Prevalence of Medication-Related Osteonecrosis of the Jaw in Patients with Breast Cancer, Prostate Cancer, and Multiple Myeloma

Medication-related osteonecrosis of the jaw is a known side-effect of antiresorptive therapy in patients with malignant diseases. Nevertheless, the exact pathogenesis is still unknown and published prevalences show a significant range. The aim of the presented paper was to assess the prevalence of osteonecrosis (ONJ) in breast cancer, prostate cancer, and multiple myeloma patients receiving parenteral antiresorptive therapy. For this reason a PubMed search was performed and 69 matching articles comprising 29,437 patients were included in the analysis. Nine-hundred fifty-one cases of jaw necrosis were described. The overall ONJ-prevalence was 2.09% in the breast cancer group, 3.8% in the prostate cancer group, and 5.16% for multiple myeloma patients.


Introduction
In 2003 Robert E. Marx reported on 36 cases of non-healing painful bone exposure in the mandible, maxilla, or both, that were unresponsive to surgical or medical treatments in patients treated with bisphosphonates as a growing epidemic [1].
This causal association was cautiously denied in a letter by Tarassof and Csermak representing Novartis, given the fact that no such reports had occurred in multiple, well-controlled clinical trials of more than 3000 cancer patients that had been conducted as far back as the early 1990s [2].
To date jaw necrosis linked to antiresorptive therapy is an accepted side effect and no longer a matter of discussion.
In 2007 bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been primarily defined as a condition of exposed, necrotic bone in the maxillofacial region that has persisted for more than eight weeks in patients who have received or are receiving treatment with bisphosphonates and have no history of radiation therapy of the jaws [3]. This definition relies on a combination of various symptoms in combination with the patient's anamnesis. Even though the condition was firstly described over ten years ago, the underlying principles of pathogenesis are not conclusively clarified yet. Common theories deal with reduced bone remodeling, impairment of local vascularization, and neoangiogenesis [4], accumulation of microcracks in devitalized bone with empty osteocyte lacunae [5], and infection of bone via osteoclast-independent bone resorption [6,7].
Three stages were specified, the main symptom being frank bone exposure in the maxillofacial region [8]. In addition, an "at-risk category" was defined for patients who have been treated with either oral or intravenous bisphosphonates, but show no apparent exposed/necrotic bone.
As experience grew in this condition, clinicians recognized that bisphosphonate-exposed patients can show clinical and radiological signs potentially indicating osteonecrosis lacking the cardinal symptom of exposed bone in the maxillofacial region. Therefore, the AAOMS updated its classification and added a stage 0 category, implying patients who show nonspecific clinical and radiological findings or symptoms that possibly correlate to osteonecrosis. These findings must not be explicable by other conditions [3]. As a study by Fedele et al. showed that patients who present BRONJ stage 0 may be at high risk of developing advanced stages of BRONJ [9], the relevance of an early diagnosis increased. It has to be mentioned that the AAOMS classification of 2009 categorized bone exposure via fistulas stage 0, implying that no invasive treatment is needed in such cases. This was revised in 2013, when each bony exposure fulfilling the criteria was counted as evident bone necrosis, no matter the extent. Furthermore, the term BRONJ was changed to MRONJ (medication-related osteonecrosis of the jaw) taking into account other pharmaceuticals that might cause jaw necrosis besides bisphosphonates.
In general the incidence rate is higher in patients with intravenous administration of bisphosphonates compared to the oral route of administration. The estimates of MRONJ for intravenous application range from around 1% [14,15] to 21% for sub-clienteles [16], but even after more than 10 years since this condition was reported there is still some lack of knowledge. The main reasons therefore are probably: Many patients are asymptomatic for a long time and, thus, may not be diagnosed or do not relate their oral symptoms to the antiresorptive therapy.
People suffering from MRONJ have various underlying diseases. They present a heterogeneous group of patients treated by independent medical specialists. A standardized oral investigation of patients at risk has still not been implemented to date. As a consequence, the definite prevalence might be higher, as demonstrated by Walter et al. [16], who showed that prevalence of BRONJ is underestimated if thorough inspection of the oral cavity is omitted.
The condition is influenced by several risk factors, such as drug potency, type of administration, as well as individual local and systemic conditions. In many cases patients receive multiple agents that interfere with bone metabolism and may, therefore, cause or benefit the development of osteonecrosis.

