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Medication-related osteonecrosis of the jaw in patients with cancer

Medication-related osteonecrosis of the jaw in patients with cancer
Literature review current through: Jan 2024.
This topic last updated: Jan 26, 2023.

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

MRONJ 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 MRONJ among patients receiving osteoclast inhibitors for cancer is more clearly established. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", 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 osteoclast inhibitors and antiangiogenic agents. The incidence, risk factors, and management strategies for MRONJ in patients receiving osteoclast inhibitors 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 — Osteonecrosis associated with bisphosphonate treatment has been referred to by several acronyms, including BRMRONJ (bisphosphonate-related MRONJ), BRON (bisphosphonate-related osteonecrosis), BON (bisphosphonate osteonecrosis), BAMRONJ (bisphosphonate-associated MRONJ), and simply MRONJ. The recognition of jaw necrosis as a complication of other drugs, including the receptor activator of nuclear factor kappa B ligand (RANKL) 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], and this terminology is also endorsed in joint guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)/American Society of Clinical Oncology (ASCO) [7].

Definition — Two working definitions of MRONJ have been proposed:

A task force convened by the American Society for Bone and Mineral Research (ASBMR) 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 2022 position paper on MRONJ is available from the AAOMS, which provides an updated definition of the condition, comparative risk estimates of developing MRONJ in patients with cancer and a history of exposure to osteoclast inhibitors and/or antiangiogenic agents, recommendations for prevention measures, and management strategies for patients with established MRONJ [8].

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

Current or previous treatment with antiresorptive therapy alone or in combination with immune modulators 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.

No history of radiation therapy to metastatic disease in the jaws.

We prefer the AAOMS definition, which has also been adopted by an international task force on osteonecrosis of the jaw [9] and in joint guidelines on MRONJ from the MASCC/ISOO/ASCO [7].

PATHOPHYSIOLOGY — Although the first cases of MRONJ were reported first in 2002, the underlying pathophysiology is still not fully elucidated. The leading proposed hypotheses to explain the unique localization of MRONJ to the jaws include oversuppression of bone turnover or remodeling, inhibition of blood supply, constant microtrauma, and infection/inflammation. None of these hypotheses seems to explain all cases [10].

The shared complication of MRONJ 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 [11]. 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 [12,13]. However, this is probably not the sole contributor since MRONJ can be, albeit rarely, observed in the absence of osteoclast inhibitor therapy. Other animal studies suggest defects in alveolar bone such as dental extractions to be potent initiators for MRONJ, with mucosal or soft tissue damage less likely to induce necrosis [14].

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 vascular endothelial growth factor (VEGF) levels [15,16]. 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 MRONJ lesions demonstrates patent vessels in the majority of cases [17,18]. Thus, it seems unlikely that MRONJ represents a form of avascular necrosis. (See 'Concurrent antineoplastic 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 [19]. 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 [20]. Although tooth extraction had been performed in most of the initial reported cases of bisphosphonate-related MRONJ, these teeth commonly had preexisting periodontal or periapical disease. Animal models indicate that both inflammation/bacterial infection and systemic administration of osteoclast inhibitors are sufficient to induce MRONJ [21-23]. (See 'Oral health-associated risk factors' below.)

Complex biofilms have been identified on the bone/tooth and mucosal surfaces around bisphosphonate-related MRONJ that are composed of actinomyces and other organisms including fungi and viruses [17,24-27]. However, it is not known whether MRONJ represents direct toxicity to the bone and/or soft tissues that becomes secondarily infected [28,29] or if a primary infection is subsequently exacerbated by the use of osteoclast inhibitors. Furthermore, it is unclear if the common presence of actinomyces in these lesions is actively contributing to the development or progression of MRONJ or is simply related to the presence of necrotic bone in an anaerobic environment [24]. 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 [26].

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 [30]) and the use of osteoclast inhibitors such as bisphosphonates or denosumab (which have a detrimental effect on macrophages, compromising the local immune response [20,31]), which sets the stage for subsequent bone destruction [11].

Accumulating evidence on risk factors for MRONJ in patients undergoing therapy with an osteoclast inhibitor (which include concomitant use of antiangiogenic therapies) supports the view that MRONJ 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, advanced periodontal disease, poorly fitting dentures, and/or a dental manipulation of some sort (eg, dental extraction) [28,32-38].

CLINICAL PRESENTATION — Areas of exposed and necrotic bone, which may remain asymptomatic for weeks, months, or even years, are the consistent hallmark of MRONJ [39]. 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 [24,39,40].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 [41,42]. In one review of 368 reported cases, MRONJ was manifested in the mandible in 65 percent, maxilla in 26 percent, and both in 9 percent [41].

Several clinical staging systems are available that can help to categorize patients according to severity and direct rational treatment. (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 should be treated prior to the initiation of osteoclast inhibitor therapies.

The radiographic features of MRONJ are relatively nonspecific [43]. MRONJ can be visualized using panoramic radiography, cone beam computed tomography (CT; to limit radiation doses) [44], or magnetic resonance imaging (MRI) [45]. However, the extent of these lesions may not be clear, especially in the early stages. In particular, radiographic findings such as poorly healing or nonhealing extraction sockets, periapical radiolucencies, and widening of the periodontal ligament space are not specific in the early stages of the disease [46].

