**MRONJ, ORN** David Power, OMS 2 Registrar #### Clinical Overview This presentation covers the critical aspects of Medication-Related Osteonecrosis of the Jaws (MRONJ) and Osteoradionecrosis (ORN), presented by David Power, OMS 2 Registrar. # OUTLINE * **MRONJ** * Causes * Pathophysiology * Risk factors * Treatment goals/options * **ORN** * Prevention * Treatment  #### Presentation Outline 1. **Medication-Related Osteonecrosis of the Jaws (MRONJ)** - Primary causes and pharmacological triggers - Underlying pathophysiology - Identification of patient risk factors - Established treatment goals and clinical options 2. **Osteoradionecrosis (ORN)** - Prevention strategies for patients undergoing radiation therapy - Current treatment modalities A rectangular white box with a black border containing the word "OUTLINE" in bold, black, uppercase letters, centered within the box. **American Association of Oral and Maxillofacial Surgeons’ Position Paper on Medication-Related Osteonecrosis of the Jaws—2022 Update** *Salvatore L. Ruggiero, DMD, MD, $\ddagger$ Thomas B. Dodson, DMD, MPH, $\dagger$* *Tara Aghaloo, DDS, MD, PhD, $\dagger$ Eric R. Carlson, DMD, MD, EdM, $\S$* *Brent B. Ward, DDS, MD, $\|$ and **Deepak Kademani, DMD, MD** $\boldsymbol{\text{\S}}$* American Association of Oral and Maxillofacial Surgeons’ Position Paper on Medication-Related Osteonecrosis of the Jaws—2022 Update Salvatore L. Ruggiero, DMD, MD; Thomas B. Dodson, DMD, MPH; Tara Aghaloo, DDS, MD, PhD; Eric R. Carlson, DMD, MD, EdM; Brent B. Ward, DDS, MD; and Deepak Kademani, DMD, MD   A panoramic X-ray image of a human skull showing dental structures, with visible teeth, jawbones, and surrounding bone density. The image includes labels 'R' and 'L' indicating right and left sides, and appears to be a medical radiographic study. A 3D reconstructed CT scan of a human skull, highlighting the cranial structure and dental implants. The image shows detailed bone anatomy with visible dental work and surrounding tissue, likely used for surgical planning or diagnostic purposes. # **WHAT IS MRONJ** * **(1) A breach in oral mucosa leading to exposed bone (or** bone that can be probed through intra/extraoral fistula) that fails to heal in 8 weeks in someone with a **(2)** history of receiving antiresorptive therapy and **(3) no** previous head and neck radiation #### Clinical Criteria for Diagnosis Medication-Related Osteonecrosis of the Jaws (MRONJ) is defined by the following three criteria: 1. A breach in oral mucosa leading to exposed bone (or bone that can be probed through an intraoral or extraoral fistula) that fails to heal within 8 weeks. 2. A history of receiving antiresorptive therapy. 3. No history of previous head and neck radiation. | Stages of MRONJ (AAOMS) | Exposed or necrotic bone | History and clinical findings | Notani et. al classification for ORNJ | Clinical features | |---|---|---|---|---| | **Stage 0** | No clinical evidence | Non-specific clinical and radiographic findings | Type I | ORNJ confined to dentoalveolar bone | | **Stage 1** | Exposed and necrotic bone, or fistulae that probes to bone | Asymptomatic with no evidence of infection | Type II | ORNJ limited to dentoalveolar bone or mandible above the inferior canal or both | | **Stage 2** | Exposed and necrotic bone, or fistulae that probes to bone | Associated with infection, Pain and erythema in the region of the exposed bone with or without purulent drainage | Type III | ORNJ involving the mandible below the inferior dental canal or pathological fracture or skin fistula | | **Stage 3** | Exposed and necrotic bone, or fistulae that probes to bone | Pain, infection, and one or more of the following: <ul><li>Exposed necrotic bone extending beyond the alveolar bone region resulting in pathological fracture</li><li>Extraoral fistula, oro-antral or oro-nasal communication</li><li>Lytic changes extending to the lower border of the mandible or sinus floor</li></ul> | Epstein et. al classification for ORNJ | Clinical features | | | | | **Type I** | Resolved, healed; a. No pathologic fracture, b. Pathologic fracture | | | | | **Type II** | Chronic persistent (nonprogressive); a. No pathologic fracture, b. Pathologic fracture | | | | | **Type III** | Active progressive; a. No pathologic fracture, b. Pathologic fracture |  #### AAOMS Staging of MRONJ - **Stage 0** - **Exposed or necrotic bone:** No clinical evidence. - **Clinical findings:** Non-specific clinical and radiographic findings. - **Stage 1** - **Exposed or necrotic bone:** Exposed and necrotic bone, or fistulae that probes to bone. - **Clinical findings:** Asymptomatic with no evidence of infection. - **Stage 2** - **Exposed or necrotic bone:** Exposed and necrotic bone, or fistulae that probes to bone. - **Clinical findings:** Associated with infection, pain, and erythema in the region of the exposed bone with or without purulent drainage. - **Stage 3** - **Exposed or necrotic bone:** Exposed and necrotic bone, or fistulae that probes to bone. - **Clinical findings:** Pain, infection, and one or more of the following: - Exposed necrotic bone extending beyond the alveolar bone region resulting in pathological fracture. - Extraoral fistula, oro-antral or oro-nasal communication. - Lytic changes extending to the lower border of the mandible or sinus floor. #### Comparative Classifications for Osteoradionecrosis (ORNJ) **Notani et al. Classification:** - **Type I:** ORNJ confined to dentoalveolar bone. - **Type II:** ORNJ limited to dentoalveolar bone or mandible above the inferior canal or both. - **Type III:** ORNJ involving the mandible below the inferior dental canal or pathological fracture or skin fistula. **Epstein et al. Classification:** - **Type I:** Resolved, healed (a. No pathologic fracture; b. Pathologic fracture). - **Type II:** Chronic persistent (nonprogressive) (a. No pathologic fracture; b. Pathologic fracture). - **Type III:** Active progressive (a. No pathologic fracture; b. Pathologic fracture). A comprehensive table comparing the staging of MRONJ (AAOMS) with clinical features, exposed or necrotic bone findings, history and clinical findings, and classifications by Notani et al. and Epstein et al. for ORNJ. The table details stages 0 to 3 of MRONJ, including symptoms like pain, infection, and pathological fractures, and classifies ORNJ into types I, II, and III based on resolution and progression. CAUSALITY * Well-known that MRONJ is rare, multifactorial, and patients exist with same clinical presentation and no exposure to antiresorptive medication * Can be linked to infections, trauma, smoking, steroids, autoimmune disease, diabetes, chemotherapy * Many patients receiving antiresorptives have other comorbidities, which are likely exacerbating or contributing factors * Definitive causality remains difficult task to prove + many confounding variables make incidence and prevalence difficult to estimate #### Multifactorial Nature of MRONJ - MRONJ is rare and multifactorial; patients may present with the same clinical symptoms without exposure to antiresorptive medication. - Potential