Objectives
To review published prevalences of ONJ in patients with the primary diseases of breast cancer, prostate cancer, and multiple myeloma, receiving parenteral antiresorptive therapy (bisphosphonates, denosumab).
Inclusion criteria were: the type of primary cancer: breast cancer, multiple myeloma, or prostate cancer; parenteral antiresorptive therapy with bisphosphonate or denosumab; and a size of patient collective of at least 10 patients.
Exclusion criteria were: review papers; duplicated articles; integrated analyses of already reported studies; and animal studies.
The reports were screened for prevalence rates, and data concerning primary disease and used antiresorptive therapy were collected.
Data analysis was performed concerning the following questions: • What is the prevalence of osteonecrosis (ONJ) relating to primary disease? • What are the prevalences before and after the adaptions of the AAOMS classification in 2009?
To assess the overall ONJ prevalence patients were grouped according to primary disease. Thus, positive ONJ cases were weighted against the total number of patients of all included studies.

Results
One-hundred forty-one articles were found. Fifty-eight papers were excluded right away after screening of abstracts because of improper article type (review papers, case reports, prevalence not reported) or inappropriate primary disease (osteoporosis, rheumatoid arthritis, giant cell carcinoma, other cancer types).
Fifteen further manuscripts were excluded after studying the full papers. The reasons therefore were: • Nine-hundred fifty-one cases of jaw necrosis were described. Amongst those, 348 had breast cancer, 161 had prostate cancer, and 442 suffered from multiple myeloma (Table 2).
Thus, the overall ONJ-prevalence was 2.09% in the breast cancer group, 3.8% in the prostate cancer group, and 5.16% for multiple myeloma patients.    Published prevalences in patients with breast cancer range from 0 to 26.7% (median 2.6%), from 0 to 20.9% (median 4.8%) in prostate cancer patients, and from 0 to 20.5% (median 5.1%) in patients with multiple myeloma (Figure 1).  Published prevalences in patients with breast cancer range from 0 to 26.7% (median 2.6%), from 0 to 20.9% (median 4.8%) in prostate cancer patients, and from 0 to 20.5% (median 5.1%) in patients with multiple myeloma (Figure 1).

Discussion
In this paper we determined the weighted prevalence of medication-related osteonecrosis of the jaw in patients with breast cancer, prostate cancer, and multiple myeloma, including 69 reports comprising 29,670 patients. Prevalence was 2.09% in the breast cancer group, 3.8% in the prostate cancer group, and 5.16% for multiple myeloma patients.
To the best of our knowledge there are three further reports addressing this issue. In 2009 Walter et al. [46] [82]. They found seven articles reporting on 97 MRONJ cases. Incidences were low and ranged between 0 and 2%, but exceeded the incidences in the zoledronate control group. Published prevalences of medication-related osteonecrosis of the jaw show a great range. Possible explanations have been discussed in the literature and may include variations in sample size, varying methods of data assessment/analysis, and limitations due to voluntary case reporting [65]. Furthermore, when evaluating the published literature we had to realize that in most papers MRONJ definition is not clearly stated. Very often descriptions are not detailed and do not refer to a specific classification system, or are even left out completely.
Despite this inhomogeneity it has been shown that the application of zoledronic acid produces a greater risk than the use of pamidronate or the combination of zoledronate and pamidronate [25]. Additionally, ONJ onset seems to be earlier among patients receiving zoledronic acid as compared to patients receiving pamidronate [18], and even later if alendronate or risedronate is used [25,83,84].
Regarding denosumab, ONJ prevalence was slightly higher compared with zoledronate, but no significant difference was found [70].
In general, ONJ develops more frequently if parenteral administration of antiresorptive agents are used [85][86][87] and significantly correlates with the number of applied doses [12,53,65]. Differences in applied dosing protocols may also be the reason for the discrepancy of ONJ prevalences in patients with different primary diseases, resulting in a higher risk for patients suffering from multiple

