determinants of MRONJ risk (13, 154, 156). The systematic review presented in Chapter 2 confirmed that chemotherapy and corticosteroid use were the most commonly reported medical comorbidities in cohort studies and case series of MRONJ (see Figure 8), but the results of the case-control study in Chapter 4 suggest that cases and controls were prescribed chemotherapy and corticosteroids in equal frequencies, and this was not associated with their risk of MRONJ (see Table 17). This is likely due to the closely regulated treatment of patients in Australia through clinical and therapeutic guidelines, and therefore matching patients by primary disease incidentally matched for certain systemic treatments. This may have effectively controlled for chemotherapy and corticosteroid use, and therefore their association with MRONJ may not be accurately reflected in the results. Regardless, chemotherapy and corticosteroids were captured in the calculation of the CPS for each patient, and this offers a more clinically useful method of assessing the risk of MRONJ than identifying specific key conditions, especially where multiple risk factors are present.

7.1.2 Dental risk factors Oral health was found to be a critical factor in MRONJ susceptibility. Patients who had fillings and extractions were six to eight times more likely to develop MRONJ. Due to the retrospective nature of the study, it was not possible to determine whether it was the underlying dental disease or the intervention provided to treat it that precipitated MRONJ, but the temporality of the relationship does not change the implications for dental care. Optimising oral health and diligent ongoing preventative dental care is critical for patients who require antiresorptive medications, and this is discussed further in Section 7.2.2. below.

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7.1.3 Haematological risk markers Full blood counts were not found to be a useful tool in assessing an individual patient’s risk of MRONJ. Cases and controls reported parameters outside of the laboratory reference range in similarly high frequencies, which was not unexpected given the health status of participants in this study. However, these findings do not preclude immune status as an important factor in MRONJ pathogenesis. There is a growing body of evidence to suggest that bone and immune systems are closely related, and it is biologically plausible that antiresorptive therapies would affect immune function given the many cells of the immune system are derived predominantly from bone marrow. The full blood counts in this study were unable to provide any information on the number or functionality of macrophages in the jawbones, and future research should aim to improve the understanding of the relationship between antiresorptives, the immune system, and MRONJ.

7.2 CLINICAL IMPLICATIONS

7.2.1 MRONJ is a multifactorial disease The results of this study support the findings of previous research that suggest MRONJ is a multifactorial disease. This has significant implications of the prevention of MRONJ, as there is not one universal causative factor that must be identified and addressed to prevent the development of disease.

Rothman’s sufficient-component cause model (SCCM) (300) is commonly used in epidemiology as a framework for understanding multicausality. The model proposes that many diseases are not produced by a single factor, but instead a minimal set of conditions or events, as shown in Figure 13. Component causes are defined as factors that contribute towards disease, but are insufficient to cause disease independently. Component causes that are required for disease to develop are referred to as necessary causes. Individual component causes can aggregate in multiple combinations to produce a sufficient cause, which is represented as a completed pie that will inevitably produce disease (300). Importantly, there can be multiple sufficient causes for the same disease, where different component causes contribute to different causal pathways in different patients. This is consistent with the variation in patient risk factors identified in this project, and reported in previous studies of MRONJ.

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Redacted

Figure 13. Rothman’s sufficient component cause model, from Rothman, 2012 (301).

Individual component causes are represented by letters. “A” represents a necessary cause that is required but insufficient for disease to develop. Different combinations of component causes aggregate to produce a sufficient cause, which is represented by a completed pie. The model shows that disease can be initiated by different risk factors in each patient, and therefore preventative strategies should target risk factors that are common to multiple causal pathways.

This framework for understanding multifactorial disease has important implications for preventative strategies. It is not necessary to address each component cause to prevent or reduce the likelihood of disease occurrence. If a single component cause can be identified and eliminated, then all causal mechanisms that contain that particular component cause will be insufficient to produce disease. For example, if component cause “B” in Figure 13 could be identified, then causal pathway I and II would be incomplete, and the rate of disease would be reduced by two-thirds. If component cause “A” could be eliminated, then all three causal pathways would be incomplete and the disease would be entirely prevented.

The challenge in assessing the risk of MRONJ has been determining which factors participate in the disease process and what the relevant weight of each factor is. Using Rothman’s SCCM as a framework and incorporating both the existing evidence regarding MRONJ pathogenesis and the findings of this project, the multifactorial pathway to the development of MRONJ is likely to include antiresorptives and antiangiogenic medications, systemic disease and immunosuppression, other pharmaceutical factors, oral diseases and conditions, and other unknown contributors that are yet to be defined.

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This is illustrated in Figure 14, and the three different pathways have been used to demonstrate that different patients will present with various combinations and relative weights of each component cause. Regardless of the composition of contributing factors, MRONJ will develop when a minimal set of disease-promoting conditions is met.

Figure 14. Proposed multifactorial disease pathway for MRONJ

It seems likely that multiple combinations of component causes can produce MRONJ, and the relative significance of each component cause will vary between patients. For example, the larger piece of pie for causal component “A” in Pathway I may represent high-dose intravenous zolendronate. In Pathway II, the larger piece of pie for causal component “D” may represent multiple extractions or other high-risk surgical procedures. In Pathway III, component “B” may represent multiple cycles of chemotherapy and long-term corticosteroid use.

7.2.2 Strategies for prevention of MRONJ Rothman’s SCCM helps to visualise which component causes are the most feasible targets for preventative strategies. For MRONJ, this appears to be dental risk factors for two reasons: firstly, because dental risk factors are reported in the great majority of cases and therefore removing this causal component will have a significant impact on the incidence of disease; and secondly, because dental risk factors are the only component cause that can be easily modified to reduce a patient’s risk of disease.

Regardless of the negative effects that antiresorptive medications may have on oral tissues and innate immune cells, these medications are necessary to manage

Chapter 7: Conclusions 95 potentially debilitating and often life-threatening systemic conditions and cannot be omitted or ceased. Antiresorptive medications have been consistently shown to significantly reduce skeletal related events, improve pain control, and increase survival rates in oncology and osteoporotic patients (10, 11, 197, 198), and therefore it is important that patients can safely benefit from antiresorptive therapy without the fear of developing MRONJ. Similarly, immune suppression is an unavoidable side effect of certain necessary medical treatments, and modifying or withholding these due to a small risk of MRONJ is not warranted. The systemic health of a patient may be a significant contributor to their risk of MRONJ, but systemic risk factors are generally chronic conditions that are exceedingly difficult to manage and are not a feasible target for risk reduction strategies. Therefore, dental professionals are best placed to reduce the incidence of MRONJ by providing effective and ongoing preventative dental care for at- risk patients. Figure 15 illustrates that by targeting dental risks factors, MRONJ can be prevented without modification of antiresorptive medications, systemic disease, polypharmacy, or other unknown contributors.

Figure 15. Effect on causal pathways for MRONJ when dental risk factors are addressed

Although the risk profile of each patient differs, eliminating oral disease, inflammation, and trauma (Casual component “D”) would prevent the development of MRONJ in each of the above theoretical causal pathways.

The results of this study suggest that individual patient factors determine susceptibility to MRONJ, and therefore tailored preventative care where the frequency and nature of dental appointments is determined by the risk profile of the patient is likely to be more appropriate than a “one-size-fits-all” approach. This concept of modifying

Chapter 7: Conclusions 96 patient care based on the individually-determined risk of disease is used in other areas of dentistry (302-304), and would be appropriate for MRONJ prevention to avoid over- and under- treatment of susceptible patients.

Draft clinical guidelines for the dental management of patients who require antiresorptive therapies have been developed based on the findings of this project and the best-available evidence on MRONJ, and are provided in Appendix J. These guidelines will be further developed in consultation with dental specialists, experienced practitioners, and physicians and then submitted for publication in the Australian Dental Journal.

7.3 RECOMMENDATIONS FOR FUTURE RESEARCH

7.3.1 Antiangiogenics and other medications associated with MRONJ The case definition of MRONJ adopted for this project included patients who had received antiangiogenic medications, but only one case and three controls had been prescribed antiangiogenics and none were antiresorptive-naïve. As a result, this project does not provide any clarification on the role of antiangiogenics in MRONJ. Antiangiogenics are increasingly used to treat various malignancies (305), and therefore it is important that their association with MRONJ is clarified so oral health professionals can make informed decisions about patient care. There are currently 35 cases of MRONJ in antiresorptive-naïve patients who received either bevacizumab, sorafenib, aflibercept, sunitinib, cabozantinib, temsirolimus, everolimus, or dasatinib (306). The number of antiangiogenic medications approved for clinical use is rapidly increasing, and future research should investigate the epidemiology, pathogenesis, and risk factors for MRONJ in antiresorptive-naïve patients.

7.3.2 Dental implants as a risk factor for MRONJ This study did not capture any cases of MRONJ related to implant surgery or implantitis and cannot comment on the role of implant-related risk factors for MRONJ. Previous studies have suggested that both implant placement and the presence of osseointegrated implants are risk factors for MRONJ (307-309), but there are currently very little data to inform the risk of MRONJ for patients seeking dental implants. This is likely to be an area of significant interest as the population ages and the number of patients being treated with antiresorptives for osteoporosis increases at the same time that dental implants are becoming an increasingly common treatment modality. Large prospective

Chapter 7: Conclusions 97 studies are needed to determine whether there is any increased risk of implant complications, failure or MRONJ in patients on antiresorptives and antiangiogenic medications.

7.3.3 Immune function and macrophages The results of this study did not find any association between the results of a full blood count and MRONJ, but this is a very limited assessment of immune function and does not provide any definitive answers on the role of natural immunity in MRONJ pathogenesis. There is in vivo and in vitro evidence to suggest that antiresorptives impair the function and survival of various immune cells (104, 125, 284-287), and future research should investigate the role of innate and adaptive immunity – both of the cell- mediated and humoral immune systems - in the pathogenesis of MRONJ.

7.3.4 CPS as a predictor of MRONJ treatment outcomes As outlined in Chapter 4, this study found that the CPS was a valid predictor of the risk of developing MRONJ. It would be pertinent to determine whether CPS could also predict treatment outcomes for patients with established MRONJ. Recently, the CPS scoring system has been validated as a predictor of outcomes, readmissions, in-hospital complications, and mortality, in older trauma patients and surgical patients (233, 251, 252, 254, 255, 258). The simplicity of the system makes it an excellent candidate for dental applications, and future research should investigate other potential applications for the CPS in the dental management of patients with significant comorbidities.

7.3.5 Translating research into practice & interdisciplinary care Although there are many aspects of MRONJ that require further investigation, translating what is currently known into better care practices for patients must be a priority. It was clear from the data collection in this project that the referral pathways for patients to access dental care before and during their antiresorptive therapy were haphazard and primarily driven by dental pain or emergencies. This reflects the nature of the public dental system in Australia, where patients are triaged for emergency care based on the severity of their symptoms, and are otherwise placed on waiting lists for general treatment and assessment. In Queensland, the Hospital and Health Service (HHS) system is decentralised and the Oral Health Services in each HHS operate independently. This creates some variation in the criteria for priority care, and there is currently no state-wide system to manage dental screening and ongoing dental care for patients on antiresorptive medications.

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Improving the dental management of patients taking antiresorptive medications will require a collaborative approach between patients, physicians, and dental clinicians. At the commencement of this project, it was hypothesised that patients at risk of MRONJ would benefit from care pathways similar to those provided to patients at risk of ORN. Oral health professionals have been incorporated into the multidisciplinary teams that plan and oversee the care of head and neck (H&N) cancer patients, and it was assumed that a similar model would be effective in preventing MRONJ. However, the findings reported in Chapter 2 showed that despite excellent pre-H&N radiation dental assessment and care, the rates of ORN were unexpectedly high. This is most likely due to the lack of continuity in dental care after radiotherapy, and failure to secure patient compliance in the oral health care plan.

For patients who require either radiation or antiresorptive therapy, more clinical research is needed to determine how to engage patients in their oral health care. It can be difficult to establish oral health as a priority for patients who are faced with a number of very serious competing health priorities. It will be important to model the costs and benefits of ongoing preventative dental care and compare this to the costs and burden of treating MRONJ and ORN to understand the economic implications of changes to oral health policies. Other models of oral health care using oral health therapists or dental assistants with a certificate in oral health promotion should be investigated to deliver services that are financially sustainable in the long term.

