Open Access
Original Article
Issue
J Oral Med Oral Surg
Volume 27, Number 3, 2021
Article Number 38
Number of page(s) 5
DOI https://doi.org/10.1051/mbcb/2021014
Published online 14 July 2021

© The authors, 2021

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

Denosumab is a human monoclonal antibody indicated in oncology and administered by subcutaneous injection at 120 mg every 4 weeks [1]. This drug prevents bone complications in adult patients with advanced malignancy with bone involvement, for patients with giant cell bone tumors unresectable or for which surgical resection is likely to cause severe morbidity [2]. It interferes in RANKL/RANK complex by playing osteoprotegerin role which conduce to inhibit osteoclastic activity and therefore to stop bone resorption [3]. It results in a limitation of tumor development [4].

However, patients undergoing this treatment are at significant risk of developing osteonecrosis of the jaw after dental extractions [57]. Indeed, it reduces bone remodeling via its anti-osteoclastic activity, but osteoclasts are also necessary for the socket's healing by remodeling the new bone matrix with a peak of activity at the 14th day after the dental extraction.

Osteonecrosis of the jaw is defined clinically by the AAOMS (American Association of Oral and Maxillofacial Surgeons) as the exposure of a necrotic bone and must fulfill several conditions [8]:

  • The patient must receive or have received a treatment which may induce osteonecrosis.

  • The bone must be exposed or accessible via a fistula for more than eight weeks.

  • The patient must not have received radiotherapy, nor have metastasis in the necrotic area.

Osteonecrosis in a patient treated with denosumab is called DRONJ (Denosumab Related Osteo Necrosis of the Jaw). The incidence of DRONJ in the context of cancer ranges between 0.5% and 2.1% after one year of treatment, 1.1% and 3% after two years, and between 1.3% and 3.2% after three years [9]. One of the main precipitating factors of such osteonecrosis of the jaw is dental extraction [10].

Adapting the tooth extraction protocol for these patients constitutes a significant means of preventing the occurrence of these lesions. This procedure has already been standardized by the SFSCMFCO (French Society of Stomatology, Maxillofacial Surgery and Oral Surgery) since 2013 and a drug holiday was proposed but without a specified duration [11,12]. It is important to note that the maximum serum concentration of denosumab is reached on the tenth day, and then decreases over 5 months with a half-life of 25.8 days [13]. Therefore, it seems coherent to consider a drug holiday given that this molecule has an elimination rate that is much faster than some bisphosphonates (10.5 years for alendronate) because it does not incorporate into bone [14,15]. The objective of this survey was firstly to identify whether practitioners use a drug holiday, and secondly, for those that did, how long they stopped this molecule for.

Method

A panel of healthcare professionals were asked to complete a questionnaire (Fig. 1). This one was disseminated online (Google Forms) through a scientific community (the French Society of Oral Surgery (SFCO)) and was made accessible for two months (12.06.2020‑12.08.2020).

thumbnail Fig. 1

Questionnaire: 8 questions on Google Form.

Results

33 healthcare professionals responded. Of the sample, 29 were dental surgeons (general practitioners, specialized in oral surgery or in oral medicine) and 4 were stomatologists (Fig. 2a). 8 worked only in private practices, 15 worked only in hospitals, and 10 work in both contexts (Fig. 2b).

Of the 33 people interviewed, 28 undertook dental extractions in patients on denosumab.

21 out of 28 used a drug holiday to perform it (Fig. 2c).

For those who stopped denosumab (21/28), 5 waited 1 month before performing dental extraction; 7 waited 2 months, 4 waited 3 months, 4 waited 4 months, and 1 waited 5 months (Fig. 2d). The median time interval was 2 months, and the average 2.47 months.

After the dental extraction, 1 waited 2 weeks before reintroducing the molecule; 4 waited 1 month, 8 waited 2 months, 6 waited 3 months, and 2 waited 4 months (Fig. 2e). The median time interval was 2 months, and the average 2.21 months.

25 out of 28 people questioned modified their surgical procedure for these patients (Fig. 2f). For example, 24 used prophylactic antibiotic treatment, 16 achieved hemostatic protocol (collagen sponge, suture), 6 hermetically closed the area using sutures (±/− with muco-periosteal flap) in order to have the least possible bone exposure, 5 disposed PRF (Platelet Rich Fibrin) (Fig. 3), and less than 8% applied other methods such as biological glue (2/28), anesthesia without adrenaline (2/28), or general anesthesia (1/28).

thumbnail Fig. 2

(a to f): Results: a. Profession; b. Practice; c. Do you stop denosumab before having a dental extraction?; d. How long do you wait between stopping denosumab and dental extraction?; e. How long do you wait between dental extraction and reintroducing denosumab?; f. Do you modify your surgical procedure during extraction in these patients?

thumbnail Fig. 3

Question 6: Protocol modifications.

