“Bis-phossy jaws” – High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw

Journal of Cranio-Maxillofacial Surgery (2008) 36, 95e103 Ó 2007 European Association for Cranio-Maxillofacial Surgery doi:10.1016/j.jcms.2007.06.008, available online at http://www.sciencedirect.com

‘‘Bis-phossy jaws’’ e High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw Mario H. ABU-ID1, Patrick H. WARNKE2,3, Joachim GOTTSCHALK4, Ingo SPRINGER2, Jo¨rg WILTFANG2, Yahya ACIL2, Paul A.J. RUSSO5, Thomas KREUSCH1 1

Department of Oral and Maxillofacial Surgery and Plastic Surgery (Head: Prof. Dr. Dr. Thomas Kreusch), Asklepios Klinik Nord, Hamburg, Germany; 2 Department of Oral and Maxillofacial Surgery (Head: Prof. Dr. Dr. Jo¨rg Wiltfang), University of Kiel, Kiel, Germany; 3 Faculty of Health Sciences and Medicine (Head: Prof. Dr. Chris Del Mar), Bond University, Gold Coast, Australia; 4 Institute for Pathology and Neuropathology (Head: Prof. Dr. Joachim Gottschalk), Asklepios Klinik Nord, Hamburg, Germany; 5 Faculty of Medicine (Head: Prof. Bruce Robinson), Royal North Shore Hospital, University of Sydney, Sydney, Australia

SUMMARY. Introduction: Bisphosphonates (BPs) have transformed our ability to treat certain malignancies, osteoporosis and hypercalcaemia. This class of drug is assumed to be well tolerated by most. There are some important caveats to this assumption, however, one of the significances being the risk of osteonecrosis of the jaw (ONJ). Material and methods: This multi-centre retrospective study examined the role of different BPs on the development of ONJ, its clinical presentation and the efficacy of various treatment modalities, comparing these findings with the available literature. Results: A total of 78 patients from 17 centres were identified with ONJ. A majority of patients identified with ONJ had used Pamidronate or Zoledronate (93.6%) intravenously. 94.9% of patients had received BP in the course of treatment for malignancies and a majority had also received prior chemotherapy or exogenous steroids. 82.1% of patients had received BP for more than 1 year. The mean time from the introduction of BP to the development of ONJ in 24 patients from our department was 31.8 months. Conclusions: The most common intraoral manifestation was exposed necrotic jawbone. Tooth extractions and oral surgical intervention appear to place patients on BP therapy at risk of ONJ, especially after intravenous BP treatments. ONJ proved in this study to be remarkably refractory to treatment, with radical resection being the only curative approach. We recommend that all patients receive necessary dental treatment prior to commencing BP therapy. Ó 2007 European Association for Cranio-Maxillofacial Surgery

Keywords: bisphosphonates, osteonecrosis, ONJ, osteomyelitis, jaw necrosis, bone infection, Zoledronate, Pamidronate

lesions, renal failure, transient fever, rapid and transient drop in serum calcium (Adami and Zamberlan, 1996) and focal osteomalacia (Boyce et al., 1984). In 2003, a previously unrecognised atypical necrosis of the jaw associated with BP administration was described for the first time (Marx, 2003). Since then a large number of case reports describing chronic BP use and associated osteonecrosis of the jaw (ONJ) have been published (Wang et al., 2003; Lugassy et al., 2004; Ruggiero et al., 2004; Abu-Id et al., 2006). All of these reports have indicated that BP-induced ONJ is a critical complication and exceptionally hard to treat. We may pay the bill for excessive use of BPs in the past with development of therapy-resistant osteonecrosis of the patient’s jaws in the future. ONJ appears clinically as denuded avascular, necrotic bone in the oral cavity. The clinical picture is very similar to conventional osteomyelitis of the jaw. This often leads to false diagnosis. The association between BP use and ONJ may not be immediately apparent to many clinicians, because of the latency in its development.

