O R I G I N A L A R T I C L E
Denosumab-related osteonecrosis of the jaw: A retrospective study
Claire Egloff-Juras
1,2| Aurelie Gallois
1,2| Julia Salleron
3| Vincent Massard
4| Gilles Dolivet
1| Julie Guillet
1,2| Berengere Phulpin
1,21Department of Head and Neck and Dental Surgery, Institut de Cancerologie de Lorraine, Vandoeuvre-les-Nancy, France
2Dental Faculty of Nancy, Universite de Lorraine, Nancy, France
3Cellule Data-biostatistiques, Institut de Cancerologie de Lorraine, Vandoeuvre-les- Nancy, France
4Department of Oncology, Institut de Cancerologie de Lorraine, Vandoeuvre-les- Nancy, France
Correspondence
Claire Egloff-Juras, Faculte d’Odontologie- Universite de Lorraine, Nancy, France.
Email: claire.juras@univ-lorraine.fr
Background: Osteonecrosis of the jaw is a very delicate side effect of Denosumab.
The aim of this retrospective study was to assess the occurrence rate of Deno- sumab-related osteonecrosis of the jaw (DRONJ) at the Cancer Institute of Lorraine (ICL) and to highlight necrosis risk factors.
Methods: To that purpose, we analyzed the medical records of 249 consecutive patients treated with Denosumab at the ICL during the past 5 years. Patients who received orofacial radiotherapy or a previous treatment with a bisphosphonate were excluded. The P-value was set at .005.
Results: A total of 141 patients treated at the ICL between January 2010 and December 2015 were included. All patients were treated with XGEVA
â. Of the 141 patients included in the study, 10 developed DRONJ. The incidence of DRONJ increases with the duration of follow-up as follows: 3% at 1 year, 7% at 2 years, and 8% from 30 months on. No risk factor for necrosis could be identified except the realization of prior dental extraction (P = .025).
Conclusion: Our results raise important questions about the dental management of these patients, in particular, concerning the healing period between dental extractions and the initiation of Denosumab.
K E Y W O R D S
Denosumab, dental management, Oncology, osteonecrosis of the jaw, retrospective, side effect
1 | I N T R O D U C T I O N
Denosumab is a monoclonal antibody which has two commercial presentations in France: Proliaâ (Amgen Inc, Thousand Oaks, CA, USA, for benign pathologies) and XGEVAâ (Amgen Inc, for malignant diseases).
It acts by inhibiting the formation, function, and survival of osteoclasts to decrease bone resorption. For that, it targets the RANK/RANK-L complex. It prevents the RANK activation by binding to the pre-osteoclast RANK-L and creates a saturation of osteoclast receptors.
Denosumab is indicated in cases of osteoporosis, Paget’s disease (bone disease, localized and with slow progression), bone giant cell
tumors, and bone metastases. It is a second-line agent for Paget’s disease if bisphosphonates are contraindicated. Denosumab is pre- scribed in almost the same indications as bisphosphonates and is gradually supplanting the latter because of its advantages. In fact, it is interesting to note that XGEVAâhas a much shorter half-life than bisphosphonates (28 days) and a shorter duration of action too (6 months vs 5-10 years for bisphosphonates) while having a higher efficiency than zoledronic acid on bone metastases development.1,2
Nevertheless, Denosumab and bisphosphonates have common side effects such as hypocalcaemia, hypersensitivity to products (skin allergic reactions, hypotension, dyspnea, and angioedema) but also an atypical femur fracture or an osteonecrosis of the jaw.3
The American Association of Oral and Maxillofacial Surgeons described the medication-related osteonecrosis of the jaw (MRONJ) as a mucosal lesion of the maxillofacial region with necrotic bone
Egloff-Juras Claire and Gallois Aurelie are co-authors.
66
|
© 2017 John Wiley & Sons A/S.Published by John Wiley & Sons Ltd
wileyonlinelibrary.com/journal/jop J Oral Pathol Med. 2018;47:66–70.
exposure (Figure 1).4,5This exposure should be at least 8 weeks old and occur in patients receiving bisphosphonates or Denosumab. It must be in an area free of radiotherapy and bone metastases to be linked to medications. This definition describes both necroses related to the use of bisphosphonates and those related to the intake of Denosumab.