Generating state-wide changes to oral health service models will be challenging and gradual, but there are considerable opportunities for dentists to make simple changes to their patient care in the meantime. Dentists and doctors need to break down the barriers that currently see the mouth treated in isolation from the rest of the body. From interactions with general medical practitioners (GPs) and endocrinologists throughout this project, there appears to be widespread concern that some dentists scare patients off their antiresorptive medications, and this frustration is echoed in the literature (282). It was also frequently stated that patients seemed to be able to take their antiresorptives without complication until they saw a dentist. To quote a very experienced endocrinologist from RBWH, “antiresorptives don’t cause MRONJ, dentists cause MRONJ.” It is hoped that the findings of this project will be used to improve the dental management of patients on antiresorptives, and that this will provide better opportunities for interdisciplinary collaboration.

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International studies have found that even in 2017, most dental students have a poor understanding of MRONJ and the pharmacology of antiresorptive drugs (310), and any practitioner that graduated prior to 2004 would not have received any undergraduate training in the pathology of MRONJ. Continuing professional development will play an important role in improving the dental care of patients on antiresorptives. The current Therapeutic Guideline recommendation (150) that medications are interrupted until CTX levels increase above a threshold for safe extractions needs to be replaced with a conservative message that focuses on preventing the incidence of new dental disease. Once dentists are more confident in managing the oral care of patients on antiresorptives, they may become more proactive in collaborating with GPs and physicians to establish referral pathways for pre-antiresorptive dental assessments.

7.4 CONCLUSIONS

MRONJ is a complex multifactorial disease of unknown pathogenesis. This study found that systemic comorbidities, polypharmacy, and dental treatment are significant risk factors for the development of MRONJ, although the nature and relative significance of these factors will vary considerably between individual patients. The cumulative severity of systemic disease and the intensity of pharmacotherapy required to treat it appears to be more important than the presence of certain high-risk diseases or medications. The CPS was validated as a clinically useful tool to relate a patient’s medical history to their risk of MRONJ, but their oral health must also be factored into the risk assessment process. The risk of MRONJ was highest in patients who required dental extractions, but patients who required non-surgical dental treatments, including fillings and dentures, were also significantly more likely to develop MRONJ. Full blood counts were not found to be a useful tool in assessing an individual patient’s risk of MRONJ. More research is needed to understand the relationship between immune function and MRONJ susceptibility.

The majority of participants in this study did not receive adequate dental care before and during their antiresorptive therapy, and the number of cases of MRONJ reported in the participating hospitals has increased over time despite improved awareness and understanding of MRONJ. There appears to be a significant opportunity to reduce the incidence of MRONJ by improving access to dental care, and this will require a coordinated and collaborative approach from patients, dental practitioners and physicians.

Chapter 7: Conclusions 100

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Appendices

Appendix A: Griffith University HREC approval

Redacted

Appendices 133

Appendix B: RBWH HREC approval

Appendices 134

Appendices 135

Redacted

Appendices 136

Appendix C: Public Health Act approval

Appendices 137

Redacted

Appendices 138

Appendix D: Supplemental Table 1 – NOS modification & interpretation

Appendix Table 1: Modified Newcastle-Ottawa Scale & Interpretation

Selection (Maximum of 4 stars) Comparability (Maximum of 2 stars) Outcome (Maximum of 3 stars)

1. Representativeness of the exposed 1. Comparability of cohorts on the basis 1. Assessment of outcome cohort of the design or analysis a. Independent blind assessment * a. Population truly representative of oncologic a. Study controls for type, dose & duration of b. Record linkage * or osteoporotic patients taking antiresorptive antiresorptive or antiangiogenic therapy * c. Self-report or antiangiogenic medications * b. Study controls for additional comparators, d. No description b. Somewhat representative of the population specifically medical and dental comorbidities * * c. Not applicable 2. Was follow-up long enough for c. Selected group of patients taking outcomes to occur? antiresorptive or antiangiogenic medications a. Yes * d. No description of derivation of the cohort b. No

2. Selection of the non-exposed cohort 3. Adequacy of follow up a. Drawn from the same community as the a. Complete follow up (all subjects exposed cohort * accounted for and no missing data) * b. Drawn from a different source b. Subjects lost to follow-up unlikely to c. No description of the derivation of the non- introduce bias - small number lost, <20% * exposed cohort c. Follow-up rate <80% d. Not applicable - e.g. case series, case d. Not stated study

3. Ascertainment of exposure a. Secure record (e.g. medical or dental record) * b. Structured interview * c. Self-reported d. No description given

4. Demonstration that outcome of interest was not present as start of study a. Yes * b. No c. Not applicable

Quality Assessment Selection (Maximum of 4 Comparability (Maximum of 2 Outcome (Maximum of 3 stars) stars) stars) GOOD 3 or 4 stars AND 1 or 2 stars AND 2 or 3 stars FAIR 3 or 4 stars AND 0 stars AND 2 or 3 stars POOR 1 or 2 stars AND 0 stars AND 1 star

Appendices 139

Appendix E: Supplemental Table 2 – Included studies (case series/cohort ≥ 5)

Appendix Table 2: Included studies in case series or cohort studies category (≥5 cases MRONJ) Newcastle-Ottawa Scale (NOS) Score

~ Included Articles for Case Series & Cohort Studies Category Selection Comparability Outcome Total (Max 4 ) (Max 2 ) (Max 3) (Max 9)

1 Abu-ID M, Warnke P, Gottschalk J, Springer I, Wiltfang J, Acil Y, Russo P, *** N/A *** 6/9 Kreusch T. 2008. “Bis-phossy jaws” - high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J Cranio-Maxill Surg. 36(2):95-103

2 Alvares Furtado I, Franco Caldas C, Lanca F, Salvado E Silva F. 2012. *** N/A *** 6/9 Anatomic factors related to bisphosphonate osteonecrosis of the jaws: a Portuguese retrospective study. Acta Med Port. 25(2):106-110

3 Aragon-Ching J, Ning Y, Chen C, Latham L, Guadagnini J, Gulley J, Arlen P, *** N/A *** 6/9 Wright J, Parnes H, Figg W, et al. 2009. Higher incidence of osteonecrosis of the jaw (ONJ) in patients with metastatic castration resistant prostate cancer treated with anti-angiogenic agents. Cancer Invest. 27(2):221-226

4 Avani-Lev K, Anavi Y, Chaushu G, Alon D, Gal G, Kaplan I. 2013. *** N/A *** 6/9 Bisphosphonate related osteonecrosis of the jaws: clinico-pathological investigation and histomorphometric analysis. Oral Surg Oral Med Oral Pathol. 115(5):660-666

5 Badros A, Terpos E, Katodritou E, Goloubeva O, Kastritis E, Verrou E, *** N/A *** 6/9 Zervas K, Baer M, Meiller T, Dimopoulos M. 2008. Natural history of osteonecrosis of the jaw in patients with multiple myeloma. J Clin Oncol. 26(36):5904-5909

6 Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, 4 N/A *** 6/9 Fenton R, Gahres N, Sausville E, Ord R, Meiller T. 2006. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 24(6):945-952

7 Bagan J, Murillo J, Jimenez Y, Poveda R, Milian M, Sanchis J, Silvestre F, *** N/A *** 6/9 Scully C. 2005. Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med. 34(2): 120-123

8 Bamias A, Kastritis E, Bamia C, Moulopoulos L, Melakopoulos I, Bozas G, *** N/A *** 6/9 Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, et al. 2005. Osteonecrosis of the jaw in cancer after treatment with bisphosphonate: incidence and risk factors. J Clin Oncol. 23(34):8580-8587

9 Bantis A, Zissimopoulos A, Sountoulides P, Kalaitzis C, Giannakopoulos S, *** N/A *** 6/9 Deftereos S, Tsakaldimis G, Thomaidis V, Touloupidis S. 2001. Bisphosphonate-induced osteonecrosis of the jaw in patients with bone metastatic, hormone-sensitive prostate cancer. Risk factors and prevention strategies. Tumori. 79(4):479-483

10 *Barasch A, Cunha-Cruz J, Curro F, DeRouen T, Gilbert G, Hujoel P, Saffod **** * *** 8/9 M, Vena D, Voinea-Griffin A, Wu H. 2013. Dental risk factors for osteonecrosis of the jaws: a CONDOR case-control study. Clin Oral Invest. 17(8):1839-1845 *Results from the two CONDOR studies were combined to give one complete data set

11 *Barasch A, Cunha-Cruz J, Curro F, Hujoel P, Sung A, Vena D, Voinea- **** * *** 8/9 Griffin AE. 2011. Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR Dental PBRN. J Dent Res. 90(4):439-444 *Results from the two CONDOR studies were combined during data collection to give one complete data set

12 Bedogni A, Saia G, Bettini G, Tronchet A, Totola A, Bedogni G, Ferronato G, *** N/A *** 6/9 Nocini P, Blandamura S. 2011. Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis. Oral Oncol. 47(5):420-424

13 Bonacina R, Mariani U, Villa F, Villa A. 2011. Preventative strategies and *** N/A *** 6/9 clinical implications for bisphosphonate-related osteonecrosis of the jaw: a review of 282 patients.

14 Bonomi M, Nortilli R, Molino A, Sava T, Santo A, Caldara A, Cetto G. 2010. *** N/A *** 6/9 Renal toxicity and osteonecrosis of the jaw in cancer patients treated with bisphosphonates: a long-term retrospective analysis. Med Oncol. 27(2):224- 229

Appendices 140

Appendix Table 2: Included studies in case series or cohort studies category (≥5 cases MRONJ) Newcastle-Ottawa Scale (NOS) Score

~ Included Articles for Case Series & Cohort Studies Category Selection Comparability Outcome Total (Max 4 ) (Max 2 ) (Max 3) (Max 9)

15 Boonyapakorn T, Schirmer I, Reichart P, Sturm I, Massenkeil G. 2008. *** N/A *** 6/9 Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol. 44(9):857-869

16 Borromeo G, Brand C, Clement J, McCullough M, Crighton L, Hepworth G, **** * *** 8/9 Wark J. 2014. A large case-control study reveals a positive association between bisphosphonate use and delayed dental healing and osteonecrosis of the jaw. J Bone Miner Res. 29(6):1363-1368

17 Cafro AM, Barbarano L, Nosari AM, D’Avanzo G, Nichelatti M, Bibas M, *** N/A *** 6/9 Gaglioti D, Taroni A, Riva F, Morra E, et al. 2008. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma. 8(2):111-116

18 Clarke B, Boyette J, Vural E, Suen J, Anaissie E, Stack B. Bisphosphonates *** N/A *** 6/9 and jaw osteonecrosis: the UAMS experience. 2007. Otolaryngol Head Neck Surg. 136(6):396-400

19 Chiu W, Chien J, Yang W, Juang J, Lee J, Tsai K. 2014. The risk of *** N/A *** 6/9 osteonecrosis of the jaws in Taiwanese osteoporotic patients treated with oral alendronate or raloxifene. J Clin Endocrinol Metab. 99(8):2729-2735

20 Choi H, Lee J, Lee JH, Kim H. 2015. Genetic association between VEGF **** ** *** 9/9 polymorphisms and BRONJ in the Korean population. Oral Dis. 21(7):866- 871

21 Danneman C, Gratz K, Riener M, Zwahlen R. 2007. Jaw osteonecrosis *** N/A *** 6/9 related to bisphosphonate therapy - a severe secondary disorder. Bone. 40(4):828-834

22 Di Fede O, Fusco V, Matranga D, Solazzo L, Gabriele M, Gaeta G, Favia G, *** N/A *** 6/9 Sprini D, Peluso F, Colella G, et al. 2013. Osteonecrosis of the jaws in patients assuming oral bisphosphonates for osteoporosis: a retrospective multi-hospital-based study of 87 Italian cases. Eur J Intern Med. 24(8):784- 790

23 Dimopoulos M, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, *** N/A *** 6/9 Migkou M, Eleftherakis-Papaiakovou E, Christoulas D, Terpos E, Bamias A. 2008. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol. 20(1):117-120

24 Diniz-Freitas M, Lopez-Cedrun J, Fernandez-Sanroman J, Garcia-Garcia A, *** N/A *** 6/9 Fernandez-Feijoo J, Diz-Dios P. 2012. Oral bisphosphonate-related osteonecrosis of the jaws: Clinical characteristics of a series of 20 cases in Spain. Med Oral Patol Oral Cir Bucal. 17(5):e751-758

25 Duarte L, dos Reis H, Tucci R, Lauria L. 2014. Bisphosphonate-related *** N/A *** 6/9 osteonecrosis of the jaws: analysis of a case series at a dental school. Spec Care Dentist. 34(2):77-83

26 Estilo C, Van Poznak C, Williams T, Bohle G, Lwin P, Zhou Q, Riedel E, *** N/A *** 6/9 Carlson D, Schoder H, Farooki A, et al. 2008. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy.