INTRODUCTION The use of bisphosphonates (BPs) has revolutionised the treatment of multiple myeloma, skeletal metastases and osteoporosis. BP medications have proven to be both clinically and commercially successful throughout the Western world. In Germany alone, the administration of BPs has increased by over 100 times in the last 10 years (Fig. 1) (Schwabe and Ziegler, 2005). BPs inhibit osteoclast-mediated bone resorption and are the standard of care for tumour-associated hypercalcaemia. They have been shown to reduce bone pain, improve quality of life, and to delay skeletal events such as pathological fractures. In addition, BPs are useful for other osteoclast-mediated diseases such as osteoporosis and Paget’s disease of bone. Randomised trials of BPs have reported a low incidence of side effects and good tolerability (Felsenberg et al., 1998; Rosen et al., 2004). However, some of the less-frequent side effects may have serious implications for affected patients, such as uveitis and scleritis, serious gastrointestinal 95

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Fig. 1 e Prescription of BPs for public patients in Germany (Schwabe and Ziegler, 2005). Pamidronate and Zoledronate were introduced in late 1999 (P) and 2002 (Z). Despite representing a minority of the total number of BPs prescribed, they were responsible for 93% of cases of ONJ. *Million defined daily doses.

A major concern is that ONJ lesions are resistant to standard therapies for osteomyelitis. Treatment with local and systemic antibiotics does not appear to be successful. No report has yet outlined a potentially successful intervention with a clear regimen for BP-induced ONJ. An unfortunate, yet frequent consequence for the patient is radical resection of the jaw. Interestingly, an historic disease with similarities to ONJ was reported in workers producing phosphorusbased matches in the 19th and 20th century. Those workers developed phosphorus necrosis of their jaws (‘‘phossy jaws’’), when producing ‘‘strike-anywhere’’ or ‘‘Lucifer’’ matches. John Walker invented these matches in 1827 and its basic part was white phosphor, such that the workers were exposed to white phosphor. Phossy jaws developed mainly around rotten teeth (Hughes et al., 1962). We have gathered data from oncologists, pathologists, orthopaedic surgeons, dentists and maxillofacial surgeons in Germany, Austria and Switzerland to identify patients with ONJ following treatment with BPs. We present a review of the literature to compare our results with existing data from other groups. The main goals were to identify those BPs with the strongest association with ONJ, to describe the clinical presentation of ONJ and potential interventions. METHODS A retrospective multi-centre study was performed. Questionnaires were sent to 82 University hospitals and specialist centres in Germany, Austria and Switzerland including mainly maxillofacial surgeons plus oncologists, pathologists and orthopaedic surgeons between December 2004 and September 2005. Doctors were asked to identify patients with osteonecrosis of their jaws and a history of BP administration. The patient’s history, clinical and histopathological findings, therapy and outcome were requested information. Besides the data gathered from the questionnaire, 24 patients with BP-induced ONJ were identified in our

clinic at Asklepios Hospital Nord, Hamburg, Germany and Department of Oral and Maxillofacial Surgery, University of Kiel. Additionally, a review of the current literature was performed to identify reports involving patients with ONJ and BP medication. RESULTS Patients Twenty-one of 82 selected centres were elected to participate in this study after completing a questionnaire. The questionnaire identified 54 cases of patients with ONJ. Our own Departments of Oral and Maxillofacial Surgery and Plastic Surgery in the Asklepios Hospital Nord, Hamburg and University of Kiel, Germany, had treated 24 cases with extensive follow-up. In all, the hospital records of 78 patients (54 + 24) were reviewed for potential precipitants of ONJ and its clinical presentation. A review of the existing literature revealed 548 previously reported cases of BP-induced ONJ (Table 1). The 78 selected patients with ONJ comprised 52 females and 26 males with a mean age of 65.6 years (range, 23e86 years; SD 10.8 years). Seventy-four of the 78 patients (94.9%) had received BPs intravenously for the treatment of malignancies (breast cancer 32, multiple myeloma 30, prostate cancer 8, lung cancer 2, leukaemia 1, and neurosarcoma 1). Three patients (3.8%) received BPs for osteoporosis and one patient (1.3%) for Paget’s disease. Pamidronate and Zoledronate were the BPs most frequently used (93.6%). Other BPs were Alendronate (2.6%), Ibandronate (1.3%) and Risedronate (1.3%). Sixty-four patients (82.1%) received BPs for more than 1 year. Development and location of ONJ In 42 patients (53.8%) ONJ developed following tooth extractions or minor surgical interventions. In 36 patients (46.2%) the BP-induced ONJ was a spontaneous event, of those 26 patients (33.3%) had edentulous jaws.

