Clin Oral Invest DOI 10.1007/s00784-016-1762-y

ORIGINAL ARTICLE

Primary wound closure after tooth extraction for prevention of medication-related osteonecrosis of the jaw in patients under denosumab Akihiko Matsumoto 1 & Masanori Sasaki 1 & Rainer Schmelzeisen 2 & Yukiko Oyama 1 & Yoshihide Mori 1 & Pit Jacob Voss 2

Received: 3 December 2015 / Accepted: 19 February 2016 # Springer-Verlag Berlin Heidelberg 2016

Abstract Objectives Some recent reports have indicated that local infection causes osteonecrosis of the jaw and described that tooth extraction may not be a direct cause of developing medication-related osteonecrosis of the jaw (MRONJ) in patients receiving antiresorptive medications. Tooth extraction and elimination of the source of infection are expected to reduce the risk of developing MRONJ. However, there is no data regarding prevention for developing osteonecrosis of the jaw in patients receiving denosumab. Therefore, the aim of this study was to investigate the outcome of tooth extractions with proper wound closure in patients receiving denosumab. Patients and methods Forty teeth in 19 patients treated with denosumab therapy were extracted under preoperative intravenous antibiotics. Patients who had already developed MRONJ in the extraction sites or who had a history of radiation therapy were excluded. During surgery, bone edges were smoothed and all wounds were closed using the doublelayered technique. Results Thirty-seven extraction sites (92.5 %) in 17 out of 19 patients (89.5 %) were healed. However, three extraction sites in two patients had complications; one patient had exposed bone and developed MRONJ (stage 1) and the other developed a mucosa fistula. Additional surgical procedures were performed and all wounds were completely healed. * Akihiko Matsumoto [email protected]

1

Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

2

Department of Oral and Maxillofacial Surgery, University Hospital Freiburg, Hugstetter St. 55, 79106 Freiburg im Breisgau, Germany

Conclusions Tooth extractions in patients receiving denosumab can be performed in an appropriate manner and result in good outcomes. Clinical relevance This study indicated that tooth extraction with proper wound closure to avoid secondary infection may be effective for the prevention of MRONJ even in high-risk patients. Keywords Osteonecrosis of the jaw . Tooth extraction . Denosumab . Prevention . MRONJ

Introduction Denosumab is a human monoclonal antibody to the receptor activator of nuclear factor-κβ ligand (RANKL). It targets RANKL and inhibits the binding of RANKL to RANK; subsequently, the differentiation and activity of osteoclast is decreased [1]. Denosumab has a high affinity to human RANKL and inhibits the activation and function of mature osteoclasts [2]. Denosumab is effective in decreasing skeletal-related events (SREs) in patients suffering from metastatic bone disease, and it is frequently used as a new medication of antiresorptive therapy [1, 3, 4]. In clinical trials, denosumab has shown excellent clinical results in comparison with bisphosphonates (BPs) for cancer and osteoporosis patients, with a greater increase in the bone mineral density and suppression of bone turnover markers [5–7]. Denosumab does not accumulate in the bone and is cleared by the reticuloendothelial system. The circulatory half-life of denosumab is approximately 26 days, and denosumab does not require dose reduction in cases of renal dysfunction [8]. Denosumab appears to be a safer treatment than BPs for patients with impaired renal function [9]. Denosumab has the potential to prevail as a new

