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Medication-related osteonecrosis of the jaw in patients with cancer
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Medication-related osteonecrosis of the jaw in patients with cancer
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Oct 13, 2016.

INTRODUCTION — Osteonecrosis of the jaw (ONJ), which was first described in 2002 [1], is a relatively uncommon but potentially serious side effect of treatment with antiresorptive agents such as intravenous (IV) high potency bisphosphonates (image 1) and denosumab, which decrease the risk of skeletal-related events (SREs) in patients with cancer and metastatic bone disease. The increased dose intensity of anti-resorptive therapy typically prescribed for cancer indications places cancer patients at a substantially higher risk for ONJ than are patients who receive them for other conditions such as osteoporosis and Paget's disease [2-5].

ONJ has also been described as a complication of cancer therapies that target angiogenesis; however, this association is more controversial with little confirmatory prospective trial data available in the setting of monotherapy with an antiangiogenic agent alone. Use of antiangiogenic agents as a risk factor for medication-related ONJ (MRONJ) among patients receiving antiresorptive agents for cancer is more clearly established. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Osteonecrosis of the jaw'.)

This topic review will describe the incidence, risk factors, staging, clinical course, prevention strategies, and management of MRONJ in patients with cancer who are receiving antiresorptive agents. The incidence, risk factors, and management strategies for MRONJ in patients receiving antiresorptive therapy for osteoporosis and other side effects associated with bisphosphonates and denosumab in patients with cancer are addressed elsewhere. (See "Denosumab for osteoporosis", section on 'Oversuppression of bone remodeling' and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

NOMENCLATURE AND DEFINITION — ONJ associated with bisphosphonate treatment has been referred to by several acronyms including BRONJ (bisphosphonate-related ONJ), BRON (bisphosphonate-related osteonecrosis), BON (bisphosphonate osteonecrosis), BAONJ (bisphosphonate-associated ONJ), and simply ONJ. The recognition of jaw necrosis as a complication of other drugs, including the RANK (receptor activator of nuclear factor kappa B) ligand inhibitor denosumab and antiangiogenic agents prompted a special committee of the American Association of Oral and Maxillofacial Surgeons (AAOMS) to recommend the term medication-related osteonecrosis of the jaw as preferred [6].

Definition — Two working definitions of MRONJ have been proposed:

A task force convened by the American Society for Bone and Mineral Research defines MRONJ as the presence of exposed bone in the maxillofacial region that does not heal within eight weeks after identification by a health care professional [2].

An updated 2014 position paper on medication-related osteonecrosis of the jaw (MRONJ) is available from the American Association of Oral and Maxillofacial Surgeons that provides an updated definition of the condition; comparative risk estimates of developing MRONJ in patients with cancer and a history of exposure to either antiresorptive and/or antiangiogenic agents; recommendations for prevention measures; and management strategies for patients with established MRONJ (table 1) [6].

Patients may be considered to have MRONJ if the following characteristics are present:

Current or previous treatment with antiresorptive or antiangiogenic agents;

Exposed bone or bone that can be probed through an intraoral or extraoral fistula(e) in the maxillofacial region that has persisted for more than eight weeks; and

No history of radiation therapy to, or obvious metastatic disease in the jawbones

We prefer the AAOMS definition, which has also been adopted by an international task force on osteonecrosis of the jaw [7].

PATHOPHYSIOLOGY — Although the first cases of MRONJ were reported over a decade ago, the underlying pathophysiology is not fully elucidated. The leading proposed hypotheses to explain the unique localization of MRONJ to the jaws include remodeling or oversuppression of bone resorption, inhibition of blood supply, constant microtrauma, and infection/inflammation. None of these hypotheses seems to explain all cases [8].

The shared complication of ONJ in cancer patients treated with high doses of denosumab or potent bisphosphonates strongly suggests that profound and prolonged inhibition of bone resorption with oversuppression of bone remodeling (ie, low bone turnover), and infection are the main mechanisms [9]. Animal data support the view that a higher rate of bone remodeling or more severe oversuppression of the bone turnover rate with bisphosphonates in the jawbones may explain the differential predisposition at this site compared with other bones in the axial or appendicular skeleton [10,11]. However, this is probably not the sole contributor since MRONJ can be, albeit rarely, observed in the absence of antiresorptive therapy.

Some have postulated that MRONJ is a form of avascular necrosis, possibly caused by inhibition of angiogenesis. In vitro experiments consistently demonstrate that zoledronic acid inhibits angiogenesis, and cancer patients treated with this agent have decreased circulating VEGF levels [12,13]. Moreover, there is a growing body of evidence linking MRONJ to antiangiogenic drugs, including bevacizumab and orally active tyrosine kinase inhibitors. However, inhibition of angiogenesis has not been reported with denosumab therapy to date. Furthermore, histologic examination of ONJ lesions demonstrates patent vessels in the majority of cases [14,15]. Thus, it seems unlikely that MRONJ represents a form of avascular necrosis. (See 'Concurrent antiangiogenic therapy' below.)

The preferential localization of MRONJ events to the mandible suggests that the more frequent microdamage inflicted on the lower jaw bone with mastication might also represent a contributory factor [16]. However, approximately one-third of cases occur in the maxillary bone. (See 'Clinical presentation' below.)

Local oral risk factors have been implicated in MRONJ pathogenesis. Histopathologic findings implicate bone necrosis and infection, although it is not clear which is primary [17]. Although tooth extraction had been performed in most of the initial reported cases of bisphosphonate-related ONJ, these teeth commonly had preexisting periodontal or periapical disease. Animal models indicate that both inflammation or bacterial infection and systemic administration of antiresorptive agents are sufficient to induce ONJ [18-20]. (See 'Oral health-associated risk factors' below.)

