MRONJ in breast cancer patients under bone modifying agents for cancer treatment-induced bone loss (CTIBL): a multi-hospital-based case series

Medication-related osteonecrosis of the jaw (MRONJ) occurs more frequently in patients receiving high doses of bisphosphonates or denosumab (RANKL-inhibitor) for metastatic cancer.

At present, a growing number of observations on MRONJ cases are emerging in patients exposed to low-dose BMAs for osteoporosis [28].

Low-dose BMA have been recently recommended for the prevention and treatment of cancer treatment-induced bone loss (CTIBL) in patients with solid tumor (breast or prostate cancer) without bone metastases.

In this scenario, these patients are considered an emerging category at risk of MRONJ development, sharing simultaneously common features of both cancer patients and osteo-metabolic patients.

The present study investigates for the first time the features at presentation and risk factors associated to MRONJ development in a series of breast cancer (BC) patients exposed to BMAs therapy for CTIBL prevention.

Cancer treatment-induced bone loss (CTIBL) has been found to be the most common long-term adverse event experienced by patients affected by BC with a peak of incidence in postmenopausal age [13].

Fifteen cases of MRONJ in patients affected by BC, without BM, under a low dose of BMAs for CTIBL prevention were collected and described.

Adjuvant ET represents the standard of care in hormone receptor-positive BC patients, which represent about 75–80% of all BC diagnoses, as it was shown to significantly reduce the risk of recurrence and cancer-related death. Adjuvant ET consists of two main drug regimens: estrogen receptor modulators and aromatase inhibitors [13]. Women affected by BC treated with ET as mainly adjuvant therapy or in premature iatrogenic menopause represent a particular subtype of patients at high-risk of fracture, due to the onset of CTIBL. As described in different guidelines [17, 29], BPs and DNB are the two classes of BMAs used in clinical practice with similar efficacy in preventing CTIBL, and they are routinely prescribed with the same dosage used in osteo-metabolic patients (low-dose BMAs) [13].

In recents RCT on BC patients without BM under a low dose of BMAs for CTIBL prevention, the incidence of MRONJ was observed between 0% and 0.5 [10, 21, 22].

As well as BC, also prostate cancer places a high burden on patients and healthcare systems, recently affecting over 1.4 million men worldwide each year [14]. Most of advanced prostate cancer patients receive Androgen Deprivation Therapy (ADT). ADT causes a rapid disruption of bone remodelling balance, which leads to net bone loss. Bone loss, as well as disruption of bone microarchitecture, continues throughout the duration of ADT and ongoing CTIBL in men with prostate cancer is superimposed upon normal age-related bone loss [30]. Hormone-sensitive advanced prostate cancer patients (without or with bone metastases) should receive low-dose BMAs to prevent CTIBL, whereas patients with castration-resistant disease and bone metastases should receive high-dose zoledronic acid or denosumab, together with anticancer treatments [17]. An attempt to adopt high-doses of denosumab (120 mg every 4 weeks) in prostate cancer patients without metastases failed to reach approval, also due to a high rate (5%) of MRONJ [17, 31].

BC patients and prostate cancer patients, both under low doses of BMAs for CTIBL prevention, are hence an emerging category at risk of MRONJ, who share simultaneously some characteristics of both cancer patients and osteo-metabolic patients. Furthermore, intermediate doses of BMAs have been administered in patients enrolled in RCTs evaluating both the prognostic effect of BMAs as adjuvant treatment in non-metastatic breast cancer, and the risk-reduction of CTIBL development as secondary endpoint.

If considered data from literature, we can consider only findings from osteo-metabolic patients under low doses of BMAs and from the same geographical area: 87 cases of MRONJ were described (mean age of 70.7 ± 9.8 years, median 72); 42 patients (42/87, 48.3%) had various general health comorbidities (e.g. diabetes mellitus, hypertension); and in 33 cases (37.9%) oral triggers for MRONJ development were detected [7]. Regarding the BPs, 77/87 (88.5%) patients were treated with alendronate (a weekly dose of 70 mg orally); the mean duration of BMAs therapy at MRONJ presentation was 44.9 (± 35.5 months, median 38 months). Bone exposure was the main presenting sign (82.8%). MRONJ was classified according to AAOMS [12], as it follows: 15 patients in stage 0 (17.2%), 12 in stage 1 (13.8%), 53 in stage 2 (60.9%) and 7 in stage 3 (8.1%). Tooth extraction for dental/periodontal diseases, was the most common trigger factor for MRONJ (57/87 patients; 65.5%) [7].

In another Italian study, fifty-three female patients affected by osteoporosis were enrolled in the study (mean age of 71.9 ± 10.2 years). Twenty-two subjects (41.5%) had hypertension, seven (13.2%) had diabetes and five (9.4%) had rheumatoid arthritis. Eight subjects were smokers (15.1%). The majority of the sample (45 subjects, 84.9%) was treated with alendronic acid (70 mg/week). Most of the lesions were located in the mandible (74%); bone exposure was found in 40 subjects (75.4%). MRONJ was classified according to AAOMS [12], as it follows: 7 in stage 1 (13.2%), 39 in stage 2 (73.6%) and 7 in stage 3 (13.2%). Tooth extraction for dental/periodontal diseases, was the most common trigger factor for MRONJ 29/53 patients (54.7%) [32].

