diagnosed with BRONJ who had received or were receiving bisphosphonates.

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2 _{Associate professor, Head of Implantology Dept., “Lucian Blaga” University of Sibiu} 3 _{Associate professor, Head of Prostehtics Dept., “Lucian Blaga” University of Sibiu} 4 _{Professor, Head of OMF Surgery Dept., “Lucian Blaga” University of Sibiu}

Corresponding author: maxfaxsurg@yahoo.com

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Bisphosphonates are used in the management of bone metastasis of different types of carcinoma and multiple myeloma. They are highly effective in bone resorption caused by osteoporosis.

Aim of the study: To monitor the patients diagnosed with BRONJ, who had received or who were receiving bisphosphonates.

Materials and method. The study presents 28 cases of bisphosphonate-related osteonecrosis of the jaws (BRONJ) monitored over an average period of 9 months.

Results and discussion. The healing rate was 25% and, after treatment, 28.5% of the patients were downgraded RQHVWDJHLQWKHFODVVLÀFDWLRQ,QRIFDVHVWKHWULJJHU was dental extraction. There is an impetuous need for multidisciplinary collaboration among the oncologist, the rheumatologist, the maxillofacial surgeon and the dentist for a correct management of this disease.

Conclusions: Bisphosphonate-related osteonecrosis of the jaw is a new entity in maxillofacial surgery. Before prescribing bisphosphonates, the patient should be instructed by the oncologist to address a dentist for thorough checkup and careful monitorization from his part during therapy. Prophylaxis plays a major part in disease management.

Keywords: osteonecrosis, bisphosphonates, surgical treatment

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Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is the condition in which the bone is exposed in the mouth, for longer than 8 weeks, in patients receiving or who had received bisphosphonate (BP) drugs, with no history of radiotherapy in the maxillofacial region. This SDWKRORJ\ ZDV ÀUVW UHSRUWHG LQ \HDUV after bisphosphonates had been introduced in medical practice. Although they had been

available for a long time, only after the 1990s their mechanisms of action were fully understood.

Chemically, they are inorganic pyrophosphate analogues, playing a major role in hard tissue mineralization. They inhibit bone calcium action and are resistant to alkaline phosphatase. Their HIÀFLHQF\ RQ WKH KDUG WLVVXH H[SODLQV WKHLU utilization in a series of diseases that can impact the bone, such as metastasis of breast [1], lung [2], prostate [3] and renal [4] carcinoma. They are also used in the treatment of multiple myeloma [5], not as curative drug for cancer therapy, but for improving the quality of life in such patients. They are also used in osteoporosis and osteopenia [6]. In spite of their large utilization, the action they exert upon the hard tissue has the unwanted effect of exposing the jaw bone in the oral cavity and of causing severe osteomyelitis-like lesions. The study describes a new pathology, requiring a prolonged treatment with hardly satisfactory results.

$LP RI WKH VWXG\: To monitor the patients diagnosed with BRONJ who had received or were receiving bisphosphonates.

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The present study included patients from 2 maxillofacial surgery centers (OMF Surgery Clinic, Sibiu District Hospital, and OMF Department of Surgery, Sibiu Military Hospital, respectively) between 2008 and 2012.

The goal of the study was to monitor the patients diagnosed with BRONJ who had

received or who were receiving bisphosphonates. Patients with a history of radiotherapy in the maxillofacial region were excluded from the study. The follow-up period ranged between 1 and 16 months, with an average of 9 months.

Focus was put on the differences appearing along the stages of the disease, correlated with the period of drug administration, drug type, method of delivery, pathology for which they had been prescribed, factors provoking it, and also with the response to nonsurgical and surgical treatment (Table 1).