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 [39]. 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 [47,48]. 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 (periodontal abscess, necrotic dental pulp with apical abscess), sarcoma, chronic sclerosing osteomyelitis (proliferative periostitis), and temporomandibular joint disorders [49]. In those rare situations where patients have been exposed to both radiation therapy and either an osteoclast inhibitor or an antiangiogenic agent, osteoradionecrosis should also 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

Osteoclast inhibitor therapy — Although potentially serious, MRONJ is a relatively uncommon complication of therapy with intravenous bisphosphonates and denosumab among patients with advanced malignancy, although it is more common in patients with cancer than in patients who are treated with osteoclast inhibitors for osteoporosis [50]. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw' and "Denosumab for osteoporosis", section on 'Adverse effects'.)

The best information on incidence in patients with advanced cancer comes from a review of data on 5677 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 skeletal-related events; the most recent data were presented in a preliminary report at the 2013 American Society of Clinical Oncology (ASCO) meeting and were updated with data from the open-label extension phase of the trials in breast and prostate cancer patients [42,51,52]. MRONJ was defined per the 2009 guidelines of the American Association of Maxillofacial Surgeons (AAOMS) [53].

The following findings were noted:

All patients were treated monthly, and the median time to onset of MRONJ was 15 to 16 months [52]. Sixty-three patients (1.9 percent) on the denosumab treatment arm developed MRONJ compared with 44 (1.3 percent) on the zoledronic acid arm. This difference was not significant between treatment groups (p = 0.08). The cumulative incidence rates of MRONJ increased with longer duration of exposure, with an incidence of 0.7 to 1.4 percent during the first year of therapy and increasing to 2 to 3.4 percent with continued treatment beyond one year [51]. When compared with the risk for MRONJ in the placebo arms of the prior intravenous bisphosphonate studies to prevent complications from skeletal metastases (range 0 to 0.19 percent [54-56]), the risk of MRONJ was 50- to 100-fold higher with the use of modern high-dose monthly intravenous bisphosphonates (ie, zoledronic acid 4 mg monthly) [42].

Dental extraction preceded the MRONJ 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, frequency of administration, and duration of use influence MRONJ risk:

The risk is higher with intravenous than with oral bisphosphonates and most commonly observed in patients receiving intensive (monthly) parenteral dosing for prevention of skeletal-related events [57-59]. The incidence of MRONJ 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 [3,32,60,61]. 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 antineoplastic therapy' below and 'Other risk factors' below.)

As an example, in a retrospective series of 3994 patients with malignancy who were receiving intravenous bisphosphonates, the median duration of pamidronate use was longer in those who developed MRONJ 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).

The higher risk with longer duration of treatment can be illustrated by results from SWOG S0702, a prospective observational cohort study designed to assess the incidence and risk factors for MRONJ in 3491 patients receiving zoledronic acid for bone metastases [62]. The cumulative incidence of MRONJ was 0.8 percent at year 1, 1.2 percent at year 2, and 2.8 percent at year 3.

Chronic treatment with zoledronic acid has been implicated as a greater contributor to the development of MRONJ than pamidronate [4,25,32,57,60,63-67]. As an example, a web-based survey of 904 patients with multiple myeloma and 299 with breast cancer identified 75 patients with MRONJ and an additional 77 with findings suspicious for early MRONJ [63]. MRONJ developed in 10 and 4 percent of those treated with zoledronic acid or pamidronate, respectively. However, the diagnosis of MRONJ was not necessarily confirmed in individuals who reported having this condition in this web-based survey. In addition, use of zoledronic acid was likely longer than with pamidronate since widespread use of pamidronate occurred during a time in which survival of these patients was much shorter.

In the Southwest Oncology Group (SWOG) 0307 trial comparing three bisphosphonates as adjuvant therapy in breast cancer, intravenous zoledronic acid was associated with a higher incidence of MRONJ (1.26 percent) compared with oral daily clodronate (0.36 percent) and oral daily ibandronate (0.77 percent) after three years of therapy [68]. (See "Use of osteoclast inhibitors in early breast cancer".)

The greater risk for MRONJ with zoledronic acid is likely due to its greater potency. However, it should be noted that zoledronic acid was administered monthly for six months and then every three months to complete three years of therapy in this trial and that monthly zoledronic acid dosing is no longer recommended for many cancer patients with bone metastases.

Whether the incidence of MRONJ might be lowered by extending the dosing interval of bisphosphonates has been addressed in the following studies:

In CALGB (Alliance) 70604, the largest study addressing dosing interval, 1822 patients with metastatic breast cancer (n = 855), prostate cancer (n = 689), or multiple myeloma (n = 278) and without prior intravenous bisphosphonate therapy were randomized to every-4-week or every-12-week zoledronic acid for two years to prevent skeletal-related events [69]. There was no statistically significant difference in the incidence of MRONJ events observed between the two arms; however, 18 patients (2 percent) in the every-four-week dosing, compared with nine patients (1 percent) in the every-12-week dosing, were diagnosed with MRONJ.

In the larger prospective observational SWOG S0702 study, which assessed the cumulative incidence of MRONJ at three years in patients with metastatic bone disease from any malignancy, a much higher risk for MRONJ was observed in those with a planned dosing interval of less than five weeks versus longer (three year cumulative rate 3.2 versus 0.7 percent, hazard ratio 4.65, 95% CI 1.46-14.8) [62].

