1. Introduction
Medication-related osteonecrosis of the jaw (MRONJ) is a serious condition that occurs as a side-effect of treatment in patients with osteoporosis or malignancies. Antiresorptive drugs are medications that target osteoclasts with the aim of preventing bone resorption and are used to treat osteoporosis, osteopenia, and a variety of other osteopathies, such as Paget’s disease. They are also used in the treatment of cancer patients with active bone metastases where antiresorptive treatment is used for the prevention of skeletal complications.
Osteonecrosis of the jaw related to bisphosphonates has been reported since the 2000s [
1] and has been proven to negatively affect quality of life, causing significant morbidity in affected patients. After denosumab was approved for the treatment of osteoporosis and metastatic bone diseases, cases of osteonecrosis of the jaw were identified and defined as denosumab-related osteonecrosis of the jaw [
2,
3]. Another drug related to the appearance of osteonecrosis is sunitinib, a multi-targeted tyrosine kinase receptor inhibitor with a potent antitumor effect that is used in second- and first-line chemotherapy in renal cell carcinoma [
4,
5]. The current definition of MRONJ summarizes osteonecrosis of the jaw resulting from bisphosphonates, denosumab, and antiangiogenic drugs, such as bevacizumab, sunitinib, and aflibercept, or other bone modifying agents (BMAs). Eating disorders, pain, and local erythema are usually the initial symptoms of MRONJ, with signs specific to a local infection appearing later and evidence of purulent secretion, with or without drainage fistula, and denudated bone as further possible occurrences. Other signs include sensory disorders, deformities of the jaw, and even pathological fractures of the jaw, especially at the mandibular level, and the appearance of maxillary oroantral communications, where the denudated bone size can vary from a few millimeters to a few centimeters in size.
The diagnosis of MRONJ requires that all of the characteristics listed in
Table 1 be present.
The optimal treatment of MRONJ is still debated and, depending on the clinical stage of the disease, general steps are recommended, such as local hygiene with antiseptic solutions, local and general antibiotic treatment, pain control, and local surgical interventions with curettage or classical sequestrectomy. The currently recommended staging of the disease is also presented in
Table 1. Modern approaches, such as piezo surgery or laser treatments, are still under investigation; however, the one thing generally acknowledged is that prevention is the most important step of treatment. Hyperbaric oxygen therapy can also improve the local healing process, and epithelization is an essential step in the management of osteonecrosis, but the costs of these treatments are still impediments.
Due to the difficulty of treating patients with MRONJ, primary prevention is the most effective management approach and awareness of the risk factors among prescribers of drugs associated with the disease is paramount for patient safety.
The aim of our study was to investigate awareness of MRONJ among BMA prescribers, their current prescribing practices, and the preventative measures currently used by different specialties for patients prescribed BMAs. The goals of our study were to evaluate current knowledge about MRONJ caused by different BMAs through a survey performed in an academic hospital in order to evaluate current gaps in knowledge with the aim of improving the quality of care and life of MRONJ patients.
3. Results
For our study, we identified 90 BMA prescribers in our hospital. Out of these, 14 were excluded due to the lack of a valid email address or to their not being available for response during the time of the study, resulting in 76 possible participants. A total of 55 BMA prescribers from different medical fields considered relevant to our purpose, including rheumatologists, oncologists, endocrinologists, and general practitioners, answered our questionnaire, which constituted a response rate of 72% and an attainability rate of 61%. Most responders were female (77%), and the average age of the responders was 40 years old. Most were endocrinologists (45%) and senior physicians (37%), and experience of prescribing BMAs was relatively well-distributed. The composition of the physician cohort is presented in
Table 3.
The physicians usually prescribed BMAs for osteoporosis (83%) and osteopenia (67%), with bone metastases presenting as a less frequent indication for treatment (20%), followed by osteogenesis imperfecta (18%) and Paget’s disease (15%). The most common BMAs prescribed were oral bisphosphonates (96%), followed by i.v. preparations (56%), with less than half using denosumab (42%) and teriparatide (35%) or other treatment options. The most commonly used medications for these patients were both second- and third-generation bisphosphonates, such as alendronate (Fosamax
®) and ibandronate (Bonviva
®), with other preparations being used far less frequently, such as denosumab (Prolia
®) and teriparatide (Forsteo
®), while sunitinib (Sutent
®) was prescribed by even fewer physicians. The complete prescribing practices of the respondents are presented in
Table 4.
Current knowledge of the definition of MRONJ was very prevalent in our responders (91%), regardless of specialty, although most prescribers preferred the previous notion of bisphosphonate-related osteonecrosis of the jaw (BRONJ) to MRONJ or antiresorptive drug-related osteonecrosis of the jaw (ARONJ)—70% vs. 17% and 13%, respectively. Most of the physicians surveyed had encountered patients with MRONJ, with an average of 62%, but there were differences related to their fields of practice, with all oncologists having encountered this complication, 60% of endocrinologists and rheumatologists, and only 36% of general practitioners.
