Medication-Related Osteonecrosis of the Jaws: Bisphosphonates and Denosumab, and New Agents

Osteonecrosis of the jaws is a well-known side-effect of antiresorptive therapy that predominantly occurs in patients suffering from malignant diseases and receiving intravenous administrations of nitrogen-containing bisphosphonates or subcutaneous administrations of denosumab, a monoclonal antibody. Less frequently it may also be observed in patients with osteoporosis who are being treated with these antiresorptive drugs This textbook provides detailed, up-to-date information on all aspects of medication-related osteonecrosis of the jaws, including clinical features, pathogenesis, treatment options, and preventive measures. It also explains safe prevention and treatment strategies for patients receiving antiresorptive drugs who require extractions, implant insertions, and other dento-alveolar surgeries. This book will be of major interest for medical and dental students, dentists, and oral and maxillofacial surgeons as well as osteologists and oncologists. Foreword 6 Contents 8 1: Pharmacological Aspects of Antiresorptive Drugs: Bisphosphonates and Denosumab 10 Introduction 10 Bisphosphonates 11 Historical Review 11 Chemistry 12 Pharmacodynamics 13 Administration and Absorption 13 Distribution Half-Life 13 Affinity to Bone 13 Uptake and Desorption of Bisphosphonates 13 Elimination of Bisphosphonates 16 Actions of Bisphosphonates 16 Direct Effects on Osteoclasts 17 Effects on Osteoblasts and Osteocytes 20 Effects on Immune System 20 Antiangiogenic Effects 21 Effects on Tumor Cells 21 Side Effects 21 Osteomyelitis/Osteonecrosis of the Jaw Bones 21 Effects of Cessation of Bisphosphonate Therapy 21 The RANK/RANKL/Osteoprotegerin System 22 Conclusions 23 References 23 2: Bisphosphonate and Denosumab Therapy: Fields of Application 25 Introduction 26 Use of Bisphosphonates in Nonmalignant Diseases 26 Bisphosphonates in Postmenopausal Osteoporosis 26 Bisphosphonates in Chronic Kidney Disease and After Renal Transplantation 26 Other Indications 27 Use of Bisphosphonates in Malignancies 27 Bisphosphonates in Multiple Myeloma Patients 28 Bisphosphonates in Breast Cancer 29 Bisphosphonates in Prostate Cancer and Other Genitourinary Malignancies 30 Denosumab as an Alternative to Bisphosphonate Therapy 31 Conclusions 32 References 32 3: Risk Factors for Medication-Related Osteonecrosis of the Jaw 35 Terminology of Osteonecrosis of the Jaw 35 Avascular/Ischemic Necrosis of the Jaw 35 Bisphosphonate-Induced, -Related, or -Associated Jaw Necrosis 36 Risk Factors for BRONJ 36 Introduction 36 Bisphosphonate Administration Itself: Type, Drug, Route, and Dose 37 Intravenous Bisphosphonates 37 Oral Bisphosphonates 39 Systemic Risk Factors (Underlying Disease, Co-Morbidities, and Co-Medications) 39 Intravenous Bisphosphonate Intake 39 Oral Bisphosphonate Intake 40 Local Risk Factors (Infections, Extractions, Pressure Sores, etc.) 40 Host Factor 41 Genetic Risk Factors 41 Surrogate Markers for BRONJ Risk 41 Risk Factors for Denosumab- 43 Conclusions 44 References 44 4: Definition, Clinical Features and Staging of Medication-Related Osteonecrosis of the Jaw 51 First Description 51 Definition 52 General Characteristics 52 Clinical Features 53 Staging According to the AAOMS 2007, 2009 and 2014 [11, 12] 56 Stage 0 57 Localisation 57 Medication-Related Osteonecrosis Occurring Outside the Oral Cavity 59 Osteonecrosis of the Jaw due to RANKL Inhibitor (Denosumab) Treatment 59 Conclusions 59 Acknowledgements 60 References 60 5: Epidemiology of Medication-­Related Osteonecrosis of the Jaw 63 Introduction 63 