ASCO guidelines on the use of intravenous zoledronic acid for the prevention of skeletal-related events in patients with metastatic breast cancer were revised in 2017 to include every 12-week dosing as an option [70]. Although a clear recommendation was not made, to reduce the risk of MRONJ, a once every 12-week dosing is preferred over every 3 to 4 week dosing for most patients with bone metastases from breast or castration-resistant prostate cancer who have neither extensive nor highly symptomatic bone metastases. In 2020, clinical practice guidelines from ESMO recommended 3 to 6 months of monthly zoledronic acid prior to switching to an every 12 week dosing schedule [71]. The rationale for this recommendation included the relatively short follow-up of the largest trial comparing every 4 week to every 12 week zoledronic acid dosing, an increased incidence of serious skeletal-related events with the 12 week dosing, no difference in ONJ events with the longer dosing schedule, and the concern of several experts on the consensus panel that patients with extensive bone disease may initially require more potent osteoclast inhibition until disease control is obtained. The extended dosing interval applies to metastatic solid tumors but not myeloma. This subject is addressed in detail elsewhere. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Dosing interval' and "Multiple myeloma: The use of osteoclast inhibitors", section on 'Should the dose interval/frequency be adjusted?'.)

Denosumab — As with bisphosphonates, dose, schedule, and duration of osteoclast inhibition are associated with MRONJ 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 MRONJ is consistently slightly higher than that seen with intravenous bisphosphonates, but the difference has not been statistically significant in any individual trial:

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 MRONJ with denosumab was slightly higher, but the difference was not statistically significant (1.9 versus 1.3 percent, p = 0.08) [52].

In the phase III clinical trial comparing denosumab with zoledronic acid in 1718 patients with newly diagnosed multiple myeloma, 4.1 percent of patients receiving denosumab compared with 2.8 percent of patients receiving zoledronic acid developed MRONJ after a median drug exposure of 16 and 15 months, respectively [72]. (See "Multiple myeloma: The use of osteoclast inhibitors".)

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 MRONJ as an endpoint), the rate of MRONJ 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) [54]. Nevertheless, MRONJ rates were consistently higher among denosumab-treated compared with zoledronic-acid-treated patients from individual trials.

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, MRONJ rates are less than 1 percent for up to five years of therapy [73]. (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 [42,74]. As an example, in an analysis of the three phase III registration trials, the incidence of developing MRONJ was 1.1 percent during the first year and 4.1 percent thereafter [52].

There are only limited data addressing less frequent dosing than every four weeks for denosumab, and this approach cannot yet be recommended. However, on a case-by-case basis, every-12-week dosing may be appropriate for informed and selected patients with bone metastases from breast cancer or castration-resistant prostate cancer. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Dosing interval'.)

Concurrent antineoplastic therapy — The incidence appears to be higher among patients with bone metastases who are receiving therapy with an antiangiogenic agent plus an osteoclast inhibitor for prevention of skeletal-related events [4,75-82]:

In a retrospective analysis of 3560 patients receiving bevacizumab-containing therapy for advanced breast cancer from two double-blind, randomized trials and a large, nonrandomized safety study, there was a trend towards increased MRONJ in those who received bisphosphonates (0.9 versus 0.2 percent) in the analysis of the pooled, randomized trials (n = 1309 patients) and 2.4 versus 0 percent in the analysis from the nonrandomized safety study (n = 2251 patients) [75].

In another report, 11 of 60 (18.3 percent) patients with metastatic castration-resistant prostate cancer administered bevacizumab, docetaxel, thalidomide, and prednisone with concurrent zoledronic acid developed MRONJ [79].

In a retrospective review of 90 patients treated with concomitant oral vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and osteoclast inhibitors, the incidence of MRONJ was 11 percent; during the first year of exposure, the risk was 6.7 percent, compared with 1.1 percent in the control group receiving osteoclast inhibitors alone [82]. MRONJ occurred earlier in patients treated concomitantly compared with those receiving osteoclast inhibitors alone (onset after a median exposure of 4.5 versus 25 months).

Interestingly, other reports have failed to find an association with coadministration of thalidomide, which has antiangiogenic as well as immunomodulatory properties [24,32,60,66,83-85].

MRONJ is also reported as a side effect in patients receiving antiangiogenic agents as monotherapy. (See 'Other medications' below.)

Concomitant use of anthracyclines may be a risk factor for MRONJ in myeloma patients treated with intravenous bisphosphonates [86].

Questions remain as to whether glucocorticoids play a similarly important role in the development of MRONJ 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 MRONJ in patients with multiple myeloma and another failing to confirm this finding in patients with multiple myeloma or breast cancer [3,87]. In the large series of patients enrolled in trials comparing zoledronic acid with denosumab described above, concomitant use of glucocorticoids was observed in 73 percent of those who developed MRONJ compared with 62 percent of those who did not [42]. (See "Clinical manifestations and diagnosis of osteonecrosis (avascular necrosis of bone)", section on 'Glucocorticoids'.)

Other medications — There are an increasing number of reports of MRONJ in patients treated with a variety of antineoplastic medications without concurrent use of an osteoclast inhibitor, including angiogenesis inhibitors, inhibitors of the mechanistic (previously called mammalian) target of rapamycin (mTOR), BRAF inhibitors, and immunotherapy; most cases are in patients receiving angiogenesis inhibitors. In a review of 42 MRONJ cases reported in the literature related to non-osteoclast inhibitor therapy, 31 were in patients receiving angiogenesis inhibitors, alone or in combination [88]. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", 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 MRONJ [3,32,42,60,63,64,89-91].

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 [42,92,93]:

In a case-control study of 60 cancer patients exposed to zoledronic acid (20 who developed MRONJ and 40 matched controls who did not), tooth extraction during bisphosphonate therapy was associated with a significant 16-fold increased risk for MRONJ [90].

In a longitudinal cohort study of 1621 cancer patients exposed to intravenous bisphosphonates, a history of dental extraction was associated with a significant 33-fold (95% CI 18-60) increased risk for MRONJ [92].