Clin Oral Invest

antiresorptive medication and the number of patients receiving denosumab therapy would thus increase. However, many oral dentists have been plagued by a problem related to antiresorptive medications. Since the first report in 2003 [10], a large number of BP-related osteonecrosis of the jaw have been reported with an increasing frequency [11]. Recently, several cases of osteonecrosis of the jaw in patients receiving other antiresorptive medicines have been reported, and the first case of denosumab-related osteonecrosis of the jaw was recently reported [12]. In 2014, the American Associated Oral and Maxillofacial Surgery (AAOMS) reported a position paper of medication-related osteonecrosis of the jaw (MRONJ) [4]. MRONJ is a serious side effect in patients receiving antiresorptive medication, especially intravenous bisphosphonate (IVBP) for the treatment of cancer-related bone disorders, such as breast cancer and multiple myeloma [4]. The greater the widespread use of BP medications worldwide, the greater the occurrence of MRONJ [11]. Patients receiving IVBP are at a high risk of developing MRONJ. The incidence of osteonecrosis of the jaw was reportedly 1 to 2 % in patients treated with IVBP and 0.1 to 0.21 % in those treated with oral BP [4]. The number of patients receiving denosumab has recently increased, and the incidence of MRONJ was reportedly 1.8 % in the combined analysis of three phase III trials in patients with metastatic bone disease receiving denosumab therapies [13]. Thus, it is crucial to discuss how to treat patients with denosumab, especially in order to prevent MRONJ [8, 9]. To date, some facilities have published several protocols for MRONJ [4, 14–16], and previous studies have attempted to clarify both the systemic and local risk factors of MRONJ. In solid cancer patients, such as breast cancer and prostate cancer, or in patients with multiple myeloma, the risk of MRONJ is higher than in patients with osteoporosis. Furthermore, patients who suffered from diabetes mellitus, anemia or received corticosteroids therapy are at a high risk of MRONJ [13, 17, 18]. Antiresorptive medication, duration of medication, route of medication, and dentoalveolar surgery are local risk factors of MRONJ. Dentoalveolar surgery, particularly tooth extraction, is considered to be a major risk factor for developing MRONJ. Indeed, several reports have indicated that tooth extraction is a common predisposing event in 52 to 62 % of patients with MRONJ [13, 19, 20]. It has been considered that dentoalveolar surgery, especially tooth extraction, is associated with the development of MRONJ. However, some authors have reported that tooth extraction in patients receiving BP was not associated with developing MRONJ [21–23]; thus, compromised tooth extraction, and subsequent elimination of the source of infection, has gained attention as a prevention strategy for developing MRONJ. It is important to reduce the incidence of MRONJ because the use of denosumab is expected to increase in the near future. However, there has been no clinical evidence to show the effectiveness of tooth extraction in patients receiving

denosumab. Therefore, it is beneficial to discuss the proper method of tooth extraction in order to reduce the rate of developing MRONJ. The aim of this present study was to examine the appropriate tooth extraction method to reduce the risk of developing MRONJ and to investigate the association between tooth extraction with secure wound closure and the development of MRONJ.

Material and methods A total of 40 teeth in 19 patients with denosumab therapy were included in this study. The teeth were extracted between April 2012 and April 2015 according to the guideline of the German Society of Oral and Maxillofacial Surgery [24] in the Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Germany. Informed consent was obtained from all individual participants included in this study. Patients who had already developed MRONJ in the extraction sites or who had a history of radiation therapy were excluded. Additionally, patients who received BP before the treatment with denosumab were excluded. Regarding the discontinuation of the drug, no drug holiday was taken into consideration. All patients received intravenous antibiotics (Penicillin 10, 000,000 IU once daily or Clindamycin 600 mg three times daily in case of penicillin allergy) for 1 day before and 1 day after the extraction. During surgery, the teeth were extracted at first and all extraction sites were closed with double-layered technique (Fig. 1). On the double-layered technique, the bone edges were smoothed and the mucoperiosteal flaps were prepared with a relieving incision and sutured with the other side of periosteal. Moreover, running sutures were taken at the alveolar crest. Appropriate primary wound closure could be obtained in the extraction site. Postsurgery, patients were followed up constantly and were instructed to have a soft food diet and not to wear dentures during the healing time. The sutures were removed at 2–3 weeks after extraction. The outcome of tooth extraction was evaluated with the clinical wound condition, and complete mucosal coverage in the extraction site without any signs of a fistula or exposed bone was defined to be a success. All patients were followed up every month at least for 3 months, in case of uneventful healing. The data were retrospectively collected from the patient records and surgical documents. Regarding the underlying disease, the medications, extraction site, and other risk factors, such as diabetes mellitus, rheumatoid arthritis, steroid therapy, and smoking, were investigated.

