I. Introduction
Antiresorptive medication is widely used for bone-related diseases in patients with osteoporosis and osteopenia, cancer metastasis, or multiple myeloma 1 .
In oncology, antiresorptive medication is used as adjunctive treatment to manage and limit tumor evolution. The medication acts directly on skeletal-related events associated with bone metastasis of solid tumors such as breast, prostate, and lung cancer and manages lytic lesions in multiple myeloma 2 , 3 .
Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction to antiresorptive drugs.( Fig. 1 ) This condition can affect both maxillary bones, with higher incidence in the mandible. The diagnosis is made when the patient was exposed, previously or currently, to antiresorptive or antiangiogenic agents and presents exposed bone that persists for more than eight weeks, without history of radiation therapy in the head and neck area 4 , 5 . A therapeutic protocol has not been established, and clinical resolution is difficult. Consequently, prevention is imperative to avoid this complication 4 , 6 , 7 .
The aim of this study was to evaluate the profile of patients on antiresorptive therapies for cancer treatment and assess presence of oral lesions, oral hygiene status, and knowledge regarding MRONJ.
II. Materials and Methods
This study was approved by the Research Ethics Committee of Erasto Gaertner Cancer Center under protocol (No. 65123116.1.0000.0098) and is indexed at the national database of research involving human subjects. The written informed consent was obtained from all patients.
This was an observational cross-sectional study that evaluated patients treated with antiresorptive agents, previously or currently. All patients were assigned to the Department of Oral and Maxillofacial Surgery at Erasto Gaertner Cancer Center, referred by the clinical oncologist of the same institution.
The study comprised patients with malignant bone pathologies and bone metastases. The patients were either a candidate for use, currently using, or previously used antiresorptive drugs. The study excluded patients with oral metastatic or metaplastic lesions, grafts or flaps on the jaws, or who had undergone radiotherapy in the region.
Demographic and clinical data were collected on patient age at consultation, sex, oral hygiene, presence of oral disease/condition, type of drug and duration of use, and knowledge regarding the risks associated with drug use.
Team calibration was performed to conduct oral hygiene analysis based on the simplified oral hygiene index (IHO-S) 8 , with a score of 0 as good hygiene, 1 as regular, and 2 and 3 as poor. The presence of one or more residual roots, teeth with open cavities, or periodontal abscesses were categorized as poor hygiene. Patients with spontaneous gingival bleeding, plaque-related periodontal hyperplasia, and spontaneous gingival suppuration, whether or not associated with tooth mobility, were included in the clinical profile of periodontal disease.
III. Results
From July 2017 to December 2018, a total of 90 patients was referred to the outpatient clinic at the Department of Oral and Maxillofacial Surgery at Erasto Gaertner Cancer Center for oral evaluation to prevent osteonecrosis.
Among the 90 patients, 64 were female and 26 male (ratio, 2.5:1). The ages ranged from 29 to 87 years, with a mean of 61 years. The underlying diseases for referring patients for antiresorptive medication use are shown in Fig. 2 .
The most commonly used antiresorptive drugs with potential risk of MRONJ were zoledronic acid, pamidronate, denosumab, trastuzumab, and gefitinib. Drug distribution, standard dose, and number of patients using the drugs are presented in Table 1 .
Evaluation of oral cavity showed a high 30% prevalence of periodontal disease in the study cohort, followed by oral candidiasis (7.8%) and proliferative lesions or vascular malformations (4.5%).
MRONJ was diagnosed in nine patients (10.0%); five were female with a mean age of 65 years. Two patients had no history of local trauma or dental procedures, and bone exposure was considered spontaneous. Five patients reported dental extraction, and the other two had experienced bone exposure associated with severe periodontal disease. Information related to MRONJ diagnosis is presented in Table 2 .
After evaluation, 63.3% of the patients were categorized as regular or poor hygiene. Based on clinical and radiographic diagnosis (grade III mobility, furcation involvement, longitudinal dental fractures, unrestorable carious lesions, advanced periodontitis), 21% of the patients had indication for extraction. Among the patients diagnosed with MRONJ, five had active periodontal disease, and only one was categorized as good oral hygiene.
Regarding patient knowledge about the side effects of medication, 60% stated not being aware of the risks of MRONJ. The subjects also stated they were not familiar with the contraindications of dental surgery in patients with a history of antiresorptive or antiangiogenic therapy.
IV. Discussion
Most studies on MRONJ focused on disease description and did not evaluate patient profile. As far as we know, this study presents the largest sample of patients using antiresorptive agents for cancer treatment in Latin America, describing the main characteristics of patients at risk of MRONJ.
MRONJ directly affects the quality of life of patients, leading to high morbidity. Due to the limited therapeutic options, treatments are not always resolutive 6 , 9 . Management can be challenging and usually requires a multidisciplinary approach, with a variety of interventions and care 7 . The indicated treatment is directly associated with disease stage and general health status 4 .