Table 1 e Review of the available literature describing patients with BP-associated ONJ Authors

n

Intravenous BP Zol

Pam

Oral BP

Indication

Pam + Zol Iba

Ale

Iba

Ris

13 4 9

5

1

1 3

1

Clo

Location

MM

BRCA

4 29 4 11 6 62 7 3 4 3

9 21 6 2 15 50 3 11 6 5 10 3 6 1 1

PRCA

OM

OP

3

3

7

3 3 4

1

Paget

Man

Max

Max + man

Estilo et al., 2004 Ruggiero et al., 2004 Bagan et al., 2005 Bamias et al., 2005 Krimmel et al., 2005 Marx et al., 2005 Melo and Obeid, 2005a,b Migliorati et al., 2005a,b Pires et al., 2005 Purcell and Boyd, 2005 Sanna et al., 2005 Shlomi et al., 2005 Farrugia et al., 2006 Zarychanski et al., 2006 Dimitrakopoulos et al., 2006 Thakkar et al., 2006 Badros et al., 2006 Dannemann et al., 2006 Wutzl et al., 2006 Other authors* Present study

13 63 10 17 25 119 11 18 12 13 10 11 23 12 11 17 22 14 17 110 78

Total (%)

626 261 (42.6) 165 (26.9) 142 (23.2) 11 (1.8) 27 (4.4) 3 (0.5) 3 (0.5) 1 (0.2) 299 (48.3) 220 (35.5) 46 (7.4) 21 (3.4) 28 (4.5) 5 (0.8) 360 (66.7) 139 (25.7) 41 (7.6)

Not specified 9 35 2 4 8 16 4 48 32 4 4 8 3 3 4 10 2 10 7 11 4 12 6 7 4 2 3 8 12 5 51 29 46 13

3 36 3 6 5

1 1

1 3

3 5

5 6 17 6 14 14

7 1

6 2

2 1

0 1

1

4 9 10 5 17 22 7 12 50 30

6 4 29 32

2 1 4 1 2 1 2

1 3 1 1 1

1 1

1

3 4

1

3

1 11 8

1 5 4

5 3

3 1

6 5 39 23 5 14 3 Not specified 81 33 8 2 Not specified 8 3 Not specified 9 1 7 3 12 10 11 7 3 Not specified 15 2 9 2 9 8 61 27 59 14

2 1 5 5 1 1 1 1 1 1 5 3 9 5

Pam ¼ Pamidronate, Zol ¼ Zoledronate, Iba ¼ Ibandronate, Ale ¼ Alendronate, Ris ¼ Risedronate, Clo ¼ Clodronate, MM ¼ multiple myeloma, BRCA ¼ breast cancer, PRCA ¼ prostate cancer, OM ¼ other malignancies, OP ¼ osteoporosis, Man ¼ mandible, Max ¼ maxilla. * Summary of 32 studies with less than 10 patients (Wang et al., 2003; Lugassy et al., 2004; Maerevoet et al., 2004; Alkemper et al., 2005; Carter et al., 2005; Ficarra et al., 2005; Hoefert and Eufinger, 2005; Katz, 2005; Lenz et al., 2005; Markiewicz et al., 2005; Melo and Obeid, 2005a,b; Merigo et al., 2005; Morris, 2005; Olson et al., 2005; Ru¨hlmann and Ku¨bler, 2005; Sarathy et al., 2005; Schirmer et al., 2005; Vannucchi et al., 2005; Viale and Lin, 2005; Capalbo et al., 2006; Carneiro et al., 2006; Goodell, 2006; Hay and Bishop, 2006; Kademani et al., 2006; Leite et al., 2006; Marunick et al., 2006; Mignogna et al., 2006; Nase and Suzuki, 2006; Pastor-Zuazaga et al., 2006; Polizzotto et al., 2006; Soileau, 2006; Tsai et al., 2006). Bis-phossy jaws 97

