ZOLEDRONATE-ASSOCIATED RECURRENCE OF OSTEONECROSIS OF JAWS

Medication-related osteonecrosis of the jaws is a commonly reported complication in patients receiving antiresorptive medications. We report a case of bone necrosis followed by comparatively fast recurrence in a patient with intravenous administration of zoledronic acid. The purpose is to focus the attention of dental practitioners on the possibility of recurrence and the importance of regular check-ups since preventive measures today are one of the most important management strategies for patients treated with zoledronate.

Zoledronic acid (Zometa®; Reclast, Novartis Pharmaceuticals) was approved in 2002. At this time, the only severe side effects were hypocaliemia and renal deteriora-tion in patients with renal insufficiency. Only 1 year after the approval, the first evidence that zoledronate is linked to osteonecrosis was reported [2].
In Bulgaria, zoledronate is mostly used. It is the most potent inhibitor of all bisphosphonates which reduce bone resorption and osteoblast activity, which leads to the accumulation of microdamages and areas of necrosis [10,11]. Its cytotoxic effect on bone cells, epithelial cells and macrophages leads to disruption of the integrity of the oral mucosa, infection and subsequently -lack of wound healing [12].
Epidemiologic data has revealed that more potent bisphosphonates, more frequent dosing, a higher cumulative dose and a longer duration of treatment are the major risk factors for the osteonecrosis. Systemic risk factors include the aforementioned, but also the presence of diabetes and other immunocompromising diseases; genetic factors and age [13].
Dentoalveolar surgery is considered to be the major local risk factor for developing MRONJ. Tooth extraction is the most common event, proved to be the initiating factor of MRONJ in almost 60% of patients [14]. Pre-existing periodontal diseases is a risk factor in almost half of the patients [15]. It is proved by clinical parameters, serum immunoglobulin G titers against Porphyromonasgingivalis and interleukin-1â, demonstrating that periodontitis and associated bacteria are important in the pathogenesis of MRONJ [16].
The risk of MRONJ in cancer patients on zoledronate therapy is approximately 1% (100 cases per 10,000 patients). Almost the same is the risk for patients on RANKL inhibiting treatment with denosumab. Intraoral administration of bisphosphonates for osteoporosis represents a smaller risk factor, compared to intravenous administration. The duration of medication administration continues to be a significant risk factor. The incidence of developing MRONJ among cancer patients exposed to zoledronate or denosumabis increasing with time -respectively 0,5% at 1st year, 1% at 2nd year and 1,3% at 3d year [17]. https://doi.org/10.5272/jimab.2020264.3348 Factors affecting the recurrence of MRONJ are not well elucidated. Probably the type and duration of administered medication are most important, together with the presence of bacterial infections in the affected area, methods of treatment used (conservative or surgical, including primary closure of secondary healing cases) [18].
Treatment strategies recommended by the guidelines of the American Association of Oral and Maxillofacial surgeons are based on the symptoms and progression of the disease. Conservative treatment includes pain control, antibiotics and antibacterial rinses. Surgical treatment is performed to remove the necrotic bone and soft tissue. Adjunctive treatment options areteriparatide; bone morphogenetic proteins, platelet concentrates and platelet-derived growth factors, low level laser therapy, hyperbaric oxygenation, medical ozone therapy [19] The purpose of the present clinical case of MRONJ is to focus on the possibility of recurrence that could be really fast in some cases. Knowledge and awareness among dentists and medical doctors for preventive measures are one of the most effective management strategies for patients treated with zoledronate.

CASE PRESENTATION
A 72 years old male patient was referred to the maxillofacial clinic with symptoms of a non-healing lesion in the area of right posterior mandible. Detailed medical history revealed that the patient was diagnosed with multiple myeloma and bone metastases in 2010. Since then he was treated with intravenous administration of zoledronate with periods of drug holidays. The main complaint of the patient was pain, which was radiating to the temporomandibular joint and discomfort while eating. No other symptoms were reported. There was no dental procedure before the development of the lesion that could initiate the necrosis. Intraoral examination revealed soft tissue destruction in the edentulous area of the right posterior mandible, with exposed necrotic alveolar bone and signs of local inflammation in the site of necrosis ( fig. 1).   Fig. 1. Clinical appearance of the edentulous lower right quadrant, with visible necrotic bone on the alveolar ridge.
Computer tomography revealed big radiotranslucent area in the right mandible, with dense woven bone osteosclerosis of the surrounding bone ( fig. 2). The patient was diagnosed with MRONJ stage 2 according to the staging system and criteria of the American association of oral and maxillofacial surgeons.
Conservative periodontal treatment was performed to reduce the inflammation and reduce the bacterial load on the remaining teeth. Then the surgical treatment was done. It consisted of complete removal of the necrotic mandible and osteoplasty of residual bone margins ( fig. 3).   The patient was followed-up each month. 6 months later, the patient came to the routine follow-up with the same complaints again, this time from the anterior maxilla. The intraoral and radiographic examination revealed a recurrence of the osteonecrosis, located in the anterior maxillary right area ( fig. 6, 7).  The same treatment (conservative and surgical) was performed.

DISCUSSION
Currently, it is not clear whether treatment with bisphosphonates should be stopped or proceeded in the presence of MRONJ. Watters et al. reported a long term follow up of 109 patients with MRONJ. 48% of them stopped i.v. bisphosphonate treatment, but there was no statistical difference in the clinical course of osteonecrosis in them, compared to those patients who did not stop the treatment [19].
Based on our surgical experience and that of others, surgical procedures should be planned and performed early in the course of management of MRONJ. It has been demonstrated that in the advanced stages 2 and 3, nonsurgical approaches are not effective in more than 50% of the cases. Surgical intervention, especially when combined with biologically active agents like platelet con-centrates, result in resolution of MRONJ, even when the patient developed recurrence of the osteonecrosis.
In order to reduce the possibility of MRONJ development and recurrence of the condition, later each patient should be evaluated individually, considering the medical history, systemic diseases, and clinical symptoms. Incidence of MRONJ may be reduced through appropriate drug holiday and/or alternative treatment.

CONCLUSION
We expect that dentists will increasingly encounter patients undergoing antiresorptive/antiangiogenic treatment, with the possibility of developing MRONJ. Currently, zoledronic acid is often used in Bulgaria. Being one of the most potent bisphosphonates, practitioners be able to anticipate the potential complication of this medication and be aware of the possibility of recurrence of the osteonecrosis that maybe sometimes fast.