Complex biofilms have been identified on the bone/tooth and mucosal surfaces around bisphosphonate-related ONJ that are composed of actinomyces and other organisms including fungi and viruses [14,21-24]. However, it is not known whether MRONJ represents direct toxicity to the bone and/or soft tissues that becomes secondarily infected [25,26] or if a primary infection is subsequently exacerbated by the use of antiresorptive agents. Furthermore, it is unclear if the common presence of actinomyces in these lesions is actively contributing to the development or progression of MRONJ, or simply related to the presence of necrotic bone in an anaerobic environment [21]. Controlled trials evaluating specific antimicrobials or therapy for actinomycosis in MRONJ have not been performed; however, antimicrobial therapy is a hallmark of all therapy for MRONJ to decrease surrounding inflammation and oral pain [23].

A central role for local monocytes and macrophages has been proposed as a unifying hypothesis to explain a link between infection (which increases macrophage recruitment to the mucosa of the oral cavity [27]) and use of bisphosphonates or denosumab (which have a detrimental effect on macrophages, compromising the local immune response [17,28]), which sets the stage for subsequent bone destruction [9].

Accumulating evidence on risk factors for ONJ in patients undergoing therapy with an antiresorptive agent (which include concomitant use of antiangiogenic therapies) supports the view that ONJ is a multifactorial process with contributions from impaired bone repair and suppression of osteoclast activity; impaired angiogenesis or vascular repair; and local factors, such as poor dental hygiene, poorly fitting dentures, and/or a dental manipulation of some sort (eg, dental extraction, advanced periodontal disease) [25,29-35].

CLINICAL PRESENTATION — Areas of exposed and necrotic bone, which may remain asymptomatic for weeks, months, or even years, are the consistent hallmark of MRONJ [36]. The lesions may become symptomatic when the surrounding soft tissues become inflamed. Signs and symptoms that may occur before the development of clinically detectable osteonecrosis include prolonged jaw pain, tooth mobility, bone enlargement, gingival swelling, erythema, and ulceration [21,36,37].These may occur spontaneously or at the site of prior dental surgery. The size of the affected area is variable and may range from a nonhealing tooth extraction site to a large section of the jawbone.

Intraoral or extraoral fistula(e) may develop when the necrotic bone becomes secondarily infected. The clinical scenario may resemble osteomyelitis. Chronic maxillary sinusitis is sometimes the presenting symptom in patients with maxillary bone involvement. Finally, some patients may present with altered sensation in the affected area due to compression of the neurovascular bundle by the inflamed surrounding bone.

The location of MRONJ is more often mandibular than maxillary (2:1 ratio), but can appear in both jaws [38,39]. In one review of 368 reported cases, ONJ was manifested in the mandible in 65 percent, maxilla in 26 percent, and both in 9 percent [38].

A clinical staging system was developed in 2007 [40], modified and published by the AAOMS in its 2014 guidelines for MRONJ that help to categorize patients according to the severity, and directs rational treatment (table 1) [6]. (See 'Staging and treatment' below.)

Imaging studies — Screening radiographic studies are often recommended to define current dental disease that may be a risk factor for MRONJ development and thus treated prior to the initiation of antiresorptive therapies.

The radiographic features of MRONJ are relatively nonspecific. MRONJ can be visualized using panoramic radiography, cone beam computed tomography (CT; to limit radiation doses) [41], or magnetic resonance imaging (MRI) [42]. However, the extent of these lesions may not be clear, especially in the early stages. In particular, radiographic findings such as poorly healing or non-healing extraction sockets, periapical radiolucencies, and widening of the periodontal ligament space are not specific in the early stages of the disease [43].

CT is more sensitive than plain radiographs to changes in bone mineralization and therefore, more likely to demonstrate areas of focal sclerosis, thickened lamina dura, early sequestrum formation, and the presence of reactive periosteal bone [36]. Delineation of the extent of the diseased area by CT may be helpful for surgical treatment planning.

Early studies demonstrating increased radiotracer uptake in regions of the jaws that subsequently developed necrosis suggest potential utility for nuclear bone scanning in patients at risk for MRONJ [44,45]. Its usefulness as a predictive tool for patients with stage 0 disease (table 1) merits continued evaluation.

Differential diagnosis — The differential diagnosis of MRONJ includes alveolar osteitis, sinusitis, gingivitis/periodontitis, caries, periapical pathology, sarcoma, chronic sclerosing osteomyelitis (proliferative periostitis), and temporomandibular joint disorders. In those rare situations where patients have been exposed both to radiation therapy and either an antiresorptive or antiangiogenic agent, osteoradionecrosis should be strongly considered. (See "Management of late complications of head and neck cancer and its treatment", section on 'Osteoradionecrosis and soft tissue necrosis' and "Oral health in cancer survivors", section on 'Osteonecrosis' and "Complications, diagnosis, and treatment of odontogenic infections" and "Temporomandibular disorders in adults" and "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis" and "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)

INCIDENCE AND RISK FACTORS

Antiresorptive therapy — Although potentially serious, MRONJ is a relatively uncommon complication of therapy with IV bisphosphonates and denosumab among patients with advanced malignancy, although it is more common in patients with cancer than in patients who are treated with antiresorptive agents for osteoporosis. (See "Denosumab for osteoporosis", section on 'Oversuppression of bone remodeling'.)

The best information on incidence in patients with advanced cancer comes from a review of data on 5723 patients with bone metastases from a wide variety of malignancies enrolled on three identically designed prospective randomized trials comparing zoledronic acid to denosumab for the prevention of skeletal related events; the most recent data were presented in a preliminary report at the 2013 American Society of Clinical Oncology (ASCO) meeting [39,46]. ONJ was defined per the 2009 guidelines of the American Association of Maxillofacial Surgeons (AAOMS) [47].

