RESEARCH

Bisphosphonate related osteonecrosis of the jaws: A clinical report and review of the literature
A. Alper PAMPU *, Mustafa ANKAYA*, Ezher Hamza DAYISOYLU*, Nuray YILMAZ ALTINTA *, Rukiye DURKAN *, Fatih TA KESEN # S Dihek Fak Derg, 2010;19:121-125
Bisphosphonate related osteonecrosis of the jaws: A clinical report and review of the literature Background: The aim of the study was to evaluate the patients with osteonecrosis which occurred as a result of biphosphonates in the light of literature. Methods: In this retrospective study; 10 patients, who were referred to our clinic by dental practicians between October 2004-2007 with a complaint of unimproved extraction socket and exposed bone area, were evaluated. None of the patients had radiotherapy and they had no maxillary or mandible metastasis. Results: 4 of the 10 patients had medical management, 6 of them had minor surgical attention and all of them recovered completely. Consultation was carried with their oncologists and as a result biphosphonate treatment was terminated or treatment manner was changed. Conclusion: The incidence of osteonecrosis related with biphosphonates increases day by day. Today, although prevention of this complication is not probable, it is possible to suppress with a good oral hygiene. All dental practicians and oncologists must consider this clinical case and take the neccessary precautions. KEY WORDS Bisphosphonates, Osteonecrosis, Jaws
Submitted: October 20, 2009 Accepted for publication: October 28, 2009

hydrolysis in acid conditions or by pyrophosphatases(4,5). The half-life of bisphosphonates in circulation is quite short, ranging from thirty minutes to two hours(6). However, once incorporated into bone tissue, they can persist up to 10 years, depending on the skeletal turnover time (4, 6). Lin et al (7) studied the pharmacokinetic properties of bisphosphonates, reported that they persist up to 12 years once they have been taken up into human bones. Once deposited on the surface of the bone, bisphosphonates are internalized by osteoclasts, causing disruption of osteoclast-mediated bone resorption (8). Bisphosphonates also have antiangiogenic properties, resulting in decreased circulating levels of vascular endothelial growth factor (9,10). Bisphosphonate-related osteonecrosis or osteomyelitis of the jaws (BRONJ) was first described by Marx and Stern(11) in 2002. BRONJ refers to a condition characterized by exposure of bone in the mandible or maxilla persisting for more than 8 weeks in a patient who has taken or currently is taking a bisphosphonate and who has no history of radiation therapy to the jaws(12). BRONJ has only been reported in the jaws. There is an increasing number of cases reported about this new clinic entity from all over the world. The aim of this article is to report 10 cases about this new phenomenon and review the literature on this subject.

Cancer patients with metastatic bone lesions often present with a multitude of complications that include pain, pathologic fracture, and hypercalcemia(1). Bisphosphonates are a new class of agents that have been increasingly recommended for use in patients with osteoporosis, Pagets disease of bone, hypercalcemia of malignancy, osteolytic bone metastases, and osteolytic lesions of multiple myeloma(2). Bisphosphonates are synthetic compounds with a chemical structure similar to that of inorganic pyrophosphate, an endogenous regulator of bone mineralization(3). While pyrophosphate is compromised of two phosphate groups linked by phosphoanhydride bonds (P-O-P structure), bisphosphonates are compromised of two phosphonate groups linked by phosphoester bonds (P-C-P structure). This structure makes them more resistant to

* Karadeniz Teknik niversitesi Di hekimli i Fakltesi A z Di ene Cerrahisi AD # Karadeniz Teknik niversitesi Di hekimli i Fakltesi Protetik Di Tedavisi AD

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PATIENTS AND METHODS Patients who were referred to our clinic by general dentists due to their refractory pain, swelling of the jaw, expose bone and non-healing extraction sockets between October 2004 and December 2007 were included in this study. None of the patients had any history of radiation therapy nor metastasis of the jaws and all of them were taking bisphosphonates. There were 10 patients in this category (Table 1). 3 patients presented maxillary bone involvement and 7 patients presented mandibular involvement. The diagnoses for bisphosphonate usage were multiple myeloma in 4 patients, breast cancer in 2 patients and osteoporosis in 4 patients. The mean age was 64.7. The duration of average Zolendronate (Zometa) and Alendronate (Fosamax) use was 40 and 31 months, respectively. The necrotic bone or symptoms appeared after a dental extraction in 3 patients, whereas it appeared spontaneously in 6 patients and in the edentulous area in a patient with removable prothesis. 7 patients had pain in the affected area while 3 of them were asymptomatic with exposed bone. Normal mucosa was observed in 4 patients while the others had exposed bone (Figure 1). Radiographic examinations revealed sequestrum or osteolysis in 5 patients, osteosclerosis in 3 patients while 2 patients did not revealed any unusual finding (Figure 2). RESULTS The management of the disease included medical treatment and, if required, various surgical procedures thereafter. The medical treatment included amphicillin/ sulbactam (Duocid) and metronidazole (Flagyl) i.v. and antimicrobial rinses with chlorhexidine for all patients. 4 patients received only medical treatment and the others had minor surgeries such as local osteoctomies or local resections. Primary wound healing occurred after surgical interventions. Histhological examinations revealed osteomyelitis or osteonecrosis. Two of the patients had further complaints related to different region of the jaw and one patient at the same region. 2 of the recurrent cases were resolved with our medical protocol and one of them had local osteoctomy under local anesthesia. With consultation