Results Nineteen patients (6 males and 13 females) receiving denosumab therapy were included in this study. The mean

Clin Oral Invest

Fig. 1 Flowchart of tooth extraction and the double-layered technique. a Tooth extraction was performed under local anesthesia. b After tooth extraction, all bony edges around the extraction site were strictly smoothened by use of a round bur (white down-pointing triangle). c

The mucoperiosteal flaps were prepared with a relieving incision to ensure tension-free wound closure (black down-pointing triangle). d All wounds were closed using the double-layered technique

age was 69.3 years (range 42–85). The underlying diseases included breast cancer (n = 7, 36.8 %), prostate cancer (n = 7, 36.8 %), and osteoporosis (n = 5, 26.3 %) (Table 1). A total of 40 (21 upper and 19 lower) teeth were extracted in this study. The extraction site was anterior (n = 15, 37.5 %), premolar (n = 12, 30 %), molar (n = 11, 27.5 %), and wisdom teeth (n = 2, 5 %) (Fig. 2). The healing processes were uneventful without any fistula or infection in 17 out of 19 patients (89.5 %). Three extraction sites (1 upper site, 2 lower sites) in two patients had complications after tooth extraction: one fistula and one exposed bone (Table 2). The patient who had an exposed bone suffered from prostate cancer during 10 months of denosumab therapy. The exposed bone remained for longer than 8 weeks without any noticeable healing; accordingly, the patient developed MRONJ (stage 1). Both patients who had complications after tooth extraction were given additional surgical treatments. Finally, both patients with complications obtained complete healing in all extraction sites and have not demonstrated recurrence thus far. One particular case was a 71-year-old female suffering from breast cancer with 24 months of denosumab therapy. The patient had a left upper molar extracted and a fistula occurred in the extraction site 3 months later. Conventional conservative treatment had no effect on complete mucosal healing. The patient underwent marginal bone resection as an additional surgical procedure, and the wound was again closed with the double-layered technique. After the additional surgical procedure, the wound obtained complete mucosal coverage and showed a successful outcome (Fig. 3).

procedures could be effective for the prevention of MRONJ even in high-risk patients. In those reports, tooth extraction and dentoalveolar surgical procedures aimed at treating and curing local infections could lead to a reduced risk of MRONJ, and these reports indicated that tooth extraction was not a potential trigger of MRONJ but rather a potential prevention strategy [21, 23]. Additionally, there have been some reports of tooth extraction in patients taking IVBP to reduce the risk of MRONJ [28, 29]. Although the proper method of tooth extraction has a potential to prevent MRONJ, there has been no evidence data of tooth extraction in patients with denosumab. Therefore, the aim of this study was to evaluate the prognosis of tooth extraction with secure wound closure in patients receiving denosumab therapy and investigate the association between compromised tooth extraction and developing MRONJ. According to previous results, the incidence of MRONJ after tooth extraction in patients with cancer exposed to IVBP ranges from 1.6 to 14.8 % [29–31]. In this study, although tooth extractions were performed in patients receiving denosumab, some ingenious attempts were added during surgery. The bone edges were smoothed and the mucoperiosteal flaps were prepared with a relieving incision to ensure tensionfree wound closure. The wounds were closed with the doublelayered technique. The incidence of developing MRONJ was only 1 (5.3 %) in 19 patients. We previously investigated the outcomes of tooth extraction in a similar manner for patients receiving BP; as a result, no occurrence of MRONJ was observed in 66 patients. Compared with the results of these studies, the present study indicated a higher incidence rate of developing MRONJ in patients with denosumab than BP; thus, further clinical data of tooth extraction in patients treated with denosumab are needed. In the present study, two patients had some complications after tooth extraction. It is important to discuss the cause of these complications. The avoidance of surgical intervention was recommended due to its risk of expanding MRONJ; however, some authors have recently indicated that prevailing infection causes MRONJ. Saia et al. showed that some cases already developed osteomyelitic or osteonecrotic changes at the tooth extraction site before extraction. Moreover, removing the

Discussion Regarding the prevention of MRONJ, some guidelines recommend early screening and appropriate dental treatment before initiating antiresorptive therapy; indeed, patients receiving appropriate dental care and who maintain optimal oral health are at a low risk of developing MRONJ [25–27]. However, there are no specific procedures for patients who have already received antiresorptive therapy. According to some reports that had been published recently, tooth extraction and surgical