Previous studies have demonstrated that the route of drug administration is associated with increased risk for MRONJ development, with oral drugs having a lower incidence than intravenous (IV) medications 5 , 10 . Therefore, MRONJ development should be considered in cancer patients in whom drugs are almost exclusively administered IV.
Most patients in the present study are female, with a 2.5:1 ratio between female and male; these females had a mean age of 60 years. Breast and prostate cancer and multiple myeloma were the most frequent malignancies in the study. Zoledronic acid was the most frequently used medication, followed by pamidronate, trastuzumab, and denosumab. Zoledronic acid has a high relative potency compared with other medications and presents a higher risk of MRONJ. Use of this medication is increasing in cancer treatments due to its efficiency, implying a greater number of patients at risk of MRONJ development 9 . Therefore, those involved in disease treatment such as oncologist, patient, and other health professionals should be aware of the need for preventive actions and constant follow-up during and after use of antiresorptive drugs 7 .
The majority of patients treated at our hospital are from the public health system, are of low-income, and have difficulty accessing oral health services. Of them, 67% of the patients were classified as regular or poor oral hygiene. In previous studies, oral health was a risk factor for MRONJ, and preventive measures must include dental consultation 4 , 5 , 11 . Other risk factors include inflammatory dental diseases, dental caries, torus mandibularis and palatinus, and traumatic factors such as unadapted dental prostheses 3 . Inflammation and bacterial infection are implicated in MRONJ pathogenesis 12 . Good oral hygiene that includes dental floss and mouthwash is an important measure to reduce risk of MRONJ 5 . Patient preparation must include extraction of compromised teeth, management of active carious lesions, pulp infections, and periodontal disease control. Most patients in the present study had their first consultation with a dentist after starting the medication, which reduced the chance of adequate oral preparation and exposed the patients to risk. On the first consultation, nine cases presented with MRONJ, and two of had no oral complaints, showing the need for preventive follow-up for early detection; other patients had undergone tooth extracted and were unaware of the risk of complications.
Patient knowledge regarding MRONJ is essential for prevention 6 , 7 . More than half of the patients evaluated were unaware of the risk for this complication. The misconception of the actual effects of the drug, which is usually referred to as a vitamin or calcium supplement, leads to lack of preventive care.
MRONJ pathophysiology is apparently multifactorial, and inflammation or infection, trauma, and decreased bone turnover are associated with disease development 1 , 4 . Although spontaneous development has been described by some authors, in most reports, MRONJ is associated with tooth extraction due to pulp infection, periapical lesions, and bacterial infections 8 , 13 , 14 . This connection was observed in an animal study, indicating that such infections precede the appearance of necrotic bone 11 , 15 , 16 .
V. Conclusion
Although preventive measures do not exclude the possibility of MRONJ, they have been shown to reduce the risk 17 , 18 . Preventive measures can be used to help potentially at-risk patients and should be encouraged. Identifying the patient profile and needs facilitates not only the preventive process, but also the emergence of new therapeutic options. Our study shows that most patients were weakened by metastatic disease, anti-neoplastic treatment, and by issues associated with aging because most subjects were over 60 years of age. Collectively, this information should be considered for management of preventive and therapeutic measures.
Authors’ Contributions
V.H.C.F. participated in study design, data collection, statistical analysis and wrote the manuscript. A.T.K. participated in data collection, statistical analysis and helped to draft the manuscript. J.V. participated in data collection, statistical analysis and helped to draft the manuscript. L.M.S. participated in study design, data collection, and final review of the manuscript. J.L.S. participated in study design and coordination, data collection, statistical analysis and final review of the manuscript. All authors read and approved the final manuscript.