BRONJ Among Osteoporotic Patients on Oral Bisphosphonates 64 BRONJ Among Oncologic Patients on Intravenous Bisphosphonates 65 Osteonecrosis of the Jaw and New Antiresorptive Drugs (Denosumab) 67 Conclusion 67 References 67 6: Imaging Modalities and Characteristics in ­ Medication-Related Osteonecrosis of the Jaw 70 Introduction 70 Panoramic Radiographs 71 Radiologic Tomographic Techniques (CT, CBCT) 71 Magnetic Resonance Imaging (MRI) 76 Nuclear Medicine Imaging Techniques 81 Conclusions 82 References 82 7: Treatment of Medication-­Related Osteonecrosis of the Jaw 85 Conclusion 93 References 94 8: Local and Microvascular Free Flaps in Patients with Medication-Related Osteonecrosis of the Jaw 98 Local Flaps 99 Mucosal Flap 99 Buccal Mucosal Flap 100 Buccal Fat Pad Flap 100 Mylohyoid Flap 100 Nasolabial Flap 102 Microvascular Free Flaps 102 Radial Forearm Flap 102 Osteocutaneous Fibular Flap 103 Conclusion 104 References 105 9: Adjuvant Treatment Options in the Management of Medication-Related Osteonecrosis of the Jaw 107 Hyperbaric Oxygen Therapy 107 Ozone Therapy 108 Laser Therapy 109 Low-Level Laser Therapy (LLLT) 109 Mini-invasive Laser Surgery 110 Conclusions 111 References 112 10: New and Innovative Treatment Strategies for Medication-Related Osteonecrosis of the Jaw 114 Introduction 114 Cell-Based Therapy in Craniofacial Tissue Engineering 115 Experimental and Clinical Cell-­Based Therapy in Medication-Related Osteonecrosis of the Jaw 116 Growth Factors in Treatment of Medication-Related Osteonecrosis of the Jaw 119 Conclusion 120 References 120 11: Microbiology and Antibiotics in the Context of Medication-Related Osteonecrosis of the Jaw 123 Bacterial Infection and MRONJ 123 Regularly Observed Microbiological Findings 126 Actinomyces 126 Candida, Fungal Infection, and Principal Considerations 127 Antibiotic Therapy 127 Antibiotics Recommended 128 Mouth Rinses as Local Therapy 129 Side Effects of Antibiotic Therapies 130 Conclusion 130 References 130 12: Histopathology of Medication-Related Osteonecrosis of the Jaw 132 Introduction 132 Macroscopic Features 133 Histopathologic Features 133 Differential Histopathologic Diagnosis 134 Osteomyelitis 134 Osteoradionecrosis 134 Medication-Related Osteonecrosis of the Jaws 135 Conclusions 136 References 137 13: Pathogenesis of Medication-­Related Osteonecrosis of the Jaw 139 Theories Regarding the Pathogenesis of BRONJ/MRONJ 140 Effects of Local Inflammations and pH on BRONJ/MRONJ Pathogenesis 141 Experimental Data Supporting the Role of Local Inflammations and pH Changes in the Pathogenesis of BRONJ 143 Clinical Data Supporting the Role of Local Inflammations and pH Changes in the Pathogenesis of BRONJ 145 Osteonecrosis Due To RANKL-­Inhibitor and VEGF-Inhibitor Treatment 145 References 146 14: Risk Reduction of Medication-Related Osteonecrosis of the Jaw 149 Introduction 149 Risk-Reduction Strategies in Patients with Cancer 150 Before Commencement of Anti-­resorptive Therapy 150 After Commencement of Anti-­resorptive Therapy 150 Patients with Previous History of Exposure to Anti-resorptive Therapy 151 Other Risk-Reduction Strategies 151 Risk-Reduction Strategies in Patients with Osteoporosis 151 Conclusions 152 References 152 15: Animal Models of Medication-Related Osteonecrosis of the Jaw 154 Animal Models in Skeletal Biology 155 Large Animal Models of Osteonecrosis of the Jaw 155 Rodent Models of Osteonecrosis of the Jaw 160 Future Directions 163 References 164 16: Dental Rehabilitation in Patients Receiving Antiresorptive Drugs 167 How Does Oral Rehabilitation Affects Oral Health-Related Quality of Life? 167 How Does Oral Rehabilitation Affect MRONJ? 