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Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: A trigger for BRONJ development?
Journal of Cranio-Maxillo-Facial Surgery 43 (2015) 847e854
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Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: A trigger for BRONJ development? € ltzsch a, Vesna Jambrovic a, Sappasith Panya a, Florian Probst a, Sven Otto a, *, Matthias Tro Oliver Ristow b, c, Michael Ehrenfeld a, Christoph Pautke a, c a b c
Department of Oral and Maxillofacial Surgery (Head: Prof. Dr. Dr. M. Ehrenfeld, MD, DDS), Ludwig-Maximilians-University, Munich, Germany Department of Oral and Maxillofacial Surgery, Ruprecht-Karls-University, Heidelberg, Germany Medizin & Aesthetik, Clinic for Oral and Maxillofacial Surgery, Lenbachplatz 2a, D-80333 Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 14 January 2015 Accepted 30 March 2015 Available online 10 April 2015
Introduction: Scientific debate outlines tooth extraction as a potential trigger for the onset of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Therefore, the aim of this study was to investigate the outcome of tooth extractions in patients receiving bisphosphonate therapy. Patients and methods: A retrospective cohort study was performed on patients with a history of oral or intravenous bisphosphonate administration and tooth extraction between 2007 and 2013 in a single university hospital oral and maxillofacial surgical unit. In all patients, extractions were performed according to the guidelines of the German Society of Oral and Maxillofacial Surgery. The outcome variable was the onset of typical BRONJ signs during postoperative follow-up. Results: In 72 subjects (53 female, 19 male; mean age 67.5 years) receiving oral (n ¼ 27) and/or intravenous (n ¼ 45) bisphosphonates due to malignant tumor (n ¼ 43) or osteoporosis (n ¼ 29), 216 tooth extractions were performed. The mean duration of intake was 36.2 months. In 67 out of 72 patients (93.1%) and 209 out of the 216 extraction sites the postoperative course was uneventful and the wounds healed without complications. Three of the 72 patients (4.2%) developed osteonecrosis of the jaw in four of the 216 extraction sites (1.9%). Duration and route of administration, oral hygiene and steroid intake were identified as potential risk factors for the development of BRONJ. Conclusion: Tooth extraction in patients receiving bisphosphonates can be performed in a safe and predictable way, even in high-risk patients, when performed according to established guidelines. It is not tooth extractions themselves, but rather prevailing infectious conditions that may be a key risk factor for the development of BRONJ. © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Keywords: Bisphosphonates Bisphosphonate-related osteonecrosis of the jaw, BRONJ Medication-related osteonecrosis of the jaw, MRONJ Prophylaxis Risk factors Tooth extractions
1. Introduction Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side-effect in patients with intravenous administration of nitrogen-containing bisphosphonates used for the treatment of bone-involving malignant diseases, especially breast cancer, multiple myeloma and prostate cancer (Abu-Id et al., 2008, Bamias et al., 2005, Otto et al., 2012). Less frequently BRONJ has been reported in osteoporotic patients receiving oral or intravenous
* Corresponding author. Department of Oral- and Maxillofacial Surgery, LudwigMaximilians-University, Lindwurmstraße 2a, München, 80337, Germany. Tel.: þ49 89 51602995; fax: þ49 89 51604746. E-mail addresses: [email protected], [email protected] (S. Otto).
administration of nitrogen-containing bisphosphonates (Otto et al., 2011a,b, Yarom et al., 2007, Otto, 2015). However, the majority of cases described in the literature occurred after preceding, so called, trigger events, which were mainly tooth extractions (Abu-Id et al., 2008, Groetz et al., 2012, Otto et al., 2012, Ruggiero et al., 2009, 2014). Therefore, dental practitioners, as well as oral and maxillofacial surgeons, feel in a precarious position when choosing appropriate treatment protocols which aim to avoid BRONJ after tooth extractions and other dentoalveolar surgical procedures. The majority of recommendations are intended to control local infection, while applying perioperative antibiotic prophylaxis and plastic wound closure (Groetz et al., 2012, Ruggiero et al., 2009 and 2014). However, data is sparse with regard to the treatment outcome of patients who were treated according to these recommendations (Heufelder et al., 2014, Otto, 2015).
http://dx.doi.org/10.1016/j.jcms.2015.03.039 1010-5182/© 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
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Therefore, the aim of this study was to investigate the clinical course after tooth extraction in patients under bisphosphonate therapy and to judge whether tooth extractions can be performed in a safe and predictable manner when following treatment recommendations. 2. Material and methods Between 2007 and 2013, 72 consecutive patients with a history of bisphosphonate treatment have undergone tooth extractions. They were identified and included in our retrospective monocentric clinical observation (Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians University, Munich, Germany). Inclusion criteria were: osteoporosis and/or malignant tumors with ongoing or previous history of oral and/or intravenous bisphosphonate treatment with necessary tooth extractions or surgical tooth removal. Exclusion criteria were history of irradiation to the head and neck area, obvious metastatic infiltration of the jawbone, and bone exposure or a previous history of BRONJ in the area of the extraction (same quadrant). The study was approved by the local ethical committee (UE Nr. 092-14). In the present study the authors and surgeons performed extractions and surgical tooth extractions according to the protocol published by the German Board of Oral and Maxillofacial Surgeons, which states that tooth extractions in patients receiving bisphosphonates should be performed (i) under prolonged perioperative antibiotic prophylaxis, (ii) in an atraumatic manner, and succeeded by (iii) smoothening of sharp bony edges, as well as (iv) thorough mucosal wound closure (Groetz et al., 2012). All patients underwent a close, center-specific follow-up. Onset of BRONJ served as the major outcome variable. BRONJ was diagnosed according to the Task Force on BRONJ, as defined by the American Association of Oral and Maxillofacial Surgeons (Ruggiero et al., 2014 and 2009). The staging of the disease was made according to the recommendations of the AAOMS 2009 (Ruggiero et al., 2009) which was in line with AAOMS 2014 for the respective cases (Ruggiero et al., 2014): Stage I: exposed necrotic bone without pain or signs of infection (asymptomatic); Stage II: exposed necrotic bone with pain and or signs of infection (symptomatic); Stage III: exposed necrotic bone with pain and or signs of infection and one or more of the following: pathological fracture, oral-cutaneous fistula, involvement of the maxillary sinus or necrosis extending to the inferior border or ramus of the mandible; Stage 0: absence of bone exposure but presence of typical clinical, radiological or histological signs of ONJ. The data collection was performed retrospectively. The patient records, including a standardized questionnaire for the patient and the general practitioner with regard to the underlying diseases and the bisphosphonate intake as well as potential risk factors (smoking, diabetes, steroid intake, etc.), which was routinely used in the studied cohort, were analysed. The respective surgeon documented data concerning the surgical procedures. The patients were followed up on a regular basis and complaints and wound healing disturbances were documented. Descriptive statistics were computed using SPSS version 16. Results are expressed as a percentage or as mean values including standard error of the mean and range. Means were compared by statistical testing (Student's t-test), where p < 0.05 was considered to be significant.
Fig. 1. Illustration of underlying diseases of patients who presented or were referred for tooth extraction and had received, or were still receiving, bisphosphonate treatment.
3. Results 3.1. Baseline characteristics 72 patients (53 female and 19 male) with a mean age of 67.5 years (SD 10.7) were included in the study. Forty-three of the patients (59.7%) suffered from malignant diseases (especially breast cancer, multiple myeloma and prostate cancer) and 29 patients (40.3%) suffered from osteoporosis as the underlying disease (see Fig. 1). The route of bisphosphonate administration was oral in 27 patients (37.5%) and intravenous (or combined) in 45 patients (62.5%). The mean duration of bisphosphonate intake was 36.2 months (SD 28.6). There was no significant difference of the duration of intake with regard to the route of administration (see Fig. 2). A total of 216 teeth (119 in the maxilla and 97 in the mandible) were extracted in 91 operations. The mean follow-up time was 14.9 months (SD: 15.0; range 1e65). 3.2. Results of mucosal integrity The postoperative course was uneventful and complete mucosal healing was achieved in 67 out of the 72 patients (93.1%), and 209 out of the 216 extraction sites (96.8%). A typical
Fig. 2. Comparison of the duration of bisphosphonate intake between the subgroups of patients who were treated with oral and intravenous routes of administration.