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Patient Sex Age/

Years BP Disease

Period of drug administration

Ceased

BP Stage Treatment Healing

1. M 56 Z MM 18 NO 2 AB S1 2. M 76 Z PC 36 YES 1 AS S 3. M 58 Z MM 16 NO 2 AB+S H 4. F 49 Z BC 29 YES 3 AB+S H 5. F 48 P BC 30 NO 2 AB S1 6. F 59 P BC 36 NO 2 AB+S R 7. F 68 P BC 31 YES 1 AS S 8. M 64 P MM 39 NO 1 AS S 9. M 46 Z MM 31 NO 2 AB S1 10. F 65 P BC 28 YES 3 AB+S H 11. F 65 Z BC 27 NO 1 AS S 12. F 52 P MM 32 NO 1 AS S 13. M 56 Z MM 36 NO 2 AB+S R 14. F 61 Z MM 29 NO 1 AS S 15. F 74 A OP 44 NO 2 AB S1 16. F 49 Z BC 24 YES 3 AB+Res H 17. M 75 Z PC 26 YES 1 AS S 18. M 65 Z PC 19 YES 1 AS S 19. F 54 Z BC 23 NO 2 AB S1 20. M 75 Z PC 26 NO 2 AB+S H 21. M 48 Z RC 35 NO 2 AB+S H 22. F 47 A OP 39 NO 1 AS S 23. F 49 A OP 42 YES 1 AS S 24. F 56 Z BC 16 NO 2 AB+S R 25. F 64 Z BC 29 NO 2 AB S1 26. F 59 Z MM 35 NO 2 AB+S H 27. F 62 Z MM 17 NO 2 AB S1 28. F 58 I OP 48 YES 2 AB S1

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The test group included 28 patients diagnosed with BRONJ, treated with bisphosphonates between 2008 and 2012. Diagnosis was established according to the recommendations of The American Association of Oral and Maxillofacial Surgeons, as follows:

- An exposed bone in the oral cavity for more than 8 weeks

- Bisphosphonate treatment in the moment of diagnosis or anterior to it

- No history of radiotherapy in the maxillofacial region

The diagnosis included an oral exam, an X-ray exam (OPG, CT), patient history, and a histopathology exam.

Out of the total number of 28 patients, 10 were males (35%) and 18 females (65%). The average age was 59. The main method of drug administration was intravenously (in 24 patients, 85.7%), only 4 patients (14.3%) receiving bisphosphonates orally. The pathology for which they received BP drugs was: breast cancer (no=9, 32%), multiple myeloma (9, 32%), prostate cancer (4, 14.3%), renal carcinoma (1) and osteoporosis (4, 14.3%).

Most of the patients (18, 64.5%) received zoledronate I.V., pamidronate I.V. (6, 21.4%), oral alendronate (3, 10.7%), and oral ibandronate (1, 3.5%).

The average time of BP therapy administration, from the onset of BRONJ, was of 36.9 months (ranging from 16 to 48 months). According to the type of BR used, the average period from the RXWEXUVWRIWKHPDODG\SDWKRORJ\XQWLOWKHÀUVW VLJQV RI %521- ZDV IRU ]ROHGURQDWH ² months (between 16-36 months), for pamidronate ² PRQWKV EHWZHHQ PRQWKV IRU alendronate 41.6 months (between 39-44 months) and for ibandronate - 48 months.

Bone exposure was observed in the following regions: molar (18, 64.3%), premolar (7, 25%), internal oblique crest (3, 10.7%), frontal (1, 3.5%).

The jaw was more affected than the maxilla (19, 68%). Stage distribution was the following: stage 2 (15, 53.5%), stage 1 (10, 35.7%), and stage 3 (3, 10.7%).

Stage distribution according to the of BP used ZDV IRU VWDJH ² SDWLHQWV ZLWK zoledronate and 1 patient (33%) with pamidronate; IRUVWDJH²SDWLHQWVZLWK]ROHGURQDWH 2 patients (13.3%) with pamidronate, 1 patient (6.6%) with ibandronate and 1 patient (6.6%) ZLWKDOHQGURQDWHIRUVWDJH²SDWLHQWV with zoledronate, 3 patients (30%) with pamidronate and 2 patients (20%) with alendronate (Fig.1).

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The major factor that caused the onset of BRONJ was: tooth extraction in 22 patients (78.5%), and denture lesions in 3 patients (10.1%). In 3 patients (10.1%), the onset was spontaneous.