The following findings were noted:

Sixty-three patients (1.9 percent) on the denosumab treatment arm developed ONJ compared with 44 (1.3 percent) on the zoledronic acid arm. This difference was not significant between treatment groups (p = 0.08) [46] When compared with the risk for ONJ in the placebo arms of the prior IV bisphosphonate studies to prevent complications from skeletal metastases (range 0 to 0.19 percent [48-50]), the risk of ONJ was 50- to 100-fold higher with the use of modern high-dose IV bisphosphonates [39].

ONJ events were documented as early as four months after starting therapy and up to 30 months after first dose of drug; the median time of drug exposure prior to the development of ONJ was 14 months in both groups [39]. The adjusted incidence of confirmed ONJ was 1.1 percent during the first year of treatment and 4.1 percent thereafter, suggesting time on therapy as a risk factor for ONJ [46].

Dental extraction preceded the ONJ event in 63 percent of cases; 82 percent had jaw pain, and a coincident oral infection was present in 48 percent of cases. (See 'Dentoalveolar surgery' below.)

Dose, duration, and type of therapy

Bisphosphonates — The potency of the bisphosphonate and duration of use influences ONJ risk:

The risk is higher with IV than with oral bisphosphonates and most commonly observed in patients receiving intensive (monthly) parenteral dosing for prevention of skeletal related events [51-53]. The incidence of ONJ observed with osteoporosis dosing of bisphosphonates is markedly lower compared with that observed in oncology patients.

The incidence is higher with longer duration of treatment, particularly when the duration of therapy exceeds four years [3,29,54,55]. This time frame may be shortened by the presence of certain comorbidities, such as chronic glucocorticoid use or concomitant administration of angiogenesis inhibitors. (See 'Concurrent antiangiogenic therapy' below and 'Other risk factors' below.)

In a retrospective series of 3994 patients with malignancy who were receiving IV bisphosphonates, the median duration of pamidronate use was longer in those who developed ONJ compared with those who did not (1.68 versus 0.59 years in breast cancer, and 1.55 versus 0.3 years in multiple myeloma [3]). The same findings were noted among patients receiving zoledronic acid (2.04 versus 0.73 years in breast cancer, and 1.85 versus 0.67 years in myeloma).

In another study, the cumulative hazard of developing ONJ increased according to the duration of IV bisphosphonate therapy (0 percent at one year to 11 percent at four years) [54]. However, these results may simply refect a longer observation period and not necessarily the duration of bisphosphonate treatment.

Chronic treatment with zoledronic acid has been implicated as a greater contributor to the development of ONJ than pamidronate [4,22,29,51,54,56-60]. As an example, a web-based survey of 904 patients with multiple myeloma and 299 with breast cancer identified 75 patients with ONJ and an additional 77 with findings suspicious for early ONJ [56]. ONJ developed in 10 and 4 percent of those treated with zoledronic acid or pamidronate, respectively. However, the diagnosis of ONJ was not necessarily confirmed in individuals who reported having this condition in this web-based survey.

In a preliminary report presented at the 2014 ASCO meeting, intravenous zoledronic acid was associated with a higher incidence of ONJ (1.15 percent) compared with oral daily clodronate (0.28 percent) and oral daily ibandronate (0.66 percent) in the SWOG 0307 trial when bisphosphonates were administered in the adjuvant setting to prevent bone metastases in patients with high risk breast cancer [61]. The greater risk for ONJ with zoledronic acid is likely due to its greater potency.

Whether the incidence of ONJ might be lowered by extending the dosing interval of bisphosphonates is unclear. While one retrospective analysis suggested a reduced rate of ONJ in patients with multiple myeloma who were treated with zoledronic acid every 12 rather than every four weeks, randomized trials conducted mainly in breast and prostate cancer have not found a lower rate of any treatment-related toxicity, including ONJ, with every-12-week rather than every-four-week dosing intervals of zoledronic acid. This subject is discussed in detail below. (See 'Lengthening the dosing interval' below.)

Denosumab — As with bisphosphonates, dose, schedule, and duration of osteoclast inhibition are associated with ONJ risk in patients treated with denosumab. The approved dose of denosumab for prevention of skeletal-related events in patients with bone metastases from solid tumors is 120 mg subcutaneously every four weeks. At this dose, the risk of ONJ is consistently slightly higher than that seen with IV bisphosphonates, but the difference is not statistically significant:

In an integrated analysis of patient-level information from all three registration trials, which were conducted identically with the only difference being the tumor type (ie, breast, prostate, or other solid tumors), the risk of ONJ with denosumab was slightly higher, but the difference was not statistically significant (1.9 versus 1.3 percent, p = 0.08) [46].

In the most recent meta-analysis of five randomized trials of denosumab versus bisphosphonates (which included the three registration trials plus two others, both of which used different dose/schedules of administration for denosumab and neither of which prospectively evaluated ONJ as an endpoint), the rate of ONJ was again higher with denosumab, but the difference was not statistically significant (1.7 versus 1.1 percent, RR 1.48, 95% CI 0.96-2.29) [48].

When denosumab has been administered at a significantly lower dose (ie, 60 mg subcutaneously every six months) for the treatment of postmenopausal or cancer therapy-related osteoporosis, ONJ has only rarely been reported. (See "Denosumab for osteoporosis", section on 'Adverse effects'.)

As with bisphosphonates, duration of therapy influences risk, although at least some data support the view that risk plateaus between years 2 and 3 [39,62]. As an example, in an analysis of the three phase III registration trials, the incidence of developing ONJ was 1.1 percent during the first year and 4.1 percent thereafter [46].

Concurrent antiangiogenic therapy — The incidence appears to be higher among patients with bone metastases who are receiving therapy with an antiangiogenic agent plus an antiresorptive agent for prevention of skeletal related events [4,63-69]:

In the above mentioned retrospective study of 3560 patients receiving bevacizumab-containing therapy for advanced breast cancer in two double-blind, randomized trials and a large, non-randomized safety study, there was a trend towards increased ONJ in those who received bisphosphonates (0.9 versus 0.2 percent) in the analysis of the randomized trials [63].