links include infections, trauma, smoking, steroids, autoimmune disease, diabetes, and chemotherapy. - Many patients receiving antiresorptives have other comorbidities that likely act as exacerbating or contributing factors. - Proving definitive causality remains difficult due to numerous confounding variables, making incidence and prevalence estimates challenging. **BISPHOSPHONATES** * Pyrophosphate analogues * **Indications:** * Prevention and treatment of postmenopausal and steroid-induced osteoporosis * Paget's diseases of bone * Hypercalcaemia of malignancy, multiple myeloma * Bony metastases (e.g. breast, prostate, lung) * Potential to improve cancer-specific survival controversial, but significant positive effect on QOL #### Characteristics and Indications Bisphosphonates are pyrophosphate analogues used for: - Prevention and treatment of postmenopausal and steroid-induced osteoporosis. - Paget's disease of bone. - Hypercalcaemia of malignancy and multiple myeloma. - Bony metastases (e.g., breast, prostate, lung). - Improving quality of life (QOL), though their effect on cancer-specific survival remains controversial. **BISPHOSPHONATES MECHANISM** * Pyrophosphate analogues that bind to hydroxyapatite binding sites on surface of bone tissue, subsequent uptake by osteoclasts impairs bone resorption ability * Non-nitrogen-containing bisphosphonates * Etidronate, tiludronate * Metabolised intracellularly and inhibit ATP-dependent enzymes, resulting in osteoclast apoptosis * Nitrogen-containing (more potent) * Alendronate, risedronate (oral), pamidronate, ibandronate, zoledronic acid (parentally) * Binds and blocks enzyme (farnesyl pyrophosphate synthase) needed for attaching osteoclast to bone surface = osteoclast detaches, impairs bone resorption #### Mechanism of Action Bisphosphonates bind to hydroxyapatite binding sites on the bone surface. Subsequent uptake by osteoclasts impairs bone resorption. - **Non-nitrogen-containing bisphosphonates** (e.g., Etidronate, tiludronate): - Metabolized intracellularly to inhibit ATP-dependent enzymes, resulting in osteoclast apoptosis. - **Nitrogen-containing bisphosphonates** (e.g., Alendronate, risedronate, pamidronate, ibandronate, zoledronic acid): - More potent; they bind and block the enzyme farnesyl pyrophosphate synthase. - This prevents the attachment of osteoclasts to the bone surface, causing them to detach and impairing resorption. **ADVERSE EFFECTS** * Hypocalcaemia and hypophosphatemia (usually transient and mild) * ONJ * Atypical fractures (particularly of the femur) * MSK pain * AF * Renal impairment * Ocular inflammation and visual disturbances * Oral bisphosphonates * Oesophageal inflammation: Swallow with water and maintain upright for 30 mins * IV bisphosphonates * Acute-phase reaction with flulike symptoms 24-72 hours after administration #### Adverse Effects - **General Effects:** - Hypocalcaemia and hypophosphatemia (usually transient and mild). - Osteonecrosis of the Jaw (ONJ). - Atypical fractures (particularly of the femur). - Musculoskeletal (MSK) pain. - Atrial Fibrillation (AF). - Renal impairment. - Ocular inflammation and visual disturbances. - **Route-Specific Effects:** - **Oral bisphosphonates:** Oesophageal inflammation (patients should swallow with water and remain upright for 30 minutes). - **IV bisphosphonates:** Acute-phase reaction with flu-like symptoms 24-72 hours post-administration. <div style="text-align: center;"> <div style="border: 2px solid black; padding: 10px; display: inline-block;"> DENOSUMAB </div> </div> <br> <ul> <li>RANK ligand inhibitor</li> <li>Monoclonal antibody against RANK ligand (RANK-L - a receptor activator of nuclear factor kappa B ligand; a ligand of osteoclast receptors)</li> <ul> <li>Reversibly inhibits bone resorption by reducing osteoclast formation and differentiation and increasing apoptosis</li> <li>Targets the RANKL by mimicking osteoprotegerin</li> <li>In contrast to BPs, RANKL inhibitors do not bind to bone - effects on bone remodeling are mostly diminished within 6 months of cessation</li> </ul> <li>Indications:</li> <ul> <li>Significant reduction in risk of vertebral, nonvertebral and hip fractures in osteoporotic patients when SC 6 monthly</li> <li>Effective in reducing skeletal-related events related to metastatic bone disease from solid tumours when administered monthly</li> <li>Also proven efficacy in treatment of giant cell tumours and fibrous dysplasia</li> </ul> </ul> #### Mechanism of Action Denosumab is a monoclonal antibody and RANK ligand (RANKL) inhibitor: - It targets RANKL (receptor activator of nuclear factor kappa B ligand) by mimicking osteoprotegerin. - It reversibly inhibits bone resorption by reducing osteoclast formation and differentiation and increasing apoptosis. - Unlike bisphosphonates, RANKL inhibitors do not bind to bone; effects on bone remodeling typically diminish within 6 months of cessation. #### Indications - Significant reduction in fracture risk (vertebral, nonvertebral, hip) in osteoporotic patients when administered subcutaneously every 6 months. - Reduction of skeletal-related events in metastatic bone disease from solid tumors when administered monthly. - Proven efficacy in treating giant cell tumors and fibrous dysplasia. # BONE CELLS - OSTEOBLASTS * Derived from mesenchymal osteoprogenitor (stem) cells located under the periosteum in the developing bone, and in medullary space later in life * Secrete osteoid to form an extracellular organic matrix on which hydroxyapatite crystals deposit + regulate its mineralisation * As bone-forming activity nears completion, some osteoblasts become enclosed in lacunae as osteocytes * RANKL * Expressed on osteoblasts and marrow stromal cells * Binds to receptor RANK (receptor for activation of nuclear factor kappa B) on macrophages (osteoclast precursor) * RANKL + RANK activates transcription factor NF-kB essential for * Differentiation osteoclasts * Suppression of osteoclast apoptosis (so they survive) * Osteoprotegerin * Secreted by osteoblasts * Soluble, high-affinity decoy ligand for RANKL, which restricts osteoclast differentiation * Express receptors for PTH, calcitriol and other promoters of bone resorption * Osteoblasts promote osteoclast differentiation via PTH-activated expression of cell surface RANKL - binds to RANK on immature osteoclasts and triggers differentiation - and downregulate osteoprotegerin #### Osteoblasts - **Origin:** Derived from mesenchymal osteoprogenitor (stem) cells located under the periosteum and in medullary spaces. - **Function:** Secrete osteoid to form the organic matrix for hydroxyapatite deposition and regulate mineralization. - **Transition:** Some osteoblasts become enclosed in lacunae as osteocytes upon completion of bone formation. - **RANKL Expression:** - Expressed on osteoblasts and marrow stromal cells. - Binds to RANK receptors on macrophages (osteoclast precursors) to activate NF-kB, essential for osteoclast differentiation and survival. - **Osteoprotegerin (OPG):** - Secreted by osteoblasts as a high-affinity decoy ligand for RANKL, restricting