Regarding prevention practices, most physicians recommended a dental check-up prior to initiating treatment with bisphosphonates (65%), but not when prescribing denosumab (47%), teriparatide (29%), or tyrosine kinase inhibitors (31%). This recommendation was not influenced by physician specialty regarding bisphosphonates, with no significant differences reported between different specialties (
p = 0.273), or denosumab (
p = 0.347); however, general practitioners were more likely to recommend it to patients when initiating teriparatide (
p = 0.032) or tyrosine kinase inhibitors (
p = 0.015). A summary of recommendations and comparisons between physicians are presented in
Table 5.
Patients who required dental treatment while on BMA therapy were more likely to be recommended temporary withdrawal of the drug only when using bisphosphonates (55%) but not when using any other BMA. This practice varied among different specialties, with general practitioners and oncologists being significantly more likely to apply this preventative measure for patients on bisphosphonates (
p = 0.041) and tyrosine kinase inhibitors (
p < 0.001) and only general practitioners for patients on teriparatide (
p = 0.025).
Table 6 presents the results of the survey regarding recommendations for drug withdrawal before dental treatments in patients with MRONJ.
4. Discussion
The study sought to draw attention to the side effects of BMA treatment in the oro-maxillofacial region. Unfortunately, in addition to the positive effects of BMA therapy used in the treatment of osteoporosis or bone metastases, the side effects remain a topic worthy of consideration.
Osteonecrosis of the jaw (ONJ) is a process of bone degradation that occurs through the action of several internal and external factors on bone tissue. During the last two decades, a strong correlation between BMA and ONJ has been reported. The correlation between dosing and the pathophysiological mechanisms of osteonecrosis due to BMA has not yet been established. One theory is related to the effect of BMA in inhibiting osteoclast differentiation and increasing apoptosis, due to the fact that the differentiation of osteoclasts has an important role in bone healing and remodeling. Another theory is related to local bacterial inflammation and infection, because periapical or periodontal pathology usually presents at the time of extraction alongside evidence of bacteriological factors, especially from the Actinomyces group, at the necrotic zone of the jawbone. [
6] Medications such as bisphosphonates [
1], denosumab [
2,
3], and sunitinib [
4,
5] have been implicated in the occurrence of MRONJ. This shows that different classes of drugs can cause MRONJ and that other agents from the same drug class should also be investigated in more controlled prospective studies aimed at assessing the risk of ONJ associated with these agents.
Among these, the bisphosphonates are most frequently involved in a condition also known as BRONJ, due to their use as a gold-standard therapy for osteoporosis, where they increase bone mineral density and decrease the risk of spine and hip fracture, and for preventing the skeletal manifestation of bone metastases. Currently, they are used both in oral and i.v. forms, and in our study more than 96% of our prescribers were still using these agents. Bisphosphonates have been shown to be beneficial in suppressing bone remodeling that helps slow bone loss in patients with osteoporosis. However, the danger posed by osteonecrosis has caused researchers to lose some of their enthusiasm for this class of drugs, and new treatment options have yet to be developed. Special attention should be paid to denosumab, which has been gaining more widespread use lately. In our study, almost 30% of prescribers, especially endocrinologists, were prescribing denosumab for osteoporosis with good results in patients with renal dysfunction. Compliance with this treatment has increased because of the biannual administration of denosumab, although more frequent administration, including monthly administration, can be used, which increases the risk of MRONJ. Prescribers should always advise patients to inform their dentist if they are using bisphosphonates or other BMAs before any dental treatment is performed.
In our study, there was a significant negative correlation between the use of tyrosine kinase inhibitors and teriparatide and the recommendation of a prior dental status check. In a systematic review of ONJ associated with sunitinib published by Vallina et al., 91% of patients received sunitinib at a dose of 50 mg/day for 1 to 36 months before the occurrence of ONJ. Due to this fact, attention should be given to those cases in which bisphosphonates and sunitinib are combined [
4].
Unfortunately, only 17% of prescribers were familiar with the definition of MRONJ, and the BRONJ term is still preferred. Continuing medical education should increase knowledge about BMA therapy and the risk of developing MRONJ, not only after bisphosphonate use, because new treatments involving the antiangiogenic activity of the targeted agents can inhibit bone remodeling and delay the healing of tissues and thus enhance the development of ONJ [
4].
Risk factors for the development of MRONJ are dental surgery, trauma, and poor oral hygiene with periodontal disease. Therefore, a dental check-up before initializing BMA treatment should be mandatory, good oral health should be ensured, and invasive treatments should be performed before any BMA initiation. Local development is primarily influenced by the drug administered, the pathology for which bisphosphonates are administered, the intravenous or oral route of administration, the dose administered, and the duration of treatment. A higher incidence is seen in patients with bone metastases receiving high doses of intravenous bisphosphonates over long periods [
6].
