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Medication-Related Osteonecrosis of the Jaws

Medication-Related Osteonecrosis of the Jaws Abstract Medication-related osteonecrosis of the jaw is an oral complication in cancer patients being treated with either antiresorptive or antiangiogenic drugs. The first reports of MRONJ were published in 2003. Hundreds of manuscripts have been published in the medical and dental literature describing the complication, clinical and radiographic signs and symptoms, possible pathophysiology, and management. Despite this extensive literature, the pathobiological mechanisms by which medication-related osteonecrosis of the jaw develops have not yet been fully delineated. The aim of this manuscript is to present current knowledge about the complication ragarding to the definition, known risk factors, and clinical management recommendations. Based on this current state of the science, we also propose research directions that have potential to enhance the management of future oncology patients who are receiving these agents. Medication-Related Osteonecrosis of the Jaws Terminology and Definition Many acronyms in the current literature collectively refer to the oral bone complication caused by antiresorptives and antiangiogenics. First identified in patients receiving an oral or intravenous (i.v.) bisphosphonate (BP) (eg, oncology patients with metastatic bone disease; osteoporotic patients with benign bone disease), the terminology for the condition has continued to evolve. In this chapter we will refer to this complication as “medication-related osteonecrosis of the jaw” (MRONJ) based on contemporary terminology. A recent update of the definition of MRONJ was proposed in the guidelines of the American Association of Maxillofacial Surgeons (1) and the American Society of Bone and Mineral Research (2); this definition has been adopted on a wide scale internationally. MRONJ is defined as an oral complication in patients in whom all of the following criteria are met: on current or previous treatment with antiresorptives or antiangiogenic agents, exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region and that has persisted for more than 8 weeks, no history of radiation therapy to the jaws or obvious metastatic disease to the jaws. The two definitions slightly differ in the statement “obvious metastatic disease,” which is not included in the article from the American Society of Bone and Mineral Research. MRONJ was first reported in the medical and dental literature in 2003, with subsequent reporting in early 2004 (3–5). Since its discovery, ongoing clinical and research developments have required modifications in the diagnosis and management of MRONJ. The oral complication was initially associated with the use of BPs. However, recently several other medications have also been reported to be associated with the development of MRONJ (8), including an antiresorptive (denosumab) (6,7) and those with antiangiogenic activity (bevacizumab, sunitinib, and sorafenib). Late-breaking data have been reported recently by the manufacturer of romosozumab, a new bone-forming monoclonal antibody. In the phase III FRAME study of women with osteoporosis, two cases of MRONJ were positively adjudicated (9). However, in a recent experimental study in mice, development of MRONJ with this drug could not be reproduced (10). This finding will require further observation of post-market use of romosozumab in the clinical setting. If MRONJ is confirmed to be a risk for patients treated with this drug, studies will be necessary to explain the mechanisms that lead to development of osteonecrosis by an agent that causes bone formation. Incidence and Risk Factors MRONJ was not seen clinically before use of antiresorptive medications. Necrotic mandibular and maxillary bone lesions were only observed in head and neck cancer patients treated with radiation therapy or in cases of severe immunosuppression and infection, most frequently in individuals infected with HIV who presented with alveolar bone necrosis resulting from severe periodontitis (11). Therefore, discussion of pathobiological mechanisms of MRONJ by necessity must consider the impact of these antiresorptive agents on alteration of bone biology in the context of MRONJ causation. Several reports have cited both incidence and prevalence of MRONJ. However, due to underreporting, bias in subjects’ recruitment, and observational studies, incidence and prevalence cannot be precisely determined. A prospective controlled study that compared use of zoledronic acid (ZA) and denosumab in a total of 5723 cancer patients showed that the overall risk of MRONJ was 1.6% (7) and specifically 1.3% in those individuals who had received ZA and 1.8% in patients who had received denosumab. Time and frequency of antiresorptives use might affect risk for development of MRONJ. For instance, in a study of prostate cancer patients who were maintained for a prolonged period of time on denosumab, risk increased to 5% (12). Others have reported the frequency of MRONJ in cancer patients to range between 0.2% and 6.7% (13). More recent studies evaluated the incidence of MRONJ in patients with bone metastasis treated sequentially with BPs and denosumab to be 6.7% in the BPs alone group and 10% in patients treated with denosumab. In this study, the incidence of MRONJ increased to 15.5% in patients treated with a BP and switched to denosumab (14). A report by the International Task Force on MRONJ stated that the estimated frequency of MRONJ in cancer patients treated with either a BP or denosumab varied between 1% and 15%, compared with frequency in osteoporosis patients that was estimated between 0.001% and 0.01% (15). Cancer patients being treated with antiangiogenics alone or in combination with BPs have also been reported to be at increased risk for MRONJ. Incidence of MRONJ in a study that evaluated the efficacy of a combination between BP and a tyrosine kinase inhibitor found a 10% incidence of MRONJ (16). Several studies have reported dental extractions as one of the main risk factors for this complication. Risk of development of MRONJ post-dental extraction has been estimated to be one in 200 (0.5%) (13). However, a second 2015 report suggests that osteonecrosis may already be present associated with local dental disease such as periodontitis or periapical infection at the time of the extraction (17). In fact, it is universally accepted that the presence of dental disease and local infection are key factors associated with the development of MRONJ (18,19). Thus, it could be speculated that the activation of dental disease due to the osteonecrosis process is what leads to the extraction. This needs to be further clarified. Of further interest is that there are to date no reports of MRONJ in the pediatric population. There is no explanation on how differently the antiresorptives affect bone metabolism in children. A large 7-year retrospective study aimed to determine the prevalence of both acute and chronic adverse events in children treated with i.v. BPs did not report any case of MRONJ (20). MRONJ is currently considered a multifactorial complication that has been demonstrated to affect primarily the head and neck area (21). In the following section, we will present an update of the science related to MRONJ and the possible impact that new discoveries can have in the prevention and early interventions to manage this important oral complication. Pathobiology: Current Paradigm and New Frontiers Discovery of this oral complication relative to BP-mediated MRONJ has further confirmed that the oral cavity may be an important target organ for adverse reactions of cancer therapies. With recently developed antiresorptive medications and antiangiogenics also now being used alone or in combination in protocols to treat a wide range of cancers, understanding the molecular mechanisms that lead to MRONJ has become increasingly important (22). At first, the possibility of MRONJ being associated with vascular changes caused by the BPs was considered (3,4). However, several other mechanistic models have been considered as well, including inhibition of bone remodeling by osteoclasts and presence of oral disease (18,19). Additional research suggests that altered immunity can also influence the formation of MRONJ (23). Because the majority of patients taking these medications do not develop MRONJ, genetic predisposition is likely a key contributor as well (24). Genetic polymorphisms have thus been investigated, but no definitive conclusions are currently evident (25). The current paradigm for MRONJ is multi-factorial (21) (Figure 1). In this model, one can see the various factors that can influence the development of MRONJ. For example, emerging data suggest that innate T lymphocytes, especially γδ T cells found in human peripheral blood, are lacking in patients treated with BPs. These individuals also are affected by conditions that compromise their immunity (23). This corroborates with the evidence that individuals with MRONJ associated with BPs lack immune resiliency, which in turn impairs their capacity to respond adequately to immunological compromise caused by nitrogen-containing BPs. Data also indicate that the oral microbiome might be an opportunistic factor and not the cause of MRONJ (23). Figure 1. View largeDownload slide Multifactorial osteonecrosis of the jaw (ONJ) model suggesting potential synergy of multiple pathways of ONJ. Reprinted from Tara Aghaloo, Renna Hazboun, and Sotirios Tetradis. Pathophysiology of Osteonecrosis of the Jaws. Oral Maxillofac Surg Clin North Am. 2015;27(4):489–496, with permission from Elsevier. Figure 1. View largeDownload slide Multifactorial osteonecrosis of the jaw (ONJ) model suggesting potential synergy of multiple pathways of ONJ. Reprinted from Tara Aghaloo, Renna Hazboun, and Sotirios Tetradis. Pathophysiology of Osteonecrosis of the Jaws. Oral Maxillofac Surg Clin North Am. 2015;27(4):489–496, with permission from Elsevier. To define the pathobiology of MRONJ, it is thus also important to understand the biological mechanisms of medications and biologics associated with the complication. This research continues to be pursued by the scientific community worldwide. Medications Associated with MRONJ Bisphosphonates Bisphosphonates (BPs) have become the standard of care in the prevention and management of bone complications in cancer patients (26–28). The i.v. BPs (eg, ZA and pamidronate) are used for treatment of patients with breast, prostate, and lung cancer that is metastatic to bone, as well as in patients with multiple myeloma (29,30). Additionally, recent literature suggests a survival advantage for patients with multiple myeloma using ZA (31,32). Several other anticancer actions are now under investigation as well (33–35). Oral formulations of BPs are also used in treatment of osteoporosis (36). BPs are potent inhibitors of osteoclastic bone resorption (37). In a patient taking BPs, particularly the aminobisphosphonate type, the medication is readily absorbed into osteoclasts with resultant impaired bone remodeling. Once incorporated within the osteoclast, aminobisphosphonate inactivates farnesyl diphosphate synthase, which inhibits the prenylation of glutamic-pyruvic transaminase (GPT)-binding proteins that results in multiple intracellular changes, including cytoskeletal disorganization, loss of ruffled border, and altered vesicular trafficking. These collective effects result in impaired resorption of bone by the osteoclast (38). The normal physiological balance between bone resorption (osteoclasts) and bone formation (osteoblasts) is thus compromised (39). Nitrogen-containing BPs are more potent drugs. Some but not all i.v. BPs are more potent than oral BPs. For instance, pamidronate is an i.v. BP, but it is less potent than oral alendronate. The risk of MRONJ is higher with pamidronate only because of its poor bioavailability. It is difficult to study the pharmacokinetics and dynamics of BPs, because the drug is not metabolized and is quickly excreted in urine and/or feces. BPs have, however, been shown to have a long biological skeletal half-life, estimated to be up to 10 years (40,41). This aspect has created a clinical dilemma for dentists and physicians when patients taking BPs or who have been exposed to the medication in the past need invasive dental treatment (42). As described in the next section, newer antiresorptive medications, such as denosumab, have been introduced to treat skeletal bone metastases in oncology patients as well as osteoporosis in the noncancer setting (12,43–46). Denosumab Denosumab is a human monoclonal antibody (IgG2) that binds to receptor activator for nuclear factor κB ligand (RANK-L) with high affinity and specificity. This interaction, similar to that of endogenous osteoprotegerin (OPG), prevents the interaction with RANK on the osteoclast membrane. By this action, denosumab inhibits osteoclast differentiation, activation, and survival. Bone formation is thus favored over bone resorption, with resultant increased bone mass and reduced risk of fractures (47). Studies have demonstrated the efficacy of denosumab in prevention of skeletal-related events in postmenopausal women (44) and in prostate cancer patients receiving androgen deprivation therapy (45). Studies comparing the efficacy of denosumab and ZA have demonstrated the superiority of denosumab in reducing skeletal-related events in cancer patients (46,48). However, and as noted above, reports have also confirmed that denosumab can place patients at risk for MRONJ (12). Furthermore, switching patients from a BP to denosumab may increase the rapidity with which MRONJ develops (49). The incidence and severity of cases are under investigation as described above (7). Antiangiogenics Antiangiogenics (eg, vascular endothelial growth factor inhibitors) represent another class of medication associated with MRONJ. These biologics are typically utilized in the treatment of various cancers in advanced stages (50–53). Prevalence, prevention, and treatment of MRONJ in patients receiving these bone-modifying agents are unclear. Antiangiogenic mechanisms have demonstrated benefit when using BPs and vascular endothelial growth factor inhibitors in the treatment of cancer with selected populations (54). In the future, new medications and biologicals will be introduced to maximize this beneficial anticancer activity of inhibiting angiogenesis. Current evidence confirms that the beneficial cancer effect of the combination of BPs and antiangiogenics also appears to increase the risk of MRONJ (55,56). Increased use of these therapies requires a clearer understanding of the mechanisms associated with the development of MRONJ in the context of risk factors as well as preventive and treatment strategies (57,58). Other Factors That May Play a Role in the Mechanistic Modeling of MRONJ Having discussed the mechanism of action of the various medications associated with bone metabolism and associated MRONJ, it is important to also consider additional factors that have been proposed to explain the process by which MRONJ develops. These mechanisms include toxicity to bone cells and suppression of bone remodeling (“inside out”), toxicity to soft tissues and infection (“outside in”), immunosuppression, genetic polymorphism, or, more likely, a combination of several factors (59–64). Synthesizing the collective mechanistic process thus requires further research. For example, a study of blood samples collected from 46 Hungarian subjects with MRONJ was conducted. Genomic DNA was extracted, and a single nucleotide polymorphism analysis of the CYP2C8 gene was performed. The study results showed that the risk of mandibular localization of MRONJ was 19.2-fold higher in subjects with the AG genotype than in subjects with the normal GG genotype (65). Of additional note is a 2019 systematic review that reported cases of MRONJ not related to bone-targeting agents (antiresorptives) (66). Forty-two cases of MRONJ associated with biologicals were identified. The medications included bevacizumab, aflibercept, sunitinib, imatinib, cabozantinib, sorafenib, regorafenib, axitinib, pazopanib, desatinib, everolimus, temsirolimus, ipilimumab, and rituximab. In addition, cases associated with inhibitors of BRAF, dafrafenib, trametinib, and the immune checkpoint inhibitor nivolumab have also been reported. For example, a 2018 study of 204 consecutive patients who developed MRONJ identified seven patients (3.4%) who had received targeted cancer therapy (67). In this 2018 study, four of the 204 patients had received targeted cancer monotherapy, while the remaining three patients had been concomitantly treated with BPs and/or denosumab. Publication of these types of cases is important so that early diagnosis of MRONJ may ensue, leading to prompt management. Although the number of cases is currently small, it is likely that additional cases of MRONJ not associated with antiresorptives will be diagnosed as use of these biologics increases in the clinical setting. Although the experience with these cases is recent, it suggests that their management may lead to a shorter time of healing and better prognosis (58). However, this needs confirmation from clinical observation. Compromised Bone Metabolism The presence of antiresorptives and/or antiangiogenics is a common factor in all patients with the diagnosis of MRONJ. However, it appears that these medications alone may not be enough to lead to MRONJ formation. The science has been addressing the role additional factors can play in the development of MRONJ. In the jawbones, frequent microfractures and bone damage result from mastication and parafunctional habits including clenching and malocclusion (68). Following bone damage, pre-osteoblasts express RANK-L on their surfaces. The ligand binds to RANK receptors on the surface of pre-osteoclasts, which in turn activates osteoclast differentiation and function. The osteoclasts bind to damaged bone and secrete acids and cathepsin K that induce resorption of the damaged bone. When the resorption phase is completed, pre-osteoblasts mature into osteoblasts and secrete OPG that inhibits RANK-L and thus stops the recruitment of pre-osteoclasts. The modeling of normal bone physiology described above contrasts distinctly with mechanisms associated with antiresorptive drugs. Therefore, “old damaged bone” is spared and new bone is deposited over damaged bone (69). Lack of resorption of bone microfractures and microdamage of the skeleton could facilitate development of osteonecrosis (70,71). The antiangiogenic mechanism of BPs or of the newer antiangiogenic drugs used in the treatment of advanced tumors could lead to compromise of intra-bony circulation and/or blood vessel neoformation, contributing to development of MRONJ. In addition to bone necrosis per se, the overlying mucosa would be injured as well and thus provide opportunity for bacterial contamination and persistence of the lesion. This “inside out” theory would be further exacerbated by the presence of trauma. A study with beagle dogs treated for 3 years with alendronate has shown that the dogs also develop bone necrosis in the nonalveolar portion of the jaws (61,72). What must be considered in this scenario, both for humans and animals, is that the oral cavity is contaminated by a very complex microflora. In addition, periodontal disease is a very common oral disease and, in this case, a constant stimulus for alveolar bone remodeling. How would this work in a system in which bone remodeling is inhibited by the antiresorptive medication? A series of micro-computed tomography studies revealed the importance of altered bone metabolism in combination with presence of dental disease (18). Evidence from a rat model suggests that periodontal disease and potent BP therapy are sufficient for development of MRONJ. The lesions in rats were strikingly similar to those in humans, consisting of micro-computed tomography evidence of bone sequestration and extensive periosteal alveolar bone formation. Histological examination revealed necrotic bone with diffuse loss of osteocytes and empty lacunae, rimming of the necrotic bone by squamous epithelium and inflammation, and bone exposure to the oral cavity (18). Additional experimental studies have confirmed similar features in mice in the presence of periapical disease (19). Further studies have demonstrated in a novel mouse model the spontaneous development of MRONJ supporting a central role of osteoclast inhibition and dental disease in the pathogenesis of MRONJ (73). Soft Tissue and Cell Toxicity As stated in the previous paragraph, preclinical studies have suggested that, in addition to bone remodeling suppression, and dental disease, there may be soft tissue and cell toxicity at the site in which osteonecrosis develops (63,74,75). It has been shown that alendronate is toxic to the subcutaneous tissue in rats, inducing inflammation, micro-abscess formation, and necrosis (76). Other investigators have shown that low concentrations of zoledronate affect human gingival fibroblasts and keratinocyte cell lines through the induction of gene-regulated apoptosis (74). This possibility, however, has been contested because denosumab does not cause soft tissue toxicity. As noted previously, BPs accumulate in the alveolar bone in the jaws with prolonged use. Surgical manipulation of the area (eg, dental extraction) produces local release of BPs from the bone due to the acidic environment. Free BPs can be incorporated by overlying epithelial cells causing additional toxicity and thus inhibiting healing (60,64). Additional research has demonstrated that pamidronate inhibits keratinocytes in culture and that dose of medication is an important determinant of cell inhibition (63). Similar toxicity can be expressed in macrophages, in dendritic cell differentiation and maturation (77), and in fibroblasts when exposed to BPs (74,78). The possible role of monocytes and macrophages in MRONJ has been reported as well (79). Macrophages are affected by BP internalization and inhibition of the cholesterol synthesis and by induction of apoptosis (80,81). A deficiency in the monocyte or macrophage cell population could facilitate establishment of local infection. Denosumab has been reported to impair monocyte migration and function by blocking RANK receptors present on the cell surface and preventing RANK-L from activating the production of proinflammatory cytokines (79). This would favor the “outside in” mechanism of MRONJ development. This modeling would involve trauma to the oral mucosa, cytotoxic effects of BPs to cells and tissues, bacterial contamination of the area, and osteonecrosis development (82). Tooth extraction has been considered one of the main risk factors for the development of MRONJ (1,83). However, several experimental studies have demonstrated that the use of an antiresorptive medication and the presence of inflammation and infection can lead to MRONJ without participation of any traumatic event (18,19,84). It is known that dental extractions are typically performed because the tooth is severely fractured or because it has lost bone support due to the presence of dental disease such as localized periodontitis and infection. Having said this, it has been demonstrated that in some cases there is already alveolar bone necrosis at time of extraction, which is a fundamental reason why there is no healing of the bone following the extraction (17). Biofilm Investigators have demonstrated the formation of biofilm on the exposed necrotic bone and claim that infection would play an important role in the mechanism of MRONJ (85–87). The role that bacterial infection contributes in the process, however, has not been fully elucidated. Actinomyces organisms are present in biopsy specimens of MRONJ. These organisms have occasionally been reported as the principal infectious agent of MRONJ and in some case of ORN (88–91). Nevertheless, there is as yet no proof whether the microorganism is the true causative agent or is present as a secondary contaminant. Thus, a pathogenic role for Actinomyces as a single organism in the pathobiology of MRONJ remains controversial. As previously discussed, other pathobiological findings include suggestion of a genetic predisposition of some individuals to MRONJ by various investigators (92–94). Oral and Systemic Immune Function Chemotherapy and corticosteroids used for treatment of oncology patients could modify local oral tissue and systemic immunity. This interaction, associated with the effects of BPs, denosumab, and antiangiogenesis as well as presence of dental disease, could contribute to the multifactorial modeling currently considered in the development of MRONJ (21). The rationale of this modeling is that the oral microflora could become increasingly pathogenic. This could potentially account for the chronic nature of these lesions and contribute to the failure of standard treatments to induce healing. Does the Pathobiology of MRONJ Related to the Presence of Dental Disease Differ from MRONJ Lesions Classified as “Spontaneous Occurrences”? It is important at this stage of evolution of the MRONJ pathobiological model to emphasize that “spontaneous occurrence” has been reported in cases for which no specific clinical cause could be identified. The lack of robustness of the literature is not unique to MRONJ and is consistent with approaches adopted by researchers relative to other diseases for which the molecular and clinical modeling are at an early phase. The classification of “spontaneous occurrence” has been important for the MRONJ domain in that characterization has distinguished cases with documented cause, in contrast with those cases in which fundamental etiology was not identifiable by the investigator. As the MRONJ pathobiological modeling matures in the future, it is anticipated that incidence of “spontaneous occurrence” will diminish and the scope of causative factors will likely expand. This dynamic may or may not increase documentation of the total number of MRONJ cases. Regardless, this evolution will increase the precision of defining MRONJ causation as derived from an increasingly sophisticated, multi-factorial pathobiological model. Clinical Presentation and Management: Successes and Barriers MRONJ has been shown to occur more frequently in the mandible than the maxilla (95). In addition, a review of reported cases in the literature confirmed an association of MRONJ with the following diagnoses: multiple myeloma 46%, breast cancer 39%, prostate 6%, osteoporosis 4%, and others 5% (96). The higher prevalence of MRONJ with i.v. BPs is related to a higher bioavailability of i.v. BPs (>60%) compared with oral BPs (<1%). ZA has been shown to be 121 times more potent as alendronate. A 2010 systematic review demonstrated that case documentation and patient follow-up by dental experts could influence the prevalence of MRONJ, considering that most of the early reports of these oral complications included retrospective studies (97). The hallmark clinical presentation of MRONJ is characterized by the presence of exposed necrotic bone in an area of the oral cavity normally covered by mucosa or the presence of a fistulous tract. The site may be surrounded by inflamed tissues, present purulent secretion, and be painful. In advanced cases when the extent of necrosis increases, patients may complain of a tingling sensation or hyposensitivity (5,98). The most recent (2014) update of the American Association of Maxillofacial Surgeons confirmed the staging for MRONJ, with broad international acceptance among health-care providers (1). This classification presents different stages of development of MRONJ based on signs and symptoms and severity. One controversial aspect of this classification is the stage zero. This stage proposes that a patient in treatment with one of the medications associated with risk for development of MRONJ presents with clinical signs and symptoms of active infection, purulent secretion via the periodontium or a fistula, or pain, but necrotic bone cannot be clinically visualized. The controversial aspect of this staging classification is in discussion in the current literature. The modeling exemplified by stage zero, however, can be a very important consideration relative to potential early diagnosis of the complication (99). In regards to clinical risk factors, several aspects have been associated with the development of MRONJ, including the exposure to i.v. medication in cancer patients, poor oral hygiene, presence of active dental disease, concomitant chemotherapy and steroid use, wearing removable dental appliances, and invasive dental procedures (eg, dental extraction) (83,97,100,101). Dental extractions have been associated with MRONJ. However, it is not yet clear whether dental extractions are the causative agent of MRONJ or if the dental extraction is the final outcome of an irreversible process that initiated with compromised bone remodeling that leads to the necessity for an invasive dental procedure. Increased time on an antiresorptive or antiangiogenic agent is also an important factor; risk for development of MRONJ increases the longer the patients are on the medication (12,102). Nitrogen-containing BPs administered via i.v. infusion in cancer patients have been associated with most of the cases reported. Patients with multiple myeloma appear to be at highest risk (97,103). Management of MRONJ Prevention Current guidelines suggest that maintenance of optimal oral hygiene as well as diagnosis and medically necessary treatment of dental disease before the start of antiresorptive therapy decrease risk of development of MRONJ (104–107). These recommendations have been included in several available guidelines for the management of patients taking antiresorptive medications (28,42,106). Treatment There are a number of key clinical aspects of MRONJ that must be considered before managing a patient who has developed the lesion: Extent of bone necrosis is difficult to diagnose based on clinical examination. There is no standard for radiographic assessment via plain film technology (eg, periapical and/or panoramic radiographs). Advanced imaging technology such as CT, cone-beam CT, MRI, and scintigraphy may be helpful to guide the determination of extent of necrosis (108). Additional imaging considerations include: There is recent preliminary evidence that selected imaging features noted on panoramic radiograph (eg, mandibular cortical index) may predict future development of BP-related ONJ (109); however, further study is needed before a definitive conclusion can be made in this regard. Use of i.v. BPs in multiple myeloma patients may lead to alterations in the radiographic presentation of multiple myeloma in the maxilla and mandible (110). Thus, clinician vigilance is required in this context when viewing panoramic radiographs in these patients. The combination of clinical and radiographic evidence cannot, however, provide definitive diagnosis of early MRONJ. Quality of life must be considered based on number of affected sites, presence of active infection and malodor, level of pain, and neural involvement. Treatment of MRONJ with radical vs conservative therapy has to be evaluated on a case-by-case basis. In a systematic review, 13 studies reported management strategies for 658 MRONJ cases (97). A wide range of treatment strategies, from discontinuing BPs before invasive dental therapy and other conservative therapy to extensive bone debridement and bone resection, have been tested. The response to therapy was not clearly specified in one-half of these studies, but resolution was reported in 12% of the cases reported. Impact of MRONJ on quality of life has not been clearly established. Studies that have examined pain symptoms associated with MRONJ have noted pain in approximately one-half of the cases reported but with statistically significant differences noted across publications (10–90%) (97,111). There is increasing evidence that surgical excision of the necrotic bone and proper wound manipulation and suture are effective for treating MRONJ (112–115). This more recent information is beginning to change the classic paradigm that has recommended conservative therapy of MRONJ in stage I and stage II. However, the decision on how to best treat this complication depends on the preference and skills of individual professionals managing the patient with MRONJ. Treatment can be guided based on the previously cited American Association of Oral and Maxillofacial Surgeons staging system (1). It appears that in initial stages (stage I), a conservative management with antiseptic mouth rinses, antibiotics to control active infection, and minor debridement of necrotic bone should be used. In more advanced stages (II and III), a surgical approach can be used (116). More recent evidence suggests that even cases in earlier stages of MRONJ appear to have better outcomes when treated surgically (117). Two key currently unanswered issues are as follows: It is unclear how best to diagnose and treat cases of MRONJ when visible necrotic bone is not present in the oral cavity (Stage 0). As additional research becomes available, clinicians managing patients with suspicion of MRONJ without visible exposed bone should be aware on the best practices to diagnose and treat this oral complication. It is also currently unclear if discontinuing BP therapy will lead to sequestration of necrotic bone and healing. It is recommended that discontinuation of therapy should be based on the current medical status of the patient. Drugs must be discontinued by the prescribing physician or oncologist, and the risks and benefits of this procedure must be discussed with the patient. It must be considered whether discontinuation could lead to reactivation of bone metastatic lesions, increase risk for pathological fracture, and increase risk for skeletal pain. Several studies have addressed whether discontinuation of therapy can improve healing of MRONJ. A recent study has demonstrated that independent of modality of treatment and MRONJ stage at diagnosis, discontinuation of BPs before or at treatment initiation is associated with a faster resolution of symptoms compared with continuing the use of the medication (118). It appears that the continuation of therapy with the antiresorptives may delay in months the resolution of MRONJ (118). Experimental investigation compared the effect of discontinuation of ZA and the RANK-L inhibitor OPG-Fc in mice after the formation of MRONJ. Ten weeks after discontinuation, there was substantial healing of the areas of osteonecrosis in animals treated with OPG-Fc but not with ZA. This observation suggests that patients with MRONJ due to denosumab may heal faster than those on ZA when therapy is discontinued (119). The use of parathyroid hormone has been reported as a possibility to rescue the osteonecrotic bone. A recent experimental study demonstrated the wound-healing effect in ovariectomized rats with MRONJ (120). Anecdotal case reports suggesting the positive effect of parathyroid hormone have been published in humans, but a prospective controlled study is lacking (121). Setting the Stage for Future Research Evidence Gaps for Current Clinical Management Prevention, with the goal of identifying those patients who are at clinically significant risk for development of MRONJ; and management of MRONJ Enhanced understanding of the impact of dosing frequency and duration of antiresorptive therapy Clinical or Translational Research with Promise for Clinical Application in the Future Further strategic development of evidence-based guidelines for the management of patients with MRONJ Development of a screening panel comprising risk factors associated with: patient characteristics (age, sex, co-morbidities, concomitant medications, genetics); oral health (periodontal disease, infection, caries, oral hygiene habits); serum markers (c-terminal telopeptide, n-terminal telopeptide, alkaline phosphatase, calcium, phosphorus, parathyroid hormone, vitamin D); dosing regimen of the antiresorptive agent (type, dose, exposure time); malignant disease (multiple myeloma, breast, prostate, lung, others) Key Research Questions Basic Science Research Based on current gaps in the evidence relative to MRONJ etiopathogenesis as described in this paper, there are a number of novel basic science research opportunities that in turn could inform translational or clinical research in the future: Effect of long-term suppression of osteoclast function on bone remodeling Effect of long-term antiresorptive medications on host immune defense mechanisms (dendritic cells, macrophages, and granulocytes) Effect of long-term antiresorptives on angiogenesis of mucosal and osseous tissues Effect of long-term antiresorptives on osteocyte viability Identification of specific markers for risk assessment and diagnosis Role of immune suppression and/or suppressed angiogenesis on development of MRONJ Impact of cumulative dose of BPs on the bone marrow environment Translational Research Development of novel methods for diagnosis and management. Design of preventive, drug-specific protocols Clinical Research Further delineation of the frequency of MRONJ across diverse cancer patient cohorts Extent to which the human cost (ie, morbidity and mortality) as well as economic cost are affecting utilization of health-care resources Best preventive strategies in relation to prioritization of oral risk factors Optimal technique to determine extent of bone necrosis (eg, imaging, biopsy, other) Decision-making regarding conservative vs more radical treatment of MRONJ, and the role if any a drug holiday would contribute to MRONJ treatment outcome Degree to which the treatment plan for management of MRONJ is influenced by the presence or absence of exposed bone Risks vs benefits of discontinuation of antiresorptive therapy relative to MRONJ prevention and/or treatment Notes Affiliations of authors: Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL (CAM); Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC (MTB); Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, and Head & Neck Cancer/Oral Oncology Program, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (DEP). C. Migliorati receives consulting fees from Amgen Inc as well as Optum Epidemiology. This consulting activity is related to the content of this manuscript. C. Migliorati received consulting fees from Colgate, which is not related to the manuscript. M. Brennan is a consultant for AFYX and Medimmune. D. Peterson receives consulting fees from Amgen Inc as well as Optum Epidemiology. This consulting activity is related to the content of this manuscript. D. Peterson also receives consulting fees from PSI CRO, SAI MedPartner LLC, and AEC Partners, and receives consulting fees from and holds equity ownership in Applied Glycan Technologies, Inc. None of this latter consulting activity is related to the content of this manuscript. For support see Funding Acknowledgement section of Monograph. References 1 Ruggiero SL , Dodson TB , Fantasia J , et al. . American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update . 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Teriparatide therapy for bisphosphonate-associated osteonecrosis of the jaw in an elderly Japanese woman with severe osteoporosis . Clin Drug Investig. 2012 ; 32 8 : 547 – 553 . Google Scholar PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Medication-Related Osteonecrosis of the Jaws

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1052-6773
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1745-6614
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10.1093/jncimonographs/lgz009
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Abstract

Abstract Medication-related osteonecrosis of the jaw is an oral complication in cancer patients being treated with either antiresorptive or antiangiogenic drugs. The first reports of MRONJ were published in 2003. Hundreds of manuscripts have been published in the medical and dental literature describing the complication, clinical and radiographic signs and symptoms, possible pathophysiology, and management. Despite this extensive literature, the pathobiological mechanisms by which medication-related osteonecrosis of the jaw develops have not yet been fully delineated. The aim of this manuscript is to present current knowledge about the complication ragarding to the definition, known risk factors, and clinical management recommendations. Based on this current state of the science, we also propose research directions that have potential to enhance the management of future oncology patients who are receiving these agents. Medication-Related Osteonecrosis of the Jaws Terminology and Definition Many acronyms in the current literature collectively refer to the oral bone complication caused by antiresorptives and antiangiogenics. First identified in patients receiving an oral or intravenous (i.v.) bisphosphonate (BP) (eg, oncology patients with metastatic bone disease; osteoporotic patients with benign bone disease), the terminology for the condition has continued to evolve. In this chapter we will refer to this complication as “medication-related osteonecrosis of the jaw” (MRONJ) based on contemporary terminology. A recent update of the definition of MRONJ was proposed in the guidelines of the American Association of Maxillofacial Surgeons (1) and the American Society of Bone and Mineral Research (2); this definition has been adopted on a wide scale internationally. MRONJ is defined as an oral complication in patients in whom all of the following criteria are met: on current or previous treatment with antiresorptives or antiangiogenic agents, exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region and that has persisted for more than 8 weeks, no history of radiation therapy to the jaws or obvious metastatic disease to the jaws. The two definitions slightly differ in the statement “obvious metastatic disease,” which is not included in the article from the American Society of Bone and Mineral Research. MRONJ was first reported in the medical and dental literature in 2003, with subsequent reporting in early 2004 (3–5). Since its discovery, ongoing clinical and research developments have required modifications in the diagnosis and management of MRONJ. The oral complication was initially associated with the use of BPs. However, recently several other medications have also been reported to be associated with the development of MRONJ (8), including an antiresorptive (denosumab) (6,7) and those with antiangiogenic activity (bevacizumab, sunitinib, and sorafenib). Late-breaking data have been reported recently by the manufacturer of romosozumab, a new bone-forming monoclonal antibody. In the phase III FRAME study of women with osteoporosis, two cases of MRONJ were positively adjudicated (9). However, in a recent experimental study in mice, development of MRONJ with this drug could not be reproduced (10). This finding will require further observation of post-market use of romosozumab in the clinical setting. If MRONJ is confirmed to be a risk for patients treated with this drug, studies will be necessary to explain the mechanisms that lead to development of osteonecrosis by an agent that causes bone formation. Incidence and Risk Factors MRONJ was not seen clinically before use of antiresorptive medications. Necrotic mandibular and maxillary bone lesions were only observed in head and neck cancer patients treated with radiation therapy or in cases of severe immunosuppression and infection, most frequently in individuals infected with HIV who presented with alveolar bone necrosis resulting from severe periodontitis (11). Therefore, discussion of pathobiological mechanisms of MRONJ by necessity must consider the impact of these antiresorptive agents on alteration of bone biology in the context of MRONJ causation. Several reports have cited both incidence and prevalence of MRONJ. However, due to underreporting, bias in subjects’ recruitment, and observational studies, incidence and prevalence cannot be precisely determined. A prospective controlled study that compared use of zoledronic acid (ZA) and denosumab in a total of 5723 cancer patients showed that the overall risk of MRONJ was 1.6% (7) and specifically 1.3% in those individuals who had received ZA and 1.8% in patients who had received denosumab. Time and frequency of antiresorptives use might affect risk for development of MRONJ. For instance, in a study of prostate cancer patients who were maintained for a prolonged period of time on denosumab, risk increased to 5% (12). Others have reported the frequency of MRONJ in cancer patients to range between 0.2% and 6.7% (13). More recent studies evaluated the incidence of MRONJ in patients with bone metastasis treated sequentially with BPs and denosumab to be 6.7% in the BPs alone group and 10% in patients treated with denosumab. In this study, the incidence of MRONJ increased to 15.5% in patients treated with a BP and switched to denosumab (14). A report by the International Task Force on MRONJ stated that the estimated frequency of MRONJ in cancer patients treated with either a BP or denosumab varied between 1% and 15%, compared with frequency in osteoporosis patients that was estimated between 0.001% and 0.01% (15). Cancer patients being treated with antiangiogenics alone or in combination with BPs have also been reported to be at increased risk for MRONJ. Incidence of MRONJ in a study that evaluated the efficacy of a combination between BP and a tyrosine kinase inhibitor found a 10% incidence of MRONJ (16). Several studies have reported dental extractions as one of the main risk factors for this complication. Risk of development of MRONJ post-dental extraction has been estimated to be one in 200 (0.5%) (13). However, a second 2015 report suggests that osteonecrosis may already be present associated with local dental disease such as periodontitis or periapical infection at the time of the extraction (17). In fact, it is universally accepted that the presence of dental disease and local infection are key factors associated with the development of MRONJ (18,19). Thus, it could be speculated that the activation of dental disease due to the osteonecrosis process is what leads to the extraction. This needs to be further clarified. Of further interest is that there are to date no reports of MRONJ in the pediatric population. There is no explanation on how differently the antiresorptives affect bone metabolism in children. A large 7-year retrospective study aimed to determine the prevalence of both acute and chronic adverse events in children treated with i.v. BPs did not report any case of MRONJ (20). MRONJ is currently considered a multifactorial complication that has been demonstrated to affect primarily the head and neck area (21). In the following section, we will present an update of the science related to MRONJ and the possible impact that new discoveries can have in the prevention and early interventions to manage this important oral complication. Pathobiology: Current Paradigm and New Frontiers Discovery of this oral complication relative to BP-mediated MRONJ has further confirmed that the oral cavity may be an important target organ for adverse reactions of cancer therapies. With recently developed antiresorptive medications and antiangiogenics also now being used alone or in combination in protocols to treat a wide range of cancers, understanding the molecular mechanisms that lead to MRONJ has become increasingly important (22). At first, the possibility of MRONJ being associated with vascular changes caused by the BPs was considered (3,4). However, several other mechanistic models have been considered as well, including inhibition of bone remodeling by osteoclasts and presence of oral disease (18,19). Additional research suggests that altered immunity can also influence the formation of MRONJ (23). Because the majority of patients taking these medications do not develop MRONJ, genetic predisposition is likely a key contributor as well (24). Genetic polymorphisms have thus been investigated, but no definitive conclusions are currently evident (25). The current paradigm for MRONJ is multi-factorial (21) (Figure 1). In this model, one can see the various factors that can influence the development of MRONJ. For example, emerging data suggest that innate T lymphocytes, especially γδ T cells found in human peripheral blood, are lacking in patients treated with BPs. These individuals also are affected by conditions that compromise their immunity (23). This corroborates with the evidence that individuals with MRONJ associated with BPs lack immune resiliency, which in turn impairs their capacity to respond adequately to immunological compromise caused by nitrogen-containing BPs. Data also indicate that the oral microbiome might be an opportunistic factor and not the cause of MRONJ (23). Figure 1. View largeDownload slide Multifactorial osteonecrosis of the jaw (ONJ) model suggesting potential synergy of multiple pathways of ONJ. Reprinted from Tara Aghaloo, Renna Hazboun, and Sotirios Tetradis. Pathophysiology of Osteonecrosis of the Jaws. Oral Maxillofac Surg Clin North Am. 2015;27(4):489–496, with permission from Elsevier. Figure 1. View largeDownload slide Multifactorial osteonecrosis of the jaw (ONJ) model suggesting potential synergy of multiple pathways of ONJ. Reprinted from Tara Aghaloo, Renna Hazboun, and Sotirios Tetradis. Pathophysiology of Osteonecrosis of the Jaws. Oral Maxillofac Surg Clin North Am. 2015;27(4):489–496, with permission from Elsevier. To define the pathobiology of MRONJ, it is thus also important to understand the biological mechanisms of medications and biologics associated with the complication. This research continues to be pursued by the scientific community worldwide. Medications Associated with MRONJ Bisphosphonates Bisphosphonates (BPs) have become the standard of care in the prevention and management of bone complications in cancer patients (26–28). The i.v. BPs (eg, ZA and pamidronate) are used for treatment of patients with breast, prostate, and lung cancer that is metastatic to bone, as well as in patients with multiple myeloma (29,30). Additionally, recent literature suggests a survival advantage for patients with multiple myeloma using ZA (31,32). Several other anticancer actions are now under investigation as well (33–35). Oral formulations of BPs are also used in treatment of osteoporosis (36). BPs are potent inhibitors of osteoclastic bone resorption (37). In a patient taking BPs, particularly the aminobisphosphonate type, the medication is readily absorbed into osteoclasts with resultant impaired bone remodeling. Once incorporated within the osteoclast, aminobisphosphonate inactivates farnesyl diphosphate synthase, which inhibits the prenylation of glutamic-pyruvic transaminase (GPT)-binding proteins that results in multiple intracellular changes, including cytoskeletal disorganization, loss of ruffled border, and altered vesicular trafficking. These collective effects result in impaired resorption of bone by the osteoclast (38). The normal physiological balance between bone resorption (osteoclasts) and bone formation (osteoblasts) is thus compromised (39). Nitrogen-containing BPs are more potent drugs. Some but not all i.v. BPs are more potent than oral BPs. For instance, pamidronate is an i.v. BP, but it is less potent than oral alendronate. The risk of MRONJ is higher with pamidronate only because of its poor bioavailability. It is difficult to study the pharmacokinetics and dynamics of BPs, because the drug is not metabolized and is quickly excreted in urine and/or feces. BPs have, however, been shown to have a long biological skeletal half-life, estimated to be up to 10 years (40,41). This aspect has created a clinical dilemma for dentists and physicians when patients taking BPs or who have been exposed to the medication in the past need invasive dental treatment (42). As described in the next section, newer antiresorptive medications, such as denosumab, have been introduced to treat skeletal bone metastases in oncology patients as well as osteoporosis in the noncancer setting (12,43–46). Denosumab Denosumab is a human monoclonal antibody (IgG2) that binds to receptor activator for nuclear factor κB ligand (RANK-L) with high affinity and specificity. This interaction, similar to that of endogenous osteoprotegerin (OPG), prevents the interaction with RANK on the osteoclast membrane. By this action, denosumab inhibits osteoclast differentiation, activation, and survival. Bone formation is thus favored over bone resorption, with resultant increased bone mass and reduced risk of fractures (47). Studies have demonstrated the efficacy of denosumab in prevention of skeletal-related events in postmenopausal women (44) and in prostate cancer patients receiving androgen deprivation therapy (45). Studies comparing the efficacy of denosumab and ZA have demonstrated the superiority of denosumab in reducing skeletal-related events in cancer patients (46,48). However, and as noted above, reports have also confirmed that denosumab can place patients at risk for MRONJ (12). Furthermore, switching patients from a BP to denosumab may increase the rapidity with which MRONJ develops (49). The incidence and severity of cases are under investigation as described above (7). Antiangiogenics Antiangiogenics (eg, vascular endothelial growth factor inhibitors) represent another class of medication associated with MRONJ. These biologics are typically utilized in the treatment of various cancers in advanced stages (50–53). Prevalence, prevention, and treatment of MRONJ in patients receiving these bone-modifying agents are unclear. Antiangiogenic mechanisms have demonstrated benefit when using BPs and vascular endothelial growth factor inhibitors in the treatment of cancer with selected populations (54). In the future, new medications and biologicals will be introduced to maximize this beneficial anticancer activity of inhibiting angiogenesis. Current evidence confirms that the beneficial cancer effect of the combination of BPs and antiangiogenics also appears to increase the risk of MRONJ (55,56). Increased use of these therapies requires a clearer understanding of the mechanisms associated with the development of MRONJ in the context of risk factors as well as preventive and treatment strategies (57,58). Other Factors That May Play a Role in the Mechanistic Modeling of MRONJ Having discussed the mechanism of action of the various medications associated with bone metabolism and associated MRONJ, it is important to also consider additional factors that have been proposed to explain the process by which MRONJ develops. These mechanisms include toxicity to bone cells and suppression of bone remodeling (“inside out”), toxicity to soft tissues and infection (“outside in”), immunosuppression, genetic polymorphism, or, more likely, a combination of several factors (59–64). Synthesizing the collective mechanistic process thus requires further research. For example, a study of blood samples collected from 46 Hungarian subjects with MRONJ was conducted. Genomic DNA was extracted, and a single nucleotide polymorphism analysis of the CYP2C8 gene was performed. The study results showed that the risk of mandibular localization of MRONJ was 19.2-fold higher in subjects with the AG genotype than in subjects with the normal GG genotype (65). Of additional note is a 2019 systematic review that reported cases of MRONJ not related to bone-targeting agents (antiresorptives) (66). Forty-two cases of MRONJ associated with biologicals were identified. The medications included bevacizumab, aflibercept, sunitinib, imatinib, cabozantinib, sorafenib, regorafenib, axitinib, pazopanib, desatinib, everolimus, temsirolimus, ipilimumab, and rituximab. In addition, cases associated with inhibitors of BRAF, dafrafenib, trametinib, and the immune checkpoint inhibitor nivolumab have also been reported. For example, a 2018 study of 204 consecutive patients who developed MRONJ identified seven patients (3.4%) who had received targeted cancer therapy (67). In this 2018 study, four of the 204 patients had received targeted cancer monotherapy, while the remaining three patients had been concomitantly treated with BPs and/or denosumab. Publication of these types of cases is important so that early diagnosis of MRONJ may ensue, leading to prompt management. Although the number of cases is currently small, it is likely that additional cases of MRONJ not associated with antiresorptives will be diagnosed as use of these biologics increases in the clinical setting. Although the experience with these cases is recent, it suggests that their management may lead to a shorter time of healing and better prognosis (58). However, this needs confirmation from clinical observation. Compromised Bone Metabolism The presence of antiresorptives and/or antiangiogenics is a common factor in all patients with the diagnosis of MRONJ. However, it appears that these medications alone may not be enough to lead to MRONJ formation. The science has been addressing the role additional factors can play in the development of MRONJ. In the jawbones, frequent microfractures and bone damage result from mastication and parafunctional habits including clenching and malocclusion (68). Following bone damage, pre-osteoblasts express RANK-L on their surfaces. The ligand binds to RANK receptors on the surface of pre-osteoclasts, which in turn activates osteoclast differentiation and function. The osteoclasts bind to damaged bone and secrete acids and cathepsin K that induce resorption of the damaged bone. When the resorption phase is completed, pre-osteoblasts mature into osteoblasts and secrete OPG that inhibits RANK-L and thus stops the recruitment of pre-osteoclasts. The modeling of normal bone physiology described above contrasts distinctly with mechanisms associated with antiresorptive drugs. Therefore, “old damaged bone” is spared and new bone is deposited over damaged bone (69). Lack of resorption of bone microfractures and microdamage of the skeleton could facilitate development of osteonecrosis (70,71). The antiangiogenic mechanism of BPs or of the newer antiangiogenic drugs used in the treatment of advanced tumors could lead to compromise of intra-bony circulation and/or blood vessel neoformation, contributing to development of MRONJ. In addition to bone necrosis per se, the overlying mucosa would be injured as well and thus provide opportunity for bacterial contamination and persistence of the lesion. This “inside out” theory would be further exacerbated by the presence of trauma. A study with beagle dogs treated for 3 years with alendronate has shown that the dogs also develop bone necrosis in the nonalveolar portion of the jaws (61,72). What must be considered in this scenario, both for humans and animals, is that the oral cavity is contaminated by a very complex microflora. In addition, periodontal disease is a very common oral disease and, in this case, a constant stimulus for alveolar bone remodeling. How would this work in a system in which bone remodeling is inhibited by the antiresorptive medication? A series of micro-computed tomography studies revealed the importance of altered bone metabolism in combination with presence of dental disease (18). Evidence from a rat model suggests that periodontal disease and potent BP therapy are sufficient for development of MRONJ. The lesions in rats were strikingly similar to those in humans, consisting of micro-computed tomography evidence of bone sequestration and extensive periosteal alveolar bone formation. Histological examination revealed necrotic bone with diffuse loss of osteocytes and empty lacunae, rimming of the necrotic bone by squamous epithelium and inflammation, and bone exposure to the oral cavity (18). Additional experimental studies have confirmed similar features in mice in the presence of periapical disease (19). Further studies have demonstrated in a novel mouse model the spontaneous development of MRONJ supporting a central role of osteoclast inhibition and dental disease in the pathogenesis of MRONJ (73). Soft Tissue and Cell Toxicity As stated in the previous paragraph, preclinical studies have suggested that, in addition to bone remodeling suppression, and dental disease, there may be soft tissue and cell toxicity at the site in which osteonecrosis develops (63,74,75). It has been shown that alendronate is toxic to the subcutaneous tissue in rats, inducing inflammation, micro-abscess formation, and necrosis (76). Other investigators have shown that low concentrations of zoledronate affect human gingival fibroblasts and keratinocyte cell lines through the induction of gene-regulated apoptosis (74). This possibility, however, has been contested because denosumab does not cause soft tissue toxicity. As noted previously, BPs accumulate in the alveolar bone in the jaws with prolonged use. Surgical manipulation of the area (eg, dental extraction) produces local release of BPs from the bone due to the acidic environment. Free BPs can be incorporated by overlying epithelial cells causing additional toxicity and thus inhibiting healing (60,64). Additional research has demonstrated that pamidronate inhibits keratinocytes in culture and that dose of medication is an important determinant of cell inhibition (63). Similar toxicity can be expressed in macrophages, in dendritic cell differentiation and maturation (77), and in fibroblasts when exposed to BPs (74,78). The possible role of monocytes and macrophages in MRONJ has been reported as well (79). Macrophages are affected by BP internalization and inhibition of the cholesterol synthesis and by induction of apoptosis (80,81). A deficiency in the monocyte or macrophage cell population could facilitate establishment of local infection. Denosumab has been reported to impair monocyte migration and function by blocking RANK receptors present on the cell surface and preventing RANK-L from activating the production of proinflammatory cytokines (79). This would favor the “outside in” mechanism of MRONJ development. This modeling would involve trauma to the oral mucosa, cytotoxic effects of BPs to cells and tissues, bacterial contamination of the area, and osteonecrosis development (82). Tooth extraction has been considered one of the main risk factors for the development of MRONJ (1,83). However, several experimental studies have demonstrated that the use of an antiresorptive medication and the presence of inflammation and infection can lead to MRONJ without participation of any traumatic event (18,19,84). It is known that dental extractions are typically performed because the tooth is severely fractured or because it has lost bone support due to the presence of dental disease such as localized periodontitis and infection. Having said this, it has been demonstrated that in some cases there is already alveolar bone necrosis at time of extraction, which is a fundamental reason why there is no healing of the bone following the extraction (17). Biofilm Investigators have demonstrated the formation of biofilm on the exposed necrotic bone and claim that infection would play an important role in the mechanism of MRONJ (85–87). The role that bacterial infection contributes in the process, however, has not been fully elucidated. Actinomyces organisms are present in biopsy specimens of MRONJ. These organisms have occasionally been reported as the principal infectious agent of MRONJ and in some case of ORN (88–91). Nevertheless, there is as yet no proof whether the microorganism is the true causative agent or is present as a secondary contaminant. Thus, a pathogenic role for Actinomyces as a single organism in the pathobiology of MRONJ remains controversial. As previously discussed, other pathobiological findings include suggestion of a genetic predisposition of some individuals to MRONJ by various investigators (92–94). Oral and Systemic Immune Function Chemotherapy and corticosteroids used for treatment of oncology patients could modify local oral tissue and systemic immunity. This interaction, associated with the effects of BPs, denosumab, and antiangiogenesis as well as presence of dental disease, could contribute to the multifactorial modeling currently considered in the development of MRONJ (21). The rationale of this modeling is that the oral microflora could become increasingly pathogenic. This could potentially account for the chronic nature of these lesions and contribute to the failure of standard treatments to induce healing. Does the Pathobiology of MRONJ Related to the Presence of Dental Disease Differ from MRONJ Lesions Classified as “Spontaneous Occurrences”? It is important at this stage of evolution of the MRONJ pathobiological model to emphasize that “spontaneous occurrence” has been reported in cases for which no specific clinical cause could be identified. The lack of robustness of the literature is not unique to MRONJ and is consistent with approaches adopted by researchers relative to other diseases for which the molecular and clinical modeling are at an early phase. The classification of “spontaneous occurrence” has been important for the MRONJ domain in that characterization has distinguished cases with documented cause, in contrast with those cases in which fundamental etiology was not identifiable by the investigator. As the MRONJ pathobiological modeling matures in the future, it is anticipated that incidence of “spontaneous occurrence” will diminish and the scope of causative factors will likely expand. This dynamic may or may not increase documentation of the total number of MRONJ cases. Regardless, this evolution will increase the precision of defining MRONJ causation as derived from an increasingly sophisticated, multi-factorial pathobiological model. Clinical Presentation and Management: Successes and Barriers MRONJ has been shown to occur more frequently in the mandible than the maxilla (95). In addition, a review of reported cases in the literature confirmed an association of MRONJ with the following diagnoses: multiple myeloma 46%, breast cancer 39%, prostate 6%, osteoporosis 4%, and others 5% (96). The higher prevalence of MRONJ with i.v. BPs is related to a higher bioavailability of i.v. BPs (>60%) compared with oral BPs (<1%). ZA has been shown to be 121 times more potent as alendronate. A 2010 systematic review demonstrated that case documentation and patient follow-up by dental experts could influence the prevalence of MRONJ, considering that most of the early reports of these oral complications included retrospective studies (97). The hallmark clinical presentation of MRONJ is characterized by the presence of exposed necrotic bone in an area of the oral cavity normally covered by mucosa or the presence of a fistulous tract. The site may be surrounded by inflamed tissues, present purulent secretion, and be painful. In advanced cases when the extent of necrosis increases, patients may complain of a tingling sensation or hyposensitivity (5,98). The most recent (2014) update of the American Association of Maxillofacial Surgeons confirmed the staging for MRONJ, with broad international acceptance among health-care providers (1). This classification presents different stages of development of MRONJ based on signs and symptoms and severity. One controversial aspect of this classification is the stage zero. This stage proposes that a patient in treatment with one of the medications associated with risk for development of MRONJ presents with clinical signs and symptoms of active infection, purulent secretion via the periodontium or a fistula, or pain, but necrotic bone cannot be clinically visualized. The controversial aspect of this staging classification is in discussion in the current literature. The modeling exemplified by stage zero, however, can be a very important consideration relative to potential early diagnosis of the complication (99). In regards to clinical risk factors, several aspects have been associated with the development of MRONJ, including the exposure to i.v. medication in cancer patients, poor oral hygiene, presence of active dental disease, concomitant chemotherapy and steroid use, wearing removable dental appliances, and invasive dental procedures (eg, dental extraction) (83,97,100,101). Dental extractions have been associated with MRONJ. However, it is not yet clear whether dental extractions are the causative agent of MRONJ or if the dental extraction is the final outcome of an irreversible process that initiated with compromised bone remodeling that leads to the necessity for an invasive dental procedure. Increased time on an antiresorptive or antiangiogenic agent is also an important factor; risk for development of MRONJ increases the longer the patients are on the medication (12,102). Nitrogen-containing BPs administered via i.v. infusion in cancer patients have been associated with most of the cases reported. Patients with multiple myeloma appear to be at highest risk (97,103). Management of MRONJ Prevention Current guidelines suggest that maintenance of optimal oral hygiene as well as diagnosis and medically necessary treatment of dental disease before the start of antiresorptive therapy decrease risk of development of MRONJ (104–107). These recommendations have been included in several available guidelines for the management of patients taking antiresorptive medications (28,42,106). Treatment There are a number of key clinical aspects of MRONJ that must be considered before managing a patient who has developed the lesion: Extent of bone necrosis is difficult to diagnose based on clinical examination. There is no standard for radiographic assessment via plain film technology (eg, periapical and/or panoramic radiographs). Advanced imaging technology such as CT, cone-beam CT, MRI, and scintigraphy may be helpful to guide the determination of extent of necrosis (108). Additional imaging considerations include: There is recent preliminary evidence that selected imaging features noted on panoramic radiograph (eg, mandibular cortical index) may predict future development of BP-related ONJ (109); however, further study is needed before a definitive conclusion can be made in this regard. Use of i.v. BPs in multiple myeloma patients may lead to alterations in the radiographic presentation of multiple myeloma in the maxilla and mandible (110). Thus, clinician vigilance is required in this context when viewing panoramic radiographs in these patients. The combination of clinical and radiographic evidence cannot, however, provide definitive diagnosis of early MRONJ. Quality of life must be considered based on number of affected sites, presence of active infection and malodor, level of pain, and neural involvement. Treatment of MRONJ with radical vs conservative therapy has to be evaluated on a case-by-case basis. In a systematic review, 13 studies reported management strategies for 658 MRONJ cases (97). A wide range of treatment strategies, from discontinuing BPs before invasive dental therapy and other conservative therapy to extensive bone debridement and bone resection, have been tested. The response to therapy was not clearly specified in one-half of these studies, but resolution was reported in 12% of the cases reported. Impact of MRONJ on quality of life has not been clearly established. Studies that have examined pain symptoms associated with MRONJ have noted pain in approximately one-half of the cases reported but with statistically significant differences noted across publications (10–90%) (97,111). There is increasing evidence that surgical excision of the necrotic bone and proper wound manipulation and suture are effective for treating MRONJ (112–115). This more recent information is beginning to change the classic paradigm that has recommended conservative therapy of MRONJ in stage I and stage II. However, the decision on how to best treat this complication depends on the preference and skills of individual professionals managing the patient with MRONJ. Treatment can be guided based on the previously cited American Association of Oral and Maxillofacial Surgeons staging system (1). It appears that in initial stages (stage I), a conservative management with antiseptic mouth rinses, antibiotics to control active infection, and minor debridement of necrotic bone should be used. In more advanced stages (II and III), a surgical approach can be used (116). More recent evidence suggests that even cases in earlier stages of MRONJ appear to have better outcomes when treated surgically (117). Two key currently unanswered issues are as follows: It is unclear how best to diagnose and treat cases of MRONJ when visible necrotic bone is not present in the oral cavity (Stage 0). As additional research becomes available, clinicians managing patients with suspicion of MRONJ without visible exposed bone should be aware on the best practices to diagnose and treat this oral complication. It is also currently unclear if discontinuing BP therapy will lead to sequestration of necrotic bone and healing. It is recommended that discontinuation of therapy should be based on the current medical status of the patient. Drugs must be discontinued by the prescribing physician or oncologist, and the risks and benefits of this procedure must be discussed with the patient. It must be considered whether discontinuation could lead to reactivation of bone metastatic lesions, increase risk for pathological fracture, and increase risk for skeletal pain. Several studies have addressed whether discontinuation of therapy can improve healing of MRONJ. A recent study has demonstrated that independent of modality of treatment and MRONJ stage at diagnosis, discontinuation of BPs before or at treatment initiation is associated with a faster resolution of symptoms compared with continuing the use of the medication (118). It appears that the continuation of therapy with the antiresorptives may delay in months the resolution of MRONJ (118). Experimental investigation compared the effect of discontinuation of ZA and the RANK-L inhibitor OPG-Fc in mice after the formation of MRONJ. Ten weeks after discontinuation, there was substantial healing of the areas of osteonecrosis in animals treated with OPG-Fc but not with ZA. This observation suggests that patients with MRONJ due to denosumab may heal faster than those on ZA when therapy is discontinued (119). The use of parathyroid hormone has been reported as a possibility to rescue the osteonecrotic bone. A recent experimental study demonstrated the wound-healing effect in ovariectomized rats with MRONJ (120). Anecdotal case reports suggesting the positive effect of parathyroid hormone have been published in humans, but a prospective controlled study is lacking (121). Setting the Stage for Future Research Evidence Gaps for Current Clinical Management Prevention, with the goal of identifying those patients who are at clinically significant risk for development of MRONJ; and management of MRONJ Enhanced understanding of the impact of dosing frequency and duration of antiresorptive therapy Clinical or Translational Research with Promise for Clinical Application in the Future Further strategic development of evidence-based guidelines for the management of patients with MRONJ Development of a screening panel comprising risk factors associated with: patient characteristics (age, sex, co-morbidities, concomitant medications, genetics); oral health (periodontal disease, infection, caries, oral hygiene habits); serum markers (c-terminal telopeptide, n-terminal telopeptide, alkaline phosphatase, calcium, phosphorus, parathyroid hormone, vitamin D); dosing regimen of the antiresorptive agent (type, dose, exposure time); malignant disease (multiple myeloma, breast, prostate, lung, others) Key Research Questions Basic Science Research Based on current gaps in the evidence relative to MRONJ etiopathogenesis as described in this paper, there are a number of novel basic science research opportunities that in turn could inform translational or clinical research in the future: Effect of long-term suppression of osteoclast function on bone remodeling Effect of long-term antiresorptive medications on host immune defense mechanisms (dendritic cells, macrophages, and granulocytes) Effect of long-term antiresorptives on angiogenesis of mucosal and osseous tissues Effect of long-term antiresorptives on osteocyte viability Identification of specific markers for risk assessment and diagnosis Role of immune suppression and/or suppressed angiogenesis on development of MRONJ Impact of cumulative dose of BPs on the bone marrow environment Translational Research Development of novel methods for diagnosis and management. Design of preventive, drug-specific protocols Clinical Research Further delineation of the frequency of MRONJ across diverse cancer patient cohorts Extent to which the human cost (ie, morbidity and mortality) as well as economic cost are affecting utilization of health-care resources Best preventive strategies in relation to prioritization of oral risk factors Optimal technique to determine extent of bone necrosis (eg, imaging, biopsy, other) Decision-making regarding conservative vs more radical treatment of MRONJ, and the role if any a drug holiday would contribute to MRONJ treatment outcome Degree to which the treatment plan for management of MRONJ is influenced by the presence or absence of exposed bone Risks vs benefits of discontinuation of antiresorptive therapy relative to MRONJ prevention and/or treatment Notes Affiliations of authors: Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL (CAM); Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC (MTB); Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, and Head & Neck Cancer/Oral Oncology Program, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (DEP). C. Migliorati receives consulting fees from Amgen Inc as well as Optum Epidemiology. This consulting activity is related to the content of this manuscript. C. Migliorati received consulting fees from Colgate, which is not related to the manuscript. M. Brennan is a consultant for AFYX and Medimmune. D. Peterson receives consulting fees from Amgen Inc as well as Optum Epidemiology. This consulting activity is related to the content of this manuscript. D. Peterson also receives consulting fees from PSI CRO, SAI MedPartner LLC, and AEC Partners, and receives consulting fees from and holds equity ownership in Applied Glycan Technologies, Inc. None of this latter consulting activity is related to the content of this manuscript. For support see Funding Acknowledgement section of Monograph. References 1 Ruggiero SL , Dodson TB , Fantasia J , et al. . American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update . 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Journal

JNCI MonographsOxford University Press

Published: Aug 1, 2019

References