Medication-related osteonecrosis of the jaw as a complication of palliative treatment of breast cancer

Introduction

Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication that can arise in patients who took or are taking anti-resorptive or antiangiogenic agents, leading to visible bone or a fistula for more than eight weeks, without any history of radiotherapy [1].
Antiresorptive drugs – including bisphosphonates (BPs) and receptor activator of nuclear factor-B ligand inhibitors – and antiangiogenic drugs [2] impair the metabolism of bone tissue, according to their properties. They disrupt bone resorption and mineralisation by their inhibitory impact on osteoclast activity, as well as calcium incorporation. Moreover, they prevent adhesion of tumour cells to the bone matrix and thus tumour-induced osteolysis and hypercalcaemia [3, 4], and exhibit cytostatic activity against tumour cells [5]. Such therapy may be applied in many diseases, associated with impairment in bone metabolism, such as osteoporosis, cancer treatment–induced bone loss or bone metastases [6]. Patients taking such medication are at high risk of post-operative complications leading to MRONJ. The bisphosphonate causing the greatest risk of MRONJ is zoledronic acid [7–9], while in comparison denosumab is considered more potent [10]. The diagnosis should be considered if a patient meets all of the following criteria: current or previous treatment with antiresorptive and/or antiangiogenic agents, exposed bone or bone that can be probed through one or more intraoral or extraoral fistulas in the maxillofacial region that has persisted for more than 8 weeks, and no history of radiation therapy to the jaws or obvious metastatic disease to the jaws [11]. A case of drug-induced necrosis of the jaw was first described in 2003 by Marx et al. [12]. An example of the far-reaching consequences resulting from dental intervention is provided by this case.

Case report

A 45-year-old woman was referred to the Clinic of the Department of Cranio-Maxillo-Facial Surgery, due to an abscess of the right submandibular region. The patient reported a history of malignant neoplasm of the right breast with bone, lung and liver metastases – T4cN2M1. She was status post chemotherapy and hormone therapy. The patient was undergoing intravenous zoledronic acid therapy, during which oral surgery without antibiotic cover was performed.
Clinical examination revealed facial asymmetry due to oedema of the submandibular region and buccal area on the right side, with the overlying skin reddened and painful on palpation. Intraorally bilateral bone exposure with necrotic area in the premolar and molar regions of the mandible was reported. There was visible grey-brown necrotic bone exposure with sequestrating bone fragments in the region of teeth 37–34 and 44–47 in the mandible. No purulent exudate or other changes on the mucous membrane were observed other than those described above.
The corresponding findings were observed on the radiograph – bilateral necrotic bone in premolar and molar parts of the alveolar part of the mandible. Large horizontal and vertical bone resorption is visible in the region of the premolars and molars of the alveolar part of the mandible, along with rarefaction of the bone structure. Sequestering bone fragments are present (Fig. 1).
Based on the clinical presentation, the patient’s disease was classified as stage 2 [11]. Antibiotic therapy (amoxicillin with clavulanic acid, metronidazole) was implemented. One week later, an incision and drainage of the submandibular abscess was performed from an extraoral access. The abscess cavity was rinsed with sodium bicarbonate and appropriately preserved. Material from the pus content was collected for bacteriological examination, which revealed the presence of Streptococcus constellatus, Streptococcus salivarius, Streptococcus mitis and Staphylococcus saprophyticus. At a later stage, it was decided to change from amoxicillin to ciprofloxacin due to the reported gastric discomfort. Recovery proceeded properly. The patient was qualified for the surgical removal of the necrotic bone area, but because of fear of surgical intervention she refused to continue the recommended treatment.
One year after the last visit, she presented to the clinic due to the pathological mobility of the mandible in the right premolar region for about two weeks. She also reported recurrent inflammation with reactivating fistulas in the right submandibular region throughout the past year. She had been taking ciprofloxacin, prescribed by a palliative care physician, chronically for several months. On extraoral examination, there was bilateral oedema of the buccal area due to chronic steroid therapy, and two constricting scars from former fistulas in the right submandibular area; the skin of this region was slightly reddened, with no signs of infiltration or fetor ex ore, and mandibular abduction was in the normal range. Intraorally, there was exposed necrotic bone in the area corresponding to teeth 48–42 and 32–36, without any pathological exudate, with swelling and redness of the mucosa around the lesion and the presence of residual food debris. A pathological mobility of the mandibular body in the area corresponding to teeth 43–44 was noted.
The patient was referred for orthopantomography, which revealed a disruption of the bone structure in the area corresponding to teeth 43–44, implying a pathological fracture, along with progression of bone tissue rarefaction in the mandible (nearly complete resorption of the cancellous bone) from the right angle to the area corresponding to tooth 36 (Fig. 2), indicating at this point stage 3 of MRONJ [11]. Exposed mandibular molar bone material was collected for bacteriological and mycological examination, which revealed the presence of Streptococcus constellatus, Streptococcus anginosus, and Candida albicans. Antibiotic therapy (clindamycin) was implemented.
The patient was scheduled for surgery. From the extraoral access, a segmental resection of the mandible was performed, using piezosurgery. It was followed by reconstruction using a titanium plate, recreating the anatomical features (Figs. 3–5). There were no complications in the perioperative or postoperative course.