In another report, 11 of 60 (18.3 percent) patients with metastatic castration resistant prostate cancer (mCRPC) administered bevacizumab, docetaxel, thalidomide, and prednisone with concurrent zoledronic acid developed ONJ [67].

In a retrospective review of 49 patients with advanced renal cell cancer who were treated with concomitant oral tyrosine kinase inhibitors (sunitinib or sorafenib) and bisphosphonates, the incidence of ONJ was 10 percent [68].

Interestingly, other reports have failed to find an association with coadministration of thalidomide, which has antiangiogenic as well as immunomodulatory properties [21,29,54,59,70-72].

In contrast, MRONJ has been rarely reported as a side effect in patients receiving antiangiogenic agents as monotherapy. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Osteonecrosis of the jaw'.)

Oral health-associated risk factors — Local risk factors, such as invasive dental procedures or concomitant oral disease increase risk for ONJ [3,29,39,54,56,57,73-75].

Dentoalveolar surgery — Dentoalveolar surgery is a major risk factor for MRONJ, although cases can occur spontaneously without a precipitating oral event.

Among patients with MRONJ, 52 to 65 percent report tooth extraction as the predisposing event [39,76,77]:

In a case-control study of 60 cancer patients exposed to zoledronic acid (20 who developed OHJ and 40 matched controls who did not), tooth extraction during bisphosphonate therapy was associated with a significant 16-fold increased risk for ONJ [74].

In a longitudinal cohort study of 1621 cancer patients exposed to IV bisphosphonates, a history of dental extraction was associated with a significant 33-fold (95% CI 18-60) increased risk for ONJ [76].

The best estimate of the absolute risk of developing ONJ following tooth extraction among cancer patients exposed to antiresorptive medications in retrospective studies is as high as 14.8 percent [78], but data from prospective trials suggest that the actual risk is lower, 1.6 to 2.8 percent [79,80]. The risk of developing MRONJ among patients exposed to antiresorptive medications for other invasive dental procedures such as dental implant placement and endodontic or periodontal procedures is unknown. However, the AAOMS committee concluded that the risk is likely comparable to that seen with tooth extraction [6].

Concomitant oral disease and other local risk factors — Other local risk factors include trauma during intubation, fractures, dentures, preexisting inflammatory dental disease (periodontal disease, periapical pathology such as abscessed teeth), dental caries, and mandibular tori (bone exostosis) [39,73-76,81].

The incidence of MRONJ may be decreasing as a result of better oral care and recognition of the increased risk from invasive dental procedures among patients receiving these drugs, as well as emphasis on regular dental exams and ongoing dental hygiene in patients receiving these agents. (See 'Prevention' below.)

Other risk factors — The incidence of MRONJ may vary according to the population under study [75]. Reports from Greece and Turkey describe a much higher incidence of MRONJ than in Italy and the United States [4,58,82]. The reasons for these differences could include differences in diagnostic criteria for MRONJ in these different regions, as well as genetic factors [83-85]. However, differences in dental hygiene and frequency of dental exams may also be major contributing factors to this geographic variation in the occurrence of this complication.

Genetic factors are receiving increased attention. Several reports describe single nucleotide polymorphisms (SNPs), many located within gene regions associated with bone turnover, collagen formation, or certain metabolic bone diseases, that are associated with the development of MRONJ [85-87]. As an example, in one genome-wide association study (GWAS), inheritance of certain polymorphisms in the RBMS3 (RNA-binding motif protein, single strand interacting 3) gene was associated with a nearly sixfold increase in the risk of developing MRONJ [85].

Concomitant use of anthracyclines may be a risk factor for ONJ in myeloma patients treated with IV bisphosphonates [88].

Questions remain as to whether glucocorticoids play a similarly important role in the development of ONJ as they do in the development of osteonecrosis at sites other than the jaw. The data are conflicting, with one series reporting use of glucocorticoids as a risk factor for ONJ in patients with multiple myeloma and another failing to confirm this finding in patients with multiple myeloma or breast cancer [3,89]. In the large series of patients enrolled on trials comparing zoledronic acid versus denosumab described above, concomitant use of glucocorticoids was observed in 73 percent of those who developed ONJ compared with 62 percent of those who did not [39]. (See "Osteonecrosis (avascular necrosis of bone)", section on 'Glucocorticoids'.)

Tumor type is variably reported as a risk factor for MRONJ. In a review of data on 5723 patients with bone metastases from a wide variety of malignancies enrolled on three identically designed prospective randomized trials comparing zoledronic acid with denosumab for the prevention of SREs, a slightly higher percentage of patients with multiple myeloma developed ONJ (3.3 versus 1.7 percent in breast cancer, 1.8 percent in prostate cancer, and 0.9 percent in other solid tumors), although only 180 myeloma patients were included in the trials [39]. Other series note a higher risk of ONJ in myeloma compared with patients who have solid tumors and metastatic bone disease [3,48,54,76,90]. However, the lower risk in patients with metastatic lung or renal cell cancer may be related to shorter survival and thus, reduced duration of antiresorptive therapy and time of observation.

Tobacco use has been inconsistently reported as a risk factor for MRONJ [74,76,81]. Smoking might represent a confounding factor given that smokers tend to have worse oral hygiene than nonsmokers.

STAGING AND TREATMENT — The 2014 American Association of Maxillofacial Surgeons (AAOMS) position paper provided a revised clinical staging system to describe the severity of MRONJ [6]. The various stages and suggested stage-specific treatment strategies are outlined in the table (table 1). However, the suggested stage-specific treatment strategies are not evidence-based, and in particular, stage 0 disease is not universally accepted [7].