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Fig. 3. (a) Preoperative intraoral view of a 68-year-old female patient with breast cancer after intravenous administration of nitrogen-containing bisphosphonates (zoledronate 4 mg every 4 weeks over 4 years); root remnants of teeth 31 and 32. It is noteworthy that this patient suffered from BRONJ in her right upper jaw which was successfully treated previously. (b) Postoperative intraoral view showing complete mucosal healing after tooth extraction, smoothening of sharp bony edges and plastic wound closure (18 months postoperatively).
example is given in Fig. 3a and b. In general there was a tendency towards delayed wound healing of the soft tissues, and the remodeling process of the extraction alveoli seemed to be slowed down even when a radiological control (panoramic radiograph) was performed months or even years after the operation (see Fig. 4aed). The vast majority of patients tolerated the surgery well, did not develop wound healing disturbances or bone
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exposure at any time, and were free of complaints at the time of the last check-up. Five patients developed wound healing disturbances. Three of the 72 patients (4.2%) developed BRONJ lesions (according to stage I AAOMS 2009 and 2014) in four of the 216 extraction sites (1.9%) (see Fig. 5). One patient developed bone exposure within the first weeks after surgery at two extraction sites which were treated successfully with local disinfective measures, including local disinfective rinses, activated photodynamic therapy (Helbo, bredent medical, Germany), and prolonged antibiotic treatment which finally resulted in complete mucosal healing (see Fig. 6). Another patient who had multiple extractions from the upper and lower jaw showed complete mucosal healing at the extraction sites but later developed ONJ in the right mandible (away from the extraction sites) due to a pressure sore caused by rubbing from a prosthesis (see Fig. 7). In 29 patients, bone samples were taken during surgery due to clinically suspicious lesions, these were evaluated histologically. In 20 of the 29 patients (69%) there were histological hints of osteomyelitis and partly or completely devitalized bone areas. Interestingly, all of these patients showed complete mucosal healing after removal of the suspicious areas and smoothening of sharp bony edges and plastic wound closure accompanied by antibiotics (mainly amoxicillin/clavulanic acid 875/125 mg orally twice per day; in case of allergy: clindamycin 600 mg 1-1-1 orally). 3.3. Evaluation of potential risk factors (patients) There was a tendency to a longer duration of bisphosphonate intake in the patient cohort who subsequently developed wound healing disturbances (Mean: 47 months; SD 38) when compared with the cohort who showed complete and uneventful healing, even though statistical significance was not reached (p ¼ 0.38). In the patient cohort who developed wound healing disturbances or ONJ, a malignant underlying disease (80%) and intravenous route of administration was more frequent (80% iv 20% oral) when compared with the cohort with uneventful healing (55.2% iv and 38.8% oral and 6% combined; malignant underlying disease 58.2% and osteoporosis 41.8%) but the difference was not statistically significant (underlying disease: p ¼ 0.64; route of administration: p ¼ 0.46). There was also a tendency to moderate or poor oral hygiene in the patient cohort with wound healing disturbances or ONJ (p ¼ 0.065) even though statistical significance was not reached. There was no statistically significant difference with regard to sex (p ¼ 0.60) and age at time of surgery (p ¼ 0.47). An overview is given in Table 1. 3.4. Evaluation of potential risk factors (extraction sites)
Fig. 4. aed: Radiological examinations of a 70-year-old male patient suffering from multiple myeloma who was treated with intravenous administrations of nitrogencontaining bisphosphonates for 7 years and was referred for extraction of teeth 17, 12, 21, 25, 26 and 34. (a) Preoperative panoramic radiograph; (bed) illustrate the delayed remodeling of the extraction socket of tooth 34; (b) detail of postoperative panoramic radiograph; (c) detail of panoramic radiograph 6 months after surgery; (d) detail of panoramic radiograph 15 months after surgery.
When evaluating each extraction site the duration of bisphosphonate intake was significantly longer within the group of extraction sites which developed a wound healing disturbance or necrosis (p ¼ 0.02), (subgroup with wound healing disturbance/ ONJ: 69.9 months; SD 29.4; versus 34.3 months; SD 29.1, in the subgroup with no wound healing disturbance). Steroid intake and poor oral hygiene was more common in the sub-cohort which developed a wound healing disturbance or ONJ (steroids p ¼ 0.045; oral hygiene: p ¼ 0.025). A malignant underlying disease and an intravenous route of bisphosphonate administration was more common within the subgroup which developed wound healing disturbances and ONJ (malignant underlying disease and intravenous route of administration: 85.7%) when compared with the extraction sites with uneventful healing (malignant underlying disease 60.3%; intravenous administration: 52.2%). However, these differences did not
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Fig. 5. A 59-year-old male patient suffering from multiple myeloma treated with intravenous administrations of nitrogen-containing bisphosphonates (zoledronate 4 mg every 4 weeks) who was referred for removal of tooth 17 which was performed under antibiotic prophylaxis with plastic wound closure. After initially uneventful healing the patient presented with exposed necrotic bone in region 17 and was diagnosed with BRONJ stage 1 according to AAOMS: (a) 6 months after extraction. After diagnosis the patient was treated surgically, including removal of necrotic bone, smoothening of sharp bony edges and plastic wound closure accompanied by antibiotic treatment (amoxicillin/clavulanic acid) which resulted in complete mucosal healing: (b) 3 months after surgery. (cee) Illustrates the corresponding panoramic radiographs: (c) pre extraction; (d) post extraction; and (e) after surgical removal of sharp bony edges.
Fig. 6. (a) A 70-year-old male patient suffering from multiple myeloma (the same patient as in Fig. 4), who was treated with intravenous administrations of nitrogen-containing bisphosphonates (zoledronate 4 mg every 4 weeks) and developed a wound healing disturbance with wound dehiscence and bone exposure 3 weeks after extraction of tooth 34 (b). The patient was then treated with local disinfective measures, including activated photodynamic therapy using the Helbo-system (bredent medical, Germany) (c) leading to complete mucosal healing 2 months after surgery (d).
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Fig. 7. A 60-year-old female patient suffering from adenocarcinoma of the lung treated with intravenous administrations of nitrogen-containing bisphosphonates (zoledronate 4 mg every 4 weeks) who was referred for multiple extractions in the upper and lower jaw; (a) preoperative intraoral view and corresponding panoramic radiograph (d). The extractions were performed including antibiotic prophylaxis, smoothening of sharp bony edges and plastic wound closure. The postoperative course was uneventful and resulted in complete mucosal healing; (b) intraoral view 18 months after extractions. Later the patient developed a BRONJ lesion (according to stage 1 AAOMS 2009 and 2014) which was caused by a pressure sore from her mandibular prosthesis more than 2 years after the extractions (c). The corresponding panoramic radiograph is shown (e).
Table 1 Evaluation of potential risk factors for wound healing disturbances after extractions in patients receiving bisphosphonates (n ¼ number of patients).
Current age (yaears) BP duration (months) Gender (m; f) Route of administration (iv; oral; combined) Underlying desease (osteoporosis; CA) Localization (UJ; LJ; UJ þ LJ) Chemo (yes; no) Steroide (yes; no) Smoking (yes; no) Vascular disease (yes; no) Oral hygiene (great; moderate; poor) a b c d
All events n ¼ 72
No-BRONJ events n ¼ 67
BRONJ events n ¼ 5
p-value
67.46 ± 10.67a 35.78 ± 29.21a 19; 53 41; 27; 4 29; 43 29; 26; 17 33; 39 40; 32 33; 39 10; 62 45; 23; 4
67.71 ± 10.78a 34.94 ± 28.60a 17; 50 37; 26; 4 28; 39 28; 25; 14 29; 38 36; 31 30; 37 9; 58 44; 19; 4
64.14 ± 9.39a 47.00 ± 38.44a 2; 3 4; 1; 0 1; 4 1; 1; 3 4; 1 4; 1 3; 2 1; 4 1; 4; 0
0.473b 0.377b 0.602d 0.461c 0.642d 0.192c 0.172d 0.373d 0.655d 0.538d 0.065c
Mean ± standard deviation. t-test for independent samples. LR-Test. Fisher's exact test.
reach statistical significance (underlying disease: p ¼ 0.25; route of administration: p ¼ 0.17). There was no statistically significant difference between the subgroups with regard to age at time of surgery (p ¼ 0.8), sex (p ¼ 0.1), localization (p ¼ 1.0), smoking (p ¼ 1.0), or vascular diseases (p ¼ 0.57). An overview is provided in Table 2.
3.5. Comparison of patient sub-cohorts with and without histological evidence of osteomyelitis/osteonecrosis at the time of tooth extraction When evaluated based on patient cases (see Table 3) there was a significantly higher risk for histological signs of osteomyelitis/
Table 2 Evaluation of potential risk factors for wound healing disturbances after extractions in patients receiving bisphosphonates (n ¼ number of extraction sites).
Current age (years) BP duration (months) Gender (m; f) Route of administration (iv; oral; combined) Underlying desease (osteoporosis; CA) Localization (UJ; LJ) Chemo (yes; no) Steroide (yes; no) Smoking (yes; no) Vascular disease (yes; no) Oral hygiene (great; moderate; poor) a b c d
Mean ± standard deviation. t-test for independent samples. LR-Test. Fisher's exact test.