27 Fehm T, Beck V, Banys M, Lipp H, Hairass M, Reinert S, Solomayer E, *** N/A *** 6/9 Wallwiener D, Krimmel M. 2009. Bisphosphonate-induced osteonecrosis of the jaw (ONJ): incidence and risk factors in patients with breast cancer and gynecological malignancies. Gynecol Oncol. 112(3):605-609

28 Freiberger J, Padilla-Burgos R, Chhoeu A, Kraft K, Boneta O, Moon R, *** N/A *** 6/9 Piantadosi C. 2007. Hyperbaric oxygen treatment and bisphosphonate- induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg. 65(7):1321-1327

29 Grisar K, Schol M, Schoenaers J, Dormaar T, Coropciuc R, Vander Poorten *** N/A *** 6/9 V, Politis C. 2016. Osteoradionecrosis and medication-related osteonecrosis of the jaw: similarities and differences. Int J Oral Maxillofac Surg. 45(12):1592-1599

Appendices 141

Appendix Table 2: Included studies in case series or cohort studies category (≥5 cases MRONJ) Newcastle-Ottawa Scale (NOS) Score

~ Included Articles for Case Series & Cohort Studies Category Selection Comparability Outcome Total (Max 4 ) (Max 2 ) (Max 3) (Max 9)

30 Gunaldi M, Afsar C, Duman B, Kara I, Tatli U, Sahin B. 2015. Effect of the **** ** *** 9/9 cumulative dose of zoledronic acid on the pathogenesis of osteonecrosis of the jaws. Oncol Lett. 10(1):439-442

31 Hallmer F, Bjornland T, Nicklasson A, Becktor J, Andersson G. 2014. *** N/A *** 6/9 Osteonecrosis of the jaw in patients treated with oral and intravenous bisphosphonates: experience in Sweden. Oral Surg Oral Med Oral Pathol Oral Radiol. 118(2):202-208

32 Hoff A, Toth B, Altundag K, Johnson M, Warneke C, Hu M, Nooka A, Sayegh *** N/A *** 6/9 G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel R, Hortobagyi G. 2008. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res. 23(6):826-836

33 Hong J, Nam W, Cha I, Chung S, Choi H, Kim KM, Kim KJ, Rhee Y, Lim S. *** N/A *** 6/9 2010. Oral bisphosphonate-related osteonecrosis of the jaw: the first report in Asia. Osteoporos Int. 21(5):847-853

34 Ibrahim T, Barbanti F, Giorgio-Marrano G, Mercatali L, Ronconi S, Vicini C, *** N/A *** 6/9 Amadori D. 2008. Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study. Oncologist. 13(3):330- 336

35 Jacobsen C, Metzler P, Obwegeser J, Zemann W, Graetz K. 2012. *** N/A *** 6/9 Osteopathology of the jaw associated with bone resorption inhibitors: what have we learned in the last 8 years? Swiss Med Wkly. 142:w13605

36 Jadu F, Lee L, Pharoah M, Reece D, Wang L. 2007. A retrospective study *** N/A *** 6/9 assessing the incidence, risk factors and comorbidities of pamidronate- related necrosis of the jaws in multiple myeloma patients. Annal Oncol. 18(12):2015-2019

37 Jarnbring F, Kashani A, Bjork A, Hoffman T, Krawiec K, Ljungman P, Lund B. **** * *** 8/9 2015. Role of intravenous dosage regimens of bisphosphonates in relation to other aetiological factors in the development of osteonecrosis of the jaws in patients with myeloma. Br J Oral Maxillofac Surg. 53(10):1007-1011

38 Kajizono M, Sada H, Sugiura Y, Soga Y, Kitamura Y, Matsuoka J, Sendo T. *** N/A *** 6/9 2015. Incidence and risk factors of osteonecrosis of the jaw in advanced cancer patients after treatment with zoledronic acid or denosumab: a retrospective cohort study. Biol Pharm Bull. 38(12):1850-1855

39 Katz J, Gong Y, Salmasinia D, Hou W, Burkley B, Ferreira P, Casanova O, **** * *** 8/9 Langaee T, Moreb J. 2011. Genetic polymorphisms and other risk factors associated with bisphosphonate induced osteonecrosis of the jaw. Int J Oral Maxillofac Surg. 40(6):605-611

40 Kos M. 2013. Incidence and risk predictors for osteonecrosis of the jaw in *** N/A *** 6/9 cancer patients treated with intravenous bisphosphonates. Arch Med Sci. 11(2):319-324

41 Kos M, Kuebler J, Luczak K, Engelke W. 2010. Bisphosphonate-related *** N/A *** 6/9 osteonecrosis of the jaws: a review of 34 cases and evaluation of risk. J Craniomaxillofac Surg. 38(4):255-259

42 Kos M, Brusco D, Kuebler J, Engelke W. 2010. Clinical comparison of *** N/A *** 6/9 patients with osteonecrosis of the jaws, with and without a history of bisphosphonates administration. Int J Oral Maxillofac Surg. 39(11):1097- 1102

43 Krimmel M, Ripperger J, Hairass M, Hoefert S, Kluba S, Reinert S. 2014. *** N/A *** 6/9 Does dental and oral health influence the development and course of bisphosphonate-related osteonecrosis of the jaws (BRONJ)? Oral Maxillofac Surg. 18(2):213-218

44 Kwon T, Lee C, Park J, Choi S, Rijal G, Shin H. 2014. Osteonecrosis *** N/A *** 6/9 associated with dental implants in patients undergoing bisphosphonate treatment. Clin Oral Impl Res. 25:632-640

45 Kyrgidis A, Vahtsevanos K, Koloutos G, Andreadis C, Boukovinas I, **** * *** 8/9 Teleioudis Z, Patrikidou A, Triaridis S. 2008. Bisphosphonate-related osteonecrosis of the jaws: a case-control study of risk factors in breast cancer patients. J Clin Oncol. 25(28)4634-4638

Appendices 142

Appendix Table 2: Included studies in case series or cohort studies category (≥5 cases MRONJ) Newcastle-Ottawa Scale (NOS) Score

~ Included Articles for Case Series & Cohort Studies Category Selection Comparability Outcome Total (Max 4 ) (Max 2 ) (Max 3) (Max 9)

46 La Verde N, Bareggi C, Garassino M, Borgonovo K, Sburlati P, Pedretti D, *** N/A *** 6/9 Bianchi C, Perrone S, Mihali D, Cobelli S, et al. 2008. Osteonecrosis of the jaw (ONJ) in cancer patients treated with Bisphosphonates: how the knowledge of a phenomenon can change its evolution. Support Care Cancer. 16(11):1311-1315

47 Lazarovici T, Yahalom R, Taicher S, Elad S, Hardan I, Yarom N. 2009. *** N/A *** 6/9 Bisphosphonate-related osteonecrosis of the jaws: a single-centre study of 101 patients. J Oral Maxillofac Surg. 67(4):850-855

48 Lee J, Cheng S, Wang J, Chiang C, Chang H, Chen H, Kok S. 2013. Factors *** N/A *** 6/9 predicting the prognosis of oral alendronate-related osteonecrosis of the jaws: A 4-year cohort study. Head Neck. 35(12):1787-1795

49 Lescaille G, Coudert A, Baaroun V, Ostertag A, Charpentier E, Javelot M, *** N/A *** 6/9 Toledo R, Goudot P, Azerad J, Berdal A, et al. 2014. Clinical study evaluating the effect of bevacizumab on the severity of zoledronic acid-related osteonecrosis of the jaw in cancer patients. Bone. 58:103-107

50 Lo J, O’Ryan F, Gordon N, Yang J, Hui R, Martin D, Hutchinson M, Lathon P, *** N/A *** 6/9 Sanchez G, Silver P, et al. 2010. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg. 68(2):243-253

51 Lopez-Cedrun J, Sanroman J, Garcia A, Penarrocha M, Feijoo J, Limeres J, *** N/A *** 6/9 Diz P. 2013. Oral bisphosphonate-related osteonecrosis of the jaws in dental implant patients: a case series. Br J Oral Maxillofac Surg. 51(8):874-879

52 Manfredi M, Merigo E, Guidotti R, Meleti M, Vescovi P. 2011. *** N/A *** 6/9 Bisphosphonate-related osteonecrosis of the jaws: a case series of 25 patients affected by osteoporosis. Int J Oral Maxillofac Surg. 40(3):277-284

53 Malden N, Lopes V. 2012. An epidemiological study of alendronate-related *** N/A *** 6/9 osteonecrosis of the jaws. A case series from the south-east of Scotland with attention given to case definition and prevalence. J Bone Miner Metab. 30(2):171-182

54 Martins MA, Martins MD, Lascala C, Curi M, Migliorati C, Tenis C, Marques *** N/A *** 6/9 M. 2012. Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: a preliminary study. Oral Oncol. 48(1):79-84

55 Marx R. 2003. Pamidronate (Aredia) and zoledronate (Zometa) induced *** N/A *** 6/9 avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 61(9):1115-1117

56 Marx R, Cillo J, Ulloa J. 2011. Oral bisphosphonate-induced osteonecrosis: *** N/A *** 6/9 risk factors, prediction of risk using CTX testing, prevention, and treatment. J Oral Maxillofac Surg. 65(12):2397-2410

57 Marx R, Sawatari Y, Fortin M, Broumand V. 2005. Bisphosphonate-Induced *** N/A *** 6/9 Exposed Bone (Osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention. J Oral Maxillofac Surg. 63(11):1567-1575

58 Maurer P, Sandulescu T, Kriwalsky M, Rashad A, Hollstein S, Stricker I, *** N/A *** 6/9 Holzle F, Kunkel M. 2011. Bisphosphonate-related osteonecrosis of the maxilla and sinusitis maxillaris. Int J Oral Maxillofac Surg. 40(3):285-91

59 Mavrokokki T, Cheng A, Stein B, Goss A. 2007. Nature and frequency of *** N/A *** 6/9 bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg. 65(3):415-423

60 Mercer E, Norton T, Woo S, Treister N, Dodson T, Solomon D. 2013. Ninety- *** N/A *** 6/9 one osteoporosis patients affected with bisphosphonate-related osteonecrosis of the jaw: a case series. Calcif Tissue Int. 93(3):241-248

61 Molcho S, Peer A, Berg T, Futerman B, Khamaisi M. 2013. Diabetes **** * *** 8/9 Microvascular disease and the risk for bisphosphonate-related osteonecrosis of the jaw: a single centre study. J Clin Endocrinol Metab. 98(11):E1807- 1812

Appendices 143

Appendix Table 2: Included studies in case series or cohort studies category (≥5 cases MRONJ) Newcastle-Ottawa Scale (NOS) Score

~ Included Articles for Case Series & Cohort Studies Category Selection Comparability Outcome Total (Max 4 ) (Max 2 ) (Max 3) (Max 9)

62 Motta A, Macedo L, Santos G, Guerreiro C, Ferrari T, Oliveira T, Santos P, **** * *** 8/9 Oliveira-Santos C, Ricz H, Xavier S, Iannetta O. 2015. Quantitative ultrasound at the hand phalanges in patients with bisphosphonate-related osteonecrosis of the jaws. Braz Oral Res [online]. 29(1):1-9

63 Nisi M, La Ferla F, Karapetsa D, Gennai S, Miccoli M, Baggiani A, Graziani *** N/A *** 6/9 F, Gabriele M. 2015. Risk factors influencing BRONJ staging in patients receiving intravenous bisphosphonates: a multivariate analysis. Int J Oral Maxillofac Surg. 44(5):586-591

64 Oizumi T, Yamaguchi K, Sato K, Takahashi M, Yoshimura G, Otsuru H, *** N/A *** 6/9 Tsuchiaya M, Hagiwara Y, Itoi E, Sugawara S, et al. 2016. A strategy against the osteonecrosis of the jaw associated with nitrogen-containing bisphosphonates (N-BPs): attempts to replace N-BPs with the Non-N-BP etidronate.