Treatment goals — The major goals of treatment for patients at risk of developing or who have MRONJ are [6]:

Prioritization and support of continued oncologic treatment

Preservation of quality of life through patient education and reassurance, control of pain and secondary infection, and prevention of extension and development of new areas of necrosis

Management strategies — Patients should be counseled regarding the possible occurrence of ONJ prior to initiating therapy with an antiresorptive agent.

Prevention

Before initiation of IV antiresorptive therapy — In view of the difficulty in treating established MRONJ, prevention is emphasized. The treatment objective is to minimize the risk of developing MRONJ.

Guidelines from the American Society of Clinical Oncology (ASCO), the AAOMS, an International Task Force on ONJ, and the European Medicines Agency (EMA) recommend that all patients have a comprehensive dental examination and preventive dentistry (preemptive extraction of unsalvageable teeth and optimized periodontal health) before beginning therapy with an antiresorptive agent or angiogenesis inhibitor [6,7,91-93]. Oral care should be provided by a dentist or dental professional who is familiar with cancer therapies and their expected adverse effects, and is committed to integrating oral care with cancer therapy [94]. The components of the evaluation should include [6]:

Non-restorable teeth and those that are not likely to be salvageable should be extracted. If systemic conditions permit, initiation of therapy with the antiresorptive or antiangiogenic agent should be delayed until the extraction site is mucosalized (14 to 21 days) or until there is adequate osseous healing. These decisions should be made jointly by the treating physician and dentist.

Whenever possible, minor dental procedures with preservation of the dental root are preferred over total tooth extraction.

Active oral infections should be treated, and sites at high risk for infection should be eliminated.

Dental prophylaxis, caries control, and conservative restorative dentistry are critical to maintaining functionally sound teeth.

Patients with full or partial dentures should be examined for areas of mucosal trauma.

Patients must be educated as to the importance of dental hygiene and regular dental evaluations, and instructed to report promptly any oral pain, swelling, or exposed bone.

The implementation of dental screening and appropriate dental treatment measures before initiating antiresorptive therapy has reduced the risk of MRONJ in several prospective studies when compared with patients who did not undergo dental prophylaxis [95-99]. As an example, in a prospective trial exploring the impact of preventive oral and maxillofacial treatment before initiation of bisphosphonate therapy, followed by an every-three-month dental follow-up in men with metastatic prostate cancer, preventive treatment significantly reduced the incidence rate of ONJ (0.0131 versus 0.073 cases per year, representing a significant 82 percent reduction in risk) [99].

Asymptomatic patients during therapy — During therapy with an antiresorptive or antiangiogenic agent, oral hygiene status should be closely monitored. Patients should maintain excellent oral hygiene (daily flossing, regular and proxy brushing, and antibacterial oral rinses) to decrease rates of periodontal disease and oral infection, and avoid invasive dental procedures if possible. Patients should be encouraged to stop smoking [43].

Patients should be asked about possible planned dental procedures prior to administration of each dose of the antiresorptive agent and reminded to avoid invasive dental procedures (dental extractions, implants, and any other procedures that involve manipulation of the jaw bone or periosteum) while being treated with these drugs. Patients should be reassured that relatively noninvasive dental procedures such as dental cleaning, repair of cavities, placement of crowns or "caps," and even routine root canals do not increase the risk of MRONJ.

Efforts to establish risk assessment by measuring fluctuations in bone turnover markers during therapy remain controversial [100-102]. These markers are a reflection of bone turnover throughout the entire skeleton and are not specific to the jaws where bone turnover rate is severely suppressed beyond other bone sites.

Lengthening the dosing interval — Every-four-week administration of bisphosphonates represents a standard approach, although the available evidence is now sufficient to recommend dosing zoledronic acid every 12 rather than 4 weeks in most patients with bone metastases from breast or prostate cancer who have neither extensive nor highly symptomatic bone metastases. On the other hand, there are only limited data addressing the efficacy of less frequent dosing of denosumab, and every-four-week administration is still the standard approach. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Dosing interval'.)

Whether or not less frequent administration of zoledronic acid reduces the incidence of ONJ is unclear. While one retrospective analysis suggested a reduced rate of ONJ in patients with multiple myeloma who received zoledronic acid every 12 weeks rather than every four weeks [60], randomized trials, conducted mainly in breast and prostate cancer, have not reported a significantly lower rate of ONJ with the longer dosing interval. As an example, the CALGB (Alliance) trial 70604, randomly assigned 1822 patients with bone metastases (833 with breast cancer, 674 with prostate cancer, 270 with myeloma, and 45 with other malignancies) to the same dose of zoledronic acid (adjusted based upon calculated creatinine clearance) every four or every 12 weeks for two years, starting with the first dose [103]. In a preliminary report presented at the 2015 annual ASCO meeting, every-12-week treatment was non-inferior in terms of reducing the frequency of skeletal-related events. The two-year cumulative incidence of ONJ overall was lower in the every-12-week dosing interval group (9 versus 18 cases, 2 versus 1 percent), but the difference was not statistically significant (p = 0.08). Additional follow-up of this and other trials is needed before it can be concluded that less frequent dosing reduces the frequency of ONJ. (See 'Bisphosphonates' above and "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Dosing interval'.)

Cessation of at-risk medication prior to invasive dental procedures — The optimal management of a patient who requires an invasive dental procedure (eg, tooth extraction, dental implant procedure, or apical endodontic treatment) during treatment with an antiresorptive or antiangiogenic agent is not established, and there are scant data to guide the clinician in this setting.

Updated 2014 guidelines from the AAOMS provided guidance about the use of drug holidays in patients receiving an oral bisphosphonate for osteoporosis, but not for patients with cancer [6]:

For patients taking an oral bisphosphonate for less than four years who do not have other clinical risk factors, no alteration in the bisphosphonate or delay in the planned surgery is necessary.

