Tooth extractions in patients with cancer receiving high-dose antiresorptive medication: a randomized clinical feasibility trial of drug holiday versus drug continuation

Abstract

Objective. Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction to high-dose antiresorptive medication (AR) in patients with cancer. A temporary discontinuation of AR (drug holiday) has been suggested to potentially reduce the risk of MRONJ after oral surgery. However, no consensus exists. The aim of the present feasibility trial was to evaluate the impact of a high-dose AR drug holiday in connection with surgical tooth extraction on the development of MRONJ and patient-reported health state.Study Design. Patients with cancer receiving high-dose AR were randomized to a drug holiday from 1 month before to 3 months after surgical tooth extraction or drug continuation. Follow-up was scheduled at 1, 3, and 6 months postoperatively. Patient health state was evaluated using the EQ-5D-5L questionnaire.Results. The study included 23 patients (11 men, 12 women). AR included denosumab (n = 13) and bisphosphonate (n = 10) with median AR durations of 9 and 17.5 months, respectively. Four denosumab patients from the drug holiday group developed MRONJ. Differences in EQ-5D-5L between the treatment groups were found in favor of drug continuation.Conclusions. The results indicate that a high-dose AR drug holiday does not prevent development of MRONJ after surgical tooth extraction and that patient-reported health state declines during a drug holiday compared with drug continuation. Objective. Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction to high-dose antiresorptive medication (AR) in patients with cancer. A temporary discontinuation of AR (drug holiday) has been suggested to potentially reduce the risk of MRONJ after oral surgery. However, no consensus exists. The aim of the present feasibility trial was to evaluate the impact of a high-dose AR drug holiday in connection with surgical tooth extraction on the development of MRONJ and patient-reported health state. Study Design. Patients with cancer receiving high-dose AR were randomized to a drug holiday from 1 month before to 3 months after surgical tooth extraction or drug continuation. Follow-up was scheduled at 1, 3, and 6 months postoperatively. Patient health state was evaluated using the EQ-5D-5L questionnaire. Results. The study included 23 patients (11 men, 12 women). AR included denosumab (n = 13) and bisphosphonate (n = 10) with median AR durations of 9 and 17.5 months, respectively. Four denosumab patients from the drug holiday group developed MRONJ. Differences in EQ-5D-5L between the treatment groups were found in favor of drug continuation. Conclusions. The results indicate that a high-dose AR drug holiday does not prevent development of MRONJ after surgical tooth extraction and that patient-reported health state declines during a drug holiday compared with drug continuation. Statement of Clinical RelevanceThe results of the present trial indicate that a high-dose antiresorptive drug holiday in relation to surgical tooth extraction has no benefit or may even have a negative effect on the development of medication-related osteonecrosis of the jaw and on patient-reported health state. The results of the present trial indicate that a high-dose antiresorptive drug holiday in relation to surgical tooth extraction has no benefit or may even have a negative effect on the development of medication-related osteonecrosis of the jaw and on patient-reported health state. Medication-related osteonecrosis of the jaw (MRONJ) is a well-known adverse reaction to antiresorptive medication (AR) and affects patients’ self-reported health state.1Ruggiero SL Dodson TB Fantasia J et al.American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw - 2014 update.J Oral Maxillofac Surg. 2014; 72: 1938-1956Abstract Full Text Full Text PDF PubMed Scopus (1393) Google Scholar,2Drudge-Coates L Van den Wyngaert T Schiødt M van Muilekom HAM Demonty G Otto S. Preventing, identifying, and managing medication-related osteonecrosis of the jaw: a practical guide for nurses and other allied healthcare professionals.Support Care Cancer. 2020; 28: 4019-4029Crossref PubMed Scopus (11) Google Scholar However, patients diagnosed with osteoporosis or malignancies with bone involvement benefit from AR. Through its bone-strengthening effect, AR reduces skeletal pain and risk of fracture and limits the progression of bone metastases;3Van Poznak CH Temin S Yee GC et al.American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer.J Clin Oncol. 2011; 29: 1221-1227Crossref PubMed Scopus (270) Google Scholar, 4Morgan GJ Davies FE Gregory WM et al.First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial.Lancet. 