The best estimate of the absolute risk of developing MRONJ following tooth extraction among cancer patients exposed to osteoclast inhibitors in retrospective studies is as high as 14.8 percent [94], but data from prospective trials suggest that the actual risk is lower, 1.6 to 2.8 percent [95,96]. The risk of developing MRONJ among patients exposed to osteoclast inhibitors 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) [42,62,89-92,97].

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 [91]. Reports from Greece and Turkey describe a much higher incidence of MRONJ than in Italy and the United States [4,65,98]. The reasons for these differences could include differences in diagnostic criteria for MRONJ in these different regions, as well as genetic factors [99-101]. 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 [101-103]. 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 [101].

Tobacco use has been inconsistently reported as a risk factor for MRONJ [90,92,97]. Smoking might represent a confounding factor given that smokers tend to have worse oral hygiene than nonsmokers.

Tumor type — 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 skeletal-related events, a slightly higher percentage of patients with multiple myeloma developed MRONJ (3.3 percent) versus breast cancer (1.7 percent), prostate cancer (1.8 percent), and other solid tumors (0.9 percent), although only 180 myeloma patients were included in the trials [42].

Other series note a higher risk of MRONJ in myeloma compared with patients who have solid tumors and metastatic bone disease [3,54,60,62,92,104]. As an example, in the S0702 prospective observational cohort study of 3491 patients with bone metastases receiving zoledronic acid, cumulative incidence of MRONJ at three years was highest for patients with myeloma (n = 702, 4.3 percent) and lowest for those with breast cancer (2.4 percent) [62].

STAGING AND TREATMENT — A well-established staging system should be used to quantify the severity and extent of MRONJ and to guide management decisions [7]. Options include the following:

The 2014 American Association of Maxillofacial Surgeons (AAOMS) position paper provided a revised clinical staging system to describe the severity of MRONJ [6], which was upheld in the 2022 publication [8]. However, the suggested stage-specific treatment strategies are not evidence based, and in particular, stage 0 disease is not universally accepted [7,9]. Year 2019 guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)/American Society of Clinical Oncology (ASCO) suggest that stage 0 be considered an indicator of increased risk of MRONJ, which could prompt referral to a dental specialist for close follow-up [7]. The various stages and suggested stage-specific treatment strategies are outlined in the table (table 1).

Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (table 2).

Year 2015 International Task Force on Osteonecrosis of the Jaw staging system for MRONJ (table 3) [9].

Staging should be performed by a clinician who is experienced with the management of MRONJ, and the same system should be used throughout the patient's MRONJ course and care [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 MRONJ prior to initiating therapy with an osteoclast inhibitor or antiangiogenic agent.

Prevention

Before initiation of an intravenous osteoclast inhibitor — In view of the difficulty in treating established MRONJ, prevention is emphasized.

We agree with joint guidelines from the MASCC/ISOO/ASCO as well as guidelines from the AAOMS, the International Task Force on Osteonecrosis of the Jaw, the European Medicines Agency (EMA), and the American Academy of Oral Medicine, which all recommend that all patients have a comprehensive dental, periodontal, and oral radiographic examination (when feasible to do so) and preventive dentistry (preemptive extraction of unsalvageable teeth and optimized periodontal health) before beginning therapy with an osteoclast inhibitor [6,7,9,105-109]. 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 [110]. Based on the assessment, a dental care plan should be developed, implemented, and coordinated between the dental specialist and the oncologist to ensure that medically necessary dental procedures are undertaken before the initiation of the osteoclast inhibitor.

The components of a complete evaluation should include the following [6,7]:

Nonrestorable teeth and those that are not likely to be salvageable should be extracted. If systemic conditions permit, initiation of therapy with the osteoclast inhibitor 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 clinician 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. Use of a systematic daily oral care plan (table 4) should be highly encouraged [7].

Modifiable risk factors for MRONJ (eg, poor oral health, ill-fitting dentures, uncontrolled diabetes, and tobacco use) should be addressed as early as possible. (See 'Incidence and risk factors' above.)

Performing the medically necessary dental care in this context may not be feasible if the patient's medical condition warrants prompt initiation of the osteoclast inhibitor (eg, rapidly progressive bone disease or acute hypercalcemia, for which the benefits of prompt initiation of an osteoclast inhibitor outweigh the risk for MRONJ). In such cases, partial or minimal evaluation protocols are suggested. Recommended dental evaluation protocols, as derived from a systematic review of dental disease management in cancer patients [111], are outlined in the table (table 5).

Follow-up by the dentist should then be performed on a routine schedule (eg, every six months) once therapy with an osteoclast inhibitor has commenced [7].

One single open-label randomized trial [112] provides some evidence, albeit of very low quality [113], that periodic dental examinations and preventive treatments may be more effective than standard care for reducing the incidence of MRONJ, although benefit from dental screening and prophylactic treatment is also supported by retrospective single-institution studies [114-119]. This study randomized 253 men with prostate cancer and bone metastases receiving intravenous zoledronic acid therapy to regular dental visits every three months versus standard of care dental delivery [112]. All patients received baseline dental visits and preventive dentistry prior to initiating bisphosphonate therapy. The primary endpoint was the incidence of MRONJ, defined as nonhealing exposed bone in the mandible or maxilla for greater than eight weeks. A 2.2 percent incidence of MRONJ was observed in the experimental arm versus 23.3 percent in the standard arm. However, the study was flawed by a high and unbalanced rate of crossover from the experimental arm to the standard arm and the data being presented "as treated" rather than in an "intention-to-treat" analysis; this led to a very low certainty of evidence grade for this trial in a Cochrane Database Review of interventions for MRONJ [113].