Discussion
In this paper we determined the weighted prevalence of medication-related osteonecrosis of the jaw in patients with breast cancer, prostate cancer, and multiple myeloma, including 69 reports comprising 29,670 patients. Prevalence was 2.09% in the breast cancer group, 3.8% in the prostate cancer group, and 5.16% for multiple myeloma patients.
To the best of our knowledge there are three further reports addressing this issue. In 2009 Walter et al. [46] [82]. They found seven articles reporting on 97 MRONJ cases. Incidences were low and ranged between 0 and 2%, but exceeded the incidences in the zoledronate control group. Published prevalences of medication-related osteonecrosis of the jaw show a great range. Possible explanations have been discussed in the literature and may include variations in sample size, varying methods of data assessment/analysis, and limitations due to voluntary case reporting [65]. Furthermore, when evaluating the published literature we had to realize that in most papers MRONJ definition is not clearly stated. Very often descriptions are not detailed and do not refer to a specific classification system, or are even left out completely.
Despite this inhomogeneity it has been shown that the application of zoledronic acid produces a greater risk than the use of pamidronate or the combination of zoledronate and pamidronate [25]. Additionally, ONJ onset seems to be earlier among patients receiving zoledronic acid as compared to patients receiving pamidronate [18], and even later if alendronate or risedronate is used [25,83,84].
Regarding denosumab, ONJ prevalence was slightly higher compared with zoledronate, but no significant difference was found [70].
In general, ONJ develops more frequently if parenteral administration of antiresorptive agents are used [85][86][87] and significantly correlates with the number of applied doses [12,53,65]. Differences in applied dosing protocols may also be the reason for the discrepancy of ONJ prevalences in patients with different primary diseases, resulting in a higher risk for patients suffering from multiple myeloma (weighted ONJ-prevalence 5.16%) compared to patients with breast cancer (weighted ONJ prevalence 2.09%).
Beyond that several additional factors influencing the risk of MRONJ have been identified. Concomitant oral disease, respectively, oral inflammation, may increase the risk of ONJ [14,67], as well as wearing of dentures [47] and anatomical circumstances. ONJ occurs more frequently in the mandible with described predilection for the molar and premolar region, as well as regions with thin mucosal coverage, like tori or the mylohyoid line [70,87,88].
Oral surgery, and above all, dental extractions, are most frequently named to increase ONJ risk around seven-to more than ten-fold [14,20,53,70,89].
Taylor et al., who reviewed the clinical records of 225 patients at risk who underwent dental extraction, identified eight ONJ cases out of 23 (34.8%) patients prescribed intravenous bisphosphonates and five ONJ cases in 202 patients (2.5%) with oral bisphosphonate administration [90]. However, the periodontal and inflammation status in the surrounding bone might be a more important factor in the development of osteonecrosis rather than the procedure of the extraction itself [91].
In addition, systemic risk factors have been described. ONJ onset seems to be more frequent in women and in advanced age [17,[86][87][88]. This might be attributed to the fact that important primary diseases, like breast cancer and osteoporosis, are more frequent in women, respectively, and that cancer and osteoporosis commonly develop with increasing age. Regarding the group of multiple myeloma patients, no difference in gender could be detected [20,25,50,87].
Furthermore, the wearing of removable mucosa-retained dentures also becomes more likely with increasing age and is a known risk factor. Patients with removable dentures are more likely to develop osteonecrosis compared to patients with fixed partial dentures and patients without substitution of potentially messing teeth [92].
Concomitant medical therapy may enhance ONJ risk, which has been particularly reported for corticosteroids and antiangiogenic therapy. A correlation to chemotherapy, diabetes, or anaemia is less substantiated [12,20,25,70], although a recently published article sees an association to a pathological glucose metabolism [93]. Altogether, systemic risk factors seem to have less impact than local variables [70].
Finally, differences in diagnostic criteria, mainly resulting from differences or alterations in classification guidelines, may also have an impact, albeit we could not detect a difference in published prevalences until 2009 compared to those since 2010, after the revision of AAOMS guidelines. It could be hypothesized that intensifying oral inspections to detect early forms (Stage 0) and possibly including patients presenting sinus tracts into verified ONJ cases, resulted in a higher prevalence as already demonstrated [63]. However, this effect might be compensated by the greater awareness towards ONJ risk and, consequently, the implementation of preventive measures. Routine dental prevention to eliminate potential sites of infection prior to antiresorptive treatment and managing risk factors in patients at risk reduces the BRONJ rate, as already described in the literature [12,50,52,94,95]. Furthermore, it has been reported that dental extraction and oral surgery are quite safe if certain rules are obeyed [13,15,96,97].

Conclusions
The exact pathogenic mechanisms of MRONJ development are still unknown, but risk factors have been described. Patients with malignant diseases carry a relevant risk for MRONJ. It has been shown that it is possible to reduce ONJ risk by implementation of routine dental preventive measures and management of known risk factors. Consequently, a close cooperation between medical specialties involved in the treatment of malignoma and multiple myeloma patients at risk is crucial to minimize ONJ prevalence.