2010; 376: 1989-1999Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar, 5Raje N Terpos E Willenbacher W et al.Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.Lancet Oncol. 2018; 19: 370-381Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar therefore, it is a necessity for many patients worldwide. High-dose ARs include bisphosphonates and monoclonal antibodies and may be administered intravenously or subcutaneously. It is documented that the risk of MRONJ increases with more frequent administration, with duration, and with dose per administration.6Otto S Pautke C Van den Wyngaert T Niepel D Schiødt M. Medication-related osteonecrosis of the jaw: prevention, diagnosis and management in patients with cancer and bone metastases.Cancer Treat Rev. 2018; 69: 177-187Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Ninety percent of all MRONJ cases occur in patients with cancer who are receiving high-dose AR, and tooth extraction is well documented as the most important independent risk factor for the onset of MRONJ.1Ruggiero SL Dodson TB Fantasia J et al.American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw - 2014 update.J Oral Maxillofac Surg. 2014; 72: 1938-1956Abstract Full Text Full Text PDF PubMed Scopus (1393) Google Scholar,6Otto S Pautke C Van den Wyngaert T Niepel D Schiødt M. Medication-related osteonecrosis of the jaw: prevention, diagnosis and management in patients with cancer and bone metastases.Cancer Treat Rev. 2018; 69: 177-187Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 7Ruggiero SL Mehrotra B Rosenberg TJ Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.J Oral Maxillofac Surg. 2004; 62: 527-534Abstract Full Text Full Text PDF PubMed Scopus (1597) Google Scholar, 8Schiodt M Reibel J Oturai P Kofod T. Comparison of nonexposed and exposed bisphosphonate-induced osteonecrosis of the jaws: a retrospective analysis from the Copenhagen cohort and a proposal for an updated classification system.Oral Surg Oral Med Oral Pathol Oral Radiol. 2014; 117: 204-213Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 9Yazdi PM Schiodt M. Dentoalveolar trauma and minor trauma as precipitating factors for medication-related osteonecrosis of the jaw (ONJ): a retrospective study of 149 consecutive patients from the Copenhagen ONJ Cohort.Oral Surg Oral Med Oral Pathol Oral Radiol. 2015; 119: 416-422Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 10Filleul O Crompot E Saussez S. Bisphosphonate-induced osteonecrosis of the jaw: a review of 2,400 patient cases.J Cancer Res Clin Oncol. 2010; 136: 1117-1124Crossref PubMed Scopus (205) Google Scholar Therefore, the American Association of Oral and Maxillofacial Surgeons (AAOMS) and multiple position papers recommend that tooth extraction be avoided in high-dose AR patients if possible.1Ruggiero SL Dodson TB Fantasia J et al.American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw - 2014 update.J Oral Maxillofac Surg. 2014; 72: 1938-1956Abstract Full Text Full Text PDF PubMed Scopus (1393) Google Scholar,11Yoneda T Hagino H Sugimoto T et al.Bisphosphonate-related osteonecrosis of the jaw: position paper from the Allied Task Force Committee of Japanese Society for Bone and Mineral Research, Japan Osteoporosis Society, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology, and Japanese Society of Oral and Maxillofacial Surgeons.J Bone Miner Metab. 2010; 28: 365-383Crossref PubMed Scopus (178) Google Scholar However, tooth extraction cannot always be avoided. A study concluded that preexisting inflammation (e.g., periodontitis, periapical disease), rather than the tooth extraction itself, is the risk factor for the development of MRONJ.12Otto S Troltzsch M Jambrovic V et al.Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development?.J Craniomaxillofac Surg. 2015; 43: 847-854Crossref PubMed Scopus (93) Google Scholar However, recent studies concluded that tooth extraction can be performed safely and in a predictable way when following the new recommendations for MRONJ prevention, including surgical tooth extraction with primary tension-free mucosal wound closure.12Otto S Troltzsch M Jambrovic V et al.Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development?.J Craniomaxillofac Surg. 2015; 43: 847-854Crossref PubMed Scopus (93) Google Scholar,13Schiodt M Ottesen C Madsen S Nielsen E Sand L Gjoedesen C. Risk of osteonecrosis of the jaws after tooth extraction of 270 teeth with alveolectomy and primary surgical closure in 111 patients on antiresorptive treatment [abstract].Int J Oral Maxillofac Surg. 2017; 46: 113Abstract Full Text Full Text PDF Google Scholar A pause, cessation, or temporary discontinuation of AR is collectively termed a “drug holiday.” A drug holiday has been proposed to reduce the risk of MRONJ.1Ruggiero SL Dodson TB Fantasia J et al.American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw - 2014 update.J Oral Maxillofac Surg. 2014; 72: 1938-1956Abstract Full Text Full Text PDF PubMed Scopus (1393) Google Scholar,14Campisi G Fedele S Fusco V Pizzo G Di Fede O Bedogni A. Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents.Future Oncol. 2014; 10: 257-275Crossref PubMed Scopus (81) Google Scholar AR drug holidays are often discussed in the literature, but whether a drug holiday reduces the risk of MRONJ after tooth extraction has never been answered directly. Furthermore, there is no international consensus regarding the use of a drug holiday. Thus, in most countries, drug holiday guidelines and position papers are based on expert opinion.15Ottesen C Schiodt M Gotfredsen K. Efficacy of a high-dose antiresorptive drug holiday to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ): a systematic review.Heliyon. 2020; 6: e03795Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Most recently, a systematic review failed to identify any high-level evidence for the efficacy of a high-dose AR drug holiday in relation to oral surgery.15Ottesen C Schiodt M Gotfredsen K. Efficacy of a high-dose antiresorptive drug holiday to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ): a systematic review.Heliyon. 2020; 6: e03795Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar On the contrary, it could not be excluded that a drug holiday could have a negative influence on patients’ health state. Despite the lack of evidence, many clinicians pause AR in connection with tooth extraction. They thereby potentially introduce an increased risk of skeletal pain, fracture risk, and potentially cancer progression during the drug holiday for these Therefore, studies of are to whether a drug holiday is when tooth extraction is in group of The aim of randomized clinical feasibility trial was to evaluate whether a drug holiday of high-dose AR to surgical tooth extraction has an impact on the development of MRONJ and on patient-reported health state compared with of the AR. trial was in with the of the Association of for 2014; Google Scholar in its and clinical practice The study was the Committee on and the The is with The study was as a feasibility trial and was at the of Oral Maxillofacial Copenhagen in the trial were all patients receiving high-dose AR from or other in the of for tooth extraction. 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Efficacy of a high-dose antiresorptive drug holiday to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ): a systematic review.Heliyon. 2020; 6: e03795Abstract Full Text Full Text PDF PubMed Scopus (23) Google S S S et holiday clinical for antiresorptive agents in medication-related osteonecrosis cases of the Bone Miner Metab. 2020; PubMed Scopus Google Scholar The trial a drug holiday the patient-reported health state using a The results of the present trial indicate that a high-dose AR drug holiday 1 month to 3 months does not prevent development of MRONJ and that the patient-reported health state declines during drug holiday compared with drug continuation. and denosumab are antiresorptive but are to are and to be when bone is osteonecrosis of the jaws: a to drug Google Scholar is a monoclonal with a of a dose is to an osteonecrosis of the jaws: a to drug Google Scholar Therefore, from a of a denosumab drug holiday could be to be more than a bisphosphonate drug holiday. However, the results of the present trial failed to indicate a and a effect of denosumab drug holiday. is in with other studies that a denosumab drug holiday has no effect on S A A M A S. Clinical and of and patients with osteonecrosis of the jaw Craniomaxillofac Surg. 2017; PubMed Scopus Google S J et of the jaw in patients with a Craniomaxillofac Surg. 2018; 46: PubMed Scopus Google Scholar and that no evidence regarding the of denosumab S M T. Medication-related osteonecrosis of the jaw: a Oral PubMed Scopus Google Scholar the present feasibility all patients receiving denosumab were with may have an effect on MRONJ However, the controlled the efficacy of a drug holiday. Thus, no studies to the present were and controlled studies have been the the of A recent retrospective cohort study et The effect of bisphosphonate discontinuation on the of medication-related osteonecrosis of the jaw after tooth Oral Maxillofac Surg. 2020; 46: PubMed Scopus (11) Google Scholar to the of MRONJ patients who surgical tooth extraction discontinuation of bisphosphonate The patient was to the present trial and drug On the of these retrospective the could not recommend a bisphosphonate drug holiday before surgical tooth extraction to reduce the risk of MRONJ. However, the study was a retrospective cohort study including 6 patients receiving high-dose AR. The of the patients were receiving AR. of the patients developed and patient was receiving