Clin Oral Invest Table 1

The characteristics of the patients who underwent tooth extraction

Total Sex

Age (y)

Male Female Sex ratio 19

6

13

Underlying disease

Mean Range Breast cancer

1:2.2 69.3

Prostate cancer

Osteoporosis Diabetes mellitus

42–85 7 (36.8 %) 7 (36.8 %) 5 (26.3 %)

infectious and suspicious lesions at the extraction site in patients with BP could confirm complete mucosal healing [32]. Otto et al. suggested that local infection changed the pH in the lesion and differential pH played an important role in the pathogenesis of osteonecrosis of the jaw. In vitro, nitrogencontaining BP had a much stronger cytotoxic effect in acid milieus compared to non-nitrogen-containing BP. In addition, BP release from osteocytes was incorporated into osteoclasts so that the function was inhibited under lower pH conditions [33]. Additionally, inflammation or bacterial infection and systemic antiresorptive drugs are sufficient to induce MRONJ [34–36]. Yamazaki et al. described that periodontal disease caused by oral bacteria leads to alveolar bone loss, which is associated with an increased risk of MRONJ [31]. In this study, patients who had already developed MRONJ before tooth extraction were excluded, and teeth diagnosed with periapical periodontitis, marginal periodontitis, residual root, and fracture root were ascribed to the infection source. Therefore, those teeth were extracted. It is still unknown whether tooth extraction or the infection is the trigger for the development of MRONJ; however, we made significant efforts to remove the infectious lesion so that granulation tissues in the sockets were curetted away as much as possible. All wounds were closed using the double-layered technique. Some authors have described that coverage with vascularized tissue can improve healing after the surgical procedures [37, 38]. Voss et al. reported the effectiveness of surgical approach for MRONJ and indicated that appropriate mucosal coverage after removing the necrotic lesion played an important role in preventing the reoccurrence of MRONJ [39]. Fig. 2 The number of extracted teeth in several sites

Risk factor

0 (0 %)

Rheumatoid arthritis

Steroid therapy Smoking

0 (0 %)

0 (0 %)

2 (10.5 %)

Owing to the double-layered technique, the wound could obtain thickened tissue, which thus prevents the occurrence of dehiscence to the alveolar bone, covering the extraction sites. The sharp bone edges in the surgical region have the risk of secondary perforation, which is supported by the finding that many MRONJ cases developed in the thin mucosal lesion [40, 41]. Heufelder et al. described the preventive treatment to be of critical importance; thus, all sharp bone edges in the region of surgery should be smoothened to minimize the risk of secondary perforation [21]. The thin oral mucosa on the sharp bone edge is easy to injure by traumatic irritation. Sharp bone edges should be removed adequately after tooth extraction; additionally, patients should be cautious to prevent traumatic mucosal perforation by dentures, food, or tongue pressure during healing treatment. In this study, all sharp bone edges were removed as much as possible and all extraction sites were closed with doublelayered technique. However, one patient occurred MRONJ in the anterior region of the lower jaw in this study, which corresponded to the findings of previous reports that MRONJ tended to develop in the lower jaw [13]. On this case, not enough bone smoothing caused dehiscence in the thin mucosa and developed MRONJ. Another one patient had a fistula after tooth extraction. This patient was previously treated with gingivectomy to eliminate the fistula; however, the fistula appeared again 1 month later. An antiseptic rinse was prescribed for 6 months; but it was not effective for a complete cure. Marginal bone resection was performed as an additional procedure at 10 months, and the marginal bone was pathologically diagnosed as necrotic bone. This case did not have any

Clin Oral Invest The characteristics of patients with complications after tooth extraction

Table 2 Case

Sex

Age

Underlying disease

Duration (M)