Discussion

In regard to the surgical procedure, 90% of practitioners questioned modify their protocol. The French recommendations are above all for bisphosphonates [12]. It could be applied to denosumab, also an anti-osteoclastic molecule. They suggest reducing inflammation or local infection before surgery with periodontal care, daily mouthwashes with chlorhexidine 0.2%, and antibiotic prophylaxis and postoperative antibiotics [1618].

The surgical procedure needs to be as less traumatic as possible, with alveolar regularization and the closure of the wound without tension [18,19]. Depending on studies a full thickness flap can be used [1820]. Few data are available about anesthesia, only one study contraindicates the use of intra-ligament or intra-papillary anesthesia. No study excludes the use of vasoconstrictors.

In this survey, both prophylactic antibiotic treatment and hermetic closure of the area with sutures comply with the recommendations [12].

The practitioners questioned agreed that the molecule must be stopped when undertaking a dental extraction. Indeed, 75% of surgeons interviewed used a drug holiday. The waiting period before performing the dental avulsion was most commonly two months, more than twice the half-life of the molecule, and practitioners reintroduced the molecule on average 2 months after dental extractions. However, osteoclastic cells intervene in the first month of sockets healing with a peak of activity at the 14th day after extraction [21]. Denosumab only had an effect on these osteoclastic cells, so theoretically, this medication could be reintroduced one month after the extraction.

The oncological benefit of denosumab should not be forgotten. The drug holiday must be as short as possible to manage metastasis development and its symptomatology. During this break the follow-up is essential and tumor markers and tumor development must be monitored. The absence of necrosis of the jaw is obviously meaningless without the absence of tumor progression.

Concerning literature, the recommendations are blurry, especially concerning denosumab. In fact European and French recommendations (2009 and 2013) only talk about bisphosphonate; and the drug-holiday mentioned for this medication must be discussed with the prescribing doctor [12,22]. An international consensus from the International Task Force on ONJ suggested to withhold denosumab for oral surgery until the socket's healing but there is no evidence [10,23]. Finally, the American Dental Association Council on Scientific Affairs conclude that there is no sufficient proves to stop antiresorptive drug therapy before a dental extraction to prevent Antiresorptive Agent-Related Osteonecrosis of the Jaw (ARONJ) [24].

Thus, the shift between practices and recommendations is still high. Too little studies are available about these subject, and there are not enough proofs to recommend denosumab drug-holiday. However, this must be even more considered if denosumab time exposure is important because ONJ incidence increases overtime from 0.5% to 2.1% after one year, to 1.1% to 3% after 2 years, and 1.3% to 3.2% after 3 years [9]. The time-related evolution of the occurrence of ONJ showed the molecule impregnation, and a drug-holiday appear more evident. Practitioner's habits are based on subjective clinical experience. Further studies (including a prospective trial) are required to determine which time interval is required, while taking exposition duration and oncologic constraints into account.

Conclusion

In the literature, the recommendation for a dental extraction procedure is already known for patients on denosumab. However, despite this recommendation, zero risk does not exist. The question is: is it possible to reduce ONJ even further by withholding denosumab?

There is no answer in the literature, however, this survey has shown that in practice healthcare professionals do stop denosumab before performing dental extraction. The results show that the average drug holiday duration for denosumab is two months before and two months after the dental extraction. This drug-holiday must be discussed with the patient's oncologist while taking into account denosumab exposition duration and oncologic constraints.

Conflicts of interest

All authors state that they have no conflicts of interest.

Acknowledgements

The authors are grateful to the French Society of Oral Surgery (SFCO) for the distribution of the questionnaire to their members.