Asymptomatic patients during therapy — During therapy with an osteoclast inhibitor or antiangiogenic agent, oral hygiene status should be closely monitored. All patients should practice good oral hygiene, including daily brushing, flossing, and use of antibacterial oral rinses, and attending recommended dental check-ups, denture fittings, and routine cleanings (table 4), to decrease rates of periodontal disease and oral infection. Invasive dental procedures should be avoided, if possible. Patients should be encouraged to stop smoking and curtail alcohol [46]. (See 'Other risk factors' above.)

Patients should be asked about possible planned dental procedures prior to administration of each dose of the osteoclast inhibitor 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 [120-122]. 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 of the osteoclast inhibitor — Every-four-week administration of bisphosphonates represents a standard approach, although, as noted above, the available evidence is now sufficient to support dosing zoledronic acid every 12 weeks rather than every 4 weeks in most patients with bone metastases from breast or castration-resistant prostate cancer who have neither extensive nor highly symptomatic bone metastases. (See 'Bisphosphonates' above and "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Dosing interval'.)

In view of the demonstration of improved overall survival among previously untreated myeloma patients receiving monthly zoledronic acid compared with daily oral clodronate in the Medical Research Council Myeloma IX trial, many clinicians do not advocate less frequent dosing of bisphosphonates for patients with myeloma in order to reduce the risk of MRONJ. This trial is discussed in detail elsewhere. (See "Multiple myeloma: The use of osteoclast inhibitors", section on 'Long-term management'.)

On the other hand, there are only limited data addressing the efficacy of less frequent dosing of denosumab, and every-four-week administration remains the standard approach. (See 'Denosumab' 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 — Elective dentoalveolar surgical procedures should be avoided, if at all possible, during treatment with an osteoclast inhibitor. (See 'Asymptomatic patients during therapy' above.)

Exceptions may be considered when a dental specialist with expertise in the prevention and management of MRONJ has reviewed the benefits and risks of the proposed invasive procedure with the patient and the oncology team [7]. Decisions about whether to continue the osteoclast inhibitor following the surgical procedure must be individualized. If dentoalveolar surgery is performed, patients should be evaluated by the dental specialist on a systematic and frequent basis (eg, every six to eight weeks) until full mucosal coverage at the surgical site has occurred. Communication with the oncology team about the status of healing (table 6) is encouraged, particularly when considering future use of an osteoclast inhibitor.

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 osteoclast inhibitor or antiangiogenic agent is not established, and there are scant data to guide the clinician in this setting. Updated 2019 guidelines from the MASCC/ISOO/ASCO state that there is insufficient evidence to support or refute the need for discontinuation of the osteoclast inhibitor before dentoalveolar surgery [7]. Administration of the osteoclast inhibitor may be deferred at the discretion of the treating clinician, in conjunction with a discussion with the patient and the oral health provider.

In the absence of data, it may also be reasonable to hold the osteoclast inhibitor 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.

Local instillation of plasma rich in growth factors — One randomized trial compared the use of a plasma rich in growth factors (PRGF) preparation instilled in the postextraction alveolus with a control group treated without PRGF after dental extractions [95]. All patients also received antibiotics for six days starting the day before the extraction. None of the 91 patients treated in the PRGF group developed MRONJ, compared with 5 of the 85 patients in the control group, within a follow-up period of up to 60 months. However, the quality of the evidence presented in this trial has been criticized as very low based on a high risk of bias in patient selection and outcome assessments, and thus, the preventive benefit of PRGF postdental extraction is considered unproven at this time [113].

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. Conservative measures comprise the initial approach to MRONJ [7]. These include antimicrobial mouth rinses, antibiotics (if clinically indicated), effective oral hygiene, and conservative surgical intervention (eg, removal of a superficial bone spicule). Aggressive surgical interventions (eg, mucosal flap elevation, block resection of necrotic bone, or soft tissue closure) may be used if MRONJ results in persistent symptoms or affects function despite initial conservative management. In advance of aggressive surgical intervention, the multidisciplinary care team and patient should discuss the risks and benefits of the proposed intervention.

General approach — In general, recommendations for management of MRONJ in patients with cancer are hindered by a lack of data. There are few prospective studies with long-term follow-up with which to guide therapy and no evidence-based guidelines [113]. Nonetheless, treatment has generally shifted away from aggressive surgical interventions to conservative therapy with limited debridement, antibiotics [7,26,123,124], 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 [25,42,125]. (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 [39].

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 [6,126]. 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 [32,127-133]. Resection may occasionally result in even larger areas of exposed and painful infected bone [25,89,127]. When indicated, surgical resection should only be performed by an experienced oral and maxillofacial surgeon [126,134].

Should the at-risk agent be discontinued? — There are no prospective data to advise the patient or clinician as to the benefits of discontinuing therapy with the osteoclast inhibitor or antiangiogenic agent in patients who develop MRONJ. While discontinuation of the offending agent might stabilize sites of MRONJ, 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 osteoclast inhibitor 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 the individual patient. There are no prospective trials to prove either strategy.

Osteoclast inhibitors — There are no prospective data to advise the patient or clinician as to the benefits of discontinuing therapy with the osteoclast inhibitor, and there is no consensus as to whether it should be discontinued or continued in patients who develop MRONJ. While discontinuation of the offending agent might stabilize sites of MRONJ, 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 an osteoclast inhibitor in the setting of bone metastases, and a worsening of disease status in patients receiving antiangiogenic agents.