Discussion

Medication-related osteonecrosis of the jaw is a disease of unclear pathogenesis [12]. There are several hypotheses, but the most likely causative factors appear to be impaired blood circulation and angiogenesis. These factors, resulting from bisphosphonate treatment, have a significant effect on the bone composite of the maxilla and mandible. Therefore, guidelines should be strictly adhered to among patients taking this group of medications. Any surgical intervention should be deferred until all conservative treatment methods have been used. If tooth extraction is required, bisphosphonate therapy must be stopped 2 months before the planned surgery. Urgent intervention in a patient on antiresorptive drugs requires an antibiotic cover. According to the recommendations, the administration of amoxicillin with clavulanic acid 1000 mg, or clindamycin 300 mg, is started the day before surgery. In patients without a medical history of MRONJ, the therapy is continued for a further 3 days. For patients with previous episodes of MRONJ, the duration of the therapy is extended to 14 days [1, 13].
A plausible hypothesis for the development of MRONJ suggests that BPs, especially those containing nitrogen, may have a toxic effect on oral squamous epithelial cells, inhibiting mucosal healing, which promotes bacterial infection and the development of bisphosphonate-related osteonecrosis of the jaw. Studies in an in vitro model showed that clodronate, which is a nitrogen-free bisphosphonate, did not have such inhibitory effects on squamous epithelial cells, while zoledronate presented the most destructive effects. The most commonly used BPs are zoledronate (63.9% of people), pamidronate (15.3%), ibandronate (9.5%), alendronate (3.8%) and other BPs (less than 1%). The highest probability of MRONJ is mainly in patients treated with BPs intravenously at oncological doses for at least 1.5–3 years [12, 14–18]. Longer duration of therapy is associated with higher risk of necrosis.
A drug that has a different mechanism of action but is also used in the treatment of bone metastases is denosumab, a monoclonal antibody directed against the ligand for the RANK receptor of osteoclasts, resulting in inhibition of bone resorption [2]. There was a study on the 3-year use of denosumab or zoledronate at oncological doses in 2046 women with breast cancer with bone metastases [19], which showed that denosumab can also cause the development of bone necrosis in the stomatognathic system – a phenomenon that is also rare, as it affects less than 1 per cent of patients, comparable to the incidence during zoledronate use.
According to the study of Ruggiero et al., stage 2 of MRONJ is diagnosed when there is bone exposure, necrosis or the presence of a fistula, with signs of infection. Patients in this stage often have no symptoms, or present with pain and swelling, due to inflammation, as in the present case. Due to the deferral of the decision to start treatment, the patient’s condition corresponded to stage 3 after one year, in which a pathological mandibular fracture was added to the previously mentioned symptoms [11]. This condition required antibiotic therapy, analgesic treatment and surgery [20]. However, in patients after intravenous bisphosphonate therapy, the potential of the affected bone to regenerate is significantly reduced, which in a large number of cases is compounded by the presence of comorbidities [21]. New treatment methods include the use of platelet-rich plasma or platelet-rich fibrin as an adjunctive method, but do not show sufficient efficacy when used alone [20–22]. Further research is needed to confirm the efficacy of such therapeutic methods and enable their incorporation into management algorithms.

Conclusions

The present case is an example of the dangers of dental procedures during antiresorption therapy. Medication-related osteonecrosis of the jaw is a serious complication that requires interdisciplinary cooperation among specialists in dentistry, oncology, and rheumatology. The additional aim of such cooperation is to raise awareness of the risk of complications among doctors of different specialties. According to the recommendations on the use of antibiotics in dentistry, surgical procedures carried out in the oral cavity require appropriate management and antibiotic cover. Patients in preparation for and during bisphosphonate therapy require regular oral health check-ups.

Disclosures

1. Institutional review board statement: Not applicable.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

REFERENCES