All events n ¼ 216
No-BRONJ events n ¼ 209
BRONJ events n ¼ 7
p-value
67.16 ± 11.54a 35.50 ± 29.75a 77; 139 115; 96; 5 84; 132 119; 97 e 94; 122 116; 100 24; 192 116; 82; 18
67.19 ± 11.65a 34.34 ± 29.14a 72; 137 109; 95; 5 83; 126 115; 94 e 88; 121 112; 97 23; 186 115; 76; 18
66.06 ± 8.32a 69.86 ± 29.36a 5; 2 6; 1; 0 1; 6 4; 3 e 6; 1 4; 3 1; 6 1; 6; 0
0.799b 0.002b 0.100d 0.170c 0.252d 1.00d e 0.045d 1.00d 0.567d 0.025c
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Table 3 Comparison of sub-cohorts with and without histological signs of BRONJ at the time of extraction (n ¼ number of patients).
Current age (years) BP duration (months) Gender (m; f) Route of administration (iv; oral; combined) Underlying desease (osteoporosis; CA) Localization (UJ; LJ; UJ þ LJ) Chemo (yes; no) Steroide (yes; no) Smoking (yes; no) Vascular disease (yes; no) Oral hygiene (great; moderate; poor) a b c d e
All events n ¼ 72
No-BRONJ events n ¼ 53
BRONJ events n ¼ 19
p-value
67.46 ± 10.67a 35.78 ± 29.21a 19; 53 41; 27; 4 29; 43 29; 26; 17 33; 39 40; 32 33; 39 10; 62 45; 23; 4
67.38 ± 10.83a 35.28 ± 29.71a 12; 41 27; 24; 2 24; 29 26; 19; 8 22; 31 27; 26 22; 31 7; 46 35; 14; 4
67.70 ± 10.47a 37.16 ± 28.48a 7; 12 14; 3; 2 5; 14 3; 7; 9 11; 8 13; 6 11; 8 3; 16 10; 9; 0
0.910b 0.812b 0.228c 0.048e 0.148c 0.007c 0.286d 0.188c 0.219c 0.717d 0.098e
Mean ± standard deviation. t-test for independent samples. c2-Test. Fisher's exact test. LR-Test.
osteonecrosis in patients with intravenous bisphosphonate intake (p ¼ 0.048). Good oral hygiene was more frequent in the patient cohort without evidence of osteomyelitis/osteonecrosis but statistical significance was not reached (p ¼ 0.098). All other potential risk factors did not show significant differences between the subcohorts. When evaluated based on extraction sites (see Table 4) there was a significant influence of the duration of bisphosphonate intake (p < 0.001), the route of administration (p ¼ 0.037), steroid intake (p ¼ 0.048) and oral hygiene (p ¼ 0.01). No significant influence of smoking (p ¼ 0.603) and vascular diseases (p ¼ 0.581) could be proven.
4. Discussion Tooth extractions and dento-alveolar surgical procedures in patients receiving bisphosphonates and other antiresorptive drugs are of rising clinical importance in the field of dentistry as well as oral and maxillofacial surgery. Based on clinical and epidemiological findings, tooth extraction often precedes the manifestation of BRONJ. Therefore, it is sometimes called a precipitating or trigger event (Abu-Id et al., 2008, Otto et al., 2012). Furthermore, tooth extractions and dentoalveolar surgical procedures have also been regarded as risk factors for the onset of BRONJ (Utreja et al., 2013). As a result, some of the guidelines even recommend avoiding tooth extractions and dentoalveolar surgery under bisphosphonate
intake whenever possible (Ruggiero et al., 2009, Yoneda et al., 2010). Several guidelines dealing with risk assessment and management of patients receiving bisphosphonates have been published by different societies (Groetz et al., 2012, Ruggiero et al., 2009 and 2014). However, the recommendations are partly contradictory. Therefore, the main aim of this study was to prove whether the recommendations published by the German society of Oral and Maxillofacial Surgery, regularly implemented in the clinical routine of our institution, are applicable and successful in this patient cohort (Groetz et al., 2012). The results of this study confirm the above-mentioned protocol to be reliable, avoiding the occurrence of osteonecrotic lesions, even though the patient cohort mainly consisted of high-risk patients with malignant underlying disease receiving intravenous bisphosphonate treatment, and also included some patients with previous BRONJ in other locations. The extraordinarily high success rate (96.8%, and uneventful healing in 209/216 extraction sites), despite the high-risk profile of the patient cohort, is in accordance with the results of Heufelder et al. who recently published a rate of 97% for complete mucosal healing (n ¼ 114/117 extraction sites) in a comparable patient cohort and using very similar preventive measures (Heufelder et al., 2014). In a patient cohort with a lower risk profile, namely osteoporotic patients with an exclusively oral route of bisphosphonate application, Mozzati et al. reported to have a 100% success rate of atraumatic tooth extractions combined with antibiotic prophylaxis in the subgroups with (n ¼ 334 patients) and
Table 4 Comparison of sub-cohorts with histological signs of BRONJ at the time of extraction (n ¼ number of extraction sites). All events n ¼ 216 Current age (years) BP duration (months) Gender (m; f) Route of administration (iv; oral; combined) Underlying desease (osteoporosis; CA) Localization (UJ; LJ) Chemo (yes; no) Steroide (yes; no) Smoking (yes; no) Vascular disease (yes; no) Oral hygiene (great; moderate; poor) a b c d e
Mean ± standard deviation. t-test for independent samples. c2-Test. Fisher's exact test. LR-Test.
a
67.16 ± 11.54 35.50 ± 29.75a 77; 139 115; 96; 5 84; 132 119; 97 e 94; 122 116; 100 24; 192 116; 82; 18
No-BRONJ events n ¼ 176 a
66.60 ± 12.04 31.65 ± 27.64a 53; 123 88; 85; 3 70; 106 102; 74 e 71; 105 96; 80 21; 155 96; 62; 18
BRONJ events n ¼ 40 a
69.63 ± 8.74 52.40 ± 33.05a 24; 16 27; 11; 2 14; 26 17; 23 e 23; 17 20; 20 3; 37 20; 20; 0
p-value 0.070b 0.001b <0.001c 0.037e 0.576c 0.076c e 0.048c 0.603c 0.581d 0.010e
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without plastic wound closure (n ¼ 366 patients) (Mozzati et al., 2013). Our findings are also in line with the results of Saia et al. (2010). Moreover, the results of our study indicated that a significant proportion of cases already had osteomyelitic or osteonecrotic changes in the bony architecture at the time of tooth extraction, which is a very important finding with regard to the pathogenesis of ONJ. In contrast to the study of Saia et al. who only had cases of BRONJ after tooth extraction in patients who had histological signs of osteomyelitis at the time of surgery, our patients who had signs of osteomyelitis/osteonecrosis at the time of tooth extraction showed complete mucosal healing. This might be due to the fact that the suspicious lesions were removed during biopsy accompanied by smoothening of sharp bony edges in our study, which is the equivalent to surgical treatment of early ONJ stages, which usually also leads to complete mucosal healing (Pautke et al., 2011, Vescovi et al., 2011, Otto et al., 2009, Otto, 2015, Ristow et al., 2014). However, in accordance with the above-mentioned authors we could confirm that surgical trauma, by means of extraction, is not the main trigger for ONJ development. Indeed, local infections seem to trigger BRONJ development. This confirms recent theories and cell cultural data which stressed the importance of local infections in the development of ONJ (Otto et al., 2010a,b, Otto, 2015). These findings were also confirmed by animal models which induced ONJ in rats only with local dental and periodontal infections (Aguirre et al., 2012). This is one of the main findings of this study, as this could lead to a shift of paradigms which means that tooth extraction and dentoalveolar surgical procedures should not necessarily be avoided in patients receiving bisphosphonates, especially when the main intention of these procedures is the eradication of a local infection which cannot be cured by conservative measures. In fact, tooth extraction and dentoalveolar surgical procedures aiming at treating and curing local infections (e.g. apical or marginal periodontitis) could actually lead to a decreased risk for the development of ONJ. The latter has to be proven by future prospective studies. In the present study, local infections were treated and overcome by the removal of infected teeth and suspicious bony lesions, and by antibiotic treatment and mucosal coverage of the extraction wounds, protecting the extraction sockets from bacterial ingrowth after extraction. With regard to the underlying diseases and the long half-life of bisphosphonates in the bone, a drug holiday was not performed in the present patient cohort. If there is no urgent need for tooth removal and further bisphosphonate treatment can be postponed, a drug holiday might be a strategy to minimize the risk for ONJ development, especially in the osteoporotic patient cohort (Marx et al., 2007). With regard to other medication-related osteonecrosis of the jaws, especially those related to denosumab intake, a more important role of for the drug holiday is possible and can be assumed taking the much shorter half-life into account (Otto et al., 2013). The main aim of a drug holiday is the optimization of bone remodeling conditions. In this respect some authors recommend measurement of C-terminal telopeptide (CTX) values in selected patient cohorts (Marx et al., 2007). As the test is not valid in patients with underlying malignant diseases and skeletal metastases it can only be used for the osteoporotic patient cohort which only rarely causes problems with regard to BRONJ development (Mozzati et al., 2013). Therefore, it was not used in the present study. In general, it is recommended that a sparse periostal denudation is performed, in order to maintain blood supply to the bone (Groetz et al., 2012). In addition, some authors recommend epi-periostal flap elevation for plastic wound closure (Migliorati et al., 2013).