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In addition to BP therapy, all patients with a diagnosis of cancer (94.9%) had received chemotherapy, 35.9% had received exogenous steroids, 10.3% had diabetes mellitus and 11.5% were regular smokers. The 24 (30.8%) patients treated in the Asklepios Hospital Nord, Hamburg and University of Kiel, Germany, had detailed records. This allowed the calculation of a mean time to induction of ONJ after BP administration of 31.8 months (range 4e120, SD 25.6, and median 24) for these patients. Those patients had mainly received Zoledronate and Pamidronate. Only two patients had been given Risedronate or Ibandronate regimen. A common intraoral manifestation of ONJ was exposed necrotic jawbone in 56 patients (71.8%) (Figs. 2a and 3a). A total of 31 patients (39.7%) had signs of acute or chronic inflammation (e.g., the presence of an abscess or fistula) while 7 patients (9.0%) suffered from nonhealing extraction sockets. Three patients (3.8%) had a pathological fracture. The ONJ lesions occurred most frequently in the mandible (59 patients; 75.6%). In 14 cases (17.9%) they appeared in the maxilla and in both jaws in 5 patients (6.4%). No case of osteonecrosis other than that of the jaws was found. The literature search revealed 301 cases (65.1%) of ONJ of the mandible and 125 cases (27.1%) of ONJ of the maxilla. In 36 cases (7.8%) both jaws had ONJ (n ¼ 462) (Table 1). Radiological and histopathological examination Roentgenographic examination revealed that ONJ lesions appeared as zones of radiolucency or sclerotic bone (Fig. 2b). In some cases we found the ‘‘persisting alveolar socket’’ (Fig. 3b) what has been described as a typical radiographic feature of ONJ (Groetz and Al-Nawas, 2006). Clinically, the lesions appeared to be smaller than as demonstrated on radiographs. Computed tomography did not reveal any further information about the anatomical extent of the lesions. Bone scintigraphy (Technetium 99 tracer injection) proved to be a useful diagnostic tool, especially for mandibular lesions. In 15 of 16 patients with mandibular lesions, scintigraphy showed large

zones of tracer up-take surrounding the areas of necrotic bone. Less tracer up-take was demonstrated in the maxillary lesions. Histopathological examination was performed in 22 of our 24 patients. This demonstrated evidence of either chronic and/or acute suppurative osteomyelitis. No manifestation of the underlying malignant disease was seen. In 13 patients (59.1%), microbiological swabs revealed gross superinfection with actinomyces. Therapy All 78 patients received systemic antibiotics (14 penicillin, 28 aminopenicillin, 37 clindamycin, and 7 others). In 54 patients (69.2%), conventional surgical treatment (e.g., local debridement, decortication, and sequestrectomy) was performed. In 25 patients (32.1%), multiple surgical interventions were necessary. Eleven (14.1%) patients were treated with local antiseptics and systemic antibiotics without surgical intervention. Four of these patients underwent hyperbaric oxygen therapy, one of whom improved clinically. Minor surgical intervention or conservative treatment as described above led to clinical resolution in 25 of 65 patients (38.5%). In 22 patients (28.2%) it was necessary to perform more radical surgical intervention. In four of these patients, a resection in continuity and in 18, a subtotal resection of the involved jaw was performed. For reconstruction after radical resection, titanium reconstruction maxi plates were inserted. One patient received a free iliac crest bone graft 1 year after resection, which healed well clinically at first but subsequently developed pseudarthrosis. After insertion of a secondary bone graft, good union was achieved. The radical procedure was curative in 19 of 22 (86.4%) patients. In total, clinical resolution of ONJ was achieved in 41 of 78 patients (55.1%) (Table 3). DISCUSSION The positive benefits, safety and efficacy of new therapies are often emphasised. This has the consequence of occasionally overshadowing and delaying the medical

Fig. 2 e (a,b) Sixty-five-year-old male patient who underwent Zoledronate therapy for multiple myeloma. ONJ developed following tooth extraction. (a): Exposed necrotic bone f the right posterior mandible. (b): Panoramic radiograph showing an osteolysis reaching the mandibular canal and leads to disturbance of sensation.

Bis-phossy jaws 99

Fig. 3 e (a,b) Sixty-eight-year-old male patient 8 months after Zoledronate therapy was initiated for skeletal metastases due to lung cancer. (a): Multiple lesions of exposed bone 5 months after extraction of teeth in the mandible. (b): Panoramic radiograph showing the typical early symptom of ‘‘persisting alveolar sockets’’.

community’s appreciation of potential side effects. It is often the case that recognition of side effects is only apparent in the post-marketing period. Sometimes this occurs after drugs have become clinical and commercial blockbusters, such as LipobayÒ or Thalidomide. As with these two drugs, the consequences can be severe and frightening for all involved. This multi-centre study was based on a questionnaire sent to oncologists, dentists and maxillofacial surgeons to identify patients with ONJ in association with BP therapy. The type of BP and the patients’ original disease were evaluated. This was compared with and found to be broadly consistent with the current literature. The majority of cases of ONJ developed following the intravenous administration of Pamidronate and Zoledronate (Table 1). Both BPs were introduced just a few years ago and have been approved for their use in certain malignant conditions. This correlates with the finding that most of the patients (94.7%) in our study received BPs for the treatment of malignancies (Table 1). We found only a few patients (5.3%) with ONJ who had received BPs for the treatment of osteoporosis or Paget’s disease. But according to the literature, osteoporosis is the main focus in BP therapy and accounts for nearly 99% of prescriptions (Fig. 1). Pamidronate and Zoledronate were the BPs most frequently used (92.7%) in both this study and in previously published cases of ONJ (Table 1). Other BPs such as orally administrated Alendronate and Risedronate played a minor role and represented 5.6%. NonaminoBPs like Clodronate were not identified in our analysis and were found in only one of the published cases (Schirmer et al., 2005). BPs were administered mainly as long term therapy. Sixty-four patients (82.1%) received BPs for more than 1 year. Published rates of ONJ in patients with multiple myeloma, breast cancer and prostate cancer with skeletal metastases who have been treated with BPs varies between 1 and 15% (Table 2). Approximately 10% of all osteomyelitis patients in oral maxillofacial surgery are diagnosed as BP-associated ONJ (Walter et al., 2006). The difference in the prevalence of ONJ in these studies appeared to correlate with both the use of different types of BP and the duration of administration. ONJ appeared earlier in the course of therapy with the use of Zoledronate compared with Pamidronate which itself was less