to oncologists the bisphosphonate therapy stopped or changed to a less potent alternative if medically possible. All of the patients now have a pain free condition and their clinical follow-up period is continuing. DISCUSSION Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is clearly a new and different clinical entity (13). Marx(12) and Miglioratti(14) have suggested that bisphosphonates may be directly responsible

Figure 1. Exposed bone on the patients right posterior lower jaw.

Figure 2. Panoramic radiograph showing the sequestrum on the right posterior lower jaw

Table 1. Patient diagnosis, proprietary name, affected jaw

Diagnosis Proprietary Name Affected Jaw Multiple Myeloma Zometa Mandible (4) (6) (7) Breast Cancer Fosamax Maxilla (2) (4) (3) Osteoporosis (4)

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for BRONJ in their patients. All the patients referred to our clinic had previously received Zoledronate or Aledronate. Although the data show an association between these drugs and osteonecrosis, they do not establish the exact relationship. Phossy jaw was first described in the mid portion of the 19th century, when it became apparent that workers in the matchmaking industry were being afflicted with an unusual necrosis of the jaws(15). Lorinser first reported these cases in 1845(16). The workers who had suffered from toothache and had extractions faced worse situations like non-healing sockets, sequestration and soft tissue infections. This phenomenon thought to be related with industrial contact with white phosphorus. Phossy jaw was eventually eradicated by changes in industrial hygiene(3). The biological and clinical potency of bisphosphonates vary greatly due to their structural variety. Generally they are divided into 2 main classes with the difference between them a function of the moieties attached to the geminal carbon at the R2 side chain which can vary in size and complexity. This is related to the presence or absence of a nitrogen atom located in the R2 group. There are a variety of bisphosphonates; those that contain nitrogen are the most potent ones known as aledronate, ibandronate, incadronate, olpadronate, pamidronate, risedronate and zoledronate; while the non nitrogen bisphosphonates are mainly clodronate, etidronate and tiludronate (2,12,17) (Table 2). At the beginning it was thought that only nitrogen containing bisphosphonates cause BRONJ but Senel et al(13) reported a patient with osteomyelitis of the mandible associated with the use of non-nitrogen-containing bisphosphonate. They had reported severe osteomyelitis of the mandible associated with the use of clodronate in a case.

Repeated doses of bisphosphonates accumulate in bone matrix and can be removed only by osteoclastmediated resorption as part of the bone turnover cycle. Since bisphosphonates are toxic to osteoclasts and prevent bone turnover, this way is prevented and bisphosphonate accumulation in bone, particularly in the jaws, cannot be safely removed(12). Risk factors for the occurence of BRONJ are very important. They can be grouped as drug-related, local risk factors, demographic and systemic risk factors(18). Drug-related risk factors are potency of the particular bisphosphonate and duration of the therapy(18-20). 6 of our patients were using Zoledronate while 4 of them were using Alendronate. Marx et al(12) mentioned that longer duration times and i.v. administrations refers to increased risk supported with our results that 6 of the patients were using Zometa with a mean duration of 40 months. Local risk factors mentioned by AAOMS (18) are including dentoalveolar surgery, local anatomy, concomitant oral diseases. Patients receiving i.v. bisphosphonates and undergoing dentoalveolar surgery are at least 7 times more likely to develop BRONJ than patients who are not having dentoalveolar surgery (18, 20, and 21). Similar to this information, 3 of our patients had BRONJ after dental interventions. From a local anatomy perspective, mandibular lingual tori, mylohyoid ridge and maxiller palatal tori are the most important places(18). AAOMS (18) has mentioned that lesions are found more commonly in the mandible than the maxilla (2:1 ratio) similiar to our results that 7 of our patients had mandibuler involvement while 3 of them had maxillary involvement. Also concomitant oral diseases such as inflammatory periapical or periodontal diseases etc. are important risk factors. Demographic and systemic factors are age, cancer diagnosis, race, osteopenia concurrent with cancer diagnosis which is supported by our results that 6 of them had malignant diseases. As mentioned by AAOMS (18) and Badros et al (20) race is a risk factor for BRONJ and we speculate that the mild symptoms like developing osteomyelitis rather than osteonecrosis and affected sides with overlying normal mucosa are the results of different pharmacogenetic factors of this regions nation. With each passing decade, there is a 9% increased risk for BRONJ in multiple myeloma patients treated with i.v. bisphosphonates (18,20). The occurrence of osteomyelitis or osteonecrosis only in the jaws is a question of wonder and several speculations have been made about this condition. Dixon et al (22) documented the remodeling rate of bone at various sites and found that the alveolar crest remodels at 10 times the rate of the tibia, 5 times the rate of the mandible at the level of the mandibular canal, and 3.5 123

Table 2. Proprietary name and relative potency of bisphosphonates.