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The authors of this paper have the opinion that periostal denudation should be limited but has to allow smoothening of sharp bony edges and detection of suspicious bone lesions, especially in highrisk patients. Therefore, a subperiostal flap elevation and enough deperiostation to achieve this ambition should be performed. Although the blood supply to the periosteum might play a role in the etiology of BRONJ (Ziebart et al., 2011) it has not been proven yet to play a key role. Early removal of ONJ lesions seems to be more important when comparing the results of Saia et al. (2010) and our investigation. With regard to potential risk factors accountable for BRONJ occurrence, there are mainly three important groups debated in scientific literature: (i) those related to the bisphosphonate intake itself, (ii) potential systemic, and (iii) local risk factors (Otto, 2015). In the present study the route of administration and the duration of intake for nitrogen-containing bisphosphonates could be confirmed as risk factors. When looking at the underlying diseases, it was mainly patients suffering from malignant diseases that developed clinical as well as histological features of BRONJ. However, being the cause for bisphosphonate intake this can also be regarded as one of the patient cohort characteristics. Interestingly, steroid intake was the only co-medication that was shown to have a statistically significant effect. With regard to local risk factors, oral hygiene seems to play a role in the risk of BRONJ development. However, the main risk factor and driver for the development of BRONJ is the presence or occurrence of local infections within the jawbone, which is in line with previous cell cultures studies (Otto et al., 2010a and b) and animal studies (Aguirre et al., 2012, Dayisoylu et al., 2014) which could prove that local infections are the main trigger for ONJ development. However, to draw final conclusions with regard to the role of various potential risk factors that are under consideration in the literature, further prospective multicenter studies which include larger numbers of patients will be necessary. The occurrence of local infection was successfully avoided by antibiotic prophylaxis, the removal of suspicious lesions, and plastic wound closure in the present study, and resulted in an uneventful postoperative course in the vast majority of cases. This is in line with recent pathogenesis theories which state that local infections and consecutive acidic pH values might play a key role in the development of BRONJ as bisphosphonates are released and activated under these circumstances (Otto, 2015), which then in turn inhibit not only osteoclast activity but also all the other cellular components of the jaw bone, including mesenchymal stem cells, osteoblasts, fibroblasts, immuno-competent and angiogenetic cells (Agis et al., 2010, Otto et al., 2010a,b, Walter et al., 2010). The role of acidic milieus and local infections could meanwhile be proven with different animal models (Aguirre et al., 2012, Dayisoylu et al., 2014). This is also in line with other clinical investigations that could prove that prophylactic measurements, prior to and during bisphosphonate treatment, which aim to avoid local infections, could significantly reduce the risk for ONJ development (Dimopoulos et al., 2009, Mozzati et al., 2013). With regard to patients with a lower risk profile (osteoporosis and oral bisphosphonate treatment for less than 3 years) there are also recommendations by different societies (Migliorati et al., 2013) stating that antibiotic prophylaxis and plastic wound closure is not necessary with regard to the low incidence of BRONJ among this patient cohort. The results of Mozzati et al. indicate that at least plastic wound closure is not mandatory in osteoporotic patients with only oral bisphosphonate intake (Migliorati et al., 2013, Mozzati et al., 2013). Future studies will have to prove the role of antibiotic prophylaxis and plastic wound closure in low risk patients. In general there is a strong need for internationally streamlined recommendations based on scientific evidence. In
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order to provide sufficient data for these recommendations further prospective clinical studies are needed. 5. Conclusion The combination of perioperative antibiotic prophylaxis, atraumatic surgery, smoothening of sharp bony edges and plastic wound closure, offer a safe and reliable strategy for tooth extraction in patients receiving oral and intravenous bisphosphonate treatment. Funding The study was not supported by research grants or any other sources. Acknowledgments The data presented is part of a doctoral thesis (VJ). Photographs were taken by Rudolf Herzig and Gerhard Poetzel. The authors like to thank Michael Simang for his assistance with regard to the statistical analysis of the data. References Abu-Id MH, Warnke PH, Gottschalk J, Springer I, Wiltfang J, Acil Y, et al: “Bis-phossy jaws” e high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J Craniomaxillofac Surg 36: 95e103, 2008 Agis H, Blei J, Watzek G, Gruber R: Is zoledronate toxic to human periodontal fibroblasts? J Dent Res 89: 40e45, 2010 Aguirre JI, Akhter MP, Kimmel DB, Pingel JE, Williams A, Jorgensen M, et al: Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis. J Bone Miner Res 27: 2130e2143, 2012 Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23: 8580e8587, 2005 Dayisoylu EH, Ungor C, Tosun E, Ersoz S, Kadioglu Duman M, Taskesen F, et al: Does an alkaline environment prevent the development of bisphosphonate-related osteonecrosis of the jaw? an experimental study in rats. Oral Surg Oral Med Oral Pathol Oral Radiol 117: 329e334, 2014 Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, et al: Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 20: 117e120, 2009 Groetz KA, Piesold J-U, Al-Nawas B: Bisphosphonat-assoziierte Kiefernekrose (BPONJ) und andere Medikamenten-assoziierte Kiefernekrosen http://www.awmf. org; In AWMF online: Heufelder MJ, Hendricks J, Remmerbach T, Frerich B, Hemprich A, Wilde F: Principles of oral surgery for prevention of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 117: e429e435, 2014 Marx RE, Cillo Jr JE, Ulloa JJ: Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65: 2397e2410, 2007 Migliorati CA, Saunders D, Conlon MS, Ingstad HK, Vaagen P, Palazzolo MJ, et al: Assessing the association between bisphosphonate exposure and delayed mucosal healing after tooth extraction. J Am Dent Assoc 144: 406e414, 2013 Mozzati M, Arata V, Gallesio G: Tooth extraction in osteoporotic patients taking oral bisphosphonates. Osteoporos Int 24: 1707e1712, 2013 Otto S. In: Otto S (ed.), Medication-related osteonecrosis of the jaws: bisphosphonates, denosumab, and new agents. New York, Dordrecht, London: Heidelberg, 2015 1-220
Otto S, Hafner S, Grotz KA: The role of inferior alveolar nerve involvement in bisphosphonate-related osteonecrosis of the jaw. J Oral Maxillofac Surg 67: 589e592, 2009 Otto S, Abu-Id MH, Fedele S, Warnke PH, Becker ST, Kolk A, et al: Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: not just a sporadic coincidence e a multi-centre study. J Craniomaxillofac Surg 39: 272e277, 2011a Otto S, Baumann S, Ehrenfeld M, Pautke C: Successful surgical management of osteonecrosis of the jaw due to RANK-ligand inhibitor treatment using fluorescence guided bone resection. J Craniomaxillofac Surg 41(7): 694e698, 2013 Oct Otto S, Hafner S, Mast G, Tischer T, Volkmer E, Schieker M, et al: Bisphosphonaterelated osteonecrosis of the jaw: is pH the missing part in the pathogenesis puzzle? J Oral Maxillofac Surg 68: 1158e1161, 2010a Otto S, Pautke C, Opelz C, Westphal I, Drosse I, Schwager J, et al: Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism. J Oral Maxillofac Surg 68: 2837e2845, 2010b Otto S, Schreyer C, Hafner S, Mast G, Ehrenfeld M, Sturzenbaum S, et al: Bisphosphonate-related osteonecrosis of the jaws e characteristics, risk factors, clinical features, localization and impact on oncological treatment. J Craniomaxillofac Surg 40: 303e309, 2012 Otto S, Sotlar K, Ehrenfeld M, Pautke C: Osteonecrosis of the jaw as a possible rare side effect of annual bisphosphonate administration for osteoporosis: a case report. J Med Case Rep 5: 477, 2011b Pautke C, Bauer F, Otto S, Tischer T, Steiner T, Weitz J, et al: Fluorescence-guided bone resection in bisphosphonate-related osteonecrosis of the jaws: first clinical results of a prospective pilot study. J Oral Maxillofac Surg 69: 84e91, 2011 Ristow O, Otto S, Troeltzsch M, Hohlweg-Majert B, Pautke C: Treatment perspectives for medication-related osteonecrosis of the jaw (MRONJ). J Craniomaxillofac Surg 43(2): 290e293, 2014 Mar Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jawse2009 update. J Oral Maxillofac Surg 67: 2e12, 2009 Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo TL, Merhotra B, et al: American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the Jawd2014 update. J Oral Maxillofac Surg 72(10): 1938e1956, 2014 Oct Saia G, Blandamura S, Bettini G, Tronchet A, Totola A, Bedogni G, et al: Occurrence of bisphosphonate-related osteonecrosis of the jaw after surgical tooth extraction. J Oral Maxillofac Surg 68: 797e804, 2010 Utreja A, Almas K, Javed F: Dental extraction as a risk factor for bisphosphonate related osteonecrosis of the jaw in cancer patients: an update. Odontostomatol Trop 36: 38e46, 2013 Vescovi P, Campisi G, Fusco V, Mergoni G, Manfredi M, Merigo E, et al: Surgerytriggered and non surgery-triggered bisphosphonate-related osteonecrosis of the Jaws (BRONJ): a retrospective analysis of 567 cases in an Italian multicenter study. Oral Oncol 47: 191e194, 2011 Walter C, Klein MO, Pabst A, Al-Nawas B, Duschner H, Ziebart T: Influence of bisphosphonates on endothelial cells, fibroblasts, and osteogenic cells. Clin Oral Investig 14: 35e41, 2010 Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S: Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 18: 1363e1370, 2007 Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, et al: Bisphosphonaterelated 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 28: 365e383, 2010 Ziebart T, Pabst A, Klein MO, Kammerer P, Gauss L, Brullmann D, et al: Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro. Clin Oral Investig 15: 105e111, 2011