Table 2 e Incidence of BP-associated ONJ in patients with malignant diseases in retrospective studies Authors

Durie et al., 2005 Bamias et al., 2005 Ortega et al., 2006 Hoff et al., 2006 Dimopoulos et al., 2006 Zervas et al., 2006 Pozzi et al., 2007

n

Incidence (%) Total

Multiple myeloma

Breast cancer

Prostate cancer

1203 252 178 4019 202

6.2 6.7 7.3 0.9 e

6.8 9.9 e 3.1 e

4.3 2.9 4.0 1.2 7.4

e 6.5 15.4 e e

303 1402

11.0 1.9

11.0 1.9

e e

e e

tardy than Alendronate (Durie et al., 2005; Hoff et al., 2006; Marx et al., 2005). It appears therefore that the use of Zoledronate or Pamidronate engenders a higher risk of the early development of ONJ when compared with Alendronate and Risedronate (Mavrokokki et al., 2007). The latter two BPs are used more widely (Fig. 1). The time for the induction of symptomatic ONJ following commencement of BP therapy was accurately recorded in patients treated in our department (n ¼ 24; 30.8%). The mean induction time was 31.8 months (range 4e120, SD 25.6, and median 24). Whilst this study focused on the development of ONJ in association with the use of BPs, there are published cases of ONJ that developed in the absence of BPs. Schwartz reported in 1982 that ONJ may develop after chemotherapy for malignancy (Schwartz, 1982). Chemotherapy is associated with other oral complications that have been described elsewhere (Sonis et al., 1978). Importantly, osteonecrosis in other sites than the jaw may also develop following long term high dose glucocorticoids without BP therapy (Zalavras et al., 2003). Tarrassoff estimated in 2003 that 2.5 million patients had received Pamidronate and Zoledronate without developing ONJ. According to Tarrassoff and the General Practice Research Database, patients with malignancies have a risk of developing osteomyelitis of the jaw that is four times that of the healthy population (Tarassoff and Csermak, 2003). Unfortunately no information was provided indicating whether or not any of these patients received radiation therapy.

100 Journal of Cranio-Maxillofacial Surgery Table 3 e Outcome of different therapies for ONJ No surgery Therapy Single minor surgery n 11 Response 5 (46%) No response/ 6 (54%) progression

Multiple minor surgery

Radical surgery*

Total

29 25 22 78 13 (45%) 7 (28%) 19 (86%) 43 (55%) 16 (55%) 18 (72%) 3 (14%) 35 (45%)

* Radical treatment with segmental resection (n ¼ 4) or marginal resection (n ¼ 18) had the best outcome and was curative in 19 of 22 (86.4%) patients. In total, clinical resolution of ONJ was only achieved in 43 of 78 patients (55.1%).