65 Ortega C, Montemurro F, Raggiuolo R, Vormola R, Nanni D, Goia F, *** N/A *** 6/9 Gilardino M, Aglietta M. 2007. Osteonecrosis of the jaw in prostate cancer patients with bone metastases treated with zoledronate: A retrospective analysis. Acta Oncol. 46(5):664-668

66 O’Ryan F, Lo J. 2012. Bisphosphonate-related osteonecrosis of the jaw in *** N/A *** 6/9 patients with oral bisphosphonate exposure: clinical course and outcomes. J Oral Maxillofac Surg. 70(8):1844-1853

67 Oteri G, Bramanti E, Nigrone V, Cicciu M. 2013. Decayed, missing and filled *** N/A *** 6/9 teeth index and periodontal health in osteoporotic patients affected by BRONJ: an observational study. J Osteoporos. 1-7.

68 Otto S, Abu-Id M, Fedele S, Warnke P, Becker S, Kolk A, Mucke T, Mast G, *** N/A *** 6/9 Kohnke R,Volkmer E, et al. 2011. Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: Not just a sporadic coincidence - a multi-centre study. J Craniomaxillofac Surg. 39(4):272-277

69 Otto S, Schreyer C, Hafner S, Mast G, Ehrenfeld M, Sturzenbaum S, Pautke *** N/A *** 6/9 C. 2012. Bisphosphonate-related osteonecrosis of the jaws - characteristics, risk factors, clinical features, localization and impact on oncological treatment. J Craniomaxillofac Surg. 40(4):303-309

70 Owosho A, Blanchard A, Levi L, Kadempour A, Rosenberg H, Yom S, *** N/A *** 6/9 Farooki A, Fornier M, Huryn J, Estilo C. 2016. Osteonecrosis of the jaw in patients treated with denosumab for metastatic tumors to the bone: a series of thirteen patients. J Craniomaxillofac Surg. 44(3):265-270

71 Pelaz A, Junquera L, Gallego L, Garcia-Consuegra L, Garcia-Martinez L, *** N/A *** 6/9 Cutilli T, Olay S. 2015. Epidemiology, pharmacology and clinical characterization of bisphosphonate-related osteonecrosis of the jaw. A retrospective study of 70 cases. Acta Otorrinolaringol Esp. 66(3):139-147

72 Pichardo S, van Merkesteyn R. 2013. Bisphosphonate related osteonecrosis *** N/A *** 6/9 of the jaws: spontaneous or dental origin? J. Oral Maxillofac. Surg. 116(3): 287-292

73 Pozzi S, Marcheselli F, Sacchi S, Baldini L, Angrilli F, Pennese E, Quarta G, *** N/A *** 6/9 Stelitano C, Caparotti G, Luminari S, et al. 2007. Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients. Leuk. Lymphoma. 48(1):56-64

74 Ripamonti C, Maniezzo M, Campa T, Fagnoni E, Brunelli C, Siabene G, *** N/A *** 6/9 Bareggi C, Ascani L, Cislaghi E. 2008. Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol. 20(1):137-145

75 Sammut S, Malden N, Lopes V, Ralston S. 2016. Epidemiological study of *** N/A *** 6/9 alendronate-related osteonecrosis of the jaw in the southeast of Scotland. Br J Oral Maxillofac Surg. 54(5):501-505

Appendices 144

Appendix Table 2: Included studies in case series or cohort studies category (≥5 cases MRONJ) Newcastle-Ottawa Scale (NOS) Score

~ Included Articles for Case Series & Cohort Studies Category Selection Comparability Outcome Total (Max 4 ) (Max 2 ) (Max 3) (Max 9)

76 Saussez S, Javadian R, Hupin C, Magremanne M, Chantrain G, Loeb I, *** N/A *** 6/9 Decaestecker C. 2009. Bisphosphonate-related osteonecrosis of the jaw and its associated risk factors: a Belgian case series. Laryngoscope. 119(2):323- 329

77 Schiodt M, Reibel J, Oturai P, Kofod T. 2014. Comparison of nonexposed *** N/A *** 6/9 and exposed bisphosphonate-induced osteonecrosis of the jaws: a retrospective analysis from the Copenhagen cohort and a proposal for an updated classification system. Oral Surg Oral Med Oral Pathol Oral Radiol. 117(2):204-213

78 Scoletta M, Arduino P, Dalmasso P, Broccoletti R, Mozzati M. 2010. *** N/A *** 6/9 Treatment outcomes in patients with bisphosphonate-related osteonecrosis of the jaws: a prospective study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 110(1):46-53

79 Smidt-Hansen T, Folkmar T, Fode K, Agerbaek M, Donskov F. 2013. *** N/A *** 6/9 Combination of zoledronic acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma. J Oral Maxillofac Surg. 71(9):1532-1540

80 Takaishi Y, Ikeo T, Nakajima M, Miki T, Fujita T. 2010. A pilot case–control **** * *** 8/9 study on the alveolar measurement in risk assessment for bisphosphonate-related osteonecrosis of the jaw. Osteoporos Int. 21(5):815- 825

81 Tardast A, Sjoman R, Loes S, Abtahi J. 2015. Bisphosphonate associated *** N/A *** 6/9 osteomyelitis of the jaw in patients with bony exposure: prevention, a new way of thinking. 2015. J Appl Oral Sci. 23(3):310-314

82 Taylor T, Bryant C, Popat S. 2013. A study of 225 patients on *** N/A *** 6/9 bisphosphonates presenting to the bisphosphonate clinic at King’s College Hospital. Br Dent J. 214(7):e18

83 Then C, Horauf N, Otto S, Pautke C, von Tresckow E, Rohnisch T, Baumann **** * *** 8/9 P, Schmidmaier R, Bumeder I, Oduncu F. 2012. Incidence and risk factors of bisphosphonate-related osteonecrosis of the jaw in multiple myeloma patients having undergone autologous stem cell transplant. Onkologie. 35(11):658-664

84 Thumbigere-Math V, Tu L, Huckabay S, Dudek A, Lunos S, Basi D, Hughes *** N/A *** 6/9 P, Leach J, Swenson K, Gopalakrishnan R. 2012. A retrospective study evaluating frequency and risk factors of osteonecrosis of the jaw in 576 cancer patients receiving intravenous bisphosphonates. Am J Clin Oncol. 35(4):386-392

85 Thumbigere-Math V, Sabino M, Gopalakrishnan R, Huckabay S, Dudek A, *** N/A *** 6/9 Basu S, Hughes P, Michalowicz B, Leach J, Swenson K, et al. 2009. Bisphosphonate-related osteoenecrosis of the jaw: clinical features, risk factors, management, and treatment outcomes of 26 patients. J Oral Maxillofac Surg. 67(9):1904-1913

86 Thumbigere-Math V, Michalowicz B, Hodges J, Tsai M, Swenson K, Rockwell **** * *** 8/9 L, Gopalakrishnan R. 2014. Periodontal disease as a risk factor for bisphosphonate-related osteonecrosis of the jaw. J Periodontol. 85(2):226- 233

87 Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis C, *** N/A *** 6/9 Boukovinas I, Koloutsos G, Teleioudis Z, Kitikidou K, Paraskevopoulos P, et al. 2009. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol. 27(32):5356- 5362

88 Van den Wyngaert T, Claeys T, Huizing M, Vermorken J, Fossion E. 2008. *** N/A *** 6/9 Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol. 20(2):331-336

89 Vandone A, Donadio M, Mozzati M, Ardine M, Polimeni M, Beatrice S, **** * *** 8/9 Ciuffreda L, Scoletta M. 2011. Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: a single-centre clinical experience.

Appendices 145

Appendix Table 2: Included studies in case series or cohort studies category (≥5 cases MRONJ) Newcastle-Ottawa Scale (NOS) Score

~ Included Articles for Case Series & Cohort Studies Category Selection Comparability Outcome Total (Max 4 ) (Max 2 ) (Max 3) (Max 9)

90 Varadarajan P, Toro J, Craig R, Schneider D, Chao J, Haile D, Freytes C. *** N/A *** 6/9 2010. Does bisphosphonate-induced osteonecrosis of the jaw (BONJ) preclude intensive chemotherapy? Oral and infectious toxicities associated with autotransplantation in patients with BONJ. Blood. 116(21):1314

91 Vescovi P, Merigo E, Meleti M, Manfredi M, Guidotti R, Nammour S. 2012. *** N/A *** 6/9 Bisphosphonates-related ostenecrosis of the jaws: a concise review of the literature and a report of a single-centre experience with 151 patients. J Oral Pathol Med. 41(3):214-221

92 Vidal-Real C, Perez-Sayans M, Suarez-Penaranda JM, Gandara-Rey JM, *** N/A *** 6/9 Garcia-Garcia A. 2015. Osteonecrosis of the jaws in 194 patients who have undergone intravenous bisphosphonate therapy in Spain. Med Oral Patol Oral Cir Bucal. 20(3):e267-272

93 Walter C, Sagheb K, Bitzer J, Rahimi-Nedjat R, Taylor K. 2014. Analysis of *** N/A *** 6/9 reasons for osteonecrosis of the jaws. Clin Oral Invest. 19(9):2221-2226

94 Walter C, Al-Nawas B, Grotz K, Thomas C, Thuroff J, Zinser V, Gamm H, *** N/A *** 6/9 Beck J, Wagner W. 2008. Prevalence and risk factors of bisphosphonate- associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate. Eur Urol. 54(5):1066-1072

95 Walter C, Al-Nawas B, Frickhofen N, Gamm H, Beck J, Reinsh L, Blum C, *** N/A *** 6/9 Grotz K, Wagner W. 2010. Prevalence of bisphosphonate associated osteonecrosis of the jaws in multiple myeloma patients. Head Face Med. 6(1):11

96 Watters A, Hansen H, Williams T, Chou J, Riedel E, Halpern J, Tunick S, *** N/A *** 6/9 Bohle G, Huryn J, Estilo C. 2013. Intravenous bisphosphonate–related osteonecrosis of the jaw: long-term follow-up of 109 patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 115(2): 192-200

97 Wessel J, Dodson T, Zavras A. 2008. Zoledronate and other risk factors **** ** *** 9/9 associated with osteonecrosis of the jaw in cancer patients: a case-control study. J Oral Maxillofac Surg. 66(4):625-631

98 Wutzl A, Eisenmenger G, Hoffman M, Czerny C, Moser D, Pietschmann P, *** N/A *** 6/9 Ewers R, Baumann A. 2006. Osteonecrosis of the jaws and bisphosphonate treatment in cancer patients. Wien Klin Wochenschr. 118(15):473-478

99 Yamazaki T, Yamori M, Yamamoto K, Saito K, Asai K, Sumi E, Goto K, *** N/A *** 6/9 Takahashi K, Nakayama T, Bessho K. 2012. Risk of osteomyelitis of the jaw induced by oral bisphosphonates in patients taking medications for osteoporosis: A hospital-based cohort study in Japan. Bone. 51(5):882-887

100 Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S. 2007. *** N/A *** 6/9 Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int. 18(10):1363-1370

101 Yazdi P, Schiodt M. 2015. Dentoalveolar trauma and minor trauma as *** N/A *** 6/9 precipitating factors for medication-related osteonecrosis of the jaw (ONJ): a retrospective study of 149 consecutive patients from the Copenhagen ONJ Cohort.