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Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: A trigger for BRONJ development? € ltzsch a, Vesna Jambrovic a, Sappasith Panya a, Florian Probst a, Sven Otto a, *, Matthias Tro Oliver Ristow b, c, Michael Ehrenfeld a, Christoph Pautke a, c a b c
Department of Oral and Maxillofacial Surgery (Head: Prof. Dr. Dr. M. Ehrenfeld, MD, DDS), Ludwig-Maximilians-University, Munich, Germany Department of Oral and Maxillofacial Surgery, Ruprecht-Karls-University, Heidelberg, Germany Medizin & Aesthetik, Clinic for Oral and Maxillofacial Surgery, Lenbachplatz 2a, D-80333 Munich, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 14 January 2015 Accepted 30 March 2015 Available online 10 April 2015
Introduction: Scientific debate outlines tooth extraction as a potential trigger for the onset of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Therefore, the aim of this study was to investigate the outcome of tooth extractions in patients receiving bisphosphonate therapy. Patients and methods: A retrospective cohort study was performed on patients with a history of oral or intravenous bisphosphonate administration and tooth extraction between 2007 and 2013 in a single university hospital oral and maxillofacial surgical unit. In all patients, extractions were performed according to the guidelines of the German Society of Oral and Maxillofacial Surgery. The outcome variable was the onset of typical BRONJ signs during postoperative follow-up. Results: In 72 subjects (53 female, 19 male; mean age 67.5 years) receiving oral (n ¼ 27) and/or intravenous (n ¼ 45) bisphosphonates due to malignant tumor (n ¼ 43) or osteoporosis (n ¼ 29), 216 tooth extractions were performed. The mean duration of intake was 36.2 months. In 67 out of 72 patients (93.1%) and 209 out of the 216 extraction sites the postoperative course was uneventful and the wounds healed without complications. Three of the 72 patients (4.2%) developed osteonecrosis of the jaw in four of the 216 extraction sites (1.9%). Duration and route of administration, oral hygiene and steroid intake were identified as potential risk factors for the development of BRONJ. Conclusion: Tooth extraction in patients receiving bisphosphonates can be performed in a safe and predictable way, even in high-risk patients, when performed according to established guidelines. It is not tooth extractions themselves, but rather prevailing infectious conditions that may be a key risk factor for the development of BRONJ. © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Keywords: Bisphosphonates Bisphosphonate-related osteonecrosis of the jaw, BRONJ Medication-related osteonecrosis of the jaw, MRONJ Prophylaxis Risk factors Tooth extractions
1. Introduction Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side-effect in patients with intravenous administration of nitrogen-containing bisphosphonates used for the treatment of bone-involving malignant diseases, especially breast cancer, multiple myeloma and prostate cancer (Abu-Id et al., 2008, Bamias et al., 2005, Otto et al., 2012). Less frequently BRONJ has been reported in osteoporotic patients receiving oral or intravenous
* Corresponding author. Department of Oral- and Maxillofacial Surgery, LudwigMaximilians-University, Lindwurmstraße 2a, München, 80337, Germany. Tel.: þ49 89 51602995; fax: þ49 89 51604746. E-mail addresses: [email protected], [email protected] (S. Otto).
administration of nitrogen-containing bisphosphonates (Otto et al., 2011a,b, Yarom et al., 2007, Otto, 2015). However, the majority of cases described in the literature occurred after preceding, so called, trigger events, which were mainly tooth extractions (Abu-Id et al., 2008, Groetz et al., 2012, Otto et al., 2012, Ruggiero et al., 2009, 2014). Therefore, dental practitioners, as well as oral and maxillofacial surgeons, feel in a precarious position when choosing appropriate treatment protocols which aim to avoid BRONJ after tooth extractions and other dentoalveolar surgical procedures. The majority of recommendations are intended to control local infection, while applying perioperative antibiotic prophylaxis and plastic wound closure (Groetz et al., 2012, Ruggiero et al., 2009 and 2014). However, data is sparse with regard to the treatment outcome of patients who were treated according to these recommendations (Heufelder et al., 2014, Otto, 2015).
http://dx.doi.org/10.1016/j.jcms.2015.03.039 1010-5182/© 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
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Therefore, the aim of this study was to investigate the clinical course after tooth extraction in patients under bisphosphonate therapy and to judge whether tooth extractions can be performed in a safe and predictable manner when following treatment recommendations. 2. Material and methods Between 2007 and 2013, 72 consecutive patients with a history of bisphosphonate treatment have undergone tooth extractions. They were identified and included in our retrospective monocentric clinical observation (Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians University, Munich, Germany). Inclusion criteria were: osteoporosis and/or malignant tumors with ongoing or previous history of oral and/or intravenous bisphosphonate treatment with necessary tooth extractions or surgical tooth removal. Exclusion criteria were history of irradiation to the head and neck area, obvious metastatic infiltration of the jawbone, and bone exposure or a previous history of BRONJ in the area of the extraction (same quadrant). The study was approved by the local ethical committee (UE Nr. 092-14). In the present study the authors and surgeons performed extractions and surgical tooth extractions according to the protocol published by the German Board of Oral and Maxillofacial Surgeons, which states that tooth extractions in patients receiving bisphosphonates should be performed (i) under prolonged perioperative antibiotic prophylaxis, (ii) in an atraumatic manner, and succeeded by (iii) smoothening of sharp bony edges, as well as (iv) thorough mucosal wound closure (Groetz et al., 2012). All patients underwent a close, center-specific follow-up. Onset of BRONJ served as the major outcome variable. BRONJ was diagnosed according to the Task Force on BRONJ, as defined by the American Association of Oral and Maxillofacial Surgeons (Ruggiero et al., 2014 and 2009). The staging of the disease was made according to the recommendations of the AAOMS 2009 (Ruggiero et al., 2009) which was in line with AAOMS 2014 for the respective cases (Ruggiero et al., 2014): Stage I: exposed necrotic bone without pain or signs of infection (asymptomatic); Stage II: exposed necrotic bone with pain and or signs of infection (symptomatic); Stage III: exposed necrotic bone with pain and or signs of infection and one or more of the following: pathological fracture, oral-cutaneous fistula, involvement of the maxillary sinus or necrosis extending to the inferior border or ramus of the mandible; Stage 0: absence of bone exposure but presence of typical clinical, radiological or histological signs of ONJ. The data collection was performed retrospectively. The patient records, including a standardized questionnaire for the patient and the general practitioner with regard to the underlying diseases and the bisphosphonate intake as well as potential risk factors (smoking, diabetes, steroid intake, etc.), which was routinely used in the studied cohort, were analysed. The respective surgeon documented data concerning the surgical procedures. The patients were followed up on a regular basis and complaints and wound healing disturbances were documented. Descriptive statistics were computed using SPSS version 16. Results are expressed as a percentage or as mean values including standard error of the mean and range. Means were compared by statistical testing (Student's t-test), where p < 0.05 was considered to be significant.