In addition to BP therapy, a majority of patients in this study were exposed to a number of other factors that themselves may have induced ONJ. Most patients had malignancies and many received chemotherapy or exogenous steroids. The pathogenesis of BP-induced ONJ is still unclear. It has been postulated that BPs suppress angiogenesis (Fournier et al., 2002; Marx et al., 2005). Hellstein and Marek postulated that the natural balance between osteoblasts and osteoclasts in bone remodelling processes is disrupted (Hellstein and Marek, 2005). Marx reported that ONJ is the result of local osteopetrosis (Marx et al., 2005). Other side effects of BPs include ulceration of the mucosa of the upper aerodigestive tract and the oral cavity, which may produce an open gate for bacterial invasion of oral bone (Gonzalez-Moles and Bagan-Sebastian, 2000). The oral cavity hosts both aerobic and anaerobic flora. Permanent bacterial invasion countered by local defences, especially in the periodontal gap between teeth and gingiva may lead to periodontitis. Both periodontitis and dental caries seem to be risk factors for ONJ (Marx et al., 2005; Walter et al., 2006). Half of the patients in our study developed ONJ after tooth extractions or minor surgical interventions. Another clinical study reports that Alendronate may reduce progression of periodontitis (Lane et al., 2005). However, ONJ has also been found in edentulous jaws. In these cases ONJ appears often spontaneously mostly on the lingual posterior sides of the mandible. These areas are often found to contain ulcers and sequestra in association with non-BPinduced ONJ (Peters et al., 1993). The microbiological swabs revealed predominantly actinomyces superinfection of ONJ. It is possible that actinomyces may be a co-factor in the pathogenesis of ONJ. In addition to their effects on the jaws, BPs also have side effects on the skeleton. The reduction in remodelling is a systemic effect that may lead to poor bone healing at any site (Komatsubara et al., 2004). Inhibition of bone mineralisation under BP treatment may lead to osteomalacia with increased fracture risk (Boyce et al., 1984). On the other hand BP can cause osteopetrosis in the growing skeleton (Whyte et al., 2003). A recently published case control study showed a higher ONJ frequency in patients with a long term persistence of low serum calcium and secondary hyperparathyroidism during Zoledronate

therapy (Ardine et al., 2006). Another systemical risk factor might be diabetes mellitus (Khamaisi et al., 2007). Historical reports regarding phosphorus-associated jaw necrosis are similar to BP-induced ONJ. Like BPs, white phosphorus significantly suppresses bone resorption (Whalen et al., 1973). White phosphorus was tested in the 19th century as a treatment for rickets (Kassowitz, 1884; Hess and Weinstock, 1926). In animal models, the oral application of white phosphorus has reduced bone resorption and led to osteopetrosis-like lesions of the skeleton (Wegner, 1872; Whalen et al., 1973). Hellstein and Marek suggested that it would be correct to make historical reference to the ‘‘phossy jaws’’ of the past in naming BP-induced ONJ as ‘‘BP osteochemonecrosis’’ or more simply, ‘‘bis-phossy jaws’’ (Hellstein and Marek, 2005). The treatment of ONJ is difficult. Minor invasive or conservative treatment with local disinfectants and antibiotics was unsuccessful in 61.5% of cases in this study. Surgical resection of the osteonecrotic lesions had a better outcome. We recommend radical surgical resection up to viable bone and hermetic wound closure with surrounding soft tissue. The border between ONJ and viable bone can often be well defined clinically. Other authors favour more conservative treatment (Marx et al., 2005; Migliorati et al., 2005a,b; Ruggiero et al., 2006) but our study showed a positive outcome in 86.4% following the radical intervention. The addition of systemic antibiotics, is useful as ONJ, is often contaminated with actinomyces. The value of hyperbaric oxygen therapy cannot be clearly defined (Lugassy et al., 2004; Ruggiero et al., 2004). As a minimum, we recommend cessation of BP therapy when ONJ occurs. CONCLUSION In the setting of cancer therapy, it is important to coordinate BP use between the oncologist and a dentist or maxillofacial surgeon. To conclude, we believe that patients can be stratified into two groups with different levels of risk for developing BP-induced ONJ: (1) High risk: patients with malignant disease receiving intravenous BP therapy (Zoledronate or Pamidronate) and/or with a history of chemotherapy, radiotherapy or current exogenous steroid use. (2) Low risk: patients taking oral BPs without a history of chemotherapy, radiation therapy or current exogenous steroid use (mainly patients with non-steroid-induced osteoporosis). With the commencement of BP therapy, consideration should be given to preventing the development of ONJ. Those identified as being at high risk should be examined by a dentist prior to commencing therapy to ensure that all critical dental or periodontal diseases have been treated before BPs are administered. Similar regimens have already been introduced for patients prior to radiation therapy involving the head-and-neck region (Migliorati et al., 2006; Piesold et al., 2006). Regular follow-up examination by a dentist is important, as

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Priv. Doz. Dr. Dr. Patrick H. WARNKE Department of Oral and Maxillofacial Surgery University of Kiel Arnold-Heller-Strasse 16, D-24105 Kiel Germany Tel.: +49 431 5972926 E-mail: [email protected] Paper received 16 March 2007 Accepted 23 June 2007