Once initiated, treatment of MRONJ becomes a challenge. The decrease in quality of life for these patients is important, with eating and speaking disorders and toothbrushing difficulties being very common because of local pain. Non-surgical treatment of ONJ aims, firstly, to improve quality of life by improving symptoms and, secondly, to stop the progression of the disease. The treatment is influenced by the stage of the disease and can vary from simple conservative measures, such as clinical and radiological follow-up, oral hygiene with antiseptic solutions, local and general antibiotic treatment, symptomatic treatment, including pain control, or, in advanced stages, minimally invasive surgery [
7] to remove sharp bone edges, or, in some cases, major surgery with partial maxillectomy or mandibular resection [
8]. In addition, treatment is influenced by the type of BMA, as evidenced by the review conducted by Bermudez-Bejarano [
7] which differentiates ONJ caused by oral bisphosphonates, where conservative treatment, clinical and radiological follow-up, minimally invasive surgical treatment, and adjuvant therapies are recommended, and i.v. bisphosphonates, where local conservative treatment, clinical and radiological follow-up, minimally invasive surgical treatment, but no adjuvant therapies are the most favorable approach [
7].
Patient dental follow-up should also include an imaging screening by X-ray, where osteolysis, bone sclerosis, bone cortical erosion, bone sequestration, and the persistence of post-extraction unhealed alveoli with no bone formation may be observed, making imaging examinations essential in the early diagnosis of osteonecrosis. In advanced stages, pathological fractures and osteolysis can extend to the inferior border of the mandible or sinus floor; also, for the identification of early stages, measuring bone density can be recommended. A simple panoramic X-ray, which is commonly used by dentists, can indicate some of the initial signs, but after that, for more accurate information regarding the dimension of the lesion, cone beam computer tomography or magnetic resonance imaging are preferred.
A systematic review to answer the question of whether drug withdrawal at the time of tooth extraction or dentoalveolar surgery is necessary to prevent the development of MRONJ was conducted [
9]. As previously mentioned, drug withdrawal is commonly used and the prescribers involved in our study tended to stop the administration of BMA before dental treatment mostly for bisphosphonates, rather than other BMAs, even though there currently is no evidence of benefit for this intervention and there are no studies that directly compare discontinuation with continuation of bisphosphonates or other BMAs. The effect of drug stoppage is still debated because of the different pharmacokinetics of BMAs. Temporary discontinuation of denosumab could be favorable due to denosumab’s short half-life but unfavorable for i.v. bisphosphonates with a longer half-life [
9], and drug interruptions should be continued for at least four months to prevent poor prognosis after surgery [
10]. Our study reinforces the idea that insufficient information is available regarding the ideal period for a drug holiday pre-operatively or post-operatively and regarding which kind of dental intervention should indicate this preventative measure. When allowed, such medication interruptions would ideally come to an end once the soft tissue has healed, and each case should be assessed separately.
Due to the multifactorial etiology of MRONJ, we recommend a multidisciplinary approach for these patients which should mandatorily include the dentist. The value of educating medical professionals about this issue and keeping current with new knowledge is immeasurable. Prescribers must be aware of MRONJ in order to properly assess the risks associated with prescribing medications associated with the condition and increase focus on necessary preventative measures. Before initiating BMA treatment, a dental check-up should be performed, any oral disease should be treated, and a good oral status should be obtained, with subsequent regular dental follow-ups necessary. It is clear that the dentist plays a crucial role in MRONJ prevention by evaluating local risk factors in patients who are undergoing BMA therapy. Patients receiving these medications should also be advised to pay closer attention to oral care and report any symptoms or signs of ONJ. Although treatment of the condition improves symptoms, curing ONJ is a difficult goal to achieve in most patients using the current methods available.
The patient should be informed regarding the risk of developing MRONJ, clear information regarding factors risk must be delivered, and the patient should be advised to maintain very good oral health to prevent the appearance of ONJ. Poor patient knowledge or comprehension of preventative measures is a significant barrier to MRONJ prevention. Improvement of oral hygiene by a preventive dental check-up must be performed. In addition, imaging examinations for these patients using X-rays should be included as screening measures, with simple panoramic X-ray or cone beam computed tomography use for the attainment of more accurate information.
Although the results of the study are very useful, there are some inherent limitations. Due to its single-center nature, our results are difficult to generalize, though they can create a snapshot of the current knowledge and practices of physicians prescribing BMAs for patients with MRONJ at an academic-hospital level in our region. Furthermore, a higher number of responders would have improved the generalizability of the results; as participation was voluntary, the number of respondents was limited.