102 Zarychanski R, Elphee E, Walton P, Johnston J. 2006. Osteonecrosis of the *** N/A *** 6/9 jaw associated with pamidronate therapy. Am J Hematol. 81(1):73-75

103 Zervas K, Verrou E, Teleioudis Z, Vahtsevanos K, Banti A, Mihou D, Krekelis *** N/A *** 6/9 D, Terpos E. 2006. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br J Haematol. 134(6):620-623

Appendices 146

Appendix F: Supplemental Table 3 – Included studies (case reports <5)

Appendix Table 3: Included studies in case reports category (<5 cases MRONJ)

~ Included Articles for Case Report Category

1 Aghaloo TL, Felsenfeld AL, Tetradis S. 2010. Osteonecrosis of the jaw in a patient on Denosumab. J Oral Maxillofac Surg. 68(5):959

2 Aghaloo TL, Tetradis S. 2017. Osteonecrosis of the jaw in the absence of antiresorptive or antiangiogenic exposure: a series of 6 cases. J Oral Maxillofac Surg. 75(1):129-142

3 Agrillo A, Nastro Siniscalchi E, Facchini A, Filiaci F, Ungari C. 2012. Osteonecrosis of the jaws in patients assuming bisphosphonates and sunitinib: two case reports. Eur Rev Med Pharmacol Sci. 16(7):952-957

4 Al-Mukhtar Y, Aga F, Hardee P. 2013. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) secondary to an oral ulcer caused by Nicorandil. Br J Oral Maxillo Surg. 51(6):e123

5 Amaral Mendes R. 2012. A severe complication of oral bisphosphonate therapy in a noncancerous patient. Oral Dis. 18:46

6 Baqain Z, Sawair F, Tamimi Z, Bsoul N, Al Edwan G, Almasad J, Abbadi A. 2010. Osteonecrosis of jaws related to intravenous bisphosphonates: the experience of a Jordanian teaching hospital. Ann R Coll Surg Engl. 92(6):489-494

7 Beattie A, Walsh JB, Casey M, McCarroll K, Stassen L. 2014. Bisphosphonate related osteonecrosis of the jaws in the osteoporotic patient. Ir J Med Sci. 183(7):s225-226

8 Bedogni A, Saia G, Ragazzo M, Bettini G, Capelli P, D’Alessandro E, Nocini P, Russo L, Muzio L, Blandamura S. 2007. Bisphosphonate-associated osteonecrosis can hide jaw metastases. Bone. 41(6):942-945

9 Borras-Blasco J, Rosique-Robles D, Costa S, Castera E, Giner-Marco V, Galan Brotons A. 2007. Possible delayed onset of osteonecrosis of the jaw in association with zoledronic acid. J Clin Pharm Ther. 32(6):651-654

10 Bouferrache K, Otaiba YM, Abarca M, Madrid C. 2013. Potential association of bisphosphonate-associated osteonecrosis of the jaw (BRONJ) with the use of tyrosine kinase inhibitor. Oral Oncol. 49:s106

11 Bucci L, Spinardi L, Trevisani F, Garuti F, Cameli V. 2016. Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma. Tumori. 102:s69-s70

12 Bujanda D, Samiento U, Suarez A, Morales J. 2006. Assessment of renal toxicity and osteonecrosis of the jaws in patients receiving zoledronic acid for bone metastasis. Ann Oncol. 18(3):556-560

13 Chatterjee R, Bajoria R, Shah F, Porter J, Fedele S. 2014. High index of suspicion for early diagnosis of alendronate- induced stage zero osteonecrosis of the jaw in thalassaemia major. Br J Haematol. 166(2):292-294

14 Chiu WY, Lee JJ, Tsai KS. 2013. Atypical femoral fractures shortly after osteonecrosis of the jaw in a postmenopausal woman taking alendronate for osteoporosis. J Clin Endocrinol Metab. 98(4):E723-E726

15 Crepin S, Laroche ML, Sarry B, Merle L. 2010. Osteonecrosis of the jaw induced by clodronate, an alkylbiphosphonate: case report and literature review. Eur J Clin Pharmacol. 66(6):547-554

16 de Boer YS, Bouma G, Wattjes MP, P, Mulder CJ, van Nieuwkerk CM. 2012. A case of autoimmune hepatitis and bisphosphonate-related osteonecrosis of the jaw. Case Rep Gastroenterol. 6(2):309-313

17 de Souza M, Stepavoi G. 2015. Case report: beware the silver nitrate stick - a risk factor for bisphosphonate-related osteonecrosis of the jaw (BRONJ). Dent Update. 42(8):735-743

18 DeSesa CR, Appugounder S, Haberland C, Johnson MP. 2016. Osteonecrosis of the jaw in association with chemotherapy in the setting of cutaneous T-cell lymphoma. J Oral Maxillofac Surg. 674(2):292-301

19 Etzelsdorf M, Eirisch G, Beck-Mannagetta J, Kassmann H, Gaggl A. 2012. Osteonecrosis of the jaws in osteoporosis after alendronate and denosumab. Oral Dis. 18:38

20 Furuya T, Maeda S, Momohara S, Taniguchi A, Yamanaka H. 2016. Dental treatments, tooth extractions, and osteonecrosis of the jaw in Japanese patients with rheumatoid arthritis: results from the IORRA cohort study. J Bone Miner Metab. 1-7

21 Gallego L, Junquera L, Diaz-Bobes C. 2011. Rubber dam clamp trauma during endodontic treatment: a risk factor of bisphosphonate-related osteonecrosis of the jaw? J Oral Maxillofac Surg. 69(6):e93-e95

22 Garcia Saenz JA, Lopez Tarruella S, Garcia Paredes B, Rodriguez Lajusticia L, Villalobos L, Diaz Rubio E. 2007. Osteonecrosis of the jaw as an adverse bisphosphonate event: three cases of bone metastatic prostate cancer patients treated with zoledronic acid. Med Oral Patol Oral Cir Bucal. 12(5):e351-e356

23 Ghorbel M, Hdiji S, Kassar O, Daoud E, Bellaaj H, Medhaffar M, Ajmi N, Mnif Z, Elloumi M. 2011. Osteonecrosis of the jaw: 2 cases report. Tunis Med. 89(1):121

24 Gruber E, Isherwood G, Mihalache G, MacBean A. 2013. A curious case of osteonecrosis of the jaws. Int J Surg. 11(8):618-619

Appendices 147

Appendix Table 3: Included studies in case reports category (<5 cases MRONJ)

~ Included Articles for Case Report Category

25 Hasegawa T, Ri S, Umeda M, Komatsubara H, Kobayashi M, Shigeta T, Yoshitomi I, Ikeda H, Shibuya Y, Asahina I et al. 2012. The observational study of delayed wound healing after tooth extraction in patients receiving oral bisphosphonate therapy. J Craniomaxillofac Surg. 41(7):558-63

26 Hoefert S, Eufinger H. 2010. Sunitinib may raise the risk of bisphosphonate-related osteonecrosis of the jaw: presentation of three cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 110(4):463-469

27 Iwamoto J, Yago K, Sato Y, Matsumoto H. 2012. Teriparatide therapy for bisphosphonate-associated osteonecrosis of the jaw in an elderly Japanese woman with severe osteoporosis. Clin Drug Investig. 32(8):547-553

28 Jain N, Chakrabarti A, Bhartia S, Chakrabartty J. 2014. Bisphosphonate related osteonecrosis of the jaw (BRONJ) in a myeloma patient: a case report. Indian J Hematol Blood Transfus. 30(2):532

29 Jowett A, Abdullakutty A, Bailey M. 2015. Pathological fracture of the coronoid process secondary to medication-related osteonecrosis of the jaw (MRONJ). Int J Surg Case Rep. 10:162-165

30 Kochish A, Ivanov S. 2015. Case osteonecrosis of the jaw in patient with postmenopausal osteoporosis after 10 years of treatment with various antiresorptive drugs. Osteporos Int. 26(1):s205

31 Lau AN, Adachi JD. 2010. Resolution of osteonecrosis of the jaw after teriparatide [recombinant human PTH-(1-34)] therapy. J Rheumatol. 37(6):1296

32 Lobato JV, Mauricio AC, Rodrigues JM, Cavaleiro MV, Cortez PP, Xavier L, Botelho C, Sooraj Hussain N, Santos JD. 2008. Jaw avascular osteonecrosis after treatment of multiple myeloma with zoledronate. J Plast Reconstr Aesthet Surg. 61(1):99-106

33 Longato L, Cavalli L, Marcucci G, Metozzi A, Giusti F, Brandi ML, Piscitelli P. 2013. Osteonecrosis of the jaw in a patient with rheumatoid artritis treated with an oral aminobisphosphonate: a clinical case report. Osteoporos Int. 24(1):s335

34 Metwally T, Burke A, Tsai J, Collins M, Boyce A. 2016. Fibrous dysplasia and medication-related osteonecrosis of the jaw. J Oral Maxillofac Surg. 74(10):1983-1999

35 Miranda-Rius J, Brunet-Llobet L, Lahor-Soler E, Gimenez-Rubio JA. 2014. Concomitant factors leading to an atypical osteonecrosis of the jaw in a patient with multiple myeloma. Case Rep Med. 2014(ID 281313):1-8

36 Murad OM, Arora S, Farag AF, Guber HA. 2007. Bisphosphonates and osteonecrosis of the jaw: a retrospective study. Endocr Pract. 13(3): 232-238

37 Nastro Siniscalchi E, Catalfamo L, Musolino C, Saverio De Ponte F. 2012. Titanium miniplates: A new risk factor for the development of the bisphosphonate-related osteonecrosis of the jaw. J Craniofac Surg. 24(1):e1-e2

38 Neuprez A, Coste S, Rompen E, Crielaard JM, Reginster JV. 2014. Osteonecrosis of the jaw in a male osteoporotic patient treated with denosumab. Osteoporos Int. 25(1):393-395

39 Neves I, Morais A, Magalhaes A. 2013. Bisphosphonate-associated osteonecrosis of the jaws in lung cancer patients. Rev Port Pneumol. 19:228-232

40 Ngan KK, Bowe J, Goodger N. 2013. The risk of bisphosphonate-related osteonecrosis of the jaw in children. A case report and literature review. Dent Update. 40(9):733-738

41 Notarnicola A, Lisi S, Sisto M, de Marino AV, D’Amore M. 2012. Possible role of oral ibandronate administration in osteonecrosis of the jaw: a case report. Int J Immunopathol Pharmacol. 25(1):311-316

42 O’Halloran M, Boyd NM, Smith A. 2014. Denosumab and osteonecrosis of the jaws - the pharmacology, pathogenesis and a report of two cases. Aus Dent J. 59(4):516-519

43 Olate S, Uribe F, Martinez F, Almeida A, Unibazo A. 2014. Osteonecrosis of the jaw in patient with denosumab therapy. Int J Clin Exp Med. 7(10):3707

44 Otto S, Troltzsch M, Jambrovic V, Panya S, Probst F, Ristow O, Ehrenfeld M, Pautke C. 2015. Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: A trigger for BRONJ development? J Craniomaxillofac Surg. 43(6):847-854

45 Pandit RS, Glueck CJ. 2014. Testosterone, anastrozole, factor V Leiden heterozygosity and osteonecrosis of the jaws. Blood Coagul Fibrinolysis. 25(3):286-288

46 Park W, Lee SH, Park KR, Rho SH, Chung WY, Kim HJ. 2012. Characteristics of bisphosphonate-related osteonecrosis of the jaw after kidney transplantation. J Craniofac Surg. 23(5):e510-e514

47 Pichardo S, Kuypers S, van Merkesteyn R. 2013. Denosumab osteonecrosis of the mandible: a new entity? A case report. J Craniomaxillofac Surg. 41(4):e65-e69

48 Pineiro-retif F, Borbalas A, Miguelez C, Zaora C, Urien A, Gonzalez F, Martin A, Rubio M, Jamal D, Barreda A et al. A case of long-term survival in woman with breast cancer. Rep Pract Oncol Radiother. 18:s198

49 Rachner TD, Platzbecker U, Felsenberg D, Hofbauer LC. 2013. Osteonecrosis of the jaw after osteoporosis therapy with denosumab following long-term bisphosphonate therapy. Mayo Clin Proc. 88(4):418-419

50 Sanna G, Preda L, Bruschini R, Cossu Rocca M, Ferretti S, Adamoli L, Verri E, Franceschelli L, Goldhirsch A, Nole F. 2006. Bisphosphonates and jaw osteonecrosis in patients with advanced breast cancer. Ann Oncol. 17(10):1512-1516

Appendices 148

Appendix Table 3: Included studies in case reports category (<5 cases MRONJ)

~ Included Articles for Case Report Category

51 Schiodt M. 2011. Herpes Zoster related osteonecrosis of the jaws. Consequences for planning of dental extractions and implant treatment? Int J Oral Maxillofac Surg. 40(10):1076

52 Schwartz HC. 1982. Osteonecrosis of the jaws: a complication of cancer chemotherapy. Head & Neck. 4(3):251-253

53 Song KE, Min YK, Lee JK, Lee KB, Joo HJ, Kwack KS, Chung YS. 2008. A probable case of oral bisphosphonate- associated osteonecrosis of the jaw and recovery with parathyroid hormone treatment. Curr Ther Res Clin Exp. 69(4):356- 362

54 Sung EC, Chan SM, Sakuri K, Chung E. 2002. Osteonecrosis of the maxilla as a complication to chemotherapy: a case report. Spec Care Dent. 22(4):142-146