168 Prosthetic Techniques and Recommendations 170 How to Handle Sore Spots 173 MRONJ Caused by Sore Spots 173 Oral Rehabilitation After MRONJ Treatment 173 Temporary Prosthesis 174 Conclusion 175 References 175 17: Dental Implants in the Context Antiresorptive Drugs and Medication-Related Osteonecrosis of the Jaw 177 Introduction 177 Implants, Bisphosphonates, and MRONJ 177 Implants as a Trigger for MRONJ 178 Bisphosphonates as a Risk Factor in Implantology 178 Implant-Associated Infections in Bisphosphonate Medication Versus Common Periimplantitis 182 Implants in Rehabilitation After MRONJ 182 Excursus: Antiresorptive Coatings of Dental Implants 184 Indicating Dental Implants in Patients with Bisphosphonate Therapy 185 Conclusion 188 References 188 18: Osteonecrosis of the Jaw in Association with Targeted Therapy 191 Introduction 191 Denosumab 192 Bevacizumab 193 Sunitinib 194 Everolimus 195 Conclusion 196 References 196 19: History of Osteonecrosis of the Jaw 199 Introduction 199 Phosphorous Necrosis and Match Making 200 Phosphorous Necrosis and Clinical Observation 200 History of Prevention and Precaution of Phosphorous Necrosis 201 The Berne Convention 202 After the Berne Ban 202 Phosphorous Necrosis and Bisphosphonate-Related Osteonecrosis of the Jaw 203 References 203 20: Future Perspectives of Bisphosphonates in Maxillofacial, Dental, and Medical Practice 204 Introduction 204 Perspectives of Bisphosphonates in Dentistry 205 Anticalculus and Anticaries Effects 205 Dental Implant Coating 205 Socket Preservation 206 Periodontitis 206 Bisphosphonates and Periimplantitis 207 Potential Applications in Other Diseases of the Maxillofacial Region 207 Additional Applications for Bisphosphonates 207 Conclusion 207 References 208 Index 213 Front Matter....Pages i-viii Pharmacological Aspects of Antiresorptive Drugs: Bisphosphonates and Denosumab....Pages 1-15 Bisphosphonate and Denosumab Therapy: Fields of Application....Pages 17-26 Risk Factors for Medication-Related Osteonecrosis of the Jaw....Pages 27-42 Definition, Clinical Features and Staging of Medication-Related Osteonecrosis of the Jaw....Pages 43-54 Epidemiology of Medication-Related Osteonecrosis of the Jaw....Pages 55-61 Imaging Modalities and Characteristics in Medication-Related Osteonecrosis of the Jaw....Pages 63-77 Treatment of Medication-Related Osteonecrosis of the Jaw....Pages 79-91 Local and Microvascular Free Flaps in Patients with Medication-Related Osteonecrosis of the Jaw....Pages 93-101 Adjuvant Treatment Options in the Management of Medication-Related Osteonecrosis of the Jaw....Pages 103-109 New and Innovative Treatment Strategies for Medication-Related Osteonecrosis of the Jaw....Pages 111-119 Microbiology and Antibiotics in the Context of Medication-Related Osteonecrosis of the Jaw....Pages 121-129 Histopathology of Medication-Related Osteonecrosis of the Jaw....Pages 131-137 Pathogenesis of Medication-Related Osteonecrosis of the Jaw....Pages 139-148 Risk Reduction of Medication-Related Osteonecrosis of the Jaw....Pages 149-153 Animal Models of Medication-Related Osteonecrosis of the Jaw....Pages 155-167 Dental Rehabilitation in Patients Receiving Antiresorptive Drugs....Pages 169-178 Dental Implants in the Context Antiresorptive Drugs and Medication-Related Osteonecrosis of the Jaw....Pages 179-192 Osteonecrosis of the Jaw in Association with Targeted Therapy....Pages 193-200 History of Osteonecrosis of the Jaw....Pages 201-205 Future Perspectives of Bisphosphonates in Maxillofacial, Dental, and Medical Practice....Pages 207-215 Back Matter....Pages 217-220