The management of MRONJ is mainly preventive with a dental consultation before prescription. During this consultation, it is impor- tant to explain to the patient the risk of necrosis and also to give him advice regarding dental hygiene. It is also important to have a regular dental follow-up (4 times a year). In case of confirmed MRONJ, medication will be suspended in accordance with the pre- scribing physician. Despite all this, healing an osteonecrosis is long and sometimes complete cure can be obtained.6
Surgery is sometimes necessary to have a perfect eviction of all the necrotic bone area and/or to eliminate a bony sequestrum. Some more severe forms require the use of more invasive surgeries such as mandibulectomy. Finally, in case of infection of the necrotic area, the use of antibiotic is necessary and a regular monitoring will be established.7
Thus, Denosumab-related osteonecrosis of the jaw (DRONJ) is a very delicate side effect of Denosumab. Indeed, the resolution of DRONJ is often long and complex. That is why the objectives of this study were to assess the occurrence rate of DRONJ at the Cancer Institute of Lorraine (Institut de Cancerologie de Lorraine, Vandoeu- vre, ICL) and to highlight necrosis risk factors.
2 | M A T E R I A L S A N D M E T H O D S
A retrospective monocentric study was conducted at the ICL by ana- lyzing the medical records of 249 consecutive patients treated with Denosumab at the ICL during the past 5 years. Patients who received orofacial radiotherapy or a previous treatment with a bis- phosphonate were excluded. The patients only followed at the ICL’s dental service and with an oncological follow-up performed in another center were also excluded from this study. The data recorded were as follows: the existence of a necrosis of the jaw, the
patients’ age, the type of cancer, an active tobacco use, an alcohol intoxication, a glucocorticoid or anti-angiogenic therapy, an ongoing chemotherapy, the existence of diabetes, pre-therapeutic dental con- sultation and realization of preventive dental extractions (performed before treatment initiation), and the existence of denture pressure sores. In fact, the type of cancer, a tobacco use, an alcohol intoxica- tion, a glucocorticoid or anti-angiogenic therapy, an ongoing chemotherapy, or diabetes are among the main risk factors for MRONJ. All the patients who benefited from a dental consultation at the ICL received a complete information about the risk of MRONJ and the necessity of a trimestrial dental follow-up.
This retrospective study was approved by our institutional research ethics committee and by the French Data Protection Authority (“Commission Nationale de l’informatique et des Liberte”
(CNIL)). It is also in accordance with the Helsinki Declaration.
The quantitative parameters were described by the median and range, and the qualitative parameters by the frequency and the per- centage. The incidence of DRONJ was described by the Kaplan- Meier method. The date of origin was the date of introduction of Denosumab. The prognostic factors were tested in univariate ana- lyses by a Cox proportional hazard model. The results are expressed by the hazard ratio and the 95% confidence interval. The level of significance was set at 0.05. Statistical analyses were performed using the SAS software (SAS Institute, Cary, NC 25513, version 9.3).
3 | R E S U L T S
A total of 141 patients treated at the ICL between January 2010 and December 2015 were included. One hundred and thirty-eight were treated with Denosumab following the appearance of bone metastases and 3 for primary bone tumors.
All patients were treated with XGEVAâ. Included patients’ char- acteristics are described in Table 1. The median follow-up time was 25 months (from 5 to 43 months).
A total of 90 patients (63.9%), that is to say all patients with a dental consultation at the ICL, were informed about the risk of DRONJ during their dental consultation and they all received the prevention tips.
Of the 141 patients included in the study, 9 developed DRONJ.
Necrosis was related to tooth extraction in 4 cases (development of DRONJ at avulsion sites, radiological persistence of non-healed alve- oli), to prosthetic injury in 3 cases (it is also interesting to note that only 3 patients with necrosis carried a dental prosthesis), and finally, 2 spontaneous DRONJ (without local injury found). The mean time between extraction and Denosumab initiation for patients with DRONJ was 4 months (from 2 weeks to 15 months).
Only, 2 cases of DRONJ occurred in patients who did not have any dental consultation and also no prevention. The incidence increased with the duration of follow-up as follows: 3% at 1 year, 7% at 2 years, and 8% from 30 months on. In June 2016, 4 patients had a complete cure of their necrosis. Only, the 36 patients (25.5%) who benefited from dental extractions were checked every month F I G U R E 1 Intra-oral appearance of maxillary Denosumab-related
osteonecrosis of the jaw
for 6 months by our dental service after Denosumab initiation.
Patients who did not require dental treatment before Denosumab continued their follow-up with their treating dentist (4 times a year).
Among patients with DRONJ, no one showed alcohol consump- tion or anti-angiogenic therapy so no conclusions can be drawn from these data. It is also important to note that among these 9 patients, 5 also benefited from concomitant chemotherapy and 2 from con- comitant targeted therapy. None of them underwent tooth extrac- tion after initiation of Denosumab. No risk factor for necrosis could be identified except the realization of dental extraction before treat- ment initiation (P= .025) (Table 2): at 36 months, the incidence of necrosis was 15.5% in the subgroup of patients (corresponding 5 patients) with prior dental extraction vs 5.4% for patients without avulsion (corresponding 4 patients). The time interval between avul- sion and necrosis was 15 months (from 2 to 29 months).