55 Taylor KH, Middlefell LS, Mizen KD. 2010. Osteonecrosis of the jaws induced by anti-RANK ligand therapy. Br J Oral Maxillofac Surg. 48(3):221-223

56 Tong CK, Ho ST, Wong SL. 2010. Osteonecrosis of the jaw after oral bisphosphonate for osteoporosis. Hong Kong Med J. 16(2):145-148

57 Valenzuela L, Bouzon C, Manas L. 2015. Bisphosphonate-related osteonecrosis of the jaw in an 80 year-old woman with diabetes mellitus: case report. J Am Geriatr Soc. 63(10):2221-2222

58 Vercruysse H Jr, de Backer T, Mommaerts MY. 2014. Outcomes of osseous free flap reconstruction in stage III bisphosphonate-related osteonecrosis of the jaw: systematic review and a new case series. J Craniomaxillofac Surg. 42(5):377-386

59 Vescovi P, Meleti M, Merigo E, Manfredi M, Fornaini C, Guidotti R, Nammour S. 2013. Case series of 589 tooth extractions in patients under bisphosphonate therapy. Proposal of a clinical protocol supported by Nd: YAG low-level laser therapy. Med Oral Patol Oral Cir Bucal. 18(4):e680-685

60 Vig N, Rahim I, Vasavadia B. 2013. Non-bisphosphonates and osteonecrosis of the jaw - are we missing something? Br J Oral Maxillofac Surg. 51(6):e125

61 Vivekanandan R, Thimmisetty R, Javeria S. 2015. Bisphosphonates cause osteomyelitis in addition to osteonecrosis of the jaw. J Gen Intern Med.30:s369

62 Walter C, Al-Nawas B, du Bois A, Buch L, Harter P, Grotz K. 2008. Incidence of bisphosphonate-associated osteonecrosis of the jaws in breast cancer patients. Cancer. 115(8):1631-1637

63 Williamson, R. 2010. Bisphosphonates and the dental practitioner: a guide to management. Ann Roy Australas Coll Dent Surg. 20:46-49

64 Yamazaki T, Yamori M, Ishizaki T, Asai K, Goto K, Takahashi K, Nakayama T, Bessho K. 2012. Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. Int J Oral Maxillofac Surg. 41(11):1397-1403

65 Zadik Y, Abu-Tair J, Yarom N, Zaharia B, Elad S. 2012. The importance of a thorough medical and pharmacological history before dental implant placement. Aust Dent J. 57(3):388-392

Appendices 149

Appendix G: Supplemental Table 4 – Included single predictor studies

Appendix Table 4: Included studies in single predictor category

~ Included Articles for Single Predictor Category

1 Arduino PG, Menegatti E, Scully C, Scoletta M, Mozzati M, Donadio M, Broccoletti R, Chiecchio A, Battaglio C, Gandolfo S. 2010. VEGF-gene polymorphisms and bisphosphonate-induced osteonecrosis of the jaws. Oral Dis. 16(6):554

2 Badros A, Philip S, Lesho P, Sadowska M, Weikel D, Meiller T, Lapidus R, Hester L, Milliron T, Goloubeva O. 2013. Cytokine alteration in multiple myeloma (MM) patients and bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ). Blood. 122(21):3153-3153

3 Bagan JV, Jimenez Y, Gomez D, Sirera R, Poveda R, Scully C. 2009. Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates. Oral Oncol. 45(9):1088-1089

4 Bedogni A, Saia G, Bettini G, Tronchet A, Totola A, Bedogni G, Tregnago P, Valenti MT, Bertoldo F, Ferronato G, et al. 2012. Osteomalacia: the missing link in the pathogenesis of Bisphosphonate-related osteonecrosis of the jaws? Oncologist. 17(8):1114-1119

5 Berenson JR, Yellin O, Crowly J, Makary A, Gravenor DS, Yang HH, Upadhyaya GH, Flinn IW, Staszewski H, Tiffany NM, et al. 2011. Prognostic factors and jaw and renal complications among multiple myeloma patients treated with zoledronic acid. Am J Hematol. 86(1):25-30

6 Beuselinick B, Wolter P, Karadimou A, Elaidi R, Dumez H, Rogiers A, Van Cann T, Willems L, Body JJ, Berkers J, et al. 2012. Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. Br J Cancer. 107(10):1665-1671

7 Bozas G, Allgar V, Greenwood G, Maraveyas A. 2011. Osteonecrosis of the jaw in patients treated with sunitinib and zoledronic acid. J Clin Oncol. 29(15):e15116-e15116

8 Brahim J, Meiller TF, Weikel DS, Scheper MA. 2011. Dental disease and myeloma associated bisphosphonate-associated osteonecrosis. Int J Oral Maxillofac Surg. 40(10):1074

9 Choi H, Lee JH, Lee JH, Kim JH. 2015. Genetic association between VEGF polymorphisms and BRONJ in the Korean population. Oral Dis. 21(7):866-871

10 Choi SY, An CH, Kim SY, Kwon TG. 2013. Bone turnover and inflammatory markers of bisphosphonate-related osteonecrosis of the jaw in female osteoporosis patients. J Oral Maxillofac Surg Med Pathol. 25(2):123-128

11 Dimopoulos MA, Kastritis E, ANagnostopoulos A, Melakopoulos I, Gika D, Moulopoulos LA, Bamia C, Terpos E, Tsionos K, Bamias A. 2006. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid. Haematologica. 91(7):968-971

12 Fleisher KE, Welch G, Kottal S, Craig RG, Saxena D, Glickman RS. 2010. Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 110(4):509- 516

13 Fusco V, Porta C, Bedogni A, Bonacina R, Lo Re S, Saia G, Vescovi P, Scoletta M. 2013. Osteonecrosis of the jaw (ONJ) in patients with renal cell cancer (RCC) treated with bisphosphonates and sunitinib or other biological agents: characteristics of 39 cases in a multicenter survey. Eur J Cancer. 49:s295

14 Goloubeva O, Scheper M, Badros A, Brahim J, Weikel D, Meiller T. 2011. Role of pre-existing dental disease, bisphosphonate-associated osteonecrosis and clinical outcomes in multiple myeloma patients. Support Care Cancer. 19(2):s212

15 Grant BT, Amenedo C, Freeman K, Kraut RA. 2008. Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases. J Oral Maxillofac Surg. 66(2):223-230

16 Gyergyay F, Nagyivanya K, Biro K, Kuronya Z, Nemeth H, Geczi L. 2015. Incidence of osteonecrosis of the jaw (ONJ) in metastatic renal cell cancer patients (mRCC) treated with zoledronic acid (ZA). J Clin Oncol. 33(15):e20649-e20649

17 Holzinger D, Seeman R, Matoni N, Ewer R, Millesi W, Wutzl A. 2014. Effect of dental implants on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 72(10):1937.e1-1937.e8

18 Jacobsen C, Metzler P, Rossle M, Obwegeser J, Zemann W, Gratz KW. 2013. Osteopathology induced by bisphosphonates and dental implants: clinical observations. Clin Oral Investig. 17(1):167-175

19 Jeffcoat MK. 2006. Safety of oral bisphosphonates: controlled studies on alveolar bone. Int J Oral Maxillofac Implants. 21(3):349-353

20 Kim JW, Kim SJ, Kong KA, Cha IH, Kim MR. 2013. Prospective biomarker evaluation in patients with osteonecrosis of the jaw who received bisphosphonates. Int J Oral Maxillofac Surg. 42(10):1188

21 Khamaisi M, Regev E, Yarom N, Avni B, Leitersdorf E, Raz I, Elad S. 2007. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab. 92(3):1172-1175

22 Kolokythas A, KarrasM, Collins E, Flick W, Miloro M, Adami G. 2015. Salivary biomarkers associated with bone deterioration in patients with medication-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 73(9):1741-1747

Appendices 150

Appendix Table 4: Included studies in single predictor category

~ Included Articles for Single Predictor Category

23 Kosa JP, Balla B, Vasilko M, Zsarko M, Takacs I, Tobias B, Nagy Z, Lazary A, Lakatos P. 2012. Examination of CYP2C8 rs1934951 polymorphism in hungarian patients suffering from bisphosphonate-induced osteonecrosis of the jaw. Osteoporos Int. 23:s373

24 Kunchur R, Need A, Hughes T, Goss A. 2009. Clinical Investigation of C-Terminal Cross-Linking Telopeptide Test in Prevention and Management of Bisphosphonate-Associated Osteonecrosis of the Jaws. J Oral Maxillofac Surg. 67(6):1167- 1173

25 Kwon YD, Ohe JY, Kim DY, Chung DJ, Park YD. 2011. Retrospective study of two biochemical markers for the risk assessment of oral bisphosphonate-related osteonecrosis of the jaws: Can they be utilized as risk markers? Clin Oral Implants Res. 22(1):100-105

26 Kwon YD, Kim DY, Obe JY, Yoo JY, Walter C. 2009. Correlation between serum C-terminal cross-linking telopeptide of type I collagen and staging of oral bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 67(12):2644-2648

27 La Ferla F, Paolicchi E, Crea F, Cei S, Graziani F, Gabrie M, Danesi R. 2012. An aromatase polymorphism (g.132810C>T) predicts risk of bisphosphonate-related osteonecrosis of the jaw. Biomark Med. 6(2):201-209

28 Lazarovici TS, Mesilaty-Gross S, Vered I, Pariente C, Kanety H, Givol N, Yahalom R, Taicher S, Yarom N. 2010. Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates. J Oral Maxillofac Surg. 68(9):2241-2247

29 Lee C, Suzuki JB. 2010. CTX biochemical marker of bone metabolism. is it a reliable predictor of bisphosphonate-associated osteonecrosis of the jaws after surgery? Part II: A prospective clinical study. Implant Dent. 19(1):29-38

30 Leung A, Lee P, Kiss A, Choyee S, Uyanne J, Akiyama K, Sedghizadeh P, Shi S, Le AD. 2012. Immune biomarkers of BRONJ in high-risk cancer patients. J Oral Maxillofac Surg. 70(9):e37

31 Marini F, Tonelli P, Cavalli L, Cavalli T, Masi L, Brandi ML, Falchetti A. 2011. Pharmacogenetics of bisphosphonate- associated osteonecrosis of the jaw. Front Biosci (Elite Ed). 3(1):364-370

32 Melea P, Bagratuni T, Terpos E, Eleutherakis-Papaiakovou E, Gavriatopoulou M, Melakopoulos I, Kastritis E, Dinopoulos MA. 2014. Genetic factors related with early onset of osteonecrosis of the jaw in patients with multiple myeloma under zoledronic acid therapy. Blood. 124(21):2115-2115

33 Miyazaki H, Nishimatsu H, Kume H, Suzuki M, Fujimura T, Fukuhara H, Enomoto Y, Ishikawa A, Igawa Y, Hirano Y, Homma Y. 2012. Leukopenia as a risk factor for osteonecrosis of the jaw in metastatic prostate cancer treated using zoledronic acid and docetaxel. BJU Int. 110(11):e520-e525

34 Mucke T, Jung M, Mitchell D, Wolff KD, Wagenpfeil S, Stockmann P, Kesting MR, Deppe H. 2016. Do measurements of inflammatory mediators in blood predict recurrence in patients with bisphosphonate-related osteonecrosis of the jaws? Br J Oral Maxillofac Surg. 54(3):286-289

35 Nicolatou-Galitis O, Razis E, Galitis E, Tsimpoukis S, Koutsoukos K, Sgouros J, Soupos N, Nikolaidi A, Barbounis V, Migliorati C. 2014. Gingival and periodontal toxicity and osteonecrosis in patients receiving targeted therapies alone or combined with zoledronic acid: a case-series and clinical implications. Support Care Cancer. 22(1):s27

36 Nicolatou-Galitis O, Papadopoulos E, Bafaloukos D, Linardou E, Galiti D, Papasotiriou I. 2014. Markers of angiogenesis and inflammation in patients with solid tumors receiving targeted therapy and/or zoledronic acid. Support Care Cancer. 22(1):s26

37 Nicolatou-Galitis O, Papadopoulou E, Razis E, Linardou E, Grossi I, Migliorati CA, Vardas E. 2012. Jaw osteonecrosis associated with medication (JOM): report of two cases with unanswered clinical research questions. Support Care Cancer. 20:s177