For patients taking an oral bisphosphonate for less than four years and who have also taken glucocorticoids or antiangiogenic medications, or for any patient who has taken a bisphosphonate for more than four years irrespective of concomitant medications, discontinuation of the oral bisphosphonate for at least two months prior to oral surgery is advisable if systemic conditions permit. The bisphosphonate should not be restarted until osseous healing has occurred.

For patients receiving antiresorptive therapy for cancer, invasive dental procedures (including placement of dental implants) should be avoided if at all possible. Non-restorable teeth may be treated by removal of the crown and endodontic treatment of the remaining roots rather than extraction. Data are scant regarding the effect of discontinuing bisphosphonates prior to invasive dental procedures if these are necessary. However, if ONJ develops, discontinuation of bisphosphonate therapy should be considered until soft tissue closure has occurred, depending on disease status. There are no studies to support or refute the strategy of stopping denosumab therapy for the prevention or treatment of MRONJ; however, in all studies to date denosumab therapy has at least been temporarily held in patients who have ONJ recovery. Likewise, there are no data to support or refute the cessation of antiangiogenic therapy in the prevention or management of MRONJ, and continued research in this area is indicated.

In the absence of data, many experts feel it is reasonable to hold the antiresorptive agent for two to three months before and after the procedure, and to restart once the mucosa is completely healed over if doing so is consistent with the oncologic goals of care.

Treatment of established MRONJ — Treatment objectives for patients with an established diagnosis of MRONJ are to eliminate pain, control infection of the soft tissue and bone, and minimize the progression or occurrence of bone necrosis.

General approach — In general, recommendations for management of MRONJ in patients with cancer are hindered by a lack of data. There are no prospective studies with long-term follow-up with which to guide therapy and no evidence-based guidelines. Nonetheless, treatment has generally shifted away from aggressive surgical interventions to conservative therapy with limited debridement, antibiotics [23,104,105], and oral rinses with chlorhexidine or hydrogen peroxide. Conservative management may result in healing in 30 to 60 percent of cases, although some cases become chronic and develop complications [22,39,106]. (See 'Outcomes' below.)

Microbial cultures from areas of exposed bone will usually isolate normal oral microbes and are not usually helpful. However, when there is extensive soft tissue involvement, microbial cultures may help to define comorbid oral infections, which may guide the selection of an appropriate antibiotic regimen [36].

Regardless of the stage of disease, areas of necrotic bone that are a source of chronic soft tissue irritation and loose bony sequestra should be removed or recontoured so that soft tissue healing can be optimized [6,107]. The extraction of symptomatic teeth within exposed, necrotic bone should be considered as it appears unlikely that extraction will worsen the established necrotic process. Otherwise, surgical resection of necrotic bone should generally be reserved for refractory or advanced cases [29,108-114]. Resection may occasionally result in even larger areas of exposed and painful infected bone [22,73,108]. When indicated, surgical resection should only be performed by an experienced oral and maxillofacial surgeon [107,115].

Discontinuation of the at-risk agent — There are no prospective data to advise the patient or physician as to the benefits of discontinuing therapy with the antiresorptive or antiangiogenic agent in patients who develop MRONJ. While discontinuation of the offending agent might stabilize sites of ONJ, reduce the risk of developing new sites, and control symptoms, treatment discontinuation could also result in a recurrence of bone pain or an increase in skeletal-related events for patients receiving antiresorptive therapy in the setting of bone metastases, and a worsening of disease status in patients receiving antiangiogenic agents. The decision must be made on a case-by-case basis, taking into account the estimated risks and benefits for an individual patient. Many clinicians, including one of the authors, discontinue therapy, at least temporarily, and restart after resolution or signs of improvement. However, others, including one of the authors, continue monthly treatment as long as the patient has not had a recent dental extraction, subsequently discontinuing the drug if the ONJ worsens significantly. There is no evidence to support either strategy, and both are appropriate.

Antiresorptive agents — It is unclear whether short-term discontinuation of antiresorptive therapy is beneficial at stabilizing sites of ONJ or can improve healing after surgical procedures. Although some reports suggest better outcomes with discontinuation of bisphosphonates for a variable period (one to six months [116]), the discontinuation of these agents could also result in recurrence of bone pain, progression of metastases, and/or an increase in SREs.

As bisphosphonates accumulate in the bone matrix and are released over months to years, the rationale for discontinuation of bisphosphonate therapy in patients who develop ONJ is the interruption of its effects on the oral soft tissues, and specifically the surrounding epithelial cells and fibroblasts and areas of inflammation. Denosumab, by contrast, is not accumulated in bone, and its effects on bone are reversible after several months of treatment discontinuation. At present, there are almost no prospective data to advise the patient or physician as to the benefits of discontinuing therapy with the antiresorptive agent once ONJ develops. In particular, because bisphosphonates have long-term skeletal retention (months to years), it is unclear if stopping treatment for any duration will alter the course of the ONJ lesion.

There are anecdotal reports on spontaneous healing of ONJ in patients receiving conservative therapy with or without discontinuation of the antiresorptive agent:

In the registration clinical trials described above, all patients with denosumab-associated ONJ had denosumab therapy discontinued. Although six patients reinitiated denosumab after resolution of ONJ, their outcomes were not specifically reported [39].

Among patients receiving monthly IV bisphosphonate therapy, there have been anecdotal reports of healing and complete resolution after several months of cessation of these agents, but there are also reports of spontaneous resolution with continued monthly therapy [88,117,118]:

One study included 97 patients with multiple myeloma who developed ONJ and were followed for a minimum of 3.2 years [73]. Patients who developed ONJ following a dental procedure could restart bisphosphonate therapy if skeletal-related events developed. Recurrent ONJ followed reinitiation of bisphosphonate in 6 of 12 patients. Patients who developed ONJ without a predisposing cause were at increased risk of recurrence after initial healing, especially if the agent was reintroduced. The hypothesis that decisions regarding discontinuation of therapy can be made on the basis of whether there was an inciting predisposing event or not needs to be prospectively validated.