4 | D I S C U S S I O N
In this study, we obtained a DRONJ rate of 1% from beginning to 6 months of treatment and of 8% until 30 months of treatment.
From 12 months of treatment, the rate reached 3% and then exceeded the average rates frequently reported in the literature (be- tween 1% and 2%).8-13However, cross-study comparisons are com- plex, due to the variability of many factors as follows: the number of patients included in the study, duration of follow-up (often less than 24 months), and the various potentially aggravating factors which are not always taken into account or do not appear in the publication.
If the statistical analyses have not been significant for risk fac- tors, it is certainly due to the low number of DRONJ studied and also because the patients with DRONJ in this study had no other comorbidities.
Moreover, DRONJ is still a rare effect of Denosumab. To increase the relevance of our results, it would have been necessary to increase the number of patients in particular by conducting a mul- ticentered study. Another difficulty limiting the number of data is that it is a retrospective study, and therefore, a large number of T A B L E 1 Patient’s characteristics
Characteristics
Age at initiation of Denosumab, Median [Range] 58.9 [26;85]
Age at DRONJ’ diagnosis, Median [Range] 61.4 [61;80]
Localization of the primary tumor, No. (%)
Unknown 3 (2.1%)
Breast 70 (49.6%)
Prostate 12 (8.5%)
Lung 20 (14.2%)
Renal 11 (7.8%)
Bone 4 (2.8%)
Head and neck 15 (10.6%)
Digestive 6 (4.4%)
Metastases, No. (%) 138 (97.9%)
Risk factors, No. (%) Non-exclusive
Corticosteroids 83 (58.9%)
Tobacco 42 (29.8%)
Alcohol 11 (7.8%)
Diabetes 15 (10.7%)
Chemotherapy 119 (84.4%)
Targeted therapies 70 (49.6%)
Anti-angiogenic 10 (7.1%)
Pretreatment dental consultation, No. (%)
ICL* 72 (51.1%)
Another dentist 18 (12.8%)
None 51 (36.1%)
Patients with avulsion before treatment 36 (25.5%) Tooth extraction before treatment (number of teeth).
Mean [Range]
2 [0;30]
Duration of treatment with Denosumab (months).
Mean [Range]
24 [0;39.6]
Results presented with median and range or frequency (No.) and per- centage (%).
*ICL Cancer Institute of Lorraine.
T A B L E 2 Predictive factors of DRONJ in univariate Cox analyses Parameters
Hazard ratio and 95% confidence interval
P- value Denosumab initiation
Before 60 years 1
After 60 years 0.77 [0.21;2.87] .699
Cancer localization
Breast 1 .129
Others 3.38 [0.70;16.27]
Tobacco Non- or ex-
smoker
1 .062
Active smoker 3.50 [0.94;13.06]
Corticosteroids
No 1 .338
Yes 0.053 [0.14;1.96]
Diabetes
No 1 .921
Yes 1.11 [0.14;9.04]
Chemotherapy
No 1 .672
Yes 1.57 [0.20;12.53]
Pretreatment dental consultation
No 1 .281
Yes 2.38 [0.49;11.48]
Tooth extraction before treatment
No 1 .025
Yes 4.51 [1.21;16.86]
Significant factors (P< .05) in univariate analyses.
patients could not be included because of missing data or inaccu- racy. Moreover, the fact that we decided to exclude patients for- merly treated with bisphosphonates also reduced our number of cases. However, in our view, this exclusion was essential because it was demonstrated that the risk of necrosis was greatly increased in patients treated with bisphosphonates and then with Denosumab.14 Moreover, it is then difficult to attribute DRONJ only to Deno- sumab.15 Now, it would be interesting to continue this work by a prospective study.
Only 36 patients (25.5%) received regular dental follow-up (1 times per month for 6 months) at the ICL. For the others, we do not know if they had a regular dental follow-up. This could be a point of improvement in our care of these patients.
In this study, only the realization of pretreatment tooth extrac- tion was found to be a risk factor for DRONJ and not a protective one. In addition, DRONJ was mostly reported in the territories where the teeth had been extracted.
The total mucosal healing had always been achieved before treatment initiation (checked and validated by a dentist, at least 6 weeks after tooth extraction). We did not find this type of event when we applied the same protocol before initiating bisphosphonate therapy. Nevertheless, it would seem that a complete bone healing is essential. This raises many questions about our management of these patients. Indeed, a complete bone healing requires 120 days in a healthy patient and here we frequently faced immunocompromised patients because of concomitant chemotherapy. In fact, 5 of the patients presenting DRONJ were undergoing chemotherapy at the time of extraction and 2 a targeted therapy. Thus, this period of cicatrization of 120 days would be a minimum because we are facing patients with delayed healing. However, it is rarely possible to delay the starting of treatment with Denosumab. So, it seems necessary to discuss each case with prescribing doctors and adapt our manage- ment to the possible healing time.