While there is no consensus on this issue, most clinicians, including several of the authors and editors associated with this topic review, discontinue therapy, at least temporarily, and restart after resolution or signs of improvement or stabilization. Because of the rarity of this complication, there is unlikely to be a prospective clinical trial to answer this question. The decision must be made on a case-by-case basis, taking into account the estimated risks and benefits for the individual patient.

It is unclear whether short-term discontinuation of osteoclast inhibitor therapy is beneficial at stabilizing sites of MRONJ 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 [135,136]), the discontinuation of these agents could also result in a recurrence of bone pain, progression of metastases, and/or an increase in skeletal-related events.

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 MRONJ 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 clinician as to the benefits of discontinuing therapy with the osteoclast inhibitor once MRONJ 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 MRONJ lesion.

There are anecdotal reports on spontaneous healing of MRONJ in patients receiving conservative therapy even if the osteoclast inhibitor is continued [42,86,89,137,138].

On the other hand, the benefits of discontinuing therapy in terms of symptom duration were shown in another series of 84 patients with established MRONJ who discontinued bisphosphonate therapy before treatment (n = 21), at the time of presentation of MRONJ (n = 38), or later (or never) in the treatment course (n = 25); patients who continued the bisphosphonate after the start of treatment had a significantly delayed resolution of symptoms compared with those who discontinued the bisphosphonate before or at presentation (median 12 versus 3 and 6 months, respectively) [136]. However, interpretation of these results must be viewed with caution since this was not a randomized study and it is likely that patients with worse MRONJ were more likely the ones that had their bisphosphonates discontinued.

Not surprisingly, guidelines from expert groups differ:

The European Myeloma Network suggests discontinuation of bisphosphonates until healing occurs, with treatment restarted if there is cancer progression [139].

Canadian consensus guidelines suggest patient education and review of indications for continued bisphosphonate therapy [140].

A 2022 position paper from the American Association of Oral Maxillofacial Surgeons defines MRONJ and advises that MRONJ is uncommon [141], and that oncology patients should receive antiresorptive agents if indicated, even if they are at risk of developing MRONJ or had MRONJ in the past.

A 2007 ASCO guideline for the role of bisphosphonates in multiple myeloma and a year 2017 guideline on the role of osteoclast inhibitors in metastatic breast cancer provide no guidance as to discontinuation versus continued use of either a bisphosphonate or denosumab in patients who develop MRONJ during therapy [70,106].

This issue was also not specifically addressed in a year 2014 consensus document from the International Task Force on Osteonecrosis of the Jaw [9].

This issue was addressed in the 2019 joint guidelines from the MASCC/ISOO/ASCO, which stated that there was insufficient evidence to support or refute the discontinuation of the osteoclast inhibitor in this setting [7]. The decision was left to the discretion of the treating clinician, in conjunction with a discussion with the patient and the oral health provider.

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 MRONJ in patients who require dental procedures during therapy and that clinical judgment of the treating clinician should guide the management plan of each patient based on individual benefit/risk assessment [142,143]. The package insert for denosumab does not address the issue of treatment continuation in patients who develop MRONJ.

Despite these varying guidelines, most oncologists (including several of the authors and editors associated with this topic review) stop or pause osteoclast inhibitor therapy when MRONJ occurs and restart therapy after complete resolution of the lesion. Preventive dentistry and early detection remain the most effective ways to prevent and/or resolve this complication of osteoclast inhibitor therapy. (See 'Prevention' above.)

Stage-specific management recommendations — 2019 guidelines on stage-specific management for patients with MRONJ from the MASCC/ISOO/ASCO are presented in the table (table 1) [7].

Nonsurgical treatment strategies — Limited data suggest potential benefit for a variety of other nonsurgical treatment strategies, including parathyroid hormone (teriparatide), pentoxifylline, and vitamin E; however, large controlled trials have not yet been performed [8]. Hyperbaric oxygen (HBO) and topical application of medical ozone have also been used as adjunctive therapies for MRONJ, but have not been proven to have efficacy [7].

Teriparatide — One small trial suggests potential benefit from a short course of teriparatide (recombinant human parathyroid hormone) [144]; similar findings were observed in a retrospective study [145]. However, longer follow-up and larger numbers of treated patients are needed to confirm the safety of teriparatide in this patient population before this treatment can be widely recommended. A short course of teriparatide can be offered to patients who have prolonged, nonhealing MRONJ prior to pursuing aggressive surgical options. The decision to use the drug should be based on an individual risk assessment by the treating clinician together with the patient, balancing the potential for short-term benefit with potential (although likely remote) safety concerns. For those who do not improve with conservative measures, we suggest teriparatide rather than surgery, typically used for a short duration (ie, eight weeks). The decision to use the drug must balance the likelihood of short-term benefit against potential (although likely remote) safety concerns.

Teriparatide, a peptide corresponding to the first 34 amino acids of human parathyroid hormone, has been used successfully to treat MRONJ in several case reports of osteoporotic patients, some of whom had atypical femur fractures [146-148]. Teriparatide is thought to improve bone healing by stimulating bone remodeling and growth when given intermittently at low doses [149]. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis".)