Fig. 1. Illustration of underlying diseases of patients who presented or were referred for tooth extraction and had received, or were still receiving, bisphosphonate treatment.
3. Results 3.1. Baseline characteristics 72 patients (53 female and 19 male) with a mean age of 67.5 years (SD 10.7) were included in the study. Forty-three of the patients (59.7%) suffered from malignant diseases (especially breast cancer, multiple myeloma and prostate cancer) and 29 patients (40.3%) suffered from osteoporosis as the underlying disease (see Fig. 1). The route of bisphosphonate administration was oral in 27 patients (37.5%) and intravenous (or combined) in 45 patients (62.5%). The mean duration of bisphosphonate intake was 36.2 months (SD 28.6). There was no significant difference of the duration of intake with regard to the route of administration (see Fig. 2). A total of 216 teeth (119 in the maxilla and 97 in the mandible) were extracted in 91 operations. The mean follow-up time was 14.9 months (SD: 15.0; range 1e65). 3.2. Results of mucosal integrity The postoperative course was uneventful and complete mucosal healing was achieved in 67 out of the 72 patients (93.1%), and 209 out of the 216 extraction sites (96.8%). A typical
Fig. 2. Comparison of the duration of bisphosphonate intake between the subgroups of patients who were treated with oral and intravenous routes of administration.
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Fig. 3. (a) Preoperative intraoral view of a 68-year-old female patient with breast cancer after intravenous administration of nitrogen-containing bisphosphonates (zoledronate 4 mg every 4 weeks over 4 years); root remnants of teeth 31 and 32. It is noteworthy that this patient suffered from BRONJ in her right upper jaw which was successfully treated previously. (b) Postoperative intraoral view showing complete mucosal healing after tooth extraction, smoothening of sharp bony edges and plastic wound closure (18 months postoperatively).
example is given in Fig. 3a and b. In general there was a tendency towards delayed wound healing of the soft tissues, and the remodeling process of the extraction alveoli seemed to be slowed down even when a radiological control (panoramic radiograph) was performed months or even years after the operation (see Fig. 4aed). The vast majority of patients tolerated the surgery well, did not develop wound healing disturbances or bone
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exposure at any time, and were free of complaints at the time of the last check-up. Five patients developed wound healing disturbances. Three of the 72 patients (4.2%) developed BRONJ lesions (according to stage I AAOMS 2009 and 2014) in four of the 216 extraction sites (1.9%) (see Fig. 5). One patient developed bone exposure within the first weeks after surgery at two extraction sites which were treated successfully with local disinfective measures, including local disinfective rinses, activated photodynamic therapy (Helbo, bredent medical, Germany), and prolonged antibiotic treatment which finally resulted in complete mucosal healing (see Fig. 6). Another patient who had multiple extractions from the upper and lower jaw showed complete mucosal healing at the extraction sites but later developed ONJ in the right mandible (away from the extraction sites) due to a pressure sore caused by rubbing from a prosthesis (see Fig. 7). In 29 patients, bone samples were taken during surgery due to clinically suspicious lesions, these were evaluated histologically. In 20 of the 29 patients (69%) there were histological hints of osteomyelitis and partly or completely devitalized bone areas. Interestingly, all of these patients showed complete mucosal healing after removal of the suspicious areas and smoothening of sharp bony edges and plastic wound closure accompanied by antibiotics (mainly amoxicillin/clavulanic acid 875/125 mg orally twice per day; in case of allergy: clindamycin 600 mg 1-1-1 orally). 3.3. Evaluation of potential risk factors (patients) There was a tendency to a longer duration of bisphosphonate intake in the patient cohort who subsequently developed wound healing disturbances (Mean: 47 months; SD 38) when compared with the cohort who showed complete and uneventful healing, even though statistical significance was not reached (p ¼ 0.38). In the patient cohort who developed wound healing disturbances or ONJ, a malignant underlying disease (80%) and intravenous route of administration was more frequent (80% iv 20% oral) when compared with the cohort with uneventful healing (55.2% iv and 38.8% oral and 6% combined; malignant underlying disease 58.2% and osteoporosis 41.8%) but the difference was not statistically significant (underlying disease: p ¼ 0.64; route of administration: p ¼ 0.46). There was also a tendency to moderate or poor oral hygiene in the patient cohort with wound healing disturbances or ONJ (p ¼ 0.065) even though statistical significance was not reached. There was no statistically significant difference with regard to sex (p ¼ 0.60) and age at time of surgery (p ¼ 0.47). An overview is given in Table 1. 3.4. Evaluation of potential risk factors (extraction sites)
Fig. 4. aed: Radiological examinations of a 70-year-old male patient suffering from multiple myeloma who was treated with intravenous administrations of nitrogencontaining bisphosphonates for 7 years and was referred for extraction of teeth 17, 12, 21, 25, 26 and 34. (a) Preoperative panoramic radiograph; (bed) illustrate the delayed remodeling of the extraction socket of tooth 34; (b) detail of postoperative panoramic radiograph; (c) detail of panoramic radiograph 6 months after surgery; (d) detail of panoramic radiograph 15 months after surgery.
When evaluating each extraction site the duration of bisphosphonate intake was significantly longer within the group of extraction sites which developed a wound healing disturbance or necrosis (p ¼ 0.02), (subgroup with wound healing disturbance/ ONJ: 69.9 months; SD 29.4; versus 34.3 months; SD 29.1, in the subgroup with no wound healing disturbance). Steroid intake and poor oral hygiene was more common in the sub-cohort which developed a wound healing disturbance or ONJ (steroids p ¼ 0.045; oral hygiene: p ¼ 0.025). A malignant underlying disease and an intravenous route of bisphosphonate administration was more common within the subgroup which developed wound healing disturbances and ONJ (malignant underlying disease and intravenous route of administration: 85.7%) when compared with the extraction sites with uneventful healing (malignant underlying disease 60.3%; intravenous administration: 52.2%). However, these differences did not
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Fig. 5. A 59-year-old male patient suffering from multiple myeloma treated with intravenous administrations of nitrogen-containing bisphosphonates (zoledronate 4 mg every 4 weeks) who was referred for removal of tooth 17 which was performed under antibiotic prophylaxis with plastic wound closure. After initially uneventful healing the patient presented with exposed necrotic bone in region 17 and was diagnosed with BRONJ stage 1 according to AAOMS: (a) 6 months after extraction. After diagnosis the patient was treated surgically, including removal of necrotic bone, smoothening of sharp bony edges and plastic wound closure accompanied by antibiotic treatment (amoxicillin/clavulanic acid) which resulted in complete mucosal healing: (b) 3 months after surgery. (cee) Illustrates the corresponding panoramic radiographs: (c) pre extraction; (d) post extraction; and (e) after surgical removal of sharp bony edges.
Fig. 6. (a) A 70-year-old male patient suffering from multiple myeloma (the same patient as in Fig. 4), who was treated with intravenous administrations of nitrogen-containing bisphosphonates (zoledronate 4 mg every 4 weeks) and developed a wound healing disturbance with wound dehiscence and bone exposure 3 weeks after extraction of tooth 34 (b). The patient was then treated with local disinfective measures, including activated photodynamic therapy using the Helbo-system (bredent medical, Germany) (c) leading to complete mucosal healing 2 months after surgery (d).
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Fig. 7. A 60-year-old female patient suffering from adenocarcinoma of the lung treated with intravenous administrations of nitrogen-containing bisphosphonates (zoledronate 4 mg every 4 weeks) who was referred for multiple extractions in the upper and lower jaw; (a) preoperative intraoral view and corresponding panoramic radiograph (d). The extractions were performed including antibiotic prophylaxis, smoothening of sharp bony edges and plastic wound closure. The postoperative course was uneventful and resulted in complete mucosal healing; (b) intraoral view 18 months after extractions. Later the patient developed a BRONJ lesion (according to stage 1 AAOMS 2009 and 2014) which was caused by a pressure sore from her mandibular prosthesis more than 2 years after the extractions (c). The corresponding panoramic radiograph is shown (e).
Table 1 Evaluation of potential risk factors for wound healing disturbances after extractions in patients receiving bisphosphonates (n ¼ number of patients).