Treatment in stage 1 consisted in mouthwashes with antiseptics, improvement of oral care for patients, follow-ups every 3 months, non-surgical dental treatments (cleanings, endodontic and odontal treatments). At the time of the study, all stage 1 patients were under close monitoring.

Stage 2 treatment included oral antiseptics (clorhexidine solution mouthwash 3 times/ day/14 days) and antibiotics (2g/day of amoxicillin + clavulanic acid and metronidazole JGD\IRUGD\V,QSDWLHQWVLQÁDPPDWLRQ persisted, so that antibiotics were delivered in I.V. form (after antibiotics sensitivity test). In 7 patients (46.6%), after a 3 month conservative treatment, a bony sequester was exposed and a procedure to remove it was performed.

The remaining bone tissue was covered with ORFDOÁDSV7KHSDWKRORJ\UHODSVHGZLWKRXWVLJQV RILQÁDPPDWLRQLQWKHSDWLHQWVZKRXQGHUZHQW this procedure.

In stage 3, 2 localizations were on the maxilla and 1 on the mandible. At the maxilla, the trigger was molar extraction, which caused the onset of BRONJ, with oroantral communication and sinusitis.

The patients were put on antibiotics therapy and, after undertaking the antibiotics sensitivity WHVWDVSHFLÀF,9ZDVLQVWDOOHGVLPLODUWRWKDW RIVWDJHGD\VODWHUZKHQWKHLQÁDPPDWLRQ ceased, resection of the necrotic bone was performed and communication was closed in 2 layers.

At the mandible site, a segmental bone UHVHFWLRQZDVSHUIRUPHGDIWHUVSHFLÀFDQWLELRWLFV treatment. B-CTX analysis was performed in the preoperative phase, the recorded values of the marker exceeding 200pg/ml. At 1, 3 and 6 month follow-ups, healing was noticed with no signs of relapse. The 3 patients stopped taking their BP drug treatment by the time of the surgery.

After analyzing the percentage of healed patients according to the BP drug involved, the UHFRUGHG UHVXOWV ZHUH IRU ]ROHGURQDWH ² KHDOHGDQGUHODSVHGIRUSDPLGURQDWH² healed and 16% relapsed. The number of patients ZDVWRRVPDOOWRKDYHDQ\VWDWLVWLFDOVLJQLÀFDQFH

The total healing rate was of 25% (a healed patient was considered to be the one with no exposed bone in the oral cavity), whereas, at the time of the study, 28% of the patients were diagnosed at an inferior stage (downgrading to stage 1).

The necrotic bone was sent to the pathology laboratory where the diagnostic of BRONJ was FRQÀUPHG)LJ )LJ1HFURWLFVSRQJ\WLVVXHERQHVWUXFWXUHZLWK KDOORZRVWHREODVWVZLWKRXWRVWHRF\WHVDQGQHFURWLF PHGXOODUWLVVXHZLWKQHFURVLVRIEDVRSKLO JUDQXORF\WHVDQGFKROHVWHUROFU\VWDOV+(; ',6&866,21

Although they are not intended as curative drugs in bone metastasis of breasts, prostate cancer or of multiple myeloma, BPs improve the quality of life [7], due to their potential to inhibit the tumor growth factors. Zoledronate BPs help to control the spread of metastatic cells of breast cancer in bone marrow [8]. These cells are resistant to the usual chemotherapy drugs, and their presence in the marrow indicates negative prognosis. The mechanism of BPs action is, on one hand, chemical, by their nature (as analogues of inorganic pyrophosphate), while, on the other, they also show cellular activity. One of their characteristics is to migrate towards areas with intense bone activity. Because of their molecular formula, they have a high resistance to hydrolysation [9]. BP drugs containing nitrogen groups in their chemical formula have not only LQFUHDVHG HIÀFDF\ EXW DOVR LQFUHDVHG WR[LFLW\ Half-life elimination of BPs is believed to be over 10 years for some types [10]. As they can bind to hydroxyapatite through hydrogen links, BPs remain in the bone tissue. In fact, repeated dosage of BPs increases their concentration inside the bone. The osteoclastic activity destroys the aged bone and, by doing this, it also incorporates BPs in the osteoclasts. These BPs act inside the osteoclasts as an analogue of important lipid particles which play a key role in cell apoptosis. And, although the osteoclasts are killed earlier, the bone growth factors and the production of new bone are active. The aged bone, not being destroyed by osteoclasts, becomes fragile, with vascular disorders and unable to protect itself against infection. This continuing process of bone activity leads, in the end, to exposure of the bone in the oral cavity [11]. Malignant processes spread cytokines that set off osteoclasts, forcing an accelerated bone phagocytization, leaving behind a bony lacuna which is colonized by cancer cells. Through their action on osteoclasts, BPs prevent spreading of bone metastasis [12]. 0RUHRYHU FDQFHU PDVVHV FDQ FDXVH VSHFLÀF syndromes, such as malignant hypercalcemia, which may be sometimes lethal. BPs have a rapid effect on the serum level of Ca. BPs have proved WKHLU HIÀFDF\ LQ SUHYHQWLQJ WKH DSSHDUDQFH RI