In another series of 14 myeloma patients with ONJ, eight patients continued treatment with the bisphosphonate, while five patients had the drug stopped, and one stopped briefly then restarted [88]. With a median of 19 (range 4 to 49) months of follow-up after the diagnosis of ONJ, two showed some worsening of the condition (one of whom discontinued therapy), five remained stable (two of whom discontinued therapy, two continued, and one had a brief break then restarted), and seven improved or completely resolved (despite continued bisphosphonate therapy in five).

Guidelines from expert groups differ:

The European Myeloma Network suggests discontinuation of bisphosphonates until healing occurs, with treatment restarted if there is disease progression [119].

Canadian consensus guidelines suggest only patient education and review of indications for continued bisphosphonate therapy [120].

A position paper published in 2014 from the AAOMS emphasized the lack of data about whether discontinuation of IV bisphosphonates in cancer patients might be beneficial in stabilizing sites of ONJ, reducing the risk of developing new sites, and controlling symptoms [6]. However, treatment discontinuation could also result in a recurrence of bone pain, progression of metastases, or an increase in skeletal-related events.

A 2007 ASCO guideline for the role of bisphosphonates in multiple myeloma, and a year 2011 guideline in the role of antiresorptive agents in metastatic breast cancer provide no guidance as to discontinuation versus continued use of either a bisphosphonate or denosumab in patients who develop ONJ during therapy [91,92].

This issue was also not specifically addressed in a year 2014 consensus document from the International Task Force on Osteonecrosis of the Jaw [7].

The US Food and Drug Administration (FDA)-approved manufacturer's package insert for both zoledronic acid and pamidronate state only that there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ in patients who require dental procedures during therapy and that clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [121,122]. The package insert for denosumab does not address the issue of treatment continuation in patients who develop ONJ.

Outcomes — The best information on outcomes of ONJ associated with antiresorptive agents comes from a review of data from three identically designed prospective randomized trials comparing zoledronic acid versus denosumab in patients with a wide variety of malignancies described above [39].

The majority of patients who developed ONJ (59 percent) received treatment with oral rinses and/or antibiotics alone, with approximately 40 percent undergoing limited oral surgeries including debridement, sequestrectomy, or extraction. All patients discontinued bone modifying therapy at ONJ diagnosis, although six patients treated with denosumab reinitiated therapy, and one patient received additional doses of zoledronic acid after the diagnosis of ONJ.

Of the 52 cases of ONJ that developed in patients treated with denosumab, 21 (40 percent) resolved, 20 (39 percent) were still present at the time of death, eight (15 percent) were ongoing, and three (6 percent) were lost to follow-up. Of the 37 patients who developed ONJ while receiving zoledronic acid, resolution of ONJ occurred in 11 patients (30 percent), 15 (41 percent) were still present at the time of death, eight (22 percent) were ongoing, and three (8 percent) were lost to follow-up. Only one patient received additional doses of zoledronic acid after the diagnosis of ONJ, and the outcome was not reported. The higher rate of resolution observed with denosumab compared with zoledronic acid in these trials (40 versus 30 percent) may be related to the reversibility of denosumab's effects. In a preliminary report of an updated analysis of this cohort presented at the 2013 ASCO meeting [46], the rate of resolution was 37 percent with denosumab (23 of 63) and 27 percent (12 of 44) with zoledronic acid.

Additional information on the natural history of ONJ comes from a report of 97 patients with multiple myeloma who were observed prospectively for a minimum of 3.2 years following the diagnosis of ONJ [123]. Bisphosphonates were stopped once ONJ was diagnosed. ONJ resolved in 62 percent, resolved and then recurred in 12 percent, and did not heal in 26 percent.

Other nonsurgical treatment strategies — Limited data suggest potential benefit for a variety of other nonsurgical treatment strategies including pentoxifylline and vitamin E, low-level laser irradiation, hyperbaric oxygen, parathyroid hormone, and topical application of medical ozone, although none can be considered a standard approach at this time.

Several nonsurgical therapies have been proposed to provide benefit for established MRONJ:

The addition of pentoxifylline and oral vitamin E in addition to antimicrobial therapy was reported to be effective in a small case series of bisphosphonate-related ONJ [124].

Benefit for topical application of medical ozone was suggested in a small series of 10 consecutive patients with ONJ related to bisphosphonate use and in other single case reports from Italy [125-127].

Case reports and small series suggest benefit from hyperbaric oxygen therapy (HBO) [38,128-130]. A small randomized trial of HBO as an adjunct to non-surgical and surgical treatment of MRONJ in 46 patients demonstrated some improvement in wound healing, pain, and quality of life at three months [131,132]. However, rates of complete gingival coverage, a major study endpoint, were not significantly better with HBO (52 versus 33 percent, p = 0.20), and there were no significant differences when outcomes were assessed at intervals beyond 3 months

There are reports that low-level laser therapy (LLLT) improves healing and symptoms related to ONJ [133-138]. However, experience is limited to small retrospective series (many of which come from one group in Parma Italy), and almost all patients received a combination of LLLT with another form of therapy, leaving open the question as to the independent contribution of LLLT [139,140].

Teriparatide (recombinant human parathyroid hormone 1-34) has been used successfully to treat ONJ in several case reports of osteoporotic patients. Teriparatide is thought to improve bone healing by stimulating bone remodeling and growth. (See "Parathyroid hormone therapy for osteoporosis".)

However, there are challenges to the use of teriparatide in patients with cancer. At present, teriparatide is limited to a 24-month cumulative treatment duration because of concerns for osteosarcoma, although these concerns may be unfounded [141]. The second problem is that anabolic treatments such as teriparatide are generally not considered viable options for most cancer patients because of generalized concerns about stimulating cellular proliferation in the bone marrow. As a result, use of this agent in cancer patients is controversial.

