Bisphosphonate-related osteonecrosis of the jaws : A report on 30 cases

Aim: To report a series of thirty cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Material and Methods: For 30 patients with BRONJ, gender, age, underlying diagnosis, type of bisphosphonate (BP), administration route and duration, location and stage of osteonecrosis, symptoms and oral health status, radiological findings of the jaws, treatment and outcome, were recorded. Results: Underlying diagnoses in the series (12 male; 18 female; mean age 70.50 ± 9.62) were: 12 multiple myeloma, 7 breast cancer, 3 prostate carcinoma, 1 kidney/lung/ bladder/mediastinal cancer, 1 chronic lymphocytic leukemia, 1 osteoporosis, 1 palatal osteosarcoma + osteoporosis, 1 non-Hodgkin’s lymphoma. Forty-seven osteonecrotic lesions were detected; 30 localized in the mandible, 17 in the maxilla; trigger events were tooth extraction in 31 cases (66%), periodontal disease in 4 (8.50%), incongruous dentures in 3 (6.40%), perimplantitis in 1 (2.10%), unknown in 8 (17%). Twenty-nine patients had received treatment using amino bisphosphonates (25 zoledronate, 2 pamidronate, 2 alendronate) and 1 clodronate; the administration route was intravenous in 27 patients, oral in 2 and intramuscular in 1. Mean number of doses to bone exposure for patients was 34.11 for zoledronate, 50.50 for pamidronate, 146 for alendronate, and 500 for clodronate. Among statistical data the only significant finding was that panoramic dental radiography gave no concrete support for diagnosis of ONJ lesions (p ≤ 0.04). Conclusions: Our case series reflects literature data. We emphasize the insufficient role of panoramic radiography to study osteonecrotic lesions and the role of poor oral hygiene.


INTRODUCTION
Bisphosphonates (BPs) are a class of drugs derived from pyrophosphates, endogenous inorganic regulators of mineralization, by substituting the oxygen atom in the basic pyrophosphate chain with a carbon; this leads to osteoclast inhibition, decreasing bone resorption [1][2][3].Different generations of BPs have been created, with distinct pharmacological potency [1][2][3].The first generation of BPs comprises etidronate and clodronate, characterized by a chlorine atom.The second generation of BPs comprises alendronate and pamidronate, in which an amino-terminal group has been introduced; these drugs have antiresorptive potency that is 10 -100 times higher than that of etidronate and clodronate.Zoledronate is a BP of the third generation, and has an imidazole ring group in the side chain with the potency about 100 times higher than pamidronate.The administration route for clodronate is intramuscular or oral or intravenous, for alendronate it is oral, and for pamidronate and zoledronate it is only intravenous [1][2][3].The effects of BPs include the reduction of bone loss and of the risk of pathological fractures; these drugs are thus administered to patients suffering from destructive bone lesions resulting from osteoclast-induced resorption [3][4][5]; they are mainly used to treat and prevent malignant hypercalcemia, skeletal-related events associated with bone metastases secondary to solid cancer, and in the management of the lesions of multiple myeloma, Paget's disease, primary and secondary hyperparathyroidism and osteoporosis [2][3][4][5][6][7][8][9][10][11].Starting from 2003, reports began to appear of necrotic bone exposure of the jaw [12,13] in patients receiving BPs for multiple myeloma and bone cancer metastases: the osteonecrotic lesions are now known as bisphosphonate-related osteonecrosis of the jaw (BRONJ) [14,15].This phenomenon has mainly been observed after intravenous administration of BPs containing nitrogen [9,12,[14][15][16][17][18][19][20][21][22][23][24][25][26].Following the early reports, several other cases of BRONJ have also been reported in osteoporosis patients treated with BPs [27][28][29][30][31][32].This study reports on 30 patients with jaw exposure who had undergone treatment with BPs.

Sample
The study received permission from the local ethics committee (EC study protocol 61/10) and was carried out in accordance with the ethical standards of the Helsinki Declaration of 1964.Thirty patients with jaw bone exposure of at least 8 weeks duration, with no history of head and neck radiation therapy, history positive for BPs therapy and negative for local radiation therapy, who had been referred to our Department between May 2005 and December 2011 were enrolled.After being informed of the aims and methods of the study, patients gave their written consent to participation.Sex, age, underlying diagnosis, type, duration, and administration route of BP treatment, time of onset of ONJ, treatment and outcome were recorded for all patients.The disease stage was registered according to AAOMS staging system [14,15].Oral examination determined oral health status, indexes of oral hygiene (GI, gingival index as per Löe and Silness; PI, plaque index, as per Silness and Löe) [33,34], location, size, and clinical symptoms of osteonecrosis.Data from instrumental analysis was also recorded.