bone metastasis in different types of cancer: lung [13], prostate [14] or breast [15] and multiple myeloma [16]. Zoledronate appears as the most effective [17] of the whole range of BPs available in drug stores. Jaws are more affected than other bones because of their accelerated turn-over and because the bone is very close to the septic oral cavity [18]. In fact, jaws have a 3 times more accelerated turn-over than the rest of the bones [19].

Compared with the patients subjected to a BP drug therapy, the incidence of BRONJ is reported to be around 1% [20], or even higher: 6-7% in oncology patients [21] or even 10% in patients suffering with myeloma [22]. According to a BRONJ analysis, the incidence in European population by the year 2008 was of 5,300 cases [23].

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0 is characterized by the lack of exposed bone, but with radiological signs. The present study did not include patients in stage 0, as it was conducted in 2 maxillofacial surgery centers, and these type of patients are more often encountered

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to generate BRONJ than oral BPs [24]. Over 90% of the cases included in the study had BP drugs taken in I.V. mode. Zoledronate is considered to be the most toxic of all BPs [25], maybe due to the fact that it is more often prescribed for its

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patients following or having followed a treatment with zoledronate. The number of BRONJ reports in patients that take BP orally is increasing [26]. This study shows that the mandible is less affected than the maxilla, which agrees with the conclusions of the vast majority of literature reports [27].

Dental extraction acts like a trigger for BRONJ [28], over 78% of the patients having a history of dental extraction prior to the onset of the pathology. Another determining element is the administration period. In the current study, the minimum period was of 16 months, with a median of over 2 years, with respect to other reports [29]. Aslo important is the dosage and frequency of administration. With the increase of the total dose, there is also an increase in the risk of BRONJ manifestation [30]. The present

study did not include a protocol for BP therapy cessation, the so-called drug holiday. Reports from the literature mention that, when the

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cessation of the BP therapy [25], but by the presence of new sites, when diagnosis appears to be influenced by the continuance or discontinuance of the therapy [31]. The treatment was applied according to AAOMS statements. In early stages (stage 1), it consisted of antiseptic mouthwashes and conservative dental procedures. In stage 2, when antibiotics were added, in 7 out of 10 cases a surgical intervention to remove the sequel was performed. Patients were monitored and, at the last follow up (12

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1. In stage 3, a bone resection was performed after the conservative treatment, and the

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the last follow-up (6 months), there was no exposed bone in the oral cavity. No relapses were recorded in stage 3, although this stage is more likely to present relapses [32], a possible explanation being the small number of cases diagnosed as stage 3. Healing rate was lower than in other studies, which reported rates up to 55% [33].

&21&/86,216

Bisphosphonate-related osteonecrosis of the jaw is a new entity in maxillofacial surgery. The treatment is time-consuming, with many relapses, and new sites developed in the same patient. Prophylaxis plays a major part in the management of this disease. Before prescribing bisphosphonates, the patient should be instructed by the oncologist to address a dentist for a thorough checkup and a careful monitorization during the therapy.

5HIHUHQFHV

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