38 Nicoletti P, Cartsos VM, Palaska PK, Shen Y, Floratos A, Zavras AI. 2012. Genomewide pharmacogenetics of bisphosphonate-induced osteonecrosis of the jaw: The role of RBMS3. Oncologist. 17(2):279-287

39 Niibe K, Ouchi T, Iwasaki R, Nakagawa T, Horie N. 2015. Osteonecrosis of the jaw in patients with dental prostheses being treated with bisphosphonates or denosumab. J Prosthodont Res. 59(1):3-5

40 O’Connell JE, Ikeagwani O, Kearns GJ. 2012. A role for C-terminal cross-linking telopeptide (CTX) level to predict the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ) following oral surgery? Ir J Med Sci. 181(2):237- 242

41 Ohbayashi Y, Nakai F, Iwasaki A, Nakai Y, Httori YM, Yamamoto Y, Nishiyama Y, Miyake M. 2015. The predictability of bisphosphonate-related osteonecrosis of the jaw using a quantitative analysis of bone scintigraphy. Int J Oral Maxillofac Surg. 44:e270

42 Pilanci KN, Alco G, Ordu C, Celebi F, Sarsenov D, Erdogan Iyigun Z, Agacayak F, Ilgun S, Ozmen V. 2015. Does trastuzumab increase ONJ development due to zoledronic acid treatment in breast cancer? Breast. 24(S1):s64

43 Polidoro S, Broccoletti R, Campanella G, Di Gaetano C, Menegatti E, Scoletta M, Lerda E, Matullo G, Vineis P, Berardi D, et al. Effects of bisphosphonate treatment on DNA methylation in osteonecrosis of the jaw. Mutat Res Genet Toxicol Environ Mutagen. 757(2):104-113

44 Quispe D, Runhua S, Burton G. 2011. Osteonecrosis of the jaw in patients with metastatic breast cancer: Ethnic and socio- economic aspects. Breast J. 17(5):510-513

45 Saia G, Blandamura S, Bettini G, Tronchet A, Totala A, Bedogni G, Ferronato G, Nocini PF, Bedogni A. 2010. Occurrence of bisphosphonate-related osteonecrosis of the jaw after surgical tooth extraction. J Oral Maxillofac Surg. 68(4):797-804

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Appendix Table 4: Included studies in single predictor category

~ Included Articles for Single Predictor Category

46 Sexton P, Walker TMW, McCann PJ. 2012. Avastin (bevacizumab): The new bisphosphonates? Ir J Med Sci. 181:s40

47 Stockmann P, Nkenke E, Englbrecht M, Schittenbauer T, Wehrhan F, Rauh C, Beckmann MW, Fasching PA, Kreusch T, Mackensen A, et al. 2013. Major histocompatibility complex class II polymorphisms are associated with the development of anti-resorptive agent-induced osteonecrosis of the jaw. J Cranio-Maxillofac Surg. 41(1):71-75

48 Such E, Cervera J, Terpos E, Bagan JV, Avaria A, Gomez I, Margaix M, Ibanez M, Luna I, Cordon L, et al. 2011. CYP2C8 gene polymorphism and bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma. Haematologica. 96(10):1557-1559

49 Tohashi K, Nakabayashi M, Kodani I, Kidani K, Ryoke K. 2016. Associations between systemic markers of bone turnover or bone mineral density and anti-resorptive agent-related osteonecrosis of the jaw in patients treated with anti-resorptive agents. Yonago Act Med. 59(1):45-53

50 Tsao C, Darby I, Ebeling PR, Walsh K, O’Brien-Simpson N, Reynolds E, Borromeo G. 2013. Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. 71(8):1360-1366

51 Vincenzi B, Napolitano A, Zoccoli A, Iuliani M, Pantano F, Papapietro N, Denaro V, Santini D, Tonini G. 2012. Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw. J Hematol Oncol. 5:56

52 Vaszilko M, Kovacs E, Restar L, Balla B, Cseplo K, Kosa J, Lakatos P. 2014. Potential significance of antiestrogen therapy in the development of bisphosphonate related osteonecrosis of the jaw. J Cranio-Maxillofac Surg. 42(8):1932-1936

Appendices 152

Appendix H: Supplemental Table – Comorbidities by disease group

Appendix Table 1: Complete list of comorbidities by broad disease group Disease group Comorbid conditions Cancer Breast cancer, prostate cancer, multiple myeloma, leukaemia, lung cancer, lymphoma, endometrial adenocarcinoma, colorectal cancer, bowel cancer, bladder cancer, oral cancer, sarcoma, dermofibrosarcoma proliferans, ovarian cancer.

Bone disease Osteoporosis, Paget’s disease, osteogenesis imperfecta, osteoarthritis, rheumatoid arthritis.

Cardiovascular disease Ischaemic heart disease/angina, atrial fibrillation, deep vein , pulmonary embolism, aortic regurgitation, dilated cardiomyopathy, bradycardia, degenerative mitral valve disease, carotid stenosis, stroke, aortic aneurysm, myocardial infarction.

Gastrointestinal disease GORD, reflux, ischaemic bowel, cirrhosis, ulcerative colitis, peptic ulcer disease, pancreatitis, Crohn’s disease, coeliac disease, hepatitis C, diverticular disease, primary biliary cirrhosis.

Respiratory disease Bronchitis, emphysema, asthma, MAC lung, pulmonary fibrosis, pneumonia, upper respiratory tract infection, bronchiectasis, mixed lung infection.

Kidney disease Chronic kidney disease, renal insufficiency, necrotising glomerulonephritis, focal segmental glomerulosclerosis, pyelonephritis

PTA diseases Hypothyroidism, hypocortisolism, hyperthyroidism, primary hypogonadism, Hashimoto’s disease, hyperparathyroidism

Blood disorders Anaemia, hyperprolactinaemia, hypoglobulinaemia, haemochromatosis, Gilbert’s syndrome, essential thrombocythemia, hypercalcaemia, T-cell lymphocytosis

Autoimmune/inflammatory Rheumatoid arthritis, polymyalgia, psoriasis, fibromyalgia, autoimmune hepatitis, severe aplastic anaemia, Sjogren’s syndrome, bullous , necrotising autoimmune myositis, ankylosing spondylitis, bursitis, gout, Grave’s disease, systemic , discoid lupus erythematous, dermatitis herpetiformis.

Mental health Anxiety, depression, schizophrenia, bipolar, epilepsy

Diabetes, hypertension and dyslipidaemia were reported in high frequency and were treated as their own categories.

Appendices 153

Appendix I: Supplemental Table - Classification of dental treatment by ADA codes

Code Item description PREVENTATIVE: Diagnostic services 011 Comprehensive oral exam 012 Periodic oral exam 022 Intraoral periapical or bitewing radiograph – per exposure* 037 - per exposure* Preventive services 111 Removal or plaque or stain 114 Removal of calculus – first appointment 115 Removal of calculus – subsequent appointment 121 Topical application of remineralisation and/or cariostatic agent 123 Concentrated remineralisation and/or cariostatic agents, application 131 Dietary analysis and advice 141 Oral hygiene instruction 142 Tobacco counselling 165 Desensitising procedure – per appointment NON-SURGICAL: Periodontics 213 Treatment of acute periodontal infection – per appointment 221 Clinical periodontal analysis & recording 222 Periodontal debridement – per tooth 232 Periodontal flap surgery – per tooth 245 Periodontal surgery involving one tooth 281 Course of non-surgical periodontal treatment 282 Continuation of periodontal treatment or maintenance subsequent to 281 Endodontics 411 Direct pulp capping 415/6 Complete chemo-mechanical preparation of canal (first & each additional) 417/8 Root canal obturation (first & each additional) 419 Extirpation of pulp or debridement of root canal(s) – emergency/palliative 445 Exploration and/or negotiation of calcified canal – per canal 451 Removal of root filling – per canal 455 Additional visit for irrigation/dressing of the root canal system – per tooth 457 Obturation of resorption defect or perforation (non-surgical) 458 Interim therapeutic root filling – per tooth Restorative services 511-5 Metallic restorations – direct (one to five surfaces) 521-5 Adhesive restorations – anterior teeth – direct (one to five surfaces) 531-5 Adhesive restorations – posterior teeth – direct (one to five surfaces) 572 Provisional (intermediate/temporary) restoration – per tooth 596 Recementing of indirect restoration Prosthodontics: 615 Full crown – veneered – indirect fixed 618 Full crown – metallic – indirect 625 Post and core for crown – indirect

Appendices 154

631 Provisional crown 643 Bridge pontic – indirect – per pontic 645 Precision or magnetic attachment 651/2 Recementing crown/veneer or bridge/splint 655 Removal of crown 661 Fitting of implant abutment Prosthodontics: 711 Complete maxillary denture removable 712 Complete mandibular denture 719 Complete maxillary and mandibular dentures 721 Partial maxillary denture – resin base 722 Partial mandibular denture - resin base 727 Partial maxillary denture – cast metal framework 728 Partial mandibular denture – cast metal framework 736 Immediate tooth replacement – per tooth 741 Adjustment of a denture 743 Relining – complete denture – processed 744 Relining – partial denture – processed 745 Remodelling – complete denture 746 Remodelling – partial denture 751 Relining – complete denture – direct 752 Relining – partial denture – direct 753 Cleaning and polishing of existing denture 754 Denture base modification 761-9 Denture repairs 771 Tissue conditioning preparatory to impressions 775 Characterisation of denture base 779 Surgical guide for an immediate denture Orthodontics 821 Active removable appliance – per arch General services 911 Palliative care 926 Individually made tray – medicament 927 Provision of medication/medicament 949 Dental treatment under general anaesthesia/sedation 961-72 Occlusal therapy Miscellaneous 984/5 Bi-maxillary oral appliance for diagnosed snoring/OSA + repair 986 Post-operative care not otherwise included 990 Treatment not otherwise included

SURGICAL 311 Removal of a tooth or part(s) thereof 314 Sectional removal of a tooth or part(s) thereof 322 Surgical removal of a tooth not requiring removal of bone/ tooth division 323 Surgical removal of a tooth requiring removal of bone 324 Surgical removal of a tooth requiring removal of bone and tooth division th From: Australian Schedule of Dental Services and Glossary 10 Edition.

Appendices 155

Appendix J: Dental management of patients at risk of MRONJ

Clinical guideline for the dental management of patients who require antiresorptive therapies.

1.0 INTRODUCTION Antiresorptive medications are used to prevent skeletal-related events in patients with metastatic cancer and multiple myeloma, and to prevent fractures in patients with osteoporosis, rheumatoid arthritis and Paget’s disease. A small percentage of patients who receive antiresorptive therapies develop medication-related osteonecrosis of the jaw (MRONJ) (1). There is also growing evidence that antiangiogenic medications are associated with MRONJ (2). The underlying mechanism of MRONJ remains unclear, but patients who are systemically unwell and who require dental interventions are at an increased risk of developing this complication (3, 4). Current evidence suggests MRONJ is a multi-factorial disease with a number of contributing component causes. Dental disease and its treatment appear to play an important role in the development of MRONJ, with the majority of cases occurring after the removal of a tooth (5). The potency and duration of antiresorptive treatment also increases the risk of MRONJ, and systemic diseases likewise contribute to patient susceptibility (1, 3, 4). As these are not modifiable risk factors, preventing dental disease and damage to the oral mucosa is the most feasible strategy to reduce the risk of MRONJ.

2.0 PRINCIPLES AND EVIDENCE The prevalence of MRONJ varies with the dose and duration of exposure to antiresorptive medications. Oncology patients are considered to be the most at-risk population for MRONJ, as they receive intravenous bisphosphonates and denosumab at doses 12-15 times higher than those prescribed for patients with post-menopausal osteoporosis (4). The prevalence of MRONJ is reported to be between 1-15% in patients receiving high-dose antiresorptives for malignancy. The risk of MRONJ in osteoporotic patients is estimated to be between 0.004-0.1% (6-8), but this increases to 0.21% after 4 years of antiresorptive therapy (1). Most patients who develop MRONJ had a tooth removed. Periodontal disease, dental infections and dentures are also commonly reported precipitators. Implant surgery, peri-implant disease, ulcers and even rubber dam clamp trauma have been reported to initiate MRONJ (5). Most patients are not receiving appropriate dental management before commencing or during their antiresorptive medications, and subsequently many require extractions and other dental interventions while on AR therapy. Preventative dental care has been consistently shown to reduce the incidence of MRONJ (9-13).