high-dose AR for cancer and was in the bisphosphonate is the of the present all the patients who developed MRONJ were in the drug holiday group and receiving denosumab et T S E et osteonecrosis of the jaw after tooth extraction in cancer a retrospective PubMed Scopus Google Scholar a retrospective cohort study with the aim of the between drug other for the development of MRONJ after tooth extraction in patients with cancer receiving high-dose AR. with the of it was found that a drug holiday no impact on MRONJ and it was concluded that tooth extraction not be in patients with preexisting inflammation was a risk factor for The effect of bisphosphonate discontinuation on the of medication-related osteonecrosis of the jaw after tooth Oral Maxillofac Surg. 2020; 46: PubMed Scopus (11) Google Scholar Therefore, the that teeth or teeth with a be for extraction before the development of more T S E et osteonecrosis of the jaw after tooth extraction in cancer a retrospective PubMed Scopus Google Scholar percent of the teeth in the present trial with and all patients who developed MRONJ after the surgical extraction preexisting MRONJ is to from an it is not to from the results of the present trial whether the MRONJ was present at or whether the MRONJ was the Patients benefit from bone-strengthening has even been associated with an increased of N Terpos E Willenbacher W et al.Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.Lancet Oncol. 2018; 19: 370-381Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar an AR drug holiday may the risk of including of bone pain and progression of bone The patients cancer during the present trial all to the drug holiday They were all receiving denosumab and with The from the present trial no between and drug versus drug but the of AR may the risk of MRONJ development in a with fracture holiday and osteonecrosis of the PubMed Scopus Google Scholar agents have been associated with the development of L Van den Wyngaert T Schiødt M van Muilekom HAM Demonty G Otto S. Preventing, identifying, and managing medication-related osteonecrosis of the jaw: a practical guide for nurses and other allied healthcare professionals.Support Care Cancer. 2020; 28: 4019-4029Crossref PubMed Scopus (11) Google H Nielsen Schiodt M osteonecrosis of the jaws associated with as and in with A of cases from the Copenhagen Cohort.Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar of the patients who developed MRONJ were with intravenously agents and The other administered and 1 and the use of the patients in the present the results indicate that there be an between and the development of MRONJ. However, it is that of the patients to the of MRONJ a connection between health and the of MRONJ studies have the impact of a drug holiday on patients’ health state. a in the patients’ health state was found at and when for at The increased with from but was at It be that multiple other factors may the patients’ on the EQ-5D-5L as cancer disease and other the However, patient-reported health state has been associated with MRONJ in the L Van den Wyngaert T Schiødt M van Muilekom HAM Demonty G Otto S. Preventing, identifying, and managing medication-related osteonecrosis of the jaw: a practical guide for nurses and other allied healthcare professionals.Support Care Cancer. 2020; 28: 4019-4029Crossref PubMed Scopus (11) Google Fede O V et management of patients at risk of medication-related osteonecrosis of the jaw: new of primary Res 2018; Scholar is in with the of the present 1 of the patients diagnosed with MRONJ a health state after MRONJ Thus, the in all patients in MRONJ was Despite expert and on the of the results of the present there are no to high-dose AR in relation to tooth the results be in the of The study is in to a retrospective it is to include more However, the indicate that an of patients be included to a MRONJ is the The trial that it was to the but not It was to not of the patient including development in cancer progression and use of but to the may be the that trial is the randomized clinical feasibility trial in group of patients with cancer as well as all patients who developed MRONJ after surgical tooth were in drug holiday. Therefore, it is whether a study be that trial a drug holiday can be the of the present it is concluded that a high-dose AR drug holiday in relation to surgical tooth extraction in the has no benefit or may even have a effect on the development of MRONJ and the patient-reported health state. The and to the who was primary on trial The the and at Copenhagen and and for regarding (drug holiday versus drug The trial not have been important and between the The for clinical during the trial and for and The present study was a from the of the was not in study or of or for

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