Current age (yaears) BP duration (months) Gender (m; f) Route of administration (iv; oral; combined) Underlying desease (osteoporosis; CA) Localization (UJ; LJ; UJ þ LJ) Chemo (yes; no) Steroide (yes; no) Smoking (yes; no) Vascular disease (yes; no) Oral hygiene (great; moderate; poor) a b c d
All events n ¼ 72
No-BRONJ events n ¼ 67
BRONJ events n ¼ 5
p-value
67.46 ± 10.67a 35.78 ± 29.21a 19; 53 41; 27; 4 29; 43 29; 26; 17 33; 39 40; 32 33; 39 10; 62 45; 23; 4
67.71 ± 10.78a 34.94 ± 28.60a 17; 50 37; 26; 4 28; 39 28; 25; 14 29; 38 36; 31 30; 37 9; 58 44; 19; 4
64.14 ± 9.39a 47.00 ± 38.44a 2; 3 4; 1; 0 1; 4 1; 1; 3 4; 1 4; 1 3; 2 1; 4 1; 4; 0
0.473b 0.377b 0.602d 0.461c 0.642d 0.192c 0.172d 0.373d 0.655d 0.538d 0.065c
Mean ± standard deviation. t-test for independent samples. LR-Test. Fisher's exact test.
reach statistical significance (underlying disease: p ¼ 0.25; route of administration: p ¼ 0.17). There was no statistically significant difference between the subgroups with regard to age at time of surgery (p ¼ 0.8), sex (p ¼ 0.1), localization (p ¼ 1.0), smoking (p ¼ 1.0), or vascular diseases (p ¼ 0.57). An overview is provided in Table 2.
3.5. Comparison of patient sub-cohorts with and without histological evidence of osteomyelitis/osteonecrosis at the time of tooth extraction When evaluated based on patient cases (see Table 3) there was a significantly higher risk for histological signs of osteomyelitis/
Table 2 Evaluation of potential risk factors for wound healing disturbances after extractions in patients receiving bisphosphonates (n ¼ number of extraction sites).
Current age (years) BP duration (months) Gender (m; f) Route of administration (iv; oral; combined) Underlying desease (osteoporosis; CA) Localization (UJ; LJ) Chemo (yes; no) Steroide (yes; no) Smoking (yes; no) Vascular disease (yes; no) Oral hygiene (great; moderate; poor) a b c d
Mean ± standard deviation. t-test for independent samples. LR-Test. Fisher's exact test.
All events n ¼ 216
No-BRONJ events n ¼ 209
BRONJ events n ¼ 7
p-value
67.16 ± 11.54a 35.50 ± 29.75a 77; 139 115; 96; 5 84; 132 119; 97 e 94; 122 116; 100 24; 192 116; 82; 18
67.19 ± 11.65a 34.34 ± 29.14a 72; 137 109; 95; 5 83; 126 115; 94 e 88; 121 112; 97 23; 186 115; 76; 18
66.06 ± 8.32a 69.86 ± 29.36a 5; 2 6; 1; 0 1; 6 4; 3 e 6; 1 4; 3 1; 6 1; 6; 0
0.799b 0.002b 0.100d 0.170c 0.252d 1.00d e 0.045d 1.00d 0.567d 0.025c
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Table 3 Comparison of sub-cohorts with and without histological signs of BRONJ at the time of extraction (n ¼ number of patients).
Current age (years) BP duration (months) Gender (m; f) Route of administration (iv; oral; combined) Underlying desease (osteoporosis; CA) Localization (UJ; LJ; UJ þ LJ) Chemo (yes; no) Steroide (yes; no) Smoking (yes; no) Vascular disease (yes; no) Oral hygiene (great; moderate; poor) a b c d e
All events n ¼ 72
No-BRONJ events n ¼ 53
BRONJ events n ¼ 19
p-value
67.46 ± 10.67a 35.78 ± 29.21a 19; 53 41; 27; 4 29; 43 29; 26; 17 33; 39 40; 32 33; 39 10; 62 45; 23; 4
67.38 ± 10.83a 35.28 ± 29.71a 12; 41 27; 24; 2 24; 29 26; 19; 8 22; 31 27; 26 22; 31 7; 46 35; 14; 4
67.70 ± 10.47a 37.16 ± 28.48a 7; 12 14; 3; 2 5; 14 3; 7; 9 11; 8 13; 6 11; 8 3; 16 10; 9; 0
0.910b 0.812b 0.228c 0.048e 0.148c 0.007c 0.286d 0.188c 0.219c 0.717d 0.098e
Mean ± standard deviation. t-test for independent samples. c2-Test. Fisher's exact test. LR-Test.
osteonecrosis in patients with intravenous bisphosphonate intake (p ¼ 0.048). Good oral hygiene was more frequent in the patient cohort without evidence of osteomyelitis/osteonecrosis but statistical significance was not reached (p ¼ 0.098). All other potential risk factors did not show significant differences between the subcohorts. When evaluated based on extraction sites (see Table 4) there was a significant influence of the duration of bisphosphonate intake (p < 0.001), the route of administration (p ¼ 0.037), steroid intake (p ¼ 0.048) and oral hygiene (p ¼ 0.01). No significant influence of smoking (p ¼ 0.603) and vascular diseases (p ¼ 0.581) could be proven.
4. Discussion Tooth extractions and dento-alveolar surgical procedures in patients receiving bisphosphonates and other antiresorptive drugs are of rising clinical importance in the field of dentistry as well as oral and maxillofacial surgery. Based on clinical and epidemiological findings, tooth extraction often precedes the manifestation of BRONJ. Therefore, it is sometimes called a precipitating or trigger event (Abu-Id et al., 2008, Otto et al., 2012). Furthermore, tooth extractions and dentoalveolar surgical procedures have also been regarded as risk factors for the onset of BRONJ (Utreja et al., 2013). As a result, some of the guidelines even recommend avoiding tooth extractions and dentoalveolar surgery under bisphosphonate
intake whenever possible (Ruggiero et al., 2009, Yoneda et al., 2010). Several guidelines dealing with risk assessment and management of patients receiving bisphosphonates have been published by different societies (Groetz et al., 2012, Ruggiero et al., 2009 and 2014). However, the recommendations are partly contradictory. Therefore, the main aim of this study was to prove whether the recommendations published by the German society of Oral and Maxillofacial Surgery, regularly implemented in the clinical routine of our institution, are applicable and successful in this patient cohort (Groetz et al., 2012). The results of this study confirm the above-mentioned protocol to be reliable, avoiding the occurrence of osteonecrotic lesions, even though the patient cohort mainly consisted of high-risk patients with malignant underlying disease receiving intravenous bisphosphonate treatment, and also included some patients with previous BRONJ in other locations. The extraordinarily high success rate (96.8%, and uneventful healing in 209/216 extraction sites), despite the high-risk profile of the patient cohort, is in accordance with the results of Heufelder et al. who recently published a rate of 97% for complete mucosal healing (n ¼ 114/117 extraction sites) in a comparable patient cohort and using very similar preventive measures (Heufelder et al., 2014). In a patient cohort with a lower risk profile, namely osteoporotic patients with an exclusively oral route of bisphosphonate application, Mozzati et al. reported to have a 100% success rate of atraumatic tooth extractions combined with antibiotic prophylaxis in the subgroups with (n ¼ 334 patients) and
Table 4 Comparison of sub-cohorts with histological signs of BRONJ at the time of extraction (n ¼ number of extraction sites). All events n ¼ 216 Current age (years) BP duration (months) Gender (m; f) Route of administration (iv; oral; combined) Underlying desease (osteoporosis; CA) Localization (UJ; LJ) Chemo (yes; no) Steroide (yes; no) Smoking (yes; no) Vascular disease (yes; no) Oral hygiene (great; moderate; poor) a b c d e
Mean ± standard deviation. t-test for independent samples. c2-Test. Fisher's exact test. LR-Test.