Ethics Approval and Consent to Participate
This study was approved by the Research Ethics Committee of Erasto Gaertner Cancer Center under protocol (No. 65123116.1.0000.0098), and the written informed consent was obtained from all patients.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
References
1 Nicolatou-Galitis O Schiødt M Mendes RA Ripamonti C Hope S Drudge-Coates L 2019 Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment Oral Surg Oral Med Oral Pathol Oral Radiol 127 117 35 https://doi.org/10.1016/j.oooo.2018.09.008 10.1016/j.oooo.2018.09.008 30393090
2 Coleman RE 1997 Skeletal complications of malignancy Cancer 80 8 Suppl 1588 94 https://doi.org/10.1002/(sici)1097-0142(19971015)80:8+<1588::aid-cncr9>3.3.co;2-z 10.1002/(sici)1097-0142(19971015)80:8+<1588::aid-cncr9>3.3.co;2-z 9362426
3 Şahin O Odabaşı O Aliyev T Tatar B 2019 Risk factors of medication-related osteonecrosis of the jaw: a retrospective study in a Turkish subpopulation J Korean Assoc Oral Maxillofac Surg 45 108 15 https://doi.org/10.5125/jkaoms.2019.45.2.108 10.5125/jkaoms.2019.45.2.108 31106139 PMC6502754
4 Ruggiero SL Dodson TB Fantasia J Goodday R Aghaloo T Mehrotra B 2014 American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update J Oral Maxillofac Surg 72 1938 56 https://doi.org/10.1016/j.joms.2014.04.031 10.1016/j.joms.2014.04.031 25234529
5 Nifosì AF Zuccarello M Nifosì L Hervas Saus V Nifosì G 2019 Osteonecrosis of the jaw in the era of targeted therapy and immunotherapy in oncology J Korean Assoc Oral Maxillofac Surg 45 3 8 https://doi.org/10.5125/jkaoms.2019.45.1.3 10.5125/jkaoms.2019.45.1.3 30847290 PMC6400698
6 Al Abdullateef A Alhareky MS 2020 Awareness among patient at risk of developing Medication Related Osteonecrosis of the Jaw (MRONJ) - a primary prevention strategy Saudi Pharm J 28 771 8 https://doi.org/10.1016/j.jsps.2020.05.004 10.1016/j.jsps.2020.05.004 32550810 PMC7292880
7 Sturrock A Preshaw PM Hayes C Wilkes S 2019 Perceptions and attitudes of patients towards medication-related osteonecrosis of the jaw (MRONJ): a qualitative study in England BMJ Open 9 e024376 https://doi.org/10.1136/bmjopen-2018-024376 10.1136/bmjopen-2018-024376 30833319 PMC6443056
8 Greene JC Vermillion JR 1964 The simplified oral hygiene index J Am Dent Assoc 68 7 13 https://doi.org/10.14219/jada.archive.1964.0034 10.14219/jada.archive.1964.0034 14076341
9 Patel V Kelleher M Sproat C Kwok J McGurk M 2015 New cancer therapies and jaw necrosis Br Dent J 219 203 7 https://doi.org/10.1038/sj.bdj.2015.680 10.1038/sj.bdj.2015.680 26361116
10 Heufelder MJ Hendricks J Remmerbach T Frerich B Hemprich A Wilde F 2014 Principles of oral surgery for prevention of bisphosphonate-related osteonecrosis of the jaw Oral Surg Oral Med Oral Pathol Oral Radiol 117 e429 35 https://doi.org/10.1016/j.oooo.2012.08.442 10.1016/j.oooo.2012.08.442 23182374
11 Tsao C Darby I Ebeling PR Walsh K Reynolds E O’Brien-Simpson N 2013 Oral health risk factors for bisphosphonate-associated jaw osteonecrosis J Oral Maxillofac Surg 71 1360 6 https://doi.org/10.1016/j.joms.2013.02.016 10.1016/j.joms.2013.02.016 23582590
12 Sandhu S Salous MH Sankar V Margalit DN Villa A 2020 Osteonecrosis of the jaw and dental extractions: a single-center experience Oral Surg Oral Med Oral Pathol Oral Radiol 130 515 21 https://doi.org/10.1016/j.oooo.2020.07.001 10.1016/j.oooo.2020.07.001 32723683
13 Poubel VLDN Silva CAB Mezzomo LAM De Luca Canto G Rivero ERC 2018 The risk of osteonecrosis on alveolar healing after tooth extraction and systemic administration of antiresorptive drugs in rodents: a systematic review J Craniomaxillofac Surg 46 245 56 https://doi.org/10.1016/j.jcms.2017.11.008 10.1016/j.jcms.2017.11.008 29233703
14 Landesberg R Woo V Cremers S Cozin M Marolt D Vunjak-Novakovic G 2011 Potential pathophysiological mechanisms in osteonecrosis of the jaw Ann N Y Acad Sci 1218 62 79 https://doi.org/10.1111/j.1749-6632.2010.05835.x 10.1111/j.1749-6632.2010.05835.x 21291478 PMC4477826
15 Gaudin E Seidel L Bacevic M Rompen E Lambert F 2015 Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: a systematic review and meta-analysis J Clin Periodontol 42 922 32 https://doi.org/10.1111/jcpe.12455 10.1111/jcpe.12455 26362756
16 Tsurushima H Kokuryo S Sakaguchi O Tanaka J Tominaga K 2013 Bacterial promotion of bisphosphonate-induced osteonecrosis in Wistar rats Int J Oral Maxillofac Surg 42 1481 7 https://doi.org/10.1016/j.ijom.2013.06.011 10.1016/j.ijom.2013.06.011 23932020
17 Dimopoulos MA Kastritis E Bamia C Melakopoulos I Gika D Roussou M 2009 Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid Ann Oncol 20 117 20 https://doi.org/10.1093/annonc/mdn554 10.1093/annonc/mdn554 18689864
18 Bramati A Girelli S Farina G Dazzani MC Torri V Moretti A 2015 Prospective, mono-institutional study of the impact of a systematic prevention program on incidence and outcome of osteonecrosis of the jaw in patients treated with bisphosphonates for bone metastases J Bone Miner Metab 33 119 24 https://doi.org/10.1007/s00774-014-0566-x 10.1007/s00774-014-0566-x 24553860