The benefit of teriparatide for MRONJ was directly addressed in a small randomized trial in which 34 patients with exposure to prior bisphosphonates or denosumab and who had a diagnosis of MRONJ [2] were randomly assigned to a once per day injection of either placebo or 20 micrograms of teriparatide for eight weeks [144]. All patients received calcium, vitamin D supplementation, and standard clinical care, which included antiseptic mouthwashes, antibiotic therapy, and limited surgical debridement. There were 10 patients with multiple lesions (five in each group), for a total of 47 distinct MRONJ lesions. The indication for antiresorptive therapy was malignant bone disease in 79 percent, and the rest had osteoporosis. Median duration of MRONJ before enrollment was 12 months and similar in both groups. Clinical stage was also similar in both groups; it was 0 or 1 in 13 patients (37 percent of the placebo group versus 40 percent of the teriparatide group), stage 2 in 15 patients (47 versus 46 percent), and stage 3 in 5 patients (16 versus 13 percent) (table 1).

The following results were noted:

By 52 weeks, 45 percent of the lesions resolved in the teriparatide group and the odds ratio (OR) for resolution at each visit (ie, the proportion of MRONJ-positive sites at each visit) was 0.15 (95% CI 0.07-0.33). In the placebo group, 33 percent of the lesions resolved by week 52, and the OR for resolution at each visit was 0.40 (95% CI 0.22-0.74). Thus, teriparatide was associated with a significantly greater rate of resolution of MRONJ lesions compared with placebo (OR for change over time in the control group 0.40 versus 0.15, p = 0.013).

Teriparatide was also associated with increased bone volume, and thus, reduced defect size in a greater proportion of patients at 52 weeks (80 versus 31 percent with placebo, OR 8.1, 95% CI 1.36-66.20).

Although the proportion of resolved lesions was higher in the teriparatide group, this difference was not statistically significant (OR 1.67, 95% CI 0.41-6.83), nor was there a difference in the proportion of patients with at least one unresolved lesion at 52 weeks (73 versus 72 percent). Furthermore, among those with persistent MRONJ, teriparatide was not associated with a significant improvement in clinical stage.

The incidence of adverse events, including gastrointestinal symptoms, musculoskeletal pain, and injection site reactions, was comparable between the two groups and most were mild. No new malignancies or worsening of preexisting malignancies were reported with teriparatide; however, the trial was underpowered and the follow-up limited for these specific safety endpoints.

The short duration of this trial is problematic, and it is not yet determined whether treatment with teriparatide achieves long-term control of MRONJ. In addition, there are challenges to the use of teriparatide in patients with cancer. There are concerns about the potential for osteosarcoma with prolonged treatment durations when the drug is used long term for treatment of osteoporosis, although these concerns may be unfounded. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Long-term risks'.)

Another 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 (including that of dormant malignant cells) in the bone marrow [149]. As a result, use of this agent in cancer patients remains controversial.

The data from this small trial, which suggest potential benefit with short duration of teriparatide use without any concerning safety signals, are somewhat reassuring. However, longer follow-up and larger numbers of treated patients are needed to confirm the safety of teriparatide in this patient population before we can feel comfortable recommending this treatment widely. In our view, this trial does provide some rationale for offering patients who have prolonged, nonhealing MRONJ an eight-week course of teriparatide prior to pursuing aggressive surgical options. The decision to use the drug should be based on an individual risk assessment by the treating clinician together with the patient, balancing proven benefits with potential (although likely remote) safety concerns.

Other strategies

The addition of pentoxifylline and oral vitamin E to antimicrobial therapy was reported to be effective in a small series of six cases of bisphosphonate-related MRONJ [150].

Benefit for topical application of medical ozone was suggested in a small series of 10 consecutive patients with MRONJ related to bisphosphonate use and in other single case reports from Italy [151-153].

Case reports and small series suggest benefit from HBO [41,154-156]. A small randomized trial of HBO as an adjunct to nonsurgical and surgical treatment of MRONJ in 46 patients demonstrated some improvement in wound healing, pain, and quality of life at three months [157,158]. 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 three months.

There are reports that low-level laser therapy (LLLT) improves healing and symptoms related to MRONJ [159-164]. 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 [165,166].

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 MRONJ in the setting of tooth extraction and the remainder in conjunction with surgical debridement for treatment of established MRONJ [167]. 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 MRONJ in the control group and none in the APC group. However, the quality of the evidence in this trial is considered very low based on a high risk of bias in patient selection and outcome assessments. Among the 14 studies examining the use of therapeutic APC in conjunction with surgical management, four included a group that was treated with APC and a group that was not treated with APC. A meta-analysis of these four studies showed that patients receiving APC had significantly reduced rates of MRONJ recurrence (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 APC as an adjunct to oral surgery procedures may be of benefit, although the quality of the evidence is limited, and randomized trials are needed. However, it is not known whether use of APC could have a negative impact on the course of the patient's underlying malignancy.

Outcomes — The clinical course of MRONJ may affect local and/or systemic treatment decisions with respect to cessation or reinitiation of medications, including osteoclast inhibitors. During the course of treatment for MRONJ, the dental specialist should communicate with the medical oncologists the objective and subjective status of the lesion: resolved, improving, stable, or progressive [7]. Proposed terms from the MASCC/ISOO/ASCO clinical practice guideline to characterize MRONJ after treatment are outlined in the table (table 6).

Some of the best information on outcomes of MRONJ associated with an osteoclast inhibitor comes from a review of data from three identically designed, prospective, randomized trials (described above) comparing zoledronic acid with denosumab in patients with a wide variety of malignancies [42].

The majority of patients who developed MRONJ (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 MRONJ diagnosis, although six patients treated with denosumab reinitiated therapy, and one patient received additional doses of zoledronic acid after the diagnosis of MRONJ.