References

  1. Lewiecki EM. New and emerging concepts in the use of denosumab for the treatment of osteoporosis. Ther Adv Musculoskelet Dis 2018;10:209–23. [CrossRef] [PubMed] [Google Scholar]
  2. VIDAL − XGEVA 120 mg sol inj − Indications [Internet]. https://www.vidal.fr/Medicament/xgeva-108977-indications.htm (consulted 28 Aug 2020) [Google Scholar]
  3. Kostenuik PJ, Nguyen HQ, McCabe J, Warmington KS, Kurahara C, Sun N, et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (Murine/Human) RANKL*. J Bone Miner Res 2009;24:182–95. [CrossRef] [PubMed] [Google Scholar]
  4. HAS - Direction de l'Evaluation Médicale, Economique et de Santé Publique; Commission de la transparence, XGEVA, Avis 11 Avril 2012. [Internet]. https://www.amgen.fr/∼/media/amgen/full/www-amgen-com/www-amgen-fr/downloads/fr-pdf-022.ashx?la=fr-FR (consulted 28 Aug 2020) [Google Scholar]
  5. Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet Lond Engl 2011;377:813–22. [Google Scholar]
  6. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:1125–32. [CrossRef] [PubMed] [Google Scholar]
  7. Aljohani S, Gaudin R, Weiser J, Tröltzsch M, Ehrenfeld M, Kaeppler G, et al. Osteonecrosis of the jaw in patients treated with denosumab: a multicenter case series. J Cranio-Maxillofac Surg 2018;46:1515–25. [Google Scholar]
  8. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, 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;72:1938–56. [CrossRef] [PubMed] [Google Scholar]
  9. Limones A, Sáez-Alcaide Lm, Díaz-Parreño Sa, Helm A, Bornstein Mm, Molinero-Mourelle P. Medication-related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab VS. zoledronic acid: a systematic review and meta-analysis. Med Oral Patol Oral Cirugia Bucal 2020;e326–36. [Google Scholar]
  10. Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, Reid IR, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015;30:3–23. [CrossRef] [PubMed] [Google Scholar]
  11. Xgeva® 120 mg, solution injectable (denosumab) − Ajout d'une nouvelle contre-indication et remise d'une carte d'information patient − Lettre aux professionnels de santé − ANSM: Agence nationale de sécurité du médicament et des produits de santé [Internet]. https://ansm.sante.fr/S-informer/Informations-de-securite-Lettres-aux-professionnels-de-sante/Xgeva-R-120-mg-solution-injectable-denosumab-Ajout-d-une-nouvelle-contre-indication-et-remise-d-une-carte-d-information-patient-Lettre-aux-professionnels-de-sante (consulted 28 Aug 2020). [Google Scholar]
  12. Société Française de Stomatologie, Chirurgie Maxillo-Faciale et Chirurgie Orale. Ostéonécrose des mâchoires en chirurgie oromaxillofaciale et traitements médicamenteux à risque (antirésorbeurs osseux, antiangiogéniques), Recommandations de Bonne Pratique. July 2013. 49 p (consulted 28 Aug 2020). [Google Scholar]
  13. Chen Q, Hu C, Liu Y, Song R, Zhu W, Zhao H, et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose denosumab in healthy Chinese volunteers: a randomized, single-blind, placebo-controlled study. PLoS ONE 2018;22;13:1–13. [Google Scholar]
  14. Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK, McCloskey EV, et al. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 1997;1;12:1700–7. [CrossRef] [PubMed] [Google Scholar]
  15. Narayanan P. Denosumab: a comprehensive review. South Asian J Cancer 2013;2:272–7. [CrossRef] [PubMed] [Google Scholar]
  16. Montefusco V, Gay F, Spina F, Miceli R, Maniezzo M, Teresa Ambrosini M, et al. Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates. Leuk Lymphoma 2008;49:2156–62. [CrossRef] [PubMed] [Google Scholar]
  17. Lodi G, Sardella A, Salis A, Demarosi F, Tarozzi M, Carrassi A. Tooth extraction in patients taking intravenous bisphosphonates: a preventive protocol and case series. J Oral Maxillofac Surg 2010;68:107–10. [CrossRef] [PubMed] [Google Scholar]
  18. Schubert M, Klatte I, Linek W, Müller B, Döring K, Eckelt U, et al. The saxon bisphosphonate register − therapy and prevention of bisphosphonate-related osteonecrosis of the jaws. Oral Oncol 2012;48:349–54. [CrossRef] [PubMed] [Google Scholar]
  19. Heufelder M, Hendricks J, Remmerbach T. Principles of oral surgery for prevention of bisphosphonate-related osteonecrosis of the jaw. Oral Maxillofac Surg 2014;117:e429-35. [Google Scholar]
  20. Mozzati M, Arata V, Gallesio G. Tooth extraction in osteoporotic patients taking oral bisphosphonates. Osteoporos Int 2013:1707–12. [CrossRef] [PubMed] [Google Scholar]
  21. Vieira AE, Repeke CE, Ferreira Junior S de B, Colavite PM, Biguetti CC, Oliveira RC, et al. Intramembranous bone healing process subsequent to tooth extraction in mice: micro-computed tomography, histomorphometric and molecular characterization. PLoS ONE 2015;10:1-22. [Google Scholar]
  22. Terpos E, Sezer O, Croucher PI, García-Sanz R, Boccadoro M, San Miguel J, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 2009;20:1303–17. [CrossRef] [PubMed] [Google Scholar]
  23. Khan AA. Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the international task force on ONJ. J Clin Densitom 2017;20:8–24. [CrossRef] [PubMed] [Google Scholar]
  24. Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar JR, Koka S, et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis. J Am Dent Assoc 2011;142:1243–51. [CrossRef] [PubMed] [Google Scholar]

All Figures

thumbnail Fig. 1

Questionnaire: 8 questions on Google Form.

In the text
thumbnail Fig. 2

(a to f): Results: a. Profession; b. Practice; c. Do you stop denosumab before having a dental extraction?; d. How long do you wait between stopping denosumab and dental extraction?; e. How long do you wait between dental extraction and reintroducing denosumab?; f. Do you modify your surgical procedure during extraction in these patients?

In the text
thumbnail Fig. 3

Question 6: Protocol modifications.

In the text

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