Several studies have evaluated the use of autologous platelet concentrates (APC, also called platelet-rich plasma) as an adjunct to oral surgery procedures. One review included 18 studies (392 patients undergoing oral surgery in conjunction with APC), four examining APC for prevention of ONJ in the setting of tooth extraction, and the remainder in conjunction with surgical debridement for treatment of established ONJ [142]. Excluding one individual case report, of the three studies on tooth extraction, only one was a randomized comparison between APC (n = 91) and no APC (n = 85); in this study, there were five cases of ONJ in the control group and none in the APC group. Among the 14 studies examining the use of therapeutic APCs in conjunction with surgical management, four included a group treated with APC and a group that was not treated with APC. A meta-analysis of these four studies showed that patients receiving the APCs had significantly reduced rates of ONJ recurrence (odds ratio [OR] 0.12, 95% CI 0.04-0.36). However, there were only five events in the APC group compared with 17 in the control group. The authors concluded that the use of APCs as an adjunct to oral surgery procedures may be of benefit, although the quality of the evidence is limited, and randomized trials are needed.

Stage-specific management recommendations — Updated year 2014 guidelines on stage specific management for patients with MRONJ from the AAOMS are presented in the table (table 1) [6].

SUMMARY AND RECOMMENDATIONS

Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon but potentially serious side effect that occurs in cancer patients treated with high-potency bisphosphonates or denosumab. The pathophysiology is likely multifactorial, with contributions from impaired bone repair/suppression of osteoclast activity; impaired angiogenesis (particularly in patients treated concurrently with antiangiogenic agents); and local factors, such as poor dental hygiene, including poorly fitting dentures, and/or a dental manipulation of some sort (eg, dental extraction, advanced periodontal disease). (See 'Pathophysiology' above.)

Areas of exposed and necrotic bone, which may remain asymptomatic for weeks, months, or even years, are the consistent hallmark of MRONJ [36]. Signs and symptoms that may occur before the development of clinically detectable osteonecrosis include prolonged jaw pain, tooth mobility, bone enlargement, gingival swelling, erythema, and ulceration. The mandible is affected twice as often as the maxillary bone. (See 'Clinical presentation' above.)

Among patients treated with antiresorptive agents for cancer, the incidence of ONJ is slightly higher with denosumab than with bisphosphonates (approximately 1.9 versus 1.3 percent). (See 'Incidence and risk factors' above.)

Dentoalveolar surgery is a major risk factor for MRONJ. The best estimate of the absolute risk of developing ONJ following tooth extraction and other dentoalveolar procedures among cancer patients exposed to antiresorptive medications is between 1.6 to 2.8 percent. (See 'Dentoalveolar surgery' above.)

A clinical staging system for MRONJ, with stage-specific recommendations for treatment, has been proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS) (table 1). (See 'Staging and treatment' above.)

We recommend that patients being considered for therapy with an antiresorptive agent be examined by a dentist and have needed dental work performed, including removal of unsalvageable teeth and optimization of periodontal health, prior to initiating therapy (Grade 1B). (See 'Before initiation of IV antiresorptive therapy' above.)

During therapy, all patients should practice good oral hygiene including daily brushing, flossing, and use of antibacterial oral rinses, and recommended dental check-ups, denture fittings, and routine cleaning. Patients should inform their dentists they are receiving antiresorptive and antiangiogenic agents so invasive dental procedures and especially extractions can be avoided while receiving active therapy. Oral exams and hygiene status should be closely monitored by the oncologist during treatment. (See 'Asymptomatic patients during therapy' above.)

Every effort should be made to avoid invasive dental procedures in patients who are receiving therapy with an antiresorptive agent. At present, no recommendations based on clinical studies can be made as to the benefit of discontinuing at-risk therapies for a short period of time (ie, "drug holiday") prior to necessary invasive dental procedures. However, it is reasonable to withhold the antiresorptive agent for two to three months before and after the invasive procedure, and then restart after the mucosa has healed if doing so is consistent with the oncologic goals of care. (See 'Cessation of at-risk medication prior to invasive dental procedures' above.)

For patients who develop ONJ while receiving therapy with an antiresorptive agent, recommendations on management are hindered by a lack of evidence. We suggest conservative management with limited debridement, antibiotic therapy as needed, and topical mouth rinses rather than aggressive surgical resection (Grade 2C). Conservative therapy may result in healing in a significant proportion of patients. Surgical resection of necrotic bone should be reserved for refractory or advanced cases, and be undertaken only by dentists or oral surgeons familiar with MRONJ. (See 'Treatment of established MRONJ' above.)

Stage-specific management recommendations for MRONJ are available from the AAOMS (table 1) [6]. (See 'Stage-specific management recommendations' above.)

There are no prospective data to advise the patient or physician as to the benefits of discontinuing therapy with the antiresorptive or antiangiogenic agent. While discontinuation of the offending agent might stabilize sites of ONJ, reduce the risk of developing new sites, and control symptoms, treatment discontinuation could also result in a recurrence of bone pain or an increase in skeletal-related events for patients receiving antiresorptive therapy in the setting of bone metastases, and a worsening of disease status in patients receiving antiangiogenic agents. The decision must be made on a case by case basis, taking into account the estimated risks and benefits for an individual patient. (See 'Discontinuation of the at-risk agent' above.)

For patients receiving antiresorptive therapy, many clinicians, including one of the authors, discontinue therapy, at least temporarily, and restart after resolution or signs of improvement or stabilization. However, others continue monthly treatment as long as the patient has not had a recent dental extraction, subsequently discontinuing the drug if the ONJ worsens significantly. There is no evidence to support either strategy, and either is appropriate.

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