a
67.16 ± 11.54 35.50 ± 29.75a 77; 139 115; 96; 5 84; 132 119; 97 e 94; 122 116; 100 24; 192 116; 82; 18
No-BRONJ events n ¼ 176 a
66.60 ± 12.04 31.65 ± 27.64a 53; 123 88; 85; 3 70; 106 102; 74 e 71; 105 96; 80 21; 155 96; 62; 18
BRONJ events n ¼ 40 a
69.63 ± 8.74 52.40 ± 33.05a 24; 16 27; 11; 2 14; 26 17; 23 e 23; 17 20; 20 3; 37 20; 20; 0
p-value 0.070b 0.001b <0.001c 0.037e 0.576c 0.076c e 0.048c 0.603c 0.581d 0.010e
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without plastic wound closure (n ¼ 366 patients) (Mozzati et al., 2013). Our findings are also in line with the results of Saia et al. (2010). Moreover, the results of our study indicated that a significant proportion of cases already had osteomyelitic or osteonecrotic changes in the bony architecture at the time of tooth extraction, which is a very important finding with regard to the pathogenesis of ONJ. In contrast to the study of Saia et al. who only had cases of BRONJ after tooth extraction in patients who had histological signs of osteomyelitis at the time of surgery, our patients who had signs of osteomyelitis/osteonecrosis at the time of tooth extraction showed complete mucosal healing. This might be due to the fact that the suspicious lesions were removed during biopsy accompanied by smoothening of sharp bony edges in our study, which is the equivalent to surgical treatment of early ONJ stages, which usually also leads to complete mucosal healing (Pautke et al., 2011, Vescovi et al., 2011, Otto et al., 2009, Otto, 2015, Ristow et al., 2014). However, in accordance with the above-mentioned authors we could confirm that surgical trauma, by means of extraction, is not the main trigger for ONJ development. Indeed, local infections seem to trigger BRONJ development. This confirms recent theories and cell cultural data which stressed the importance of local infections in the development of ONJ (Otto et al., 2010a,b, Otto, 2015). These findings were also confirmed by animal models which induced ONJ in rats only with local dental and periodontal infections (Aguirre et al., 2012). This is one of the main findings of this study, as this could lead to a shift of paradigms which means that tooth extraction and dentoalveolar surgical procedures should not necessarily be avoided in patients receiving bisphosphonates, especially when the main intention of these procedures is the eradication of a local infection which cannot be cured by conservative measures. In fact, tooth extraction and dentoalveolar surgical procedures aiming at treating and curing local infections (e.g. apical or marginal periodontitis) could actually lead to a decreased risk for the development of ONJ. The latter has to be proven by future prospective studies. In the present study, local infections were treated and overcome by the removal of infected teeth and suspicious bony lesions, and by antibiotic treatment and mucosal coverage of the extraction wounds, protecting the extraction sockets from bacterial ingrowth after extraction. With regard to the underlying diseases and the long half-life of bisphosphonates in the bone, a drug holiday was not performed in the present patient cohort. If there is no urgent need for tooth removal and further bisphosphonate treatment can be postponed, a drug holiday might be a strategy to minimize the risk for ONJ development, especially in the osteoporotic patient cohort (Marx et al., 2007). With regard to other medication-related osteonecrosis of the jaws, especially those related to denosumab intake, a more important role of for the drug holiday is possible and can be assumed taking the much shorter half-life into account (Otto et al., 2013). The main aim of a drug holiday is the optimization of bone remodeling conditions. In this respect some authors recommend measurement of C-terminal telopeptide (CTX) values in selected patient cohorts (Marx et al., 2007). As the test is not valid in patients with underlying malignant diseases and skeletal metastases it can only be used for the osteoporotic patient cohort which only rarely causes problems with regard to BRONJ development (Mozzati et al., 2013). Therefore, it was not used in the present study. In general, it is recommended that a sparse periostal denudation is performed, in order to maintain blood supply to the bone (Groetz et al., 2012). In addition, some authors recommend epi-periostal flap elevation for plastic wound closure (Migliorati et al., 2013).
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The authors of this paper have the opinion that periostal denudation should be limited but has to allow smoothening of sharp bony edges and detection of suspicious bone lesions, especially in highrisk patients. Therefore, a subperiostal flap elevation and enough deperiostation to achieve this ambition should be performed. Although the blood supply to the periosteum might play a role in the etiology of BRONJ (Ziebart et al., 2011) it has not been proven yet to play a key role. Early removal of ONJ lesions seems to be more important when comparing the results of Saia et al. (2010) and our investigation. With regard to potential risk factors accountable for BRONJ occurrence, there are mainly three important groups debated in scientific literature: (i) those related to the bisphosphonate intake itself, (ii) potential systemic, and (iii) local risk factors (Otto, 2015). In the present study the route of administration and the duration of intake for nitrogen-containing bisphosphonates could be confirmed as risk factors. When looking at the underlying diseases, it was mainly patients suffering from malignant diseases that developed clinical as well as histological features of BRONJ. However, being the cause for bisphosphonate intake this can also be regarded as one of the patient cohort characteristics. Interestingly, steroid intake was the only co-medication that was shown to have a statistically significant effect. With regard to local risk factors, oral hygiene seems to play a role in the risk of BRONJ development. However, the main risk factor and driver for the development of BRONJ is the presence or occurrence of local infections within the jawbone, which is in line with previous cell cultures studies (Otto et al., 2010a and b) and animal studies (Aguirre et al., 2012, Dayisoylu et al., 2014) which could prove that local infections are the main trigger for ONJ development. However, to draw final conclusions with regard to the role of various potential risk factors that are under consideration in the literature, further prospective multicenter studies which include larger numbers of patients will be necessary. The occurrence of local infection was successfully avoided by antibiotic prophylaxis, the removal of suspicious lesions, and plastic wound closure in the present study, and resulted in an uneventful postoperative course in the vast majority of cases. This is in line with recent pathogenesis theories which state that local infections and consecutive acidic pH values might play a key role in the development of BRONJ as bisphosphonates are released and activated under these circumstances (Otto, 2015), which then in turn inhibit not only osteoclast activity but also all the other cellular components of the jaw bone, including mesenchymal stem cells, osteoblasts, fibroblasts, immuno-competent and angiogenetic cells (Agis et al., 2010, Otto et al., 2010a,b, Walter et al., 2010). The role of acidic milieus and local infections could meanwhile be proven with different animal models (Aguirre et al., 2012, Dayisoylu et al., 2014). This is also in line with other clinical investigations that could prove that prophylactic measurements, prior to and during bisphosphonate treatment, which aim to avoid local infections, could significantly reduce the risk for ONJ development (Dimopoulos et al., 2009, Mozzati et al., 2013). With regard to patients with a lower risk profile (osteoporosis and oral bisphosphonate treatment for less than 3 years) there are also recommendations by different societies (Migliorati et al., 2013) stating that antibiotic prophylaxis and plastic wound closure is not necessary with regard to the low incidence of BRONJ among this patient cohort. The results of Mozzati et al. indicate that at least plastic wound closure is not mandatory in osteoporotic patients with only oral bisphosphonate intake (Migliorati et al., 2013, Mozzati et al., 2013). Future studies will have to prove the role of antibiotic prophylaxis and plastic wound closure in low risk patients. In general there is a strong need for internationally streamlined recommendations based on scientific evidence. In
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order to provide sufficient data for these recommendations further prospective clinical studies are needed. 5. Conclusion The combination of perioperative antibiotic prophylaxis, atraumatic surgery, smoothening of sharp bony edges and plastic wound closure, offer a safe and reliable strategy for tooth extraction in patients receiving oral and intravenous bisphosphonate treatment. Funding The study was not supported by research grants or any other sources. Acknowledgments The data presented is part of a doctoral thesis (VJ). Photographs were taken by Rudolf Herzig and Gerhard Poetzel. The authors like to thank Michael Simang for his assistance with regard to the statistical analysis of the data. References Abu-Id MH, Warnke PH, Gottschalk J, Springer I, Wiltfang J, Acil Y, et al: “Bis-phossy jaws” e high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J Craniomaxillofac Surg 36: 95e103, 2008 Agis H, Blei J, Watzek G, Gruber R: Is zoledronate toxic to human periodontal fibroblasts? J Dent Res 89: 40e45, 2010 Aguirre JI, Akhter MP, Kimmel DB, Pingel JE, Williams A, Jorgensen M, et al: Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis. J Bone Miner Res 27: 2130e2143, 2012 Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23: 8580e8587, 2005 Dayisoylu EH, Ungor C, Tosun E, Ersoz S, Kadioglu Duman M, Taskesen F, et al: Does an alkaline environment prevent the development of bisphosphonate-related osteonecrosis of the jaw? an experimental study in rats. Oral Surg Oral Med Oral Pathol Oral Radiol 117: 329e334, 2014 Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, et al: Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 20: 117e120, 2009 Groetz KA, Piesold J-U, Al-Nawas B: Bisphosphonat-assoziierte Kiefernekrose (BPONJ) und andere Medikamenten-assoziierte Kiefernekrosen http://www.awmf. org; In AWMF online: Heufelder MJ, Hendricks J, Remmerbach T, Frerich B, Hemprich A, Wilde F: Principles of oral surgery for prevention of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 117: e429e435, 2014 Marx RE, Cillo Jr JE, Ulloa JJ: Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65: 2397e2410, 2007 Migliorati CA, Saunders D, Conlon MS, Ingstad HK, Vaagen P, Palazzolo MJ, et al: Assessing the association between bisphosphonate exposure and delayed mucosal healing after tooth extraction. J Am Dent Assoc 144: 406e414, 2013 Mozzati M, Arata V, Gallesio G: Tooth extraction in osteoporotic patients taking oral bisphosphonates. Osteoporos Int 24: 1707e1712, 2013 Otto S. In: Otto S (ed.), Medication-related osteonecrosis of the jaws: bisphosphonates, denosumab, and new agents. New York, Dordrecht, London: Heidelberg, 2015 1-220
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