Site

Risk factor

Complication

Additional procedure

1

M

76

Prostate cancer

10

21┐

Smoking

Exposed bone

Necrosectomy + wound closure

2

F

71

Breast cancer

24

└6

−

Fistula

Marginal bone resection + wound closure

exposed bone in the extraction site. Thus, we speculated that the necrotic lesion expanded under the mucosa due to a second infection from the fistula. This case suggested that inappropriate wound closure could be an inflectional pathway and lead to the risk of expanding MRONJ. Moreover, two cases with complications in this study could not obtain primary closure and remained in the inflectional pathway, intraoral to dentoalveolar bone. These cases have the potential to develop MRONJ under the mucosa without exposed bone. Marginal bone resection as an additional surgical procedure contributes to the prevention of recurrent MRONJ due to the removal of the affected bone lesion. However, it is difficult to distinguish affected bone from normal bone. Pautke et al. and Otto et al. described a successful treatment modality, fluorescence-guided bone resection in MRONJ, which is expected to gain widespread use as an objective method to define the extent of resection. In this study, the affected bone was removed using a bar until healthy, bleeding bone was present. All cases could eventually obtain

complete mucosal coverage after additional procedures by means of the wound closure technique described above, and there has been no occurrence of MRONJ thus far. These results indicated that marginal bone resection with primary wound closure could prevent the development of MRONJ, even if some complications occur after tooth extraction. With regard to the discontinuation of antiresorptive therapy, some authors have discussed that there was no benefit of taking a drug holiday to prevent MRONJ because BPs have a low circulation; thus, BPs has a very strong affinity for hydroxyapatite crystals and long-term antiresorptive effects persist [23, 42]. Moreover, there is no evidential report to indicate the efficacy of denosumab discontinuation in reducing the risk of MRONJ. Although Otto et al. stated that a drug holiday should be taken before a surgical procedure [43], the effectiveness of denosumab discontinuation must be clarified in further research. In this study, the discontinuation of medications was not taken into consideration for all patients. However, two patients receiving denosumab had complications and one of

Fig. 3 Perioperative and postoperative presentations in cases requiring additional surgical procedures. a Following elevation of the mucoperiosteal flaps in the fistula lesion. Granulation tissues in the sockets and gray-colored bone were observed. b Bleeding on the surface of the bone after marginal bone resection and curetting granulation tissue. c After confirming mobilization of the periosteal

flap, first layer suturing was performed. d Due to the running suture, secure wound closure was achieved in the lesion. e No infection signs were observed at 3 weeks after the additional surgical procedure. f Complete mucosal coverage at 2 months after the additional surgical procedure

Clin Oral Invest

them developed MRONJ. This study suggests that further studies are needed to clarify the necessity of denosumab discontinuation. The development of MRONJ involves many risk factors, especially in patients suffering from solid cancer who are at a high risk of MRONJ [44, 45]. In this study, two patients who had complications suffered from breast cancer and prostate cancer. MRONJ developed in the patient who suffered from prostate cancer and had a smoking habit. Most patients receiving antiresorptive therapy concomitantly receive other various therapeutic agents such as corticosteroids [46]. No patient was taking corticosteroids therapy in this study; however, further investigation of risk factors which may influence the prognosis of tooth extraction is necessary. It has been considered that surgical intervention, particularly tooth extraction, could be a crucial risk factor for developing MRONJ. However, the definitive result of this study indicated the effectiveness of tooth extraction with the proper method to prevent MRONJ. In order to provide sufficient evidence, further prospective clinical studies are needed.

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Conclusions Antiresorptive medications are undeniably necessary to prevent SREs in patients suffering from bone consuming diseases. A growing demand, especially denosumab therapy as an alternative medication of BPs, of antiresorptive medications is expected in the elderly society. However, MRONJ is a serious side effect of antiresorptive medications, which significantly impairs the patient’s quality of life. Nevertheless, it is not an established prevention strategy for MRONJ. Therefore, it is necessary to discuss the proper method of extraction for preventing MRONJ. The present study demonstrated that compromised teeth were uneventfully extracted in patients receiving denosumab, and MRONJ did not always occur after tooth extraction. Complete smoothing of the bone edges and secure wound closure in the extraction site are most likely to contribute to the successful results. This study supported the theory that the proper method of tooth extraction is effective for preventing MRONJ.

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Compliance with ethical standards Conflict of interest The authors declare that they have no competing interests.

14.

Funding This study was not funded. 15. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent This type of study formal consent is not required.

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