osteoclast differentiation. - Osteoblasts regulate resorption via PTH-activated expression of RANKL and downregulation of OPG. # OSTEOCYTES * Major cell type of mature bone, distributed throughout matrix and interconnected by dendritic processes to form a complex network * Derived from osteoblasts that have become enclosed within the rigid matrix * Help to control calcium and phosphate levels, detect mechanical forces, and translate them into biologic activity (mechanotransduction) * Secretes RANKL to activate osteoclasts * Produces Sclerostin which inhibits osteoblasts #### Characteristics and Functions - Major cell type of mature bone, distributed throughout the matrix and interconnected by dendritic processes. - Derived from osteoblasts enclosed within the rigid matrix. - **Mechanotransduction:** Detect mechanical forces and translate them into biologic activity. - **Regulation:** Help control calcium and phosphate levels. - **Signaling:** - Secretes RANKL to activate osteoclasts. - Produces Sclerostin, which inhibits osteoblasts. # **OSTEOCLASTS** * Large, specialised multinucleated macrophages located on the surface of bone * Responsible for structural changes - decalcify and remove bones - resorb bone * Differentiate from myeloid stem cells via macrophage-colony-forming units * Regulated by macrophage-colony stimulating factor (secreted by osteoblasts), and RANKL (expressed by osteoblasts) * Responsible for the local removal of bone during growth and remodelling * Dissolve bone minerals by secreting acid and neutral proteases (predominantly matrix metalloproteases) * Stimulated to resorb bone by signals from local cells (osteoblasts, macrophages, lymphocytes) and PTH, calcitriol * Calcitonin, produced by C cells of thyroid, reduce osteoclast activity #### Characteristics and Functions - Large, specialized multinucleated macrophages located on the bone surface. - **Bone Resorption:** Responsible for decalcifying and removing bone during growth and remodeling. - **Differentiation:** Develop from myeloid stem cells via macrophage-colony-forming units, regulated by M-CSF and RANKL (secreted/expressed by osteoblasts). - **Mechanism:** Dissolve bone minerals by secreting acid and neutral proteases (predominantly matrix metalloproteases). - **Regulation:** Stimulated by signals from osteoblasts, macrophages, lymphocytes, PTH, and calcitriol. Calcitonin reduces osteoclast activity. <table> <tr> <td colspan="2" rowspan="3"> <p>Osteoblasts and<br>their precursors</p> </td> </tr> <tr> <td>(secrete)</td> <td>(secrete)</td> </tr> <tr> <td> <p><strong>RANK ligand<br>(RANKL)</strong></p> </td> <td> <p><strong>Osteoprotegerin<br>(OPG)</strong></p> </td> </tr> <tr> <td colspan="2"> <p>---></p> </td> <td> <p>-------></p> </td> </tr> <tr> <td colspan="2" rowspan="2"> <p><strong>Macrophages/<br>osteoclasts</strong></p><p>RANK</p> </td> <td> <p>RANKL bound<br>to OPG not<br>available to<br>bind with RANK</p> </td> </tr> <tr> <td> <p>↓</p> </td> </tr> <tr> <td rowspan="3"> <p>(triggered by<br>binding of<br>RANKL and RANK)</p> </td> <td> <p>Differentiation<br>of macrophages<br>into osteoclasts</p> </td> <td rowspan="3"> <p>Blocks action<br>of RANK</p> </td> </tr> <tr> <td> <p>Suppression<br>of osteoclast<br>apoptosis</p> </td> </tr> <tr> <td> <p>↓</p> </td> <td> <p>↓</p> </td> </tr> <tr> <td colspan="2"> <p>↑ Osteoclast<br>action</p> </td> <td rowspan="3"> <p>↑ Osteoclast<br>action</p> </td> </tr> <tr> <td colspan="2"> <p>Osteoclast action<br>outpaces<br>osteoblast action</p> </td> <td> <p>Osteoblast action<br>outpaces<br>osteoclast action</p> </td> </tr> <tr> <td colspan="2"> <p>↓</p> </td> <td> <p>↓</p> </td> </tr> <tr> <td colspan="2"> <p>↓ Bone mass</p> </td> <td> <p>↑ Bone mass</p> </td> </tr> <tr> <td colspan="3"> <p>● **FIGURE 19-22 Role of osteoblasts in governing osteoclast**<br>**development and activity.**</p> </td> </tr> </table>  #### Role of Osteoblasts in Governing Osteoclast Activity - **RANKL Pathway:** Osteoblasts and their precursors secrete RANK ligand (RANKL), which binds to RANK on macrophages/osteoclasts. This triggers differentiation and suppresses apoptosis, leading to increased osteoclast action and decreased bone mass. - **OPG Pathway:** Osteoblasts also secrete Osteoprotegerin (OPG), which acts as a decoy. RANKL bound to OPG is unavailable to bind with RANK. This blocks RANK action, allowing osteoblast activity to outpace osteoclast activity, leading to increased bone mass. This diagram illustrates the role of osteoblasts in governing osteoclast development and activity. It shows that osteoblasts secrete RANK ligand (RANKL), which promotes osteoclast differentiation and activity, leading to decreased bone mass. Conversely, osteoblasts also secrete osteoprotegerin (OPG), which binds to RANKL and prevents it from activating RANK on osteoclasts, thereby inhibiting osteoclast activity and promoting increased bone mass. **DENOSUMAB (AGAIN)** * **RANK ligand inhibitor** * **Monoclonal antibody against RANK ligand (RANK-L - a receptor activator of nuclear factor kappa B ligand; a ligand of osteoclast receptors)** * Reversibly inhibits bone resorption by reducing osteoclast formation and differentiation and increasing apoptosis * Targets the RANKL by mimicking osteoprotegerin * In contrast to BPs, RANKL inhibitors do not bind to bone - effects on bone remodeling are mostly diminished within 6 months of cessation * **Indications:** * Significant reduction in risk of vertebral, nonvertebral and hip fractures in osteoporotic patients when SC 6 monthly * Effective in reducing skeletal-related events related to metastatic bone disease from solid tumours when administered monthly * Also proven efficacy in treatment of giant cell tumours and fibrous dysplasia #### Summary of Denosumab Characteristics - **Mechanism:** Reversibly inhibits bone resorption by targeting RANKL; effects diminish within 6 months of cessation as it does not bind to bone. - **Indications:** - Osteoporosis (6-monthly SC). - Metastatic bone disease (monthly). - Giant cell tumors and fibrous dysplasia. # **MRONJ PATHOPHYSIOLOGY** Multifactorial process, and likely that multiple hypotheses can explain overall pathophysiology * **Bone Remodelling Inhibition** * **Inflammation or Infection** * **Angiogenesis Inhibition** * **Innate or Acquired Immune Dysfunction** * **Genetic Factors**  #### Pathophysiology Hypotheses MRONJ is a multifactorial process likely explained by several overlapping mechanisms: - Bone Remodelling Inhibition - Inflammation or Infection - Angiogenesis Inhibition - Innate or Acquired Immune Dysfunction - Genetic Factors A yellow rectangular box with the text "MRONJ PATHOPHYSIOLOGY" in bold black letters, serving as a title for the slide. # BONE REMODELING INHIBITION * Leading hypothesis * Antiresorptive medications have direct effects on osteoclast formation, differentiation or function * Animal jaws demonstrate absent osteoclasts around alveolar bone of DMB-treated mice * Human bone specimens show increased number of non-functional osteoclasts surrounding necrotic bone in BP-treated patients * Animal