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3.0 DENTAL MANAGEMENT PRIOR TO COMMENCING ANTIRESORPTIVES Identifying patients before they start their antiresorptive medications is a critical component of this guideline. Dental clinics should actively liaise with oncology departments, endocrinologists, rheumatologists and general medical practitioners in their local area so that physicians are aware of the available dental services and referral pathways. Inter-professional collaboration is fundamental to the successful implementation of these guidelines.

3.1 Comprehensive oral exam Patients must receive a thorough dental examination that includes: careful consultation about their medical history, visual inspection of extra-oral and intra-oral structures, palpation of neck node regions, and a panoramic radiograph that is, where practicable, interpreted by a specialist Dental and Maxillofacial Radiologist (DMFR). A periodontal screening and assessment (PSR) should be completed, and patients who score ≥3 in ≥2 sextants require a full periodontal assessment. All remaining teeth must be vitality tested. Intraoral periapical radiographs are required for any implants, root filled teeth, fixed prosthodontic work, teeth with questionable clinical appearance, and teeth that do not respond to pulp testing. Bitewing radiographs are required to assess the interproximal surfaces of any remaining posterior teeth. Check the fit of all dentures, especially along the lingual flange. Examine the health of the underlying mucosa and the cleanliness of the denture. Confirm with the patient that they have brought all of their removable prostheses to their appointment.

3.2 Risk assessment, patient education & oral hygiene instruction Patients who are receiving high doses of antiresorptives for oncologic reasons and patients who have received lower dose antiresorptives for more than three years have a higher risk of developing MRONJ. Patients who list multiple comorbidities and medications in their medical histories are also at an increased risk of MRONJ, as are patients who have poor oral hygiene and require frequent dental interventions. There appears to be a compounding effect where multiple risk factors are present. It is important to be aware of the risk profile of each patient, but all risk assessments are largely arbitrary until the underlying mechanism of MRONJ has been clearly defined. The presence of risk factors may shorten the recommended recall period for the patient, but the treatment recommendations and the importance of optimal oral hygiene apply equally for all patients. The patient must be informed of the small inherent risk of MRONJ with antiresorptive medications, but this conversation must be carefully worded to ensure the importance of their antiresorptive therapy is clear and that the patient does not become excessively fearful of MRONJ. It should be clear to the patient that maintaining good oral health will significantly reduce their small risk of this complication. It is important that the patient understands that regular dental appointments will provide an opportunity to detect lesions in the early stages of MRONJ, which can be managed conservatively and respond more predictably to treatment. Patients should receive appropriate oral hygiene instruction taking into consideration their manual dexterity and remaining dentition. Patients with removable dentures should be taught how to clean their dentures and to report any sore spots immediately. It is very important that patients know to remove their dentures as soon as they develop an ulcer and to leave them out until they have been reviewed and adjusted by a dentist.

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3.3 Optimising oral health The patient should be treated as required to resolve any pathological conditions in the oral cavity. The primary intention is the stabilise the mouth and obtain sufficient compliance from the patient with their regular self-care to preserve the remaining dentition and avoid any future infections or inflammation that require interventional treatment. Extracting teeth prior to starting antiresorptives is not necessarily an effective risk-reduction strategy, because constructing a new denture over recent extraction sites is not a low risk procedure for this patient group. Teeth and dentures should be cleaned, and patients who have deep periodontal probing depths or do not respond favourably to the first round of non-surgical periodontal therapy should be referred to a periodontist. A non-favourable response to treatment includes deterioration of ≥2mm clinical attachment loss on any tooth, or minimal change to overall bleeding on probing score. Any periodontally-compromised tooth must be vitality tested to determine if there is an endodontic component to the lesion. A periodontist is best placed to decide which teeth can be reasonably expected to survive for the preceding 5-10years. Teeth that are deemed hopeless or at high risk of recurring infection by the periodontist should be removed. Carious lesions should be filled and defective restorations need to be replaced. Fixed prosthodontic treatment can be completed where indicated and agreeable to the patient, but must be followed up with a 6-month post-operative radiograph and vitality testing for teeth that have not been endodontically treated. Removable dentures are an important risk factor for MRONJ and any new prosthesis should be carefully inspected for sharp or overextended areas before being issued to the patient. The patient must be recalled frequently after issue to prevent ulceration of the underlying mucosa. Teeth with endodontic lesions should be extirpated, and the patient rebooked to complete root canal treatment as soon as possible. Difficult cases should be referred to an endodontist. Existing root canal treatments should be assessed radiographically and clinically for signs of re- infection. Any teeth that require re-treatment should be referred to an endodontist. Root canal therapy and crown amputation should be considered in preference to extraction for teeth with poor restorative viability. Teeth with circumferential bone loss to the apex that are mobile in an axial direction should be removed. Root remnants should also be removed. Unerupted teeth that are completely covered by bone and soft tissue do not require extraction. Systemic risk factors must also be identified and addressed. Diabetic patients with glycated haemoglobin levels above 7.5% should be referred to an endocrinologist for management. Patients who smoke require smoking cessation counselling and a smoking cessation clinical pathway should be initiated. Once the treatment plan is complete, the patient must be rescheduled for a recall appointment. The clinician should use their best judgement and consideration of the risk factors for MRONJ in section 4.2, the patient’s caries risk (14) and periodontal risk (15) to determine the most appropriate recall interval. Where possible, patients should be seen at least every 6 months so that any new dental problems are detected early and can be treated conservatively. Ongoing review also provides an opportunity for early detection of suspicious MRONJ lesions.

3.5 Communicating with the managing physician The treating clinician must provide the patient’s physician with a letter that outlines the dental risk factors for the patient and the recommended recall interval for ongoing dental care. It is important that the doctor who is prescribing the antiresorptive medications is aware of patients

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who have poor oral hygiene and those that require frequent review appointments. Doctors may be able to direct poorly compliant patients back for ongoing dental care. It is also helpful for the treating doctor to have a dental report for each patient as this may assist in conversations about MRONJ risk with concerned patients.

4.0 DENTAL MANAGEMENT DURING ANTIRESORPTIVE THERAPY 4.1 Periodic examination & preventative care Patients should be recalled every six months for a dental exam, and this must include a PSR (or a full periodontal assessment for patients in supportive periodontal therapy (SPT). Bitewing and periapical radiographs should be taken where indicated (see Section 3.1) every two years. Teeth should be professionally cleaned every year, unless the patient has been previously diagnosed with periodontal disease and requires more frequent SPT. Oral hygiene instruction should be repeated. The appropriateness of the recall interval should be reviewed at each appointment and shortened if the patient continues to present with new disease.

4.2 Interventional treatment (not including extractions) Restorations, endodontic treatment, periodontal treatment and prosthodontic work can be completed as required, but any dental treatment should be planned with consideration of the patient’s medical condition. Patients with metastatic cancer should be managed conservatively and preservation of the patient’s quality of life is a key consideration. Patients with non- oncologic diseases should be managed as per any other dental patient with the exception of implants (see Section 4.4). Clinicians should be aware that there are rare case reports where simple procedures have initiated MRONJ, and take care to avoid trauma to the during dental treatment. Repairs, relines, and new dentures must be reviewed very frequently once issued to prevent trauma to the underlying mucosa. Patients who require interventional treatment should be reviewed more regularly to prevent the incidence of new disease.

4.3 Extractions Extractions are the most commonly reported initiator of MRONJ and should be considered a last resort for patients on antiresorptives. Endodontic treatment and root amputation should be attempted in preference to extraction, especially for patients with metastatic cancer who are at highest risk of MRONJ. The risk of the extraction must be considered in light of their incurable disease status, and every attempt should be made to treat the infection but retain the tooth, where possible. For non-oncologic patients, endodontic and periodontal treatment options should be exhausted before extraction is offered. Where extraction is unavoidable, there is no evidence that CTX tests are predictive of the risk of MRONJ and should not be used to guide clinical decisions (3, 16, 17). There is currently insufficient evidence to support the routine use of antibiotics to reduce the risk of MRONJ after oral surgery (18). Extractions should be timed according to Section 4.5 below. Review the patient weekly until complete mucosal coverage is observed, and refer to an oral and maxillofacial surgeon if the site has not completely healed at 8 weeks, or earlier if serious healing complications occur.

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4.4 Implant therapy Implant therapy is contraindicated for patients with metastatic cancer (3). Implant therapy can be considered for patients with osteoporosis, but it is important to remember that there are reported cases of both implant-surgery related and implant-presence related MRONJ (19, 20). The risk period for implants is not limited to the peri-operative period, and persists for as long as the implant remains in-situ. Suitability for implants should be determined with consideration of standard contraindications for implants, such as smoking, poorly-controlled diabetes, active periodontal disease, and poor oral hygiene. The risk of MRONJ from implants may need to be weighed against the risk of MRONJ from a poorly fitting denture in some patients. Implant placement should be timed according to Section 4.5 below.

4.5 Timing of surgical procedures and drug holidays Patients with osteoporosis may continue their bisphosphonates or denosumab if invasive dental treatment, including extraction or implant surgery, is required (3, 21). There is a serious risk of rebound fracture if denosumab is withheld or delayed (22, 23). The current recommendation is to perform any surgical procedures at 4 months after the most recent dose of denosumab (21). This allows two months to observe healing before the next scheduled dose is due. If healing complications do occur, the clinician should consult with the managing doctor to see if the next dose can be safely delayed. This prevents any unnecessary or prolonged interruption to antiresorptive therapy. Oncologic patients for whom surgical procedures cannot be avoided should be referred to an oral and maxillofacial surgeon for management.

4.6 Communication with managing physician Ongoing communication with the managing physician is critical to ensure optimal outcomes for the patient. Establishing collegiate relationships with the oncologists, endocrinologists, general practitioners, and other physicians involved in the care of these patients also increases the likelihood that other patients will be referred for dental assessment prior to starting antiresorptive therapy.

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zoledronic acid–A prospective study over 6 years. Journal of Cranio-Maxillofacial Surgery. 2016;44(10):1689-93. 14. Bratthall D, Hänsel Petersson G. Cariogram – a multifactorial risk assessment model for a multifactorial disease. Community Dentistry and Oral Epidemiology. 2005;33(4):256-64. 15. Lang NP, Tonetti MS. Periodontal risk assessment (PRA) for patients in supportive periodontal therapy (SPT). Oral Health and Preventative Dentistry. 2003;1(1):7-16. 16. Enciso R, Keaton J, Saleh N, Ahmadieh A, Clark GT, Sedghizadeh PP. Assessing the utility of serum C-telopeptide cross-link of type 1 collagen as a predictor of bisphosphonate- related osteonecrosis of the jaw: A systematic review and meta-analysis. The Journal of the American Dental Association. 2016. 17. Dal Prá K, Lemos C, Okamoto R, Soubhia A, Pellizzer E. Efficacy of the C-terminal telopeptide test in predicting the development of bisphosphonate-related osteonecrosis of the jaw: a systematic review. International Journal of Oral and Maxillofacial Surgery. 2017;46(2):151-6. 18. Scottish Dental Clinical Effectiveness Programme. Oral health management of patients at risk of medication-related osteonecrosis of the jaw. March 2017. Available from: http://www.sdcep.org.uk/published-guidance/medication-related-osteonecrosis-of-the-jaw/ 19. Giovannacci I, Meleti M, Manfredi M, Mortellaro C, Lucchina AG, Bonanini M, et al. Medication-related osteonecrosis of the jaw around dental implants: implant surgery-triggered or implant presence-triggered osteonecrosis? Journal of Craniofacial Surgery. 2016;27(3):697- 701. 20. Guazzo R, Sbricoli L, Ricci S, Bressan E, Piattelli A, Iaculli F. Medication-related osteonecrosis of the jaw and dental implants failures: a systematic review. Journal of Oral Implantology. 2017;43(1):51-7. 21. McClung MR. Cancel the denosumab holiday. Osteoporosis International. 2016;27(5):1677-82. 22. Niimi R, Kono T, Nishihara A, Hasegawa M, Sudo A. Rebound-associated vertebral fractures after discontinuation of denosumab for the treatment of maxillitis. Osteoporosis International. 2018;29(3):769-72. 23. Leaney A, Sztal-Mazer S. Rebound vertebral fracture in the dental chair during a tooth extraction whilst on a treatment holiday from denosumab to avoid ONJ! Bone. 2018;108:43.

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