Statistical Analysis
Statistical analysis was performed using SPSS (SPSS Inc.Chicago, US) for Windows, version 12, with p < 0.05 considered significant.

RESULTS
Having given their written informed consent, all patients were examined; no side effects were observed during the examinations.A total of 47 osteonecrotic lesions were detected in 30 patients (12 m; 18 f), fourteen afflicted by metastases of solid carcinomas (7 breast cancer, 3 prostate cancer and one respectively bladder, lung, kidney, mediastinal cancer), twelve by multiple myeloma, and one respectively by osteoporosis and palate osteosarcoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma, osteoporosis.Onset of BRONJ was earlier in women (mean age 66.55 years old, min 43.25) than in men (mean age 68.12 years old, min 51.66) (Table 1).BRONJ occurred in 29 patients (96.60%) who had been treated with aminoBPs (zoledronate, pamidronate, alendronate).Zoledronate alone (4 mg IV every 4 weeks) was administered to 21 patients (70% of the series); 4 patients (13.40%) switched from pamidronate to zoledronate; other 2 patients (6.70%) received pamidronate (90 mg IV every 4 weeks): one (3.35%)pamidronate alone and one (3.35%)switched from zoledronate to pamidronate; further 2 patients (6.70%) took alendronate (70 mg OS weekly).Only one patient (3.30%) with osteoporosis took a bisphosphonate containing chlorine (100 mg IM weekly) (Table 2).The onset of BRONJ was earlier in patients receiving zoledronate, alone or following pamidronate.The mean number of doses, administered IV, for patients affected by metastases of solid cancers, multiple myeloma, or osteoporosis + osteosarcoma, was 34.11 doses (min 8, max 61, SD + 12.15) in the case of zoledronate and 50.50 doses (minimum 37, maximum 64, SD ± 19.09) in the case of pamidronate.The single patient with chronic lymphocytic leukemia, and the one with non-Hodgkin's lymphoma, respectively took 32 and approximately 260 oral doses of alendronate.The mean time to onset of ONJ was 146 weeks.However, patients also took high doses of corticosteroids to treat leukemia and lymphoma.Only one patient (3.30%) with osteoporosis took a bisphosphonate containing chlorine intramuscularly, approximately 500 doses (about 10 years) (Table 2).Oral examination showed that 5 patients were totally edentulous (4 women and 1 man), all wearing with removable dentures; in the 25 dentate patients oral health status and oral hygiene were poor: the mean value of the plaque index (PI) was 2.00 and this one of gingival index (GI) was 1.85 (Table 3).Of the 47 osteonecrotic lesions, 17 (36.15%)were in the maxilla (8 right; 9 left) and 30 (63.85%) in the mandible (13 right; 17 left).Sixteen patients had lesions in the mandible alone, 9 in the maxilla alone, and 5 had lesions in both jaws; this confirms reports in the literature indicating a higher percentage of BRONJ in the mandible.The stages of the lesions are reported in Table 4 and the trigger events are given in Table 5.Of our series, 23 patients (76.65%) reported symptoms, while 7 (23.35%)were completely asymptomatic at the time of observation.Twenty-one patients (70%) reported pain; 19 (63.30%) had signs of inflammation of the tissues surrounding the lesion; 13 (43.30%)showed swelling of the tissues surrounding the exposed bone; 13 (43.30%)reported difficulty in mastication; 3 (10%) had a cutaneous fistula; 2 (6.70%) an oromaxillary fistula; 1 (3.30%) had a mandibular fracture.The signs of BRONJ mentioned in the radiologists' reports are "structural alteration of trabecular bone, osteolytic lesion, cortical bone erosion, areas of bone destruction, osteosclerosis, radiolucent lesion corresponding to empty socket, small or extensive radiopaque sequestra, presence of periosteal reaction, mucoperiosteal thickening in the maxillary sinuses, oroantral communication" [26,[35][36][37][38].All patients (N = 30) at the time of the examination had a recent panoramic radiograph (OPT), but in only 8 ( 1).Conversely, NMR and CT imaging offer a range of findings, depending on the stage and extension of lesions, confirming that these examinations are more reliable for diagnosing osteonecrotic lesions.Used in combination with clinical findings, these imagines improve treatment planning [39][40][41][42].Only 2 patients with ONJ (6.70%) in our series had been sub- jected to a dental care protocol aimed at preventing osteonecrosis before start of BP treatment.Seven patients in the series were treated with topical maintenance therapy only, 13 with topical and systemic pharmacological treatment to palliate symptoms associated with systemic infection of the tissues surrounding the area of osteonecrosis; 5 with topical, pharmacological and surgical revision of the lesions under local anesthesia; 5 with topical, pharmacological, surgical revision under local anesthesia and surgical resection under general anesthesia.The outