Medication-related osteonecrosis of the jaw: a narrative review of risk factors, diagnosis, and management

Introduction

According to the American Association of Oral & Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) is defined as (I) current or previous treatment with an antiresorptive, such as bisphosphonate (BP) and denosumab, or antiangiogenic agents; (II) exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for longer than 8 weeks; and (III) no history of radiation therapy to the jaws or obvious metastatic disease to the jaws (1). Those at risk for MRONJ include osteoporotic and oncologic patients treated with antiresorptive and/or antiangiogenics. Cancer patients treated with high-dose antiresorptives are at the highest risk with an incidence of up to 1.9% (1), but recent population-based studies reveal an incidence of up to 6.6% (2) . Of note, MRONJ is a rare disease and studies with smaller sample sizes tend to overestimate incidence.

Since the release of the AAOMS white paper in 2014, there has been a growing list of contributory drugs and risk factors, strategies for diagnosis, and treatment techniques. This narrative review aims to provide an up-to-date and detailed summary of the risk factors, diagnosis, and management for MRONJ. We present this article in accordance with the Narrative Review reporting checklist (available at https://fomm.amegroups.com/article/view/10.21037/fomm-21-106/rc).

Methods

A search of the literature was performed, using PubMed, OVID, Lexicomp, and UpToDate databases for articles published from 2002 to 2021, prioritizing articles from 2014 until and including 2021, in English. Medical Subject Heading search terms and free text terms in different combinations were used to research the subjects addressed in this review. The following terms and variants were searched: medication-related osteonecrosis of the jaw, bisphosphonate-associated osteonecrosis of the jaw, antiresorptive, antiangiogenic, extraction, periodontal disease, periapical disease, cancer, pathogenesis, bone remodelling, infection, immunity, diagnosis, computed tomography (CT), Actinomyces, C-terminal cross-linking telopeptide (CTX), drug holiday, conservative therapy, surgical therapy, teriparatide, and statin. Articles were sorted by cited references, and systematic reviews of randomized controlled trials and prospective cohorts were prioritized. This search was supplemented by reviewing the references of pertinent articles and including them in the search. Articles with full-text available online were selected and analyzed. Data were presented in text in the form of a narrative review. Citations were tracked using Mendeley version 1.19.8. The search strategy has been summarized in Table 1 and an example using OVID-Embase has been employed in Table 2.

Discussion

Etiology and risk factors

MRONJ has a multifactorial etiology and occurs from a combination of initiation factors, patient related factors, and medication related factors.

Initiation factors

Invasive procedures

Dentoalveolar surgery is a major risk factor precipitating osteonecrosis of the jaw (ONJ) in antiresorptive and/or antiangiogenic treated patients. In particular, tooth extraction has been cited in prospective trials as the common precipitating factor in 61.8% of MRONJ cases (3). Following tooth extraction, AAOMS estimates the risk of developing MRONJ at 0.5% and up to 14.8% in patients exposed to oral and intravenous (IV) BPs, respectively (1). There is a lack of data defining MRONJ risk following dental implant placement, endodontic, or periodontal procedures that involve manipulation of bone, but the AAOMS estimates a comparable risk with tooth extraction (1).

Other initiation factors

MRONJ may also occur spontaneously from mucosal trauma, thin overlying mucosa, or excess biting force. A randomized controlled trial in rats demonstrated that oral mucosa injury was an initiating factor for MRONJ, but was less likely to induce ONJ than tooth extraction (4). Chronic irritation from an ill-fitting denture causing mucosal trauma may act as an initiating factor for MRONJ (5). Studies have demonstrated an increased prevalence of MRONJ among denture wearers in cancer patients treated with IV BPs (6).

MRONJ is more prevalent in areas of bony prominences, such as exostoses, tori, and mylohyoid ridge, because the overlying mucosa is thin and poorly vascularized (7). Thin overlying mucosa and large tori that are often traumatized may lead to ulceration and possible initiation of MRONJ pathogenesis (5).

Excess biting force leading to microdamage may be another cause of spontaneous MRONJ. In rats exposed to IV BP, a decrease in bone remodelling led to a significantly greater amount of microcrack accumulation compared with placebo (8). These microcracks have been suggested to compromise the biomechanical integrity of the jawbone and to act as a nidus for infection and subsequent osteonecrosis (8). Excess biting forces may also explain the 2-fold increase in incidence of MRONJ in the mandible compared with the maxilla (9). In particular, the posterior mandible is subject to the highest loading forces and reflects the greatest prevalence of MRONJ (9). Traumatic occlusion may also be a contributing factor.

Patient-related factors

Oral risk factors

Patients may present with oral or systemic factors that increase their risk for MRONJ. Oral risk factors include periapical and periodontal disease, ill-fitting dentures, and traumatic occlusion. Periapical and/or periodontal disease are found more commonly among patients who develop MRONJ compared with those at high risk but don’t develop MRONJ (10,11). In mice models, the combination of periapical or periodontal disease and IV BP therapy was sufficient to induce MRONJ (12,13). Clinically, most reported MRONJ cases occur after extraction of teeth with periapical disease or periodontal disease (12). Additionally, improvements in dental hygiene has shown to prevent MRONJ in cancer patients (14). However, inflammatory dental disease as a risk factor for MRONJ may be confounded by tooth extraction, a strong initiating factor.

As described in the initiating factors section, ill-fitting dentures and traumatic occlusion may lead to spontaneous MRONJ from mucosal trauma and microcrack accumulation.

Systemic risk factors

Systemic risk factors include cancer type and comorbidities that impair immunity. Cancer types at risk for MRONJ from antiresorptive therapy include primary bone malignancy, such as multiple myeloma, and solid tumours with bone metastases, such as breast, prostate, and lung cancers (15). MRONJ occurrence is the greatest in multiple myeloma, followed by lung, prostate, and breast cancer (15).

Cancer types at risk for MRONJ from antiangiogenics include metastatic renal cell carcinoma, ovarian cancer, breast cancer, colorectal cancer, non-small-cell lung cancer, and glioblastoma multiforme (16). Antiangiogenic-related MRONJ occurrence among antiresorptive-naïve cancer patients is the greatest in metastatic renal cell carcinoma, followed by metastatic colorectal cancer and metastatic breast cancer (16). Metastatic renal cell carcinoma demonstrates a further increase in MRONJ incidence when treated with antiangiogenics in combination with antiresorptives, especially with sunitinib or bevacizumab and IV zoledronate (17,18).

Comorbidities that impair immunity include rheumatoid arthritis, uncontrolled diabetes, chronic corticosteroid use, and smoking. All of these factors are inconsistently associated with an increased risk of MRONJ. Rheumatoid arthritis patients who develop osteoporosis as a complication may be prescribed an oral BP, which poses a theoretically low risk for MRONJ (19). Randomized controlled trials in mice demonstrate that rheumatoid arthritis is significantly associated with MRONJ if IV zoledronate is given at an oncological dose (20). However, most rheumatoid arthritis patients receive a much lower dose, thus this association is weak.

Uncontrolled diabetes is thought to increase MRONJ risk through multiple pathways of injury. High blood sugar alters macrophage function, inhibits bone remodelling, and leads to microvascular ischemia—all of which contribute to MRONJ pathogenesis (21). Diabetic mice have shown a higher prevalence of MRONJ, but human studies show variable association with MRONJ (21). Thus, uncontrolled diabetes is not an established risk factor for MRONJ.

Chronic use of glucocorticoids has been shown to cause osteonecrosis at sites other than the jaw, such as the hip, from a decrease in bone perfusion and osteocyte apoptosis (22). However, controlled trials in cancer patients treated with antiresorptives and concomitant glucocorticoids only showed a marginal increase in MRONJ incidence compared to those treated with antiresorptives alone (3).

Smoking is thought to be a risk factor for MRONJ, but evidence is equivocal (15,23). Smoking is associated with poor oral health, which in turn, increases risk for MRONJ (23).

Medication-related risk factors

Medication-related risk factors pertain to treatment with BPs, denosumab, and antiangiogenics. There is also a growing list of drugs associated with MRONJ.

Antiresorptives

Antiresorptive therapy include BPs and receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitors, both of which inhibit bone remodeling for the management of osteoporosis, primary bone malignancy, and solid tumours with bony metastases. BPs are classified via their side chain groups into either nitrogen containing BPs (N-BPs) or simple BPs (S-BPs), which have differing mechanisms of action (24). N-BPs inhibit farnesyl pyrophosphate synthase to block cholesterol biosynthesis leading to osteoclast apoptosis (24). S-BPs do not contain nitrogen and are instead metabolized into non-hydrolysable adenosine triphosphate (ATP), which is cytotoxic and accumulates in osteoclasts to trigger apoptosis (24). The ability for BPs to inhibit farnesyl pyrophosphate synthase determines potency, where the presence of a nitrogen containing side chain may increase a BPs antiresorptive potency by 10–10,000 folds with respect to S-BPs (24). For its strong affinity for hydroxyapatite and high molecular stability, BPs typically have a very long half-life and may persist in bone for the patient’s lifetime (24).

Denosumab is a human monoclonal antibody with affinity for the cytokine RANK-L (25). Normal bone remodelling depends on a balance of RANK-L and osteoprotegerin, both released by osteoblasts (25). RANK-L binds to its receptor (RANK) on osteoclast and osteoclast precursors to trigger bone resorption, whereas osteoprotegerin binds RANK-L to prevent its interaction with RANK (25). Like osteoprotegerin, denosumab binds RANK-L to inhibit the activation, migration, differentiation, and fusion of hematopoietic cells of osteoclast lineage to decrease bone resorption (25). Different from BPs, denosumab does not accumulate in bone tissue, thus is fully reversible with a half-life of approximatively 25–28 days (25).

It has been well established that the risk of MRONJ in antiresorptive exposed patients depends on dose, schedule, and duration (1). For BPs, there is a greater risk of MRONJ with IV compared with oral administration because of increased bioavailability (140-fold); zoledronate compared with pamidronate because of increased potency (100-fold); treatment duration over four years; and IV zoledronate on a monthly compared with 12-week dosing schedule because of greater cumulative dose (24,26,27). Similarly, there is a greater risk of MRONJ when denosumab is prescribed at the higher dose and frequency of 120 mg every month to treat cancer versus 60 mg every 6 months to treat osteoporosis (28). Recently, studies have demonstrated that by extending the dosing interval of IV zoledronate from 4 to 12 weeks in breast cancer patients, MRONJ incidence decreased without an increase in skeletal related event (29). There has been limited safety data addressing the effect of extending the dosing interval for denosumab from 4 to 12 weeks in preventing skeletal related events (30).

Antiangiogenic agents

Antiangiogenic agents are increasingly being used in targeted cancer therapy to inhibit tumour angiogenesis (31). By modulating growth factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), these drugs prevent the formation of new blood vessels from pre-existing ones to inhibit tumour growth (31). There are three categories of antiangiogenic agents targeting VEGF, including anti-VEGF monoclonal antibodies (bevacizumab), VEGF decoy receptor (aflibercept), and small molecular tyrosine kinase inhibitors (TKIs) that block VEGF receptors downstream (sunitinib, cabozantinib, sorafenib, dasatinib) (31). Moreover, other agents that target mammalian target of rapamycin (mTOR) inhibit angiogenesis by affecting the production of VEFG and PDGF (temsirolimus, everolimus) (31).

The antiangiogenics mentioned above have been shown to be associated with MRONJ in antiresorptive naïve patients (16). In addition, antiangiogenics in combination with antiresorptives demonstrate a greater risk of MRONJ than in those treated with antiresorptives alone, especially bevacizumab or sunitinib in combination with IV zoledronate (17,18).

Drug of emerging importance related to MRONJ

There has been an increasing number of case reports demonstrating that MRONJ is not limited to antiresorptives and antiangiogenic agents, but may also be associated with other drugs. Raloxifene, methotrexate, and tocilizumab have demonstrated a link with MRONJ, although the relationship is insufficiently characterized.

Raloxifene is a selective estrogen receptor modulator used to prevent osteoporosis in post-menopausal women (32). Raloxifene is preferred over BPs in younger patients with fewer risk factors for new osteoporotic fractures (32). Although the relationship between MRONJ and raloxifene is not as strong compared to its association with other antiresorptives, case reports have described MRONJ in raloxifene treated patients without a history of BP use (33,34). Further studies with sufficient power are required to explore this rare clinical event.

Methotrexate is an antimetabolite that inhibits DNA synthesis and replication (35). Methotrexate and BPs may be used to treat rheumatoid arthritis, and complications leading to oral bone exposure may arise from both these medications. Methotrexate may cause lymphoproliferative disorder, which rarely manifests in the oral cavity to cause bone exposure (35). Recently, Henien et al. described 2 cases of MRONJ in long-standing arthritis patients treated with low-dose methotrexate in the absence of lymphoproliferative disorder, antiresorptives, or antiangiogenics (36).

Tocilizumab is an anti-interleukin-6-receptor monoclonal antibody used to treat rheumatoid arthritis. In 2018, Bindakhil and Mupparapu reported a case of osteomyelitis with features of MRONJ in a osteoporosis and rheumatoid arthritis patient treated with tocilizumab, with no history of BP use (37). Furthermore, tocilizumab and sarilumab, another inhibitor of interleukin-6 signalling, are currently being investigated in clinical trials for off-label use to reduce mortality in critically ill COVID-19 patients (38). As a result of increased use, there is a potential risk that dentists may encounter a higher number of patients at risk for MRONJ in the future.

Pathogenesis

Oversuppression of bone remodeling

The oversuppression of osteoclastic bone resorption by antiresorptives may play a role in the development of ONJ. Since both BP and denosumab are associated with ONJ but inhibit bone turnover through different mechanisms of action, this strongly suggests that oversuppression of bone is a contributory factor. Suppressing bone turnover leads to the accumulation of non-renewed, hypermineralized bone and a decrease in microvasculature, which predisposes the bone to osteonecrosis upon injury. The differential predisposition of MRONJ for the jaws occurs because alveolar bone shows increased remodeling rates compared to bones in the axial and appendicular skeleton, as per animal data (39). As a result, antiresorptives preferentially target osteoclasts at sites of increased turnover in the jaws. This preference is also seen at local sites of increased turnover, such as extraction sites or areas of periodontal/periapical inflammation, which demonstrate higher accumulation of BPs as per mouse data (40). Preliminary clinical findings show that the administration of teriparatide, a synthetic recombinant human parathyroid hormone, has shown to improve MRONJ symptoms (41). Teriparatide indirectly stimulates osteoclasts to counter suppression during antiresorptive therapy, which supports the oversuppression of bone remodeling hypothesis.

However, a clinical study showed that bone turnover in the mandible and maxilla is not overly suppressed by BPs, thus oversuppression is likely not the sole causative factor for MRONJ (42). Additionally, ONJ has yet to be reported among patients with metabolic conditions of reduced bone turnover, such as hypoparathyroidism.

Infection and impaired immunity

Infection and impaired immunity may be possible contributing factors to MRONJ development. Poor oral hygiene and inflammatory dental disease have shown to be highly associated with MRONJ. Bacteria are also commonly cultured from biopsy of necrotic bone, which implicates infection as a pathological mechanism. However, there is uncertainty about whether necrosis precedes or follows infection and the role of infection as a pathological trigger has been questioned.

The oral cavity is particularly susceptible to infection and osteonecrosis because of the presence of potentially pathogenic bacteria, frequent opportunities for injury, and close proximity to bone (43). During injury, wound healing is impaired by antiresorptive-mediated local immune depression, which facilitates infection leading to necrosis (43).

BPs have been shown to cause direct soft tissue and immune cell toxicity. In vitro studies demonstrate that BPs localize to oral epithelium to induce apoptosis and decrease proliferation, which predisposes the oral mucosa to breakdown or disrupted healing after trauma (44,45). Upon disruption of the oral mucosal barrier, bacteria invade the wound site and trigger an inflammatory response which increases bone resorption. Bone resorption is exacerbated in the presence of BPs, which inhibit bone remodelling. BPs have also been shown to alter macrophage migration and morphology, leading to local immune depression to facilitate infection (43). A clinical study has shown greater macrophage immunosuppression in MRONJ compared with osteonecrosis from other causes, which supports a link between the two (46).

Denosumab does not cause soft tissue toxicity, but RANK receptors are present on immune cells, such as macrophages (47). Through inhibition of RANK-L, denosumab decreases macrophage function and survival (47), which may contribute to infection in MRONJ.

Angiogenesis inhibition

Inhibition of angiogenesis may contribute to MRONJ pathogenesis through bone ischemia leading to necrosis upon injury. Both IV zoledronate and antiangiogenic agents inhibit angiogenesis. In vitro studies demonstrate that zoledronate inhibits endothelial cell proliferation, migration, and adhesion (48), and cancer patients treated with IV zoledronate demonstrate lower circulating VEGF levels (49). In cancer patients treated with IV zoledronate, inhibition of angiogenesis, measured through serum VEGF levels, has been shown to be a potential predictive marker for MRONJ (50).

Antiangiogenics, such as sunitinib, have shown causative effects in MRONJ development. A metastatic renal cell carcinoma patient with established MRONJ from IV zoledronate and concomitant sunitinib exhibited improved symptoms upon discontinuation of sunitinib (51). This same patient experienced worsening of MRONJ symptoms upon resumption of sunitinib (51), supporting the role of the involvement of antiangiogenics in MRONJ pathogenesis.

The inhibition of angiogenesis is not likely to be the central factor in MRONJ development because MRONJ has been shown to occur in the absence of angiogenesis inhibition. For instance, in vitro studies have shown that denosumab does not inhibit angiogenesis (52).

Diagnosis

Currently, the diagnosis of MRONJ based on clinical parameters alone. Findings during imaging are non-specific but may contribute to early detection and provide aid in surgical treatment planning. Histologic features are not specific for MRONJ among other osteonecrotic lesions. The relationship between blood tests and MRONJ has yet to be established.

Clinical presentation

The hallmark sign of MRONJ is exposed areas of bone that persists for greater than 8 weeks, despite appropriate management (53). These areas of exposed bone may remain asymptomatic for weeks, months, or years, and symptoms may not arise until the surrounding soft tissue becomes inflamed (53). Before osteonecrosis becomes clinically detectable, a patient may present with non-specific oral, dental, or soft tissue symptoms. Common intraoral findings include tooth mobility, non-healing ulcerations, and local bone or soft tissue infections (53). Some patients may experience paresthesia in the affected areas because of neurovascular compression from surrounding inflammation (53). Patients with orofacial pain may experience non-odontogenic tooth pain, dull aching mandibular bone pain that may radiate to the temporomandibular joint, and maxillary sinus pain (53). Chronic maxillary sinusitis secondary to osteonecrosis with or without oral antral fistula may be a presenting symptom in patients with maxillary bone involvement (53). Intraoral or extraoral fistulae may develop when necrotic bone becomes secondarily infected (53).

After reviewing patient symptoms, follow-up with a thorough medical history is required to distinguish a clinical picture of MRONJ. Investigations into initiating factors, patient-related factors, and medications-related factors can be used to determine which patients are at high risk. Excluding a history of radiation therapy and metastases to the jaws is crucial for diagnosis, especially because many candidates for MRONJ present with cancer.

The size and severity of lesions are classified by the AAOMS on a grading system from stage 0 to stage 3.

Imaging

The American Society of Clinical Oncology (ASCO) and Cancer Care Ontario recommends that a routine dental exam with radiographs and any pending dental problems be tended to before commencement of BPs (54). As a baseline, intraoral radiographs and a panoramic image should be taken (54). Intraoral and panoramic imaging are important tools for detecting dental disease and monitoring for osteonecrotic changes in the jaws. The presence of dental disease, such as periodontal and periapical disease, increases risk of MRONJ and should be detected early. Early stage MRONJ often show little abnormalities on plain radiographs because of a lack of decalcification, but non-specific findings may be present. CT is more sensitive to changes in bone density than plain radiographs and have an enhanced ability to detect early osteonecrotic changes. In descending order of prevalence, radiographic features of MRONJ include mixed lytic-sclerotic areas, osteolytic changes, osteosclerosis, cortical bone erosion, poorly healing or non-healing extraction socket, periodontal ligament widening, mandibular canal involvement, and thickening of the lamina dura (55). More progressed disease may also reveal periosteal reaction, sequestrum, pathological fracture, and density confluence of cortical and cancellous bone (55).

CT may be used to delineate ONJ lesions for surgical treatment planning, but imaging may underestimate the extent and severity of affected bone (53). CT is accurate for detecting changes in progressed MRONJ after bony destruction but has limited ability to detect early changes in bony architecture with early disease. As an adjunct for surgical treatment planning, fluorodeoxyglucose (FDG) positron emission tomography (PET) with CT may be used, which has shown to detect metabolic changes in ONJ before bone destruction that may not be detected with conventional plain film and CT imaging (56). FDG PET-CT may facilitate the decision between marginal versus segmental resection, depending on FDG uptake superior versus inferior to the mandibular canal (57).

Biopsy and pathology

The histopathological features of MRONJ does not provide a conclusive diagnosis distinguishing osteonecrosis from other causes, such as osteoradionecrosis and chronic osteomyelitis. Factors such as bone status (vital, necrotic, reactive), presence of osteoclasts, inflammation, vascularization, and presence of bacteria were not specific for MRONJ (58,59). Instead, histologic staining for Actinomyces species is a common finding among MRONJ lesions (58). In advanced stages, exposed bone may become secondarily infected and can involve surrounding soft tissue. Signs of secondary infection include purulent discharge from exposed bone and soft tissue erythema. In these cases, microbial culture may be used to guide antibiotic therapy in an attempt to resolve infection. Typically, microbial culture of exposed bone reveals normal oral microbes, but patients with extensive soft tissue involvement may show biofilms with bacteria in combination with fungi and viruses, which are difficult to treat without targeted therapy. If surgical intervention is chosen, biopsy of resected bone may be useful in ruling out other pathology, such as jaw metastases in cancer patients (60). Histologic analysis of resected bone margins may not correlate with clinical outcome because relevant prognostic factors have yet to be identified (60). Resected bone does not exhibit any unique physical properties that would lead to reliable MRONJ diagnosis.

Serum testing

CTX is released during type 1 collagen degradation, and serum levels are used as a biomarker for bone turnover (61). Antiresorptives lead to lower CTX levels, and Marx et al. previously proposed that fasting CTX levels below 150 pg/mL suggests oversuppression of bone turnover, which may serve as a prognostic factor for MRONJ risk (62). However, this strategy has not been supported by the literature, and CTX <150 pg/mL is not associated with an increased prevalence of MRONJ (61).

Management

Prevention before therapy

Prior to commencement of antiresorptive and/or antiangiogenic therapy, the patient should be informed that these medications are associated with a low incidence of MRONJ. Risk can increase if the appropriate measures are not taken by patients and health care providers. MRONJ may be prevented by limiting patient related factors, initiation factors, and medication related factors.

Patients should be counselled to minimize modifiable risk factors for MRONJ, such as poor oral hygiene, smoking, and uncontrolled diabetes mellitus (11). Preventive measures before the onset of treatment and regular follow-up every 3 months have shown to significantly reduce the incidence of MRONJ (63).

If the underlying condition permits, commencement of medications should be delayed until appropriate dental treatment is rendered, such as scaling, restoring caries, controlling periodontal and periapical disease, extracting non-restorable and/or hopeless teeth, relining ill-fitting dentures, and possible removal of bony tori. Controlling dental disease before therapy will reduce the risk for MRONJ and minimize the need for extractions during therapy. Ideally, all extractions should take place before therapy, and medications should be suspended until adequate mucosal healing at 45–60 days (11). Removable dentures should be inspected for sore spots or areas of mucosal trauma, especially along the lingual flange, and relined if necessary (5). Prophylactic excision of bony prominences, such as exostoses or tori, may play a role in decreasing the risk of MRONJ (7). The choice to excise should be determined case-by-case and is based on the extent of surgery required, the frequency of traumatizing bony prominences, and the thinness of overlying mucosa.

In regard to medication-related triggers of ONJ, health care providers should be aware of the following updates to clinical guidelines. ASCO demonstrated that there was no difference in skeletal related events when patients with metastatic breast cancer were treated with 4 mg of IV zoledronate every 3–4 weeks or every 12 weeks (64). Thus, a longer dosing should be considered, when possible, to avoid an increased risk of MRONJ from more frequent exposure. Also, the Food and Drug Administration (FDA) demonstrated little benefit to IV zoledronate or oral alendronate use beyond 3 or 5 years, respectively, in the post-menopausal osteoporosis population who do not have a high risk of fracture (65,66). Specifically, there was no difference in bone mineral density or fracture incidence in osteoporosis patients who continued BP therapy past 3–5 years when compared to placebo (65,66). Therefore, discontinuation of BP therapy after 3–5 years should be considered, when possible, to decrease the risk for MRONJ from long-term use.

Prevention during/after therapy

During antiresorptive and/or antiangiogenic therapy, conservative dental treatments are recommended, such as scaling, restorative, and endodontic treatment, in order to maintain good oral health (11). Orthodontic treatment is possible, but longer treatment times and poor tooth movement should be expected because of decreased bone remodeling from antiresorptive therapy (67). Adjustments to removable prostheses should be made if compression to soft tissue is present, and fixed prostheses should be planned with supragingival margins to facilitate oral hygiene (11).

Additional considerations should be taken for invasive procedures that involve manipulation of alveolar bone. Elective dentoalveolar surgery, such as implant and mucogingival surgery, should be avoided, but surgery is indicated if aimed at eliminating infection that cannot otherwise be resolved (11). Withholding antiresorptives and/or antiangiogenics prior and after dentoalveolar surgery (drug holiday) may be considered. Drug holidays are typically initiated 1 week prior to an invasive procedure (except bevacizumab), and drug resumption occurs 4–6 weeks after or until adequate mucosal healing (11). The use of drug holidays for BPs is controversial, and the current ASCO guidelines state that there is insufficient evidence to support or refute its use, considering its long half-life (68). It is thought that withdrawal of BPs decrease localization to the extraction site to prevent BP antiangiogenic effects to promote wound healing (11). However, since BPs remain in the bone for years after termination of therapy, a drug holiday may be ineffective (69).

For denosumab prescribed for osteoporosis, the dosing schedule includes a 6-month latency, wherein invasive procedures may be performed, thereby avoiding the need for a drug holiday. Invasive procedures should be performed 4 weeks after the last injection of denosumab, beyond its half-life, and no later than 6 weeks before the next injection (11). For denosumab prescribed in cancer patients with a 1-month dosing schedule, the provider must decide if the benefits outweigh the risks for a drug holiday. A drug holiday may be beneficial in preventing MRONJ because of the short half-life, but denosumab has shown an increased rate in progression-free survival compared with BP in cancer patients (69). Currently, there are no studies that show drug holiday for denosumab has any effect in preventing MRONJ (69).

Bevacizumab should be suspended for 6–7 weeks before an invasive procedure because of its increased risk for wound healing complications (70). Bevacizumab may be resumed 4–6 weeks after surgery, and other antiangiogenics, like sunitinib and everolimus, may follow the typical course for drug holidays (11).

There are limitations in studying the effectiveness of drug holidays because MRONJ has a low incidence and there is a great variation within patients, impairing the ability to conduct high quality studies. If a drug holiday is chosen, this decision must be agreed upon with the prescribing physician and must be in the best interest and safety of the patient.

Other preventive measures for dentoalveolar surgery in high-risk patients include antibiotic prophylaxis and applying autologous platelet concentrates. In invasive procedures, peri-operative antibiotics have shown to have a protective effect against MRONJ by mitigating infection (71). Penicillin, tetracyclines, and metronidazole have shown a moderate effect for MRONJ prevention (71). Platelet concentrates are commonly used in regenerative procedures in dentistry to promote soft tissue wound healing, but its use in preventing MRONJ at extraction sites is not established. There is no significant difference between using or forgoing platelet concentrates to prevent MRONJ after extraction, but its use has not shown to be detrimental (72).

Treatment of MRONJ

The treatment goals for MRONJ include (I) preventing the spread of MRONJ or new sites of necrosis; (II) preserving quality of life by relieving symptoms of pain and controlling infection; (III) educating the patient about the importance of oral hygiene and follow-ups with the dentist (53). Treatment depends on the severity of MRONJ lesion, and AAOMS recommends a graded approach. Generally, treatment is divided into conservative and aggressive therapy. Conservative therapy comprises of good oral hygiene, antimicrobial mouth rinses, systemic antibiotics, and limited debridement (68). Aggressive therapy includes surgical intervention, such as mucosal flap elevation, resection of necrotic bone, and soft tissue closure (68).

Regardless of stage of disease, removal of necrotic bone and loose sequestrae should be considered to relieve source of soft tissue irritation (1). Moreover, extraction of symptomatic teeth within exposed, necrotic bone does not appear to exacerbate the established necrotic process and should be considered to preserve quality of life (1). Stage 0 patients should be informed that there is approximatively 50% chance of progression to stage 1, 2, or 3 and appropriate conservative measures should be taken (73). Conservative measures are the first choice in MRONJ therapy and are effective for stages 0 and 1 (74). However, this approach in stage 2 and 3 most often provides symptomatic relief and may not lead to complete resolution (75). Approximatively less than 20% to above 50% of MRONJ lesions resolve via conservative management (75). Aggressive therapy is a more curative option but is only indicated in severe MRONJ with pathological fracture, extensive osteolysis, and extraoral and/or intraoral fistula (76). Aggressive therapy is also indicated in symptomatic MRONJ refractory to conservative measures (76). A 90% success rate has been reported in MRONJ managed via surgical resection (77).

Aggressive therapy is more predictable in early stage MRONJ because complete resection of necrotic bone is possible without injury to adjacent anatomical structures (76). It is thought that necrotic bone has no ability to revitalize and acts as a nidus for infection and further progression (78). Therefore, the rationale of removal of necrotic bone in stage 1 or 2 MRONJ is to promote complete healing without local infection and improve quality of life (78). Giudice et al. prospective cohort has shown high success in lesion downstaging and mucosal healing with stage 1 and 2 surgical intervention (78). Also, El-Rabbany et al. systematic review and meta-analysis compares surgical versus medical therapy for MRONJ, which demonstrates better resolution with lower rates of relapse in the surgery group (79). Nevertheless, the decision for early surgery should be balanced by patient health status and compliance. A patient may be a greater candidate for conservative therapy with increased compliance for keeping the affected area clean and attending follow-up appointments.

Later stage MRONJ patients suffer higher morbidity because of the size of resection required, which may lead to anesthesia or paresthesia of the mandibular nerve, discontinuity of the mandible, and/or hemimaxillectomy (76). In larger defects, reconstruction techniques include local and free flaps. Pedicled buccal fat pad flaps have a very rich vascular supply and have shown reasonable success in oral mucosa reconstruction in defects up to 62 mm × 18 mm (80). These local flaps demonstrate no severe donor site morbidity and high aesthetics because of good color match to adjacent oral mucosa (80). Free flaps with microvascular reconstruction may be used to address larger defects. Caution should be taken when using autogenous grafts in cancer patients with bone malignancy because the possibility of transferring cancer cells to the oral cavity (81). Studies have yet to assess this risk, but reports from case studies have demonstrated that free flaps have over 96% success rate in MRONJ reconstruction (82). Fibular grafts are favoured in cancer patients because the fibula has a low incidence of primary bone malignancy or metastatic bone disease (60). Typically, grafts from the iliac crest and scapula are preferred for oral reconstruction because of rich bone marrow, but they are more commonly affected by malignancy (60). A PET scan or bone scintigraphy may be used to assess donor site viability and to rule out cancer (60).

An additional consideration for cancer patients is that bone morphogenic proteins are contraindicated because they promote cancer development, which limits their use in reconstruction (83). For patients without a history of bone malignancy, case reports have shown preliminary results supporting the use of bone morphogenic proteins for reconstruction in severe MRONJ (84).

Emerging therapies for MRONJ

Other emerging therapies have limited data demonstrating a potential benefit and none are considered a standard approach as of today.

Teriparatide has been FDA approved for treatment of osteoporotic patients without cancer or prior radiation to bone (41). For its ability to stimulate bone remodelling, teriparatide has been suggested as treatment for MRONJ refractory to conventional conservative measures prior to pursuing surgical intervention. A small randomized trial studying patients with MRONJ secondary to osteoporosis or bone malignancy showed a significantly greater rate of resolution in patients supplemented with teriparatide compared to conservative measures alone (85). This study found no incidence of new malignancy or worsening of pre-existing malignancy after 8 weeks of intermittent, low dose teriparatide treatment (85). However, this study was underpowered and follow-up was insufficient to properly characterize these safety endpoints. Teriparatide has shown an increased rate of osteosarcoma in preclinical trials, but post-marketing surveillance has yet to demonstrate a relationship between osteosarcoma and teriparatide in humans (85). Its use remains controversial and further studies are required.

Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors typically used for hyperlipidemia but have also shown angiogenic, immunomodulatory, and antibacterial properties (86). Adachi et al. propose that Statins may play a role in the prevention of MRONJ. In rats at high risk for MRONJ, a single local injection of Fluvastatin into the socket following extraction significantly prevented MRONJ development (86). Further studies are required to assess its effects in humans.

Summary

The patients at highest risk for MRONJ are those treated with antiresorptives at an oncologic dose after dentoalveolar surgery. Diagnosis is primarily based on clinical factors, but imaging may help determine sites of oral disease at high risk of MRONJ and the extent of an MRONJ lesion for surgical treatment planning. MRONJ may be prevented by treating oral disease before initiation of antiresorptive therapy and avoiding dentoalveolar surgery during/after antiresorptive therapy. MRONJ lesions should be managed conservatively in stage 0 and 1 but treated surgically in stage 2 and 3.

Among these findings, there are many emerging risk factors, strategies for diagnosis, and treatment methods. A major limitation of MRONJ research is that it is a rare clinical entity and studies are typically underpowered to observe a significant result. Therefore, large scale studies are required in the future to observe new ways to characterize patient risk, detect disease early, and treat appropriately based on severity. Through this research, providers are able to use the most up-to-date information to advance clinical care for MRONJ patients.

Acknowledgments

Funding: None.

Footnote

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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. J Oral Maxillofac Surg 2014;72:1938-56. Erratum in: J Oral Maxillofac Surg 2015 Jul;73(7):1440. J Oral Maxillofac Surg. 2015 Sep;73(9):1879. [Crossref] [PubMed]
2. Hallmer F, Bjarnadottir O, Götrick B, et al. Incidence of and risk factors for medication-related osteonecrosis of the jaw in women with breast cancer with bone metastasis: a population-based study. Oral Surg Oral Med Oral Pathol Oral Radiol 2020;130:252-7. [Crossref] [PubMed]
3. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012;23:1341-7. [Crossref] [PubMed]
4. Zandi M, Dehghan A, Janbaz P, et al. The starting point for bisphosphonate-related osteonecrosis of the jaw: Alveolar bone or oral mucosa? A randomized, controlled experimental study. J Craniomaxillofac Surg 2017;45:157-61. [Crossref] [PubMed]
5. Watts NB, Grbic JT, Binkley N, et al. Invasive Oral Procedures and Events in Postmenopausal Women With Osteoporosis Treated With Denosumab for Up to 10 Years. J Clin Endocrinol Metab 2019;104:2443-52. [Crossref] [PubMed]
6. Schiodt M, Vadhan-Raj S, Chambers MS, et al. A multicenter case registry study on medication-related osteonecrosis of the jaw in patients with advanced cancer. Support Care Cancer 2018;26:1905-15. [Crossref] [PubMed]
7. Withdrawal: "Torus lesions of the jaw: Diagnosis and clinical implications" Gary G. Ghahremani, David R. Naimi, Zohreh K. Ghahremani. Int J Clin Pract 2021;75:e13697. [PubMed]
8. Kim JW, Landayan ME, Lee JY, et al. Role of microcracks in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw. Clin Oral Investig 2016;20:2251-8. [Crossref] [PubMed]
9. Wan JT, Sheeley DM, Somerman MJ, et al. Mitigating osteonecrosis of the jaw (ONJ) through preventive dental care and understanding of risk factors. Bone Res 2020;8:14. [Crossref] [PubMed]
10. Lorenzo-Pouso AI, Pérez-Sayáns M, Chamorro-Petronacci C, et al. Association between periodontitis and medication-related osteonecrosis of the jaw: A systematic review and meta-analysis. J Oral Pathol Med 2020;49:190-200. [Crossref] [PubMed]
11. Di Fede O, Panzarella V, Mauceri R, et al. The Dental Management of Patients at Risk of Medication-Related Osteonecrosis of the Jaw: New Paradigm of Primary Prevention. Biomed Res Int 2018;2018:2684924. [Crossref] [PubMed]
12. Kang B, Cheong S, Chaichanasakul T, et al. Periapical disease and bisphosphonates induce osteonecrosis of the jaws in mice. J Bone Miner Res 2013;28:1631-40. [Crossref] [PubMed]
13. Aghaloo TL, Kang B, Sung EC, et al. Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat. J Bone Miner Res 2011;26:1871-82. [Crossref] [PubMed]
14. Bramati A, Girelli S, Farina G, et al. Prospective, mono-institutional study of the impact of a systematic prevention program on incidence and outcome of osteonecrosis of the jaw in patients treated with bisphosphonates for bone metastases. J Bone Miner Metab 2015;33:119-24. [Crossref] [PubMed]
15. Van Poznak CH, Unger JM, Darke AK, et al. Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer. JAMA Oncol 2021;7:246-54. [Crossref] [PubMed]
16. Pimolbutr K, Porter S, Fedele S. Osteonecrosis of the Jaw Associated with Antiangiogenics in Antiresorptive-Naïve Patient: A Comprehensive Review of the Literature. Biomed Res Int 2018;2018:8071579. [Crossref] [PubMed]
17. Fusco V, Porta C, Saia G, et al. Osteonecrosis of the Jaw in Patients With Metastatic Renal Cell Cancer Treated With Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature. Clin Genitourin Cancer 2015;13:287-94. [Crossref] [PubMed]
18. Guarneri V, Miles D, Robert N, et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 2010;122:181-8. [Crossref] [PubMed]
19. Lescaille G, Coudert AE, Baaroun V, et al. Osteonecrosis of the jaw and nonmalignant disease: is there an association with rheumatoid arthritis? J Rheumatol 2013;40:781-6. [Crossref] [PubMed]
20. de Molon RS, Hsu C, Bezouglaia O, et al. Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study. J Bone Miner Res 2016;31:1596-607. [Crossref] [PubMed]
21. Peer A, Khamaisi M. Diabetes as a risk factor for medication-related osteonecrosis of the jaw. J Dent Res 2015;94:252-60. [Crossref] [PubMed]
22. Weinstein RS. Glucocorticoid-induced osteonecrosis. Endocrine 2012;41:183-90. [Crossref] [PubMed]
23. Tsao C, Darby I, Ebeling PR, et al. Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg 2013;71:1360-6. [Crossref] [PubMed]
24. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 2008;83:1032-45. [Crossref] [PubMed]
25. Hanley DA, Adachi JD, Bell A, et al. Denosumab: mechanism of action and clinical outcomes. Int J Clin Pract 2012;66:1139-46. [Crossref] [PubMed]
26. Horikawa A, Miyakoshi N, Shimada Y, et al. A comparative study between intravenous and oral alendronate administration for the treatment of osteoporosis. Springerplus 2015;4:675. [Crossref] [PubMed]
27. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99-102; discussion 99-102. [Crossref] [PubMed]
28. Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol 2018;19:370-81. [Crossref] [PubMed]
29. Himelstein AL, Foster JC, Khatcheressian JL, et al. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 2017;317:48-58. [Crossref] [PubMed]
30. Liu C, Wang L, Liu L, et al. Efficacy and safety of de-escalation bone- modifying agents for cancer patients with bone metastases: a systematic review and meta-analysis. Cancer Manag Res 2018;10:3809-23. [Crossref] [PubMed]
31. Al-Husein B, Abdalla M, Trepte M, et al. Antiangiogenic therapy for cancer: an update. Pharmacotherapy 2012;32:1095-111. [Crossref] [PubMed]
32. Foster SA, Foley KA, Meadows ES, et al. Characteristics of patients initiating raloxifene compared to those initiating bisphosphonates. BMC Womens Health 2008;8:24. [Crossref] [PubMed]
33. Baur DA, Altay MA, Teich S, et al. Osteonecrosis of the jaw in a patient on raloxifene: a case report. Quintessence Int 2015;46:423-8. [PubMed]
34. Bindakhil M, Shanti RM, Mupparapu M. Raloxifene-induced osteonecrosis of the jaw (MRONJ) with no exposure to bisphosphonates: clinical and radiographic findings. Quintessence Int 2021;0:2-7. [PubMed]
35. Furukawa S, Oobu K, Moriyama M, et al. Oral Methotrexate-related Lymphoproliferative Disease Presenting with Severe Osteonecrosis of the Jaw: A Case Report and Literature Review. Intern Med 2018;57:575-81. [Crossref] [PubMed]
36. Henien M, Carey B, Hullah E, et al. Methotrexate-associated osteonecrosis of the jaw: A report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol 2017;124:e283-7. [Crossref] [PubMed]
37. Bindakhil MA, Mupparapu M. Osteomyelitis of the mandible exhibiting features of medication-related osteonecrosis in a patient with history of tocilizumab treatment. J Orofac Sci 2018;10:53-5.
38. REMAP-CAP Investigators. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med 2021;384:1491-502. [Crossref] [PubMed]
39. Allen MR, Kubek DJ, Burr DB. Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs. J Bone Miner Res 2010;25:98-105. [Crossref] [PubMed]
40. Cheong S, Sun S, Kang B, et al. Bisphosphonate uptake in areas of tooth extraction or periapical disease. J Oral Maxillofac Surg 2014;72:2461-8. [Crossref] [PubMed]
41. Kakehashi H, Ando T, Minamizato T, et al. Administration of teriparatide improves the symptoms of advanced bisphosphonate-related osteonecrosis of the jaw: preliminary findings. Int J Oral Maxillofac Surg 2015;44:1558-64. [Crossref] [PubMed]
42. Ristow O, Gerngroß C, Schwaiger M, et al. Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in pathogenesis of bisphosphonate-related osteonecrosis? J Oral Maxillofac Surg 2014;72:903-10. [Crossref] [PubMed]
43. Zhang W, Gao L, Ren W, et al. The Role of the Immune Response in the Development of Medication-Related Osteonecrosis of the Jaw. Front Immunol 2021;12:606043. [Crossref] [PubMed]
44. Taniguchi N, Osaki M, Onuma K, et al. Bisphosphonate-induced reactive oxygen species inhibit proliferation and migration of oral fibroblasts: A pathogenesis of bisphosphonate-related osteonecrosis of the jaw. J Periodontol 2020;91:947-55. [Crossref] [PubMed]
45. Bae S, Sun S, Aghaloo T, et al. Development of oral osteomucosal tissue constructs in vitro and localization of fluorescently-labeled bisphosphonates to hard and soft tissue. Int J Mol Med 2014;34:559-63. [Crossref] [PubMed]
46. Hoefert S, Schmitz I, Weichert F, et al. Macrophages and bisphosphonate-related osteonecrosis of the jaw (BRONJ): evidence of local immunosuppression of macrophages in contrast to other infectious jaw diseases. Clin Oral Investig 2015;19:497-508. [Crossref] [PubMed]
47. Ferrari-Lacraz S, Ferrari S. Do RANKL inhibitors (denosumab) affect inflammation and immunity? Osteoporos Int 2011;22:435-46. [Crossref] [PubMed]
48. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302:1055-61. [Crossref] [PubMed]
49. Santini D, Vincenzi B, Dicuonzo G, et al. Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 2003;9:2893-7. [PubMed]
50. Vincenzi B, Napolitano A, Zoccoli A, et al. Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw. J Hematol Oncol 2012;5:56. [Crossref] [PubMed]
51. Brunello A, Saia G, Bedogni A, et al. Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 2009;44:173-5. [Crossref] [PubMed]
52. Misso G, Porru M, Stoppacciaro A, et al. Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid. Cancer Biol Ther 2012;13:1491-500. [Crossref] [PubMed]
53. Allen MR, Ruggiero SL. A review of pharmaceutical agents and oral bone health: how osteonecrosis of the jaw has affected the field. Int J Oral Maxillofac Implants 2014;29:e45-57. [Crossref] [PubMed]
54. Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2017;35:2062-81. [Crossref] [PubMed]
55. Dutra KL, Haas LF, Zimmermann GS, et al. Prevalence of radiographic findings on jaws exposed to antiresorptive therapy: a meta-analysis. Dentomaxillofac Radiol 2019;48:20180112. [Crossref] [PubMed]
56. Fleisher KE, Raad RA, Rakheja R, et al. Fluorodeoxyglucose positron emission tomography with computed tomography detects greater metabolic changes that are not represented by plain radiography for patients with osteonecrosis of the jaw. J Oral Maxillofac Surg 2014;72:1957-65. [Crossref] [PubMed]
57. Fleisher KE, Pham S, Raad RA, et al. Does Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography Facilitate Treatment of Medication-Related Osteonecrosis of the Jaw? J Oral Maxillofac Surg 2016;74:945-58. [Crossref] [PubMed]
58. Shuster A, Reiser V, Trejo L, et al. Comparison of the histopathological characteristics of osteomyelitis, medication-related osteonecrosis of the jaw, and osteoradionecrosis. Int J Oral Maxillofac Surg 2019;48:17-22. [Crossref] [PubMed]
59. De Antoni CC, Matsumoto MA, Silva AAD, et al. Medication-related osteonecrosis of the jaw, osteoradionecrosis, and osteomyelitis: A comparative histopathological study. Braz Oral Res 2018;32:e23. [Crossref] [PubMed]
60. Qaisi M, Montague L. Bone Margin Analysis for Osteonecrosis and Osteomyelitis of the Jaws. Oral Maxillofac Surg Clin North Am 2017;29:301-13. [Crossref] [PubMed]
61. Awad ME, Sun C, Jernigan J, et al. Serum C-terminal cross-linking telopeptide level as a predictive biomarker of osteonecrosis after dentoalveolar surgery in patients receiving bisphosphonate therapy: Systematic review and meta-analysis. J Am Dent Assoc 2019;150:664-675.e8. [Crossref] [PubMed]
62. Marx RE, Cillo JE Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007;65:2397-410. [Crossref] [PubMed]
63. Mücke T, Deppe H, Hein J, et al. Prevention of bisphosphonate-related osteonecrosis of the jaws in patients with prostate cancer treated with zoledronic acid - A prospective study over 6 years. J Craniomaxillofac Surg 2016;44:1689-93. [Crossref] [PubMed]
64. Van Poznak C, Somerfield MR, Barlow WE, et al. Role of Bone-Modifying Agents in Metastatic Breast Cancer: An American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update. J Clin Oncol 2017;35:3978-86. [Crossref] [PubMed]
65. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2012;27:243-54. [Crossref] [PubMed]
66. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006;296:2927-38. [Crossref] [PubMed]
67. Lotwala RB, Greenlee GM, Ott SM, et al. Bisphosphonates as a risk factor for adverse orthodontic outcomes: a retrospective cohort study. Am J Orthod Dentofacial Orthop 2012;142:625-634.e3. [Crossref] [PubMed]
68. Yarom N, Shapiro CL, Peterson DE, et al. Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. J Clin Oncol 2019;37:2270-90. [Crossref] [PubMed]
69. Ottesen C, Schiodt M, Gotfredsen K. Efficacy of a high-dose antiresorptive drug holiday to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ): A systematic review. Heliyon 2020;6:e03795. [Crossref] [PubMed]
70. Zhang H, Huang Z, Zou X, et al. Bevacizumab and wound-healing complications: a systematic review and meta-analysis of randomized controlled trials. Oncotarget 2016;7:82473-81. [Crossref] [PubMed]
71. Bermúdez-Bejarano EB, Serrera-Figallo MÁ, Gutiérrez-Corrales A, et al. Prophylaxis and antibiotic therapy in management protocols of patients treated with oral and intravenous bisphosphonates. J Clin Exp Dent 2017;9:e141-9. [PubMed]
72. Fortunato L, Bennardo F, Buffone C, et al. Is the application of platelet concentrates effective in the prevention and treatment of medication-related osteonecrosis of the jaw? A systematic review. J Craniomaxillofac Surg 2020;48:268-85. [Crossref] [PubMed]
73. Soundia A, Hadaya D, Mallya SM, et al. Radiographic predictors of bone exposure in patients with stage 0 medication-related osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol 2018;126:537-44. [Crossref] [PubMed]
74. Comas-Calonge A, Figueiredo R, Gay-Escoda C. Surgical treatment vs. conservative treatment in intravenous bisphosphonate-related osteonecrosis of the jaws. Systematic review. J Clin Exp Dent 2017;9:e302-7. [Crossref] [PubMed]
75. Ristow O, Otto S, Troeltzsch M, et al. Treatment perspectives for medication-related osteonecrosis of the jaw (MRONJ). J Craniomaxillofac Surg 2015;43:290-3. [Crossref] [PubMed]
76. Wilde F, Heufelder M, Winter K, et al. The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:153-63. [Crossref] [PubMed]
77. Carlson ER, Basile JD. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2009;67:85-95. [Crossref] [PubMed]
78. Giudice A, Barone S, Diodati F, et al. Can Surgical Management Improve Resolution of Medication-Related Osteonecrosis of the Jaw at Early Stages? A Prospective Cohort Study. J Oral Maxillofac Surg 2020;78:1986-99. [Crossref] [PubMed]
79. El-Rabbany M, Sgro A, Lam DK, et al. Effectiveness of treatments for medication-related osteonecrosis of the jaw: A systematic review and meta-analysis. J Am Dent Assoc 2017;148:584-594.e2. [Crossref] [PubMed]
80. Rotaru H, Kim MK, Kim SG, et al. Pedicled buccal fat pad flap as a reliable surgical strategy for the treatment of medication-related osteonecrosis of the jaw. J Oral Maxillofac Surg 2015;73:437-42. [Crossref] [PubMed]
81. Nocini PF, Saia G, Bettini G, et al. Vascularized fibula flap reconstruction of the mandible in bisphosphonate-related osteonecrosis. Eur J Surg Oncol 2009;35:373-9. [Crossref] [PubMed]
82. Sacco R, Sacco N, Hamid U, et al. Microsurgical Reconstruction of the Jaws Using Vascularised Free Flap Technique in Patients with Medication-Related Osteonecrosis: A Systematic Review. Biomed Res Int 2018;2018:9858921. [Crossref] [PubMed]
83. Beachler DC, Yanik EL, Martin BI, et al. Bone Morphogenetic Protein Use and Cancer Risk Among Patients Undergoing Lumbar Arthrodesis: A Case-Cohort Study Using the SEER-Medicare Database. J Bone Joint Surg Am 2016;98:1064-72. [Crossref] [PubMed]
84. Kim MS, Kim KJ, Kim BJ, et al. Immediate reconstruction of mandibular defect after treatment of medication-related osteonecrosis of the jaw (MRONJ) with rhBMP-2/ACS and miniplate: Review of 3 cases. Int J Surg Case Rep 2020;66:25-9. [Crossref] [PubMed]
85. Sim IW, Borromeo GL, Tsao C, et al. Teriparatide Promotes Bone Healing in Medication-Related Osteonecrosis of the Jaw: A Placebo-Controlled, Randomized Trial. J Clin Oncol 2020;38:2971-80. [Crossref] [PubMed]
86. Adachi N, Ayukawa Y, Yasunami N, et al. Preventive effect of fluvastatin on the development of medication-related osteonecrosis of the jaw. Sci Rep 2020;10:5620. [Crossref] [PubMed]