In a third Italian study, 36 patients receiving BPs for the treatment of osteoporosis were described. There were 32 females (88.8%), and the mean age of the patients was 72.8 (± 10.1). Cardiovascular disease was the most detected comorbidity (23/36; 63.9%), followed by anxiety and/or depression, diabetes and lipid disorders. The most commonly administered BPs was alendronate (n = 26; 72.2%). The most common location of MRONJ was the mandible (29/36; 80.6%). MRONJ was classified according to AAOMS [12], as it follows: 4 in stage 0 (11.1%); 18 in stage 1 (50%), 11 in stage 2 (30.6%) and 3 in stage 3 (8.3%). The presence of a potential oral trigger was recorded in 24 (66.7%), with the most common being dental extraction [33].

The patients under BMA therapy for CTIBL could show some assumed systemic risk factors for MRONJ similar to those of cancer patients with BM, such as chemotherapy or steroids intake, whereas at the same time the prevention of CTIBL is based on a low dose of BMAs, with the same therapeutic scheme of osteo-metabolic patients [2, 6, 8].

In this case series, regarding the local risk factors, PD and PD-related tooth extraction were both reported (15.38% and 38.46% of patients enrolled, respectively). On the basis of current literature, these two variables could be considered as a “unicum” trigger of the most frequent dental disease is PD, implying the disease and its extreme resolution [2, 8, 34]. In detail, tooth extraction has been described as one of the major risk factors for the onset of MRONJ; however, it is indicated only in the presence of endodontic and/or periodontal diseases, in patients at risk of MRONJ, when a conservative approach is not possible, and a good tooth prognosis is not guaranteed. Hence, dental infections are basically the main reason for dental extraction, and they are local risk factors already present for long periods before surgical procedures (e.g. severe periodontitis will be a determinant for a tooth with poor prognosis). Indeed, among local risk factors, the role of periodontal infections and the oral microbiome is becoming increasingly outstanding in MRONJ onset. These conditions are associated with inflammatory responses, that may directly or indirectly affect the alveolar bone and stimulate bone resorption, and so, under the effect of BMAs, the MRONJ onset [34‐37]. Furthermore, there is increasing evidence that signs and symptoms of dental/periodontal infection are significantly associated with histological alveolar bone necrosis even prior to dental extractions and MRONJ development [34, 38].

Based on the literature and the present findings, it is our opinion that it is possible to distinguish at least three main common categories of patients at risk of MRONJ [3, 8, 13, 39, 40]:

All patients at risk of MRONJ should be subjected to primary preventive measures (even after commencing BMAs), with the aim to maintain and/or re-establish as soon as possible a sufficient level of oral health [3, 41, 42]. The preventive measures in cancer patients with BM or multiple myeloma should be done strictly before the administration of MRONJ-related medications, and in osteo-metabolic patients within its first six months. Furthermore, the patients taking BMAs should undergo periodic dental visits for early diagnosis of MRONJ: every four months for patients assuming a high dose of BMAs with/without antiangiogenics medication intake; every six months for patients assuming a low dose of BMAs [3, 9].

To date, data on MRONJ onset in BC patients and hormone-sensitive prostate cancer patients under low doses of BMAs for CTIBL prevention are still scarce and uncertain. Moreover, no recommendations for MRONJ have been published dedicated to BC patients under low doses of BMAs for CTIBL prevention or treatment. Apparently, they could be assimilated, with regard to MRONJ prevention workflows, to osteo-metabolic patients.

Another point of attention is that for BC females it should be taken into account also that they could previously have received BMAs at low doses before CTIBL prevention, to treat or prevent primary osteoporosis, increasing their BPs cumulative dose or BMAs time of assumption.

Noteworthy, it is important to remember that BC patients may develop bone metastases along their clinical history [43]. The risk of MRONJ onset in these patients will most likely increase drastically over time due to the development of BM that requires BMAs at high doses. Consequently, BC patients already treated with low doses BMAs (due to CTIBL) could be later treated with high doses of BMAs in combination or not with anti-angiogenic medication after developing BM. Furthermore, the previous prolonged BMA treatment could lead to a high-risk of MRONJ in a potentially short time after the start of high dose BMA therapy.

From a practical point of view, if a given cancer patient under CTIBL develops BM, before the assumption of high dose BMAs, the oral condition must be re-evaluated by dental examination and, when necessary, also thanks to a new radiological dental exam. Additionally, cancer patients that develop BM will be included in a follow-up program every 4 months, instead of every 6 months. It would be helpful to perform together with dental examination professional oral hygiene [3, 41, 42].

A drawback of this study might be the retrospective set-up of the study design; however, all the centres involved have done their best to collect long-term data (over 6 years) from heterogeneous groups of patients at risk of MRONJ. Furthermore, other limitations of the present study are the small sample size, and the lack of data on endodontic diseases.