Of the 52 cases of MRONJ 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 at the time of publication. Of the 37 patients who developed MRONJ while receiving zoledronic acid, resolution of MRONJ occurred in 11 (30 percent), 15 (41 percent) had MRONJ still present at the time of death, eight (22 percent) had ongoing MRONJ, and three (8 percent) were lost to follow-up at the time of publication. Only one patient received additional doses of zoledronic acid after the diagnosis of MRONJ, 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 [52], the rate of resolution was 37 percent with denosumab (23 of 63) and 27 percent with zoledronic acid (12 of 44).

Additional information on the natural history of MRONJ 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 MRONJ [168]. Bisphosphonates were stopped once MRONJ was diagnosed. MRONJ resolved in 62 percent, resolved and then recurred in 12 percent, and did not heal in 26 percent.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Medication-related osteonecrosis of the jaw".)

SUMMARY AND RECOMMENDATIONS

Definition and clinical features

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. (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. Clinically detectable osteonecrosis may be preceded by prolonged jaw pain, tooth mobility, bone enlargement, gingival swelling, erythema, and/or ulceration. (See 'Clinical presentation' above.)

Incidence and risk factors

Among patients treated with an osteoclast inhibitor for cancer, the incidence of MRONJ is slightly higher with denosumab than with bisphosphonates, and it increases with greater treatment duration. Lengthening the interval between treatments from every 4 weeks to every 12 weeks may lower the risk. (See 'Incidence and risk factors' above.)

Dentoalveolar surgery is a major risk factor for MRONJ. (See 'Dentoalveolar surgery' above.)

Assessing severity and prevention/treatment

Several clinical staging systems for MRONJ with stage-specific treatment recommendations are available, including one from the American Association of Oral and Maxillofacial Surgeons (AAOMS) (table 1) and one from an international consensus group (table 3). (See 'Staging and treatment' above.)

In view of the difficulty in treating established MRONJ, prevention is emphasized:

-Modifiable risk factors for MRONJ (eg, poor oral health, ill-fitting dentures, uncontrolled diabetes, and tobacco use) should be addressed as early as possible.

-Patients being considered for therapy with an osteoclast inhibitor should be examined by a dentist prior to treatment initiation and needed dental work (eg, removal of unsalvageable teeth and optimization of periodontal health) should be performed prior to initiating therapy. (See 'Before initiation of an intravenous osteoclast inhibitor' above.)

If the patient's medical condition warrants prompt initiation of the osteoclast inhibitor (eg, rapidly progressive bone disease or acute hypercalcemia, for which the benefits of treatment outweigh the risk for MRONJ) partial or minimal evaluation protocols are suggested. Recommended dental evaluation protocols are outlined in the table (table 5).

-During therapy, all patients should practice good oral hygiene, including daily brushing, flossing, and use of antibacterial oral rinses, and attending recommended dental check-ups, denture fittings, and routine cleanings (table 4). Patients should inform their dentists they are receiving an osteoclast inhibitor and/or antiangiogenic agents so invasive dental procedures, especially extractions, can be avoided. (See 'Asymptomatic patients during therapy' above.)

If an invasive dental procedure is unavoidable during osteoclast inhibitor therapy, evidence is lacking regarding the benefit of discontinuing at-risk therapies for a short period of time (ie, "drug holiday"). However, we suggest withholding the osteoclast inhibitor for two to three months before and after the invasive procedure (Grade 2C), with resumption 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 MRONJ while receiving therapy with an osteoclast inhibitor, recommendations on management are hindered by a lack of robust evidence. Treatment objectives are to eliminate pain, control infection of the soft tissue and bone, and minimize the progression or occurrence of bone necrosis (see 'Treatment of established MRONJ' above):

-For most patients, we suggest initial conservative management (antimicrobial mouth rinses, antibiotics [if clinically indicated (table 1)], effective oral hygiene, and limited debridement) rather than aggressive surgical resection (Grade 2C). A short course of teriparatide (ie, eight weeks) can be offered to patients who have prolonged, nonhealing MRONJ prior to pursuing aggressive surgical options. The decision to use the drug must balance the likelihood of short-term benefit against potential (although likely remote) safety concerns. (See 'Teriparatide' above.)

-We reserve aggressive surgical interventions (eg, mucosal flap elevation, block resection of necrotic bone, or soft tissue closure) should be reserved for refractory or advanced cases.

-Limited data suggest potential benefit for a variety of other nonsurgical treatment strategies, including parathyroid hormone (teriparatide), pentoxifylline and vitamin E, low-level laser irradiation, hyperbaric oxygen, and topical application of medical ozone, although none can yet be considered a standard approach. (See 'Nonsurgical treatment strategies' above.)

-There are no prospective data to advise the patient or clinician as to the benefits of discontinuing therapy with an osteoclast inhibitor or antiangiogenic agent, and there is no consensus on this point. While discontinuation of the offending agent might stabilize sites of MRONJ, 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 osteoclast inhibitor therapy in the setting of bone metastases, and a worsening of disease status in patients receiving antiangiogenic agents. (See 'Should the at-risk agent be discontinued?' above.)

Although many oncologists, including several authors and editors associated with this topic review, discontinue the offending agent until the MRONJ is healed, there is no consensus on this point. The decision about whether to interrupt therapy must be individualized and made in concert with the dental and oncologic team and patient. Because of the rarity of this complication, there is unlikely to be a prospective clinical trial to answer this question. The decision must be made on a case-by-case basis, taking into account the estimated risks and benefits for the individual patient.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed to an earlier version of this topic review.

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Topic 96863 Version 32.0

References

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