Proprietary Bisphosphonate Etidronate Tiludronate Alendronate Residronate Ibandronate Pamidronate Zolendronate Name Didronel Skelid Fosamax Actonel Boniva Aredia Zometa Relative Potency 1 50 1000 1000 1000 10005000 10000

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times the rate of the mandible at the inferior border. As a result, the alveolar bone of the jaws has a greater uptake of bisphosphonates and readily accumulates at higher concentration. By this time if a trauma such as a tooth removal occurs, the alveolar bone can no longer respond with new bone formation from osteoclastic bone resorption followed by new bone formation, and it becomes necrotic. The overlying mucosa is subsequently deprived of its supporting blood supply from the underlying bone and breaks down, leading to clinically observed exposed bone(12). Prior to the treatment with bisphosphonates, the patient should have a thorough oral examination, any unsalvageable teeth should be removed, all invasive dental procedures should be completed, and optimal periodontal health should be achieved(18). The patients should be educated about this situation. The protocols of initiation to radiotherapy or chemotherapy should be used on patients who are to start these medications. There should be a multidisciplinary approach between the dental professionals or maxillofacial surgeons and medical oncologists. In addition, because dental surgery seems to be a precipitating event in the occurrence of most cases of BRONJ, it seems appropriate to recommend alternatives to tooth extraction for patients with a history of receiving bisphosphonates(23). Restorative dentistry should be performed to eliminate caries and defective restorations. Crowns and more extensive fixed prosthodontic work may not be appropriate for some patients. Prosthodontic appliances should be evaluated for fit, stability and occlusion. Necessary adjustments should be made(24). Denture stresses on mucosa should be minimized in edentulous or partially edentulous patients(25). Relining a denture with a soft liner to promote a better fit and to minimize soft-tissue trauma and pressure points is recommended as one of our patients manifested BRONJ because of trauma caused by a removable prosthesis. There is no consensus over the treatment of BRONJ. Marx(12), Ruggerio et al(2), and AAOMS(18) staged the BRONJ patients and offered guidelines according to this classifications. Our treatmeant choices are parallel to these guidelines. Another interesting subject about this situation is that although no clinical data support long-term efficacy and benefit beyond 2 years, patients with lytic bone disease continue bisphosphonate therapy indefinitely, a practice endorsed by the American Society of Clinical Oncology(26). In the light of all factors, alternative treatment protocols with bisphosphonates should be studied as Novartis declared their phase 3 observations about a once-yearly infusion of Zolendronate for the treatment of postmenopausal osteoporosis which can 124

reduce the risk for developing BRONJ(27). We also advise to consulate with the oncologists for a drug cessation or a less potent bisphosphonate usage. A new complication of bisphosphonate use which is called bisphosphonate-related osteonecrosis of the jaws seems to be growing. All dental professions and oncologists should be aware of this new clinical entity and further investigation is needed to completely elucidate this phenomenon.

enelerin bifosfonat ile ilikli osteonekrozu: Klinik rapor ve literatr derlemesi Giri: Bu al mann amac literatr deerlendirmesi ile bifosfonata bal osteonekroz grlen hastalar deerlendirmektir. Metod: Bu retrospektif al mada Ekim 2004-2007 arasnda iyile memi ekim soketi ve ekspoze kemik dokusu bulunan, di hekimleri tarafndan kliniimize ynlendirilen 10 hasta deerlendirilmi tir. Hastalarn hibirinde radyoterapi hikayesi ve mandibula veya maksillaya metastaz hikayesi yoktur. Sonular: 4 hastaya medikal tedavi verilmi, 6 hastaya ise minr cerrahi giri im uygulanm tr ve hastalarn hepsi iyile mi tir. Onkoloji konsltasyonu sonucu hastalarn bifosfonat tedavisi kesilmi veya baka bir tedavi ile dei tirilmi tir. Tart ma: Bifosfonata bal ene nekrozu grlme s kl gn getike artmaktadr. Gnmzde bu komplikasyonun tamamen nne gemek muhtemel deilken, iyi bir oral hijyenle bu komplikasyonu azaltmak mmkndr. Btn di hekimleri ve onkologlar bu klinik olguyu gz nnde tutmal ve gerekli tedbirleri almaldrlar. Anahtar eneler Kelimeler: Bifosfonatlar, Osteonekroz,

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Correspondence Address: Yrd. Do. Dr. A. Alper Pampu Karadeniz Teknik niversitesi Di hekimli i Fakltesi A z Di ene Cerrahisi AD Kamps/Trabzon Tel: 0 462 3774756 E mail: alperpampu@hotmail.com

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