We could describe two scenarios. In the first case, the treatment ini- tiation may be delayed and so all compromised teeth (symptomatic or not) could be avulsed. In the second case, where a minimum of 120 days cannot be met, dental extraction should be kept to a minimum and only concern symptomatic teeth. The existence of a potential infection site shall not involve tooth extraction in this second case. In all cases, dental close monitoring will be necessary after introduction of Denosumab.
In this study, we could not identify the existence of a prosthetic injury as a risk factor for DRONJ due to a lack of data. Nevertheless, it is important to note that a prosthetic injury is the cause of 3 of the 9 cases of DRONJ found (that is to say 1/3 of the cases of necrosis). The American Association of Oral and Maxillofacial Sur- geons identifies prosthodontic treatments as an important risk factor of MRONJ.5Khan et al16indicated that wearing a denture involved a twofold increased risk of MRONJ. This risk must therefore be an important message in our preventive measures.
A recent publication of the American Association of Oral and Maxillofacial Surgeons recognizes that DRONJ can occur without bone exposure4 which constitutes a real diagnostic challenge. This should make us consider our definition of DRONJ. In fact, with the
Denosumab, we are increasingly confronted with this type of necro- sis evolving without clinical signs.17
5 | C O N C L U S I O N
As we have seen previously, Denosumab has great benefits for the patient in terms of carcinology. But, it also involves a risk of DRONJ that increases strongly with time and more and more often it con- fronts us with DRONJ without bone exposure.
Our results raise important questions about the dental manage- ment of these patients who seem to need to be treated differently from patients going to benefit from treatment with bisphosphonates.
A questioning concerning indications of treatment with Denosumab also seems necessary.
A C K N O W L E D G M E N T
The authors gratefully acknowledge the support of the Cancer Insti- tute of Lorraine (ICL) and the Dental Faculty of Nancy, without which this study could not have been completed.
C O N F L I C T O F I N T E R E S T None.
O R C I D
Claire Egloff-Juras http://orcid.org/0000-0002-1078-481X
R E F E R E N C E S
1. Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in a patient on Denosumab. J Oral Maxillofac Surg. 2010;68:959-963.
2. Grey A, Reid IR. Differences between the bisphosphonates for the prevention and treatment of osteoporosis. Ther Clin Risk Manag.
2006;2:77-86.
3. Chen F, Pu F. Safety of Denosumab versus zoledronic acid in patients with bone metastases: a meta-analysis of randomized con- trolled trials. Oncol Res Treat. 2016;39:453-459.
4. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res.
2007;22:1479-1491.
5. Ruggiero 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;72:1938-1956.
6. You T min, Lee K-H, Lee S-H, Park W. Denosumab-related osteonecrosis of the jaw: a case report and management based on pharmacokinetics. Oral Surg Oral Med Oral Pathol Oral Radiol 2015;120:548-553.
7. Goodday RH. Preventive strategies for patients at risk of medica- tion-related osteonecrosis of the jaw. Oral Maxillofac Surg Clin North Am. 2015;27:527-536.
8. Stopeck AT, Lipton A, Body J-J, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients
with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132-5139.
9. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resis- tant prostate cancer: a randomised, double-blind study. Lancet.
2011;377:813-822.
10. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer.
2012;48:3082-3092.
11. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of deno- sumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14:901-908.
12. Bartsch R, Steger GG, Gnant M, Ziebermayr R. Breast Cancer: Rank Ligand Inhibition. Breast Care (Basel). 2010;5:320-325.
13. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metas- tases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125-1132.
14. Qi W-X, Tang L-N, He A-N, Yao Y, Shen Z. Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of
seven randomized controlled trials. Int J Clin Oncol. 2014;19:403- 410.
15. Campisi G, Fedele S, Fusco V, Pizzo G, Di Fede O, Bedogni A. Epi- demiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antire- sorptive agents. Future Oncol. 2014;10:257-275.
16. Khan A, Morrison A, Cheung A, Hashem W, Compston J.
Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015.
Osteoporos Int. 2016;27:853-859.
17. Turner B, Drudge-Coates L, Ali S, et al. Osteonecrosis of the jaw in patients receiving bone-targeted therapies: an overview-part I. Urol Nurs. 2016;36:111-116, 154.
How to cite this article: Egloff-Juras C, Gallois A, Salleron J, et al. Denosumab-related osteonecrosis of the jaw: A retrospective study. J Oral Pathol Med. 2018;47:66–70.
https://doi.org/10.1111/jop.12646