studies evaluating withdrawal of BPs or DMB further highlight importance of remodelling in MRONJ prevention and resolution * Rodents with established ONJ failed to resolve when antiresorptives were withdrawn * BUT discontinuing DMB (not BPs) prior to extraction successfully prevented MRONJ development in rats #### Impact of Antiresorptives - This is the leading hypothesis for MRONJ pathophysiology. - Antiresorptive medications directly affect osteoclast formation, differentiation, and function. - **Evidence:** - Animal models show absent osteoclasts in alveolar bone following treatment. - Human specimens show non-functional osteoclasts surrounding necrotic bone in bisphosphonate (BP) treated patients. - **Drug Withdrawal Studies:** - Established ONJ in rodents did not resolve upon withdrawal of antiresorptives. - However, discontinuing Denosumab (but not BPs) prior to extraction successfully prevented MRONJ development in rats. **INFLAMMATION OR INFECTION** * Most studies report tooth extraction as major inciting event for MRONJ, but is clear that most had pre-existing periodontal or periapical disease * Presence of inflammatory cytokines at site of MRONJ support strong role of inflammation * Evidence of increased systemic inflammation and its contribution to MRONJ - mice with experimentally-induced RA had more severe MRONJ with increased bone resorption, more pronounced radiographic features, intense local inflammatory infiltrate, and larger areas of histologic necrosis * Presence of bacteria on exposed necrotic bone also contributes to disease severity * Poor OH and biofilm presence associated with MRONJ development, and OH maintenance and dental prophylaxis before initiating antiresorptive therapy can decrease MRONJ prevalence * Clinical treatment protocols to reduce biofilm and eradicate infection have emerged as important alternatives to debridement and resection #### Role of Dental Disease and Biofilm - Tooth extraction is the major inciting event, but most cases involve pre-existing periodontal or periapical disease. - Inflammatory cytokines at MRONJ sites support the role of inflammation. - **Systemic Factors:** Mice with induced Rheumatoid Arthritis (RA) showed more severe MRONJ features (increased bone resorption and necrosis). - **Bacterial Contribution:** - Bacteria on exposed necrotic bone contribute to disease severity. - Poor oral hygiene and biofilm presence are associated with MRONJ development. - Dental prophylaxis before initiating therapy can decrease prevalence. Clinical protocols focusing on biofilm reduction are important alternatives to surgical debridement. # ANGIOGENESIS INHIBITION * BPs such as zoledronic acid directly inhibit angiogenesis in vitro and in vivo, and animal models demonstrate decreased vascularity in sites of MRONJ and decreased microvessel numbers during early stages of healing * BPs also inhibit angiogenesis normally seen during healing of sockets * Both BPs and DMB shown to decrease arterial area, venous area, and overall vascularity of periodontal tissues during early and late MRONJ development * Antioangiogenic medications (VEGF inhibitors, tyrosine kinase inhibitors, immunomodulatory drugs) associated with MRONJ (much lower incidence than ARs) * MM patients on both antiresorptive and antiangiogenic medications have a higher MRONJ prevalence #### Vascular Impact - Bisphosphonates (e.g., zoledronic acid) inhibit angiogenesis in vitro and in vivo. - Animal models show decreased vascularity and microvessel numbers at MRONJ sites and during socket healing. - Both BPs and Denosumab decrease arterial and venous area in periodontal tissues. - **Antiangiogenic Medications:** VEGF inhibitors, tyrosine kinase inhibitors, and immunomodulatory drugs are associated with MRONJ (though at a lower incidence than antiresorptives). - **Combination Therapy:** Multiple Myeloma (MM) patients on both antiresorptive and antiangiogenic medications show a higher MRONJ prevalence. **INNATE OR ACQUIRED IMMUNE DYSFUNCTION** * Well-known that patients with medical comorbidities (diabetes, RA, immunocompromised state) at significantly higher risk of MRONJ with or without exposure to antiresorptive agents * Replenishing area of nonhealing MRONJ lesions with mesenchymal stem cells to overcome immune dysfunction is potential area of therapeutic interest * Preclinical studies demonstration healing or prevention of MRONJ lesions after systemic infusion with adipose or bone marrow-derived MSC #### Comorbidities and Therapeutic Interests - Patients with diabetes, RA, or immunocompromised states are at significantly higher risk for MRONJ. - **Mesenchymal Stem Cells (MSCs):** There is therapeutic interest in using MSCs to overcome immune dysfunction. Preclinical studies show healing or prevention of MRONJ lesions after systemic infusion of adipose or bone marrow-derived MSCs. **GENETIC FACTORS** * Increasing evidence supporting role of single-nucleotide polymorphisms associated with MRONJ * Located within gene associated with either bone turnover, collagen formation or metabolic bone diseases * Other genes reported to increase MRONJ risk through their role in angiogenesis, bone remodelling and immune responses e.g. PPAR gamma, CYP2C8 and others * Overall, current studies document either a weak or no association between genetic factors measured and risk for MRONJ #### Single-Nucleotide Polymorphisms (SNPs) - Evidence suggests a role for SNPs in genes associated with bone turnover, collagen formation, or metabolic bone diseases. - Other implicated genes involve angiogenesis and immune response (e.g., PPAR gamma, CYP2C8). - **Current Consensus:** Most studies document a weak or no association between measured genetic factors and MRONJ risk. <div style="background-color: yellow; border: 1px solid black; padding: 10px;"> <h1 style="text-align: center;">RISK FACTORS</h1> </div> * Medication-related * Cancer patients * Osteoporosis patients * Non-malignant bone disease * Local factors * Demographic and systemic factors  #### Overview of Risk Categories - **Medication-related factors:** (Cancer, Osteoporosis, and Non-malignant bone disease patients) - **Local factors** - **Demographic and systemic factors** A yellow rectangular box with the title 'RISK FACTORS' in bold black text, serving as a heading for a list of risk factors below it. **MEDICATION-RELATED** **– CANCER PATIENTS** * Risk of MRONJ is higher in malignancy group (<5%) compared to osteoporosis group (<0.05%) * MRONJ risk among cancer patients * Risk of MRONJ among cancer patients exposed to **zoledronate** clusters <5%, ranges from 0-18% (may be explained by varying durations of follow-up) * 2-10 times higher than cancer patients treated with placebo * Risk of MRONJ with **denosumab** ranges from 0-6.9% with most studies <5% * Risk is comparable to **zoledronate** * Numerous other families of medications implicated as risk factors but evidence is level 5 (isolated case reports, mini case series) - identifying single medication as being aetiologic agent for MRONJ unlikely * TKIs (sunitinib), monoclonal antibodies (bevacizumab), fusion proteins (aflibercept), mTOR inhibitors (everolimus), selective oestrogen receptor modulators (raloxifene), immunosuppressants (methotrexate and corticosteroids) #### Risk in Oncology Patients - **General Risk:** MRONJ risk is higher in the malignancy group (<5%) compared to the osteoporosis group (<0.05%). - **Zoledronate:** Risk clusters <5% (range 0-18%), which is 2-10 times higher than placebo. - **Denosumab:** Risk ranges from 0-6.9% (most studies <5%), comparable to zoledronate. - **Other Medications:** Level 5 evidence (case reports) implicates other drugs, though a single etiologic agent is unlikely: - Tyrosine Kinase Inhibitors (sunitinib) - Monoclonal antibodies (bevacizumab) - Fusion proteins (aflibercept) - mTOR inhibitors (everolimus) - Selective oestrogen receptor modulators (raloxifene) - Immunosuppressants (methotrexate and corticosteroids) **MEDICATION-RELATED** **– OSTEOPOROSIS PATIENTS** * **Bisphosphonates** * Osteoporosis clinical trials - placebo = 0-0.2%; BPs = 0.02-0.05% * IV zoledronate risk <0.02% (e.g. 2 per 10,000) * Oral bisphosphonates risk <0.05% * **RANK-L inhibitors** * Denosumab - risk reported to be 0.3% (range 0.04-0.3) after 10 years of follow-up (significantly higher than BPs) * Romosuzumab (0.03-0.05%) comparable to aledronate (0.05%) - additional research needed to refine association and risk estimate for MRONJ #### Risk Estimates - **Bisphosphonates:** - Clinical trials: 0.02-0.05% (Placebo: 0-0.2%). - IV Zoledronate: <0.02% (approx. 2 per 10,000). - Oral Bisphosphonates: <0.05%. - **RANK-L Inhibitors:** - Denosumab: Reported at 0.3% (range 0.04-0.3) after 10 years of follow-up, which is significantly higher than BPs. - Romosuzumab: 0.03-0.05%, comparable to alendronate. **NON-MALIGNANT BONE DISEASE** * DMB for management of aggressive giant cell tumours * Risk of MRONJ in two studies ranged from 0.7-5% * Comparable to risk of MRONJ in DMB for malignancies (0-6.9%) * Very limited data for MRONJ in paediatric population for osteogenesis imperfecta * One SR of 486 subjects found no cases of MRONJ (small sample sizes) #### Giant Cell Tumors and Pediatric Data - **Giant Cell Tumors:** Denosumab treatment carries a risk of 0.7-5%, comparable to malignancy risks. - **Pediatric Population:** Very limited data regarding osteogenesis imperfecta. One systematic review of 486 subjects found no cases of MRONJ, though sample sizes were small. DURATION OF THERAPY • Duration of therapy • Recent SR by Ng et al, risk of MRONJ among cancer patients treated with zoledronate was 1.6-4% after 2 years, and 3.8 to 18% >2 years • DMB risk was 1.9% <2 years, and 6.9% >2 years of exposure #### Cumulative Exposure Risk - **Zoledronate (Cancer patients):** Risk is 1.6-4% after 2 years, increasing to 3.8-18% after more than 2 years. - **Denosumab:** Risk is 1.9% at <2 years, increasing to 6.9% after more than 2 years of exposure. <div style="background-color: #f0f0f0; padding: 20px;"> <div style="background-color: yellow; border: 1px solid black; text-align: center; padding: 10px;"> <strong style="font-size: 1.5em;">RISK FACTORS</strong> </div> <ul> <li>Medication-related <ul> <li>Cancer patients</li> <li>Osteoporosis patients</li> <li>Non-malignant bone disease</li> </ul> </li> <li>Local factors <ul> <li>Dento-alveolar operations</li> <li>Anatomic factors</li> <li>Concomitant oral disease</li> </ul> </li> <li>Demographic and systemic factors</li> </ul> </div>  #### Summary of Risk Factors - **Medication-related:** Cancer, osteoporosis, and non-malignant bone disease. - **Local factors:** Dento-alveolar operations, anatomic factors, and concomitant oral disease. - **Demographic and systemic factors.** A bright yellow rectangular box with the text 'RISK FACTORS' in bold, black capital letters, serving as a title for the content below. The box is positioned at the top of the slide, above a bulleted list of risk factors categorized into medication-related, local, and demographic/systemic factors. # **LOCAL FACTORS** # **- DENTO-ALVEOLAR OPERATIONS** * Most common identifiably predisposing factor for MRONJ * Tooth extraction cited as predisposing event in 62-82% of patients with MRONJ * **Current estimates for risk of MRONJ post exo** * Osteoporotic patients exposed to BPs 0-0.15%, DMB 1% * Cancer patients exposed to BPs 1.6-14.8% - cluster between 1 and 5%, similar to estimates of ORN following extraction in irradiated patients * Risk of MRONJ for other dentoalveolar operations such as implant placement and endo or perio procedures is unknown * AAOMS cautions these procedures in cancer patients exposed to ARs and recommends osteoporosis patients be informed of potential risks, albeit low, including MRONJ, early and late implant failure (described in case reports and clinical trials) * Early = implant surgery-triggered * Late = implant presence-triggered * Reviews show majority of implant-related necrosis were late and often at sites of implants placed prior to BPs - common presentation was an en bloc failure where osseointegration of implant is maintained within sequestrum #### Dento-alveolar Operations - **Tooth Extraction:** The most common predisposing factor, cited in 62-82% of MRONJ cases. - **Risk Post-Extraction:** - Osteoporotic patients: BPs (0-0.15%), Denosumab (1%). - Cancer patients: BPs (1.6-14.8%), similar to ORN risk in irradiated patients. - **Implants and Other Procedures:** - Risk for implants, endodontic, or periodontal procedures is unknown. - AAOMS recommends caution in cancer patients and informing osteoporosis patients of low risks for MRONJ and implant failure. - **Implant Failure Types:** - Early: Triggered by surgery. - Late: Triggered by the presence of the implant; often presents as "en bloc" failure where the implant is maintained within a sequestrum. LOCAL FACTORS - ANATOMIC FACTORS * More likely to appear in the mandible (75%) than maxilla (25%) but can appear in both (4.5%) * Denture use associated with increased risk for MRONJ among cancer patients exposed to zoledronate #### Site and Appliance Factors - **Location:** More common in the mandible (75%) than the maxilla (25%); both sites are involved in 4.5% of cases. - **Denture Use:** Associated with increased MRONJ risk among cancer patients exposed to zoledronate. **LOCAL FACTORS** **- CONCOMITANT ORAL DISEASE** * Pre-existing inflammatory dental disease (perio/periapical pathology) cited as a significant risk factor * Among cancer patients with MRONJ, pre-existing dental disease was a risk factor among 50% * Given common treatment is extraction, pre-existing disease may confound the relationship between exo and risk for MRONJ (did it expose it or was it the precipitating event) #### Pre-existing Conditions - Inflammatory dental diseases (periodontal or periapical pathology) are significant risk factors. - Among cancer patients with MRONJ, pre-existing dental disease was present in 50% of cases. - Pre-existing disease may confound the relationship between extraction and MRONJ (i.e., whether the extraction caused the condition or simply exposed a pre-existing necrotic site). **DEMOGRAPHIC/SYSTEMIC FACTORS** * **Sex** * Higher prevalence in females - likely reflection of underlying disease for which agents prescribed for e.g. osteoporosis, breast cancer * **Age** * <24 treated with ARs for benign bone disease have not demonstrated any risk for MRONJ after extended duration of therapy * SR studies had small sample sizes and lack of other MRONJ-related risk factors * Corticosteroids associated with increased risk, especially when given in conjunction with Ars * Comorbid conditions inconsistently reported to increase risk (e.g. anaemia, diabetes, cancer type) * Tobacco use variably reported as risk-factor #### Systemic Influences - **Sex:** Higher prevalence in females, likely reflecting the demographics of osteoporosis and breast cancer. - **Age:** Patients <24 years old treated for benign bone disease have not demonstrated MRONJ risk even after extended therapy. - **Corticosteroids:** Associated with increased risk, especially when used with antiresorptives. - **Comorbidities:** Conditions such as anaemia, diabetes, and specific cancer types are inconsistently reported as risk factors. - **Tobacco:** Variably reported as a risk factor. # **RISK FACTOR SUMMARY** * **Risk of MRONJ significantly greater in cancer patients compared to OP** * **Risk of MRONJ in OP continues to be very low regardless of drug type (BPs, DMB, romosozumab) or dosing schedule** #### Key Risk Findings - The risk of MRONJ is significantly greater in cancer patients compared to osteoporosis patients. - In osteoporosis patients, the risk remains very low regardless of drug type (BPs, Denosumab, romosozumab) or dosing schedule. **HOW TO ASSESS RISK/WHEN TO REFER** * Risk based on why they’re on it, dose and risk, duration of therapy, concomitant drug use, surgical insult (eg number of teeth, perio, mx/md) #### Risk Evaluation Assessment should be based on: - Reason for medication use. - Dose and duration of therapy. - Concomitant drug use. - Surgical insult (e.g., number of teeth, periodontal status, location in maxilla/mandible). <div style="text-align: center;"> <div style="border: 2px solid black; display: inline-block; padding: 10px 20px;"> MANAGEMENT </div> </div> * Treatment goals * Prevention * Treatment strategies * Non-operative * Operative  #### Management Components - Treatment goals - Prevention - Treatment strategies (Non-operative and Operative) A rectangular box with a black border containing the word "MANAGEMENT" in bold, uppercase letters, centered within the box. The box is positioned at the top of the page and appears to be a title or heading for the content below it. **TREATMENT GOALS** * Prevention * Prioritisation and support of continued oncologic treatment * Prioritisation and support of continued bone health and prevention of fragility fractures * Preservation of life through * Patient education and reassurance * Control of pain * Control of secondary infection * Prevention of extension of lesion and development of new areas of necrosis #### Primary Objectives - Prevention of MRONJ. - Prioritization of continued oncologic treatment and bone health (prevention of fragility fractures). - Preservation of quality of life through: - Patient education and reassurance. - Pain control. - Control of secondary infection. - Prevention of lesion extension and new areas of necrosis. **PREVENTION** * Need to recognise importance of coordinated dental care and pretreatment management in minimising risk of MRONJ - emphasis on multidisciplinary approach * Optimisation of oral health * Robust level of support for early screening and initiation of appropriate dental care prior to antiresorptive therapy * Treatment planning should include a thorough examination and radiographic assessment * Identify both acute infection and sites of potential infection * Need to consider patient motivation and education, fluoride application, chx rinses, tooth mobility, perio, root fragments, caries, periapical pathology, edentulism and denture stability (especially posterior lingual flange region) * If systemic conditions permit, initiation of antiresorptive therapy should be delayed until dental health is optimised * Similarly, if conditions permit, therapy should be delayed until surgical sites have mucosalised or there is adequate osseous healing #### Pre-treatment Management - **Multidisciplinary Approach:** Coordinated dental care is essential before starting antiresorptive therapy. - **Oral Health Optimization:** Early screening and treatment of acute or potential infection sites. - **Assessment Factors:** Evaluate patient motivation, fluoride needs, tooth mobility, periodontal status, root fragments, caries, and denture stability (especially the posterior lingual flange). - **Timing:** If systemic conditions allow, delay antiresorptive therapy until dental health is optimized and surgical sites have mucosalized or achieved adequate osseous healing. # **PREVENTION** * Cessation of at-risk medication therapy (drug holiday) prior to * Practice of drug holidays to mitigate MRONJ risk accepted and recommended by several international professional societies, but evidence to support or refute such positions remains inconclusive * Since few events are reported, RCTs provide insufficient data to create sound treatment protocols * Concern regarding a drug holiday is the loss of efficacy of antiresorptive therapy with development of skeletal-related events and fragility fractures * Need to consider disease-related risk (cancer vs OP), drug frequency, duration of therapy, comorbidities, other medications, degree of underlying dental pathology, extent of surgery * Special concern should be considered for suspending RANKL inhibitors in OP patients - several studies demonstrate a rebound increase in bone resorption following cessation, resulting in increased risk of multilevel vertebral fractures * Planned surgery can be completed 3-4 months following last dose when level of osteoclast inhibition is waning, then reinstituted 6-8 weeks post surgery * Bone turnover markers * No biomarkers are validated for clinical decision-making #### Drug Holidays and Biomarkers - **Drug Holidays:** The practice of suspending medication to mitigate risk is recommended by some societies, but evidence remains inconclusive. - Risks include loss of antiresorptive efficacy and fragility fractures. - **RANKL Inhibitor Caution:** Cessation in osteoporosis patients can cause a rebound increase in bone resorption and multilevel vertebral fractures. - **Timing:** Planned surgery may be performed 3-4 months after the last dose (when inhibition wanes) and reinstituted 6-8 weeks post-surgery. - **Bone Turnover Markers:** No biomarkers are currently validated for clinical decision-making. **TREATMENT STRATEGIES** * Decision of nonoperative vs operative needs to be patient-specific * Risk-benefit ratio (including QOL with current symptomology) * Ability to perform good wound care to prevent infection and disease spread * Morbidity from major surgical procedure * Oral function or dental rehab after marginal or segmental * Radiographic imaging of utmost importance in evaluation of lesions * 3D imaging can identify forming or fully formed sequestra and potentially decrease invasiveness of surgery #### Clinical Considerations - Decisions must be patient-specific, weighing the risk-benefit ratio and quality of life. - Factors include the ability to perform wound care, surgical morbidity, and post-resection oral function. - **Imaging:** 3D imaging is critical for identifying sequestra and planning less invasive surgery. | 72M, 6/12 | |---| | **DENOSUMAB FOR** | | **OSTEOPOROSIS** |  #### Case Context - Example: 72-year-old male, 6 months of Denosumab for osteoporosis. A close-up photo of a patient's mouth during a dental examination, showing a dental probe and mirror in use. The patient is a 72-year-old male, as indicated by the text overlay, and the image is related to a case involving denosumab for osteoporosis. # NON-OPERATIVE THERAPY FIGURE 2. Non-operative therapies. <table> <tr> <td colspan="3"> <table> <tr> <td style="border: 1px solid black; padding: 10px; text-align: center;"> <strong>Stage 1</strong><br> Local wound care to exposed bone.<br> Antimicrobial rinses.<br> Removal of mobile/well-formed<br> sequestrum. </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> <strong>Stage 2</strong><br> Local wound care to exposed bone.<br> Antimicrobial rinses.<br> Removal of mobile/well-formed<br> sequestrum. Systemic antibiotics.<br> Pain control. </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> <strong>Stage 3</strong><br> Local wound care to exposed bone.<br> Antimicrobial rinses.<br> Removal of mobile/well-formed<br> sequestrum. Systemic antibiotics<br> (oral/IV). Pain control. </td> </tr> <tr> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> </tr> <tr> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Disease<br> resolution </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Disease<br> resolution </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Disease<br> resolution </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Regression to<br> Stage 1, or stable<br> Stage 2 disease </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Stable Stage 3<br> disease </td> </tr> <tr> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> </tr> <tr> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Continue with<br> non-operative<br> tx </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Stable Stage 1<br> disease </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Continue with<br> non-operative<br> tx </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Progression<br> of disease </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Continue with<br> non-operative<br> tx </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Consider operative therapy<br> if there is improvement in<br> medical status </td> </tr> <tr> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> </tr> <tr> <td colspan="2" style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> </tr> <tr> <td colspan="2" style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> </tr> <tr> <td colspan="2" style="border: 1px solid black; padding: 10px; text-align: center;"> Re-staging </td> <td style="text-align: center;"> <img src="arrow_down.png" alt="arrow down"> </td> <td style="border: 1px solid black; padding: 10px; text-align: center;"> Stage 3<br> treatment </td> </tr> </table> </td> </tr> </table>  #### Protocol by Stage - **Stage 1:** Local wound care, antimicrobial rinses, and removal of mobile/well-formed sequestrum. If resolved or stable, continue non-operative care. - **Stage 2:** Local wound care, antimicrobial rinses, removal of mobile sequestrum, systemic antibiotics, and pain control. If disease progresses, restage for Stage 3 treatment. - **Stage 3:** Local wound care, antimicrobial rinses, removal of mobile sequestrum, systemic antibiotics (oral/IV), and pain control. Consider operative therapy if medical status allows. FIGURE 2 shows a flowchart detailing non-operative therapies for three stages of disease. Stage 1 involves local wound care, antimicrobial rinses, and sequestrum removal, leading to disease resolution or stable Stage 1 disease. Stage 2 includes systemic antibiotics and pain control, with outcomes of disease resolution, regression to Stage 1, or progression to Stage 3 treatment. Stage 3 involves oral/IV antibiotics and pain control, with outcomes of disease resolution, stable Stage 3 disease, or consideration of operative therapy if medical status improves. **NON-OPERATIVE THERAPY** * Efficacy of nonoperative therapies is well documented in the literature and can be useful in all stages, especially where significant comorbidities preclude operative treatment * Can result in stabilisation of disease or cure in earlier stages (sequestration and resolution) * Heavy focus on patient education, reassurance, control of pain, control of secondary infection to allow for sequestration of exposed, necrotic bone * Stage 1 * Chlorhexidine wound care and improved OH to remove biofilm from necrotic surface * Surgery may not be indicated in absence of progression and adequate QOL * Stage 2 * Likely struggle with wound care, may require antibiotics for symptom control * Little evidence to suggest use of adjunctive therapies, e.g. hyperbaric oxygen or ozone therapy, can lead to resolution * Use of vitamin E and pentoxifylline as an adjunct have been reported only in case studies * **Randomized, prospective, placebo-controlled trial is underway** * Active clinical and radiographic surveillance is critical in all stages to monitor for signs of disease progression and offer early operative intervention #### Efficacy and Surveillance - Non-operative therapy is useful for all stages, particularly when comorbidities preclude surgery. - **Stage 1 Focus:** Chlorhexidine rinses and biofilm removal; surgery is often not indicated if asymptomatic. - **Stage 2 Focus:** Symptom control via antibiotics. Adjunctive therapies (HBO, ozone, Vitamin E, pentoxifylline) lack strong evidence; trials are ongoing. - **Surveillance:** Active clinical and radiographic monitoring is essential to detect progression early. ## **OPERATIVE THERAPY** * Increasingly reported as a viable option with high success rates for all stages of disease * Has demonstrated maintenance of mucosal coverage, improved QOL, and expedient resumption of antiresorptive therapy for all stages * Patients with progressive clinical or radiographic, or more advance disease at presentation, surgical resection should be performed without instituting prolonged nonoperative measures * Segmental or marginal resection, and partial maxillectomy can be applied to patients with all stages * Require margins beyond the borders of necrotic bone to an area of vital, bleeding bone * Control of comorbid conditions is paramount - physiologically compromised patients (e.g. distant metastases) may not respond favourably to resection and may develop refractory disease * Benefit of drug holidays prior to has not been substantiated #### Indications and Techniques - Operative therapy is a viable option with high success rates across all stages, improving quality of life and allowing resumption of medication. - **Surgical Timing:** For progressive or advanced disease, resection should be performed without prolonged non-operative delays. - **Resection Margins:** Segmental or marginal resections require margins extending to vital, bleeding bone. - **Comorbidities:** Physiologically compromised patients (e.g., those with distant metastases) may have a higher risk of refractory disease. - **Drug Holiday:** The benefit of a pre-operative drug holiday has not been substantiated. **OPERATIVE THERAPIES FOR MANDIBULAR DISEASE** | Stage 1 | Stage 2 | Stage 3 | | :---: | :---: | :---: | | | Systemic antibiotics | Systemic antibiotics | | Disease located above neurovascular canal | | | | | Disease located at or below neurovascular canal in an atrophic or edentulous mandible | | | Marginal resection | Segmental resection | Segmental resection | | \multicolumn{3}{|c|}{Periodic clinical and radiographic evaluations to ensure proper healing with investigation for new primary disease} |  #### Mandibular Surgical Management - **Stage 1:** Marginal resection (if disease is located above the neurovascular canal). - **Stage 2:** - Systemic antibiotics. - Segmental resection (if disease is at or below the neurovascular canal in an atrophic/edentulous mandible). - **Stage 3:** - Systemic antibiotics. - Segmental resection. *Note: All stages require periodic clinical and radiographic evaluation to ensure healing and monitor for new disease.* A flowchart titled 'Operative Therapies for Mandibular Disease' illustrating a three-stage treatment protocol. Stage 1 involves marginal resection for disease located above the neurovascular canal. Stage 2 and Stage 3 involve systemic antibiotics and segmental resection for disease at or below the neurovascular canal in atrophic or edentulous mandibles. All stages conclude with periodic clinical and radiographic evaluations to ensure healing and monitor for new primary disease. **OPERATIVE THERAPIES FOR MAXILLARY DISEASE** <table> <tr> <td>Stage 1</td> <td>Stage 2</td> <td>Stage 3</td> </tr> <tr> <td> <p>Disease located inferior to the sinus floor</p> <p>Alveolectomy</p> </td> <td> <p>Systemic antibiotics</p> <p>Disease located at or superior to floor of maxillary sinus</p> <p>Partial infrastructure maxillectomy</p> </td> <td> <p>Systemic antibiotics</p> <p>Partial infrastructure maxillectomy</p> </td> </tr> </table> <p>Periodic clinical and radiographic evaluations to ensure proper healing with investigation for new primary disease</p>  #### Maxillary Surgical Management - **Stage 1:** Alveolectomy (if disease is located inferior to the sinus floor). - **Stage 2:** - Systemic antibiotics. - Partial infrastructure maxillectomy (if disease is at or superior to the floor of the maxillary sinus). - **Stage 3:** - Systemic antibiotics. - Partial infrastructure maxillectomy. *Note: Periodic clinical and radiographic evaluations are required to ensure proper healing and investigate for new primary disease.* A flowchart titled "OPERATIVE THERAPIES FOR MAXILLARY DISEASE" that outlines three stages of treatment. Stage 1 involves alveolectomy for disease located inferior to the sinus floor. Stage 2 and Stage 3 involve systemic antibiotics followed by partial infrastructure maxillectomy for disease located at or superior to the floor of the maxillary sinus. All paths converge to a final step of periodic clinical and radiographic evaluations to ensure proper healing and investigate for new primary disease. **BREAK** * 15 minutes  #### Scheduled Break - Duration: 15 minutes A rectangular figure with a light green background and a dark border, containing the word "BREAK" in bold, black, uppercase letters centered within the rectangle. [^1]: Original PDF page 1: [[W2.1 MRONJ.pdf#page=1|W2.1 MRONJ, p.1]] [^2]: Original PDF page 2: [[W2.1 MRONJ.pdf#page=2|W2.1 MRONJ, p.2]] [^3]: Original PDF page 3: [[W2.1 MRONJ.pdf#page=3|W2.1 MRONJ, p.3]] [^4]: Original PDF page 4: [[W2.1 MRONJ.pdf#page=4|W2.1 MRONJ, p.4]] [^5]: Original PDF page 5: [[W2.1 MRONJ.pdf#page=5|W2.1 MRONJ, p.5]] [^6]: Original PDF page 6: [[W2.1 MRONJ.pdf#page=6|W2.1 MRONJ, p.6]] [^7]: Original PDF page 7: [[W2.1 MRONJ.pdf#page=7|W2.1 MRONJ, p.7]] [^8]: Original PDF page 8: [[W2.1 MRONJ.pdf#page=8|W2.1 MRONJ, p.8]] [^9]: Original PDF page 9: [[W2.1 MRONJ.pdf#page=9|W2.1 MRONJ, p.9]] [^10]: Original PDF page 10: [[W2.1 MRONJ.pdf#page=10|W2.1 MRONJ, p.10]] [^11]: Original PDF page 11: [[W2.1 MRONJ.pdf#page=11|W2.1 MRONJ, p.11]] [^12]: Original PDF page 12: [[W2.1 MRONJ.pdf#page=12|W2.1 MRONJ, p.12]] [^13]: Original PDF page 13: [[W2.1 MRONJ.pdf#page=13|W2.1 MRONJ, p.13]] [^14]: Original PDF page 14: [[W2.1 MRONJ.pdf#page=14|W2.1 MRONJ, p.14]] [^15]: Original PDF page 15: [[W2.1 MRONJ.pdf#page=15|W2.1 MRONJ, p.15]] [^16]: Original PDF page 16: [[W2.1 MRONJ.pdf#page=16|W2.1 MRONJ, p.16]] [^17]: Original PDF page 17: [[W2.1 MRONJ.pdf#page=17|W2.1 MRONJ, p.17]] [^18]: Original PDF page 18: [[W2.1 MRONJ.pdf#page=18|W2.1 MRONJ, p.18]] [^19]: Original PDF page 19: [[W2.1 MRONJ.pdf#page=19|W2.1 MRONJ, p.19]] [^20]: Original PDF page 20: [[W2.1 MRONJ.pdf#page=20|W2.1 MRONJ, p.20]] [^21]: Original PDF page 21: [[W2.1 MRONJ.pdf#page=21|W2.1 MRONJ, p.21]] [^22]: Original PDF page 22: [[W2.1 MRONJ.pdf#page=22|W2.1 MRONJ, p.22]] [^23]: Original PDF page 23: [[W2.1 MRONJ.pdf#page=23|W2.1 MRONJ, p.23]] [^24]: Original PDF page 24: [[W2.1 MRONJ.pdf#page=24|W2.1 MRONJ, p.24]] [^25]: Original PDF page 25: [[W2.1 MRONJ.pdf#page=25|W2.1 MRONJ, p.25]] [^26]: Original PDF page 26: [[W2.1 MRONJ.pdf#page=26|W2.1 MRONJ, p.26]] [^27]: Original PDF page 27: [[W2.1 MRONJ.pdf#page=27|W2.1 MRONJ, p.27]] [^28]: Original PDF page 28: [[W2.1 MRONJ.pdf#page=28|W2.1 MRONJ, p.28]] [^29]: Original PDF page 29: [[W2.1 MRONJ.pdf#page=29|W2.1 MRONJ, p.29]] [^30]: Original PDF page 30: [[W2.1 MRONJ.pdf#page=30|W2.1 MRONJ, p.30]] [^31]: Original PDF page 31: [[W2.1 MRONJ.pdf#page=31|W2.1 MRONJ, p.31]] [^32]: Original PDF page 32: [[W2.1 MRONJ.pdf#page=32|W2.1 MRONJ, p.32]] [^33]: Original PDF page 33: [[W2.1 MRONJ.pdf#page=33|W2.1 MRONJ, p.33]] [^34]: Original PDF page 34: [[W2.1 MRONJ.pdf#page=34|W2.1 MRONJ, p.34]] [^35]: Original PDF page 35: [[W2.1 MRONJ.pdf#page=35|W2.1 MRONJ, p.35]] [^36]: Original PDF page 36: [[W2.1 MRONJ.pdf#page=36|W2.1 MRONJ, p.36]] [^37]: Original PDF page 37: [[W2.1 MRONJ.pdf#page=37|W2.1 MRONJ, p.37]] [^38]: Original PDF page 38: [[W2.1 MRONJ.pdf#page=38|W2.1 MRONJ, p.38]] [^39]: Original PDF page 39: [[W2.1 MRONJ.pdf#page=39|W2.1 MRONJ, p.39]] [^40]: Original PDF page 40: [[W2.1 MRONJ.pdf#page=40|W2.1 MRONJ, p.40]] [^41]: Original PDF page 41: [[W2.1 MRONJ.pdf#page=41|W2.1 MRONJ, p.41]] [^42]: Original PDF page 42: [[W2.1 MRONJ.pdf#page=42|W2.1 MRONJ, p.42]] [^43]: Original PDF page 43: [[W2.1 MRONJ.pdf#page=43|W2.1 MRONJ, p.43]] [^44]: Original PDF page 44: [[W2.1 MRONJ.pdf#page=44|W2.1 MRONJ, p.44]] [^45]: Original PDF page 45: [[W2.1 MRONJ.pdf#page=45|W2.1 MRONJ, p.45]] [^46]: Original PDF page 46: [[W2.1 MRONJ.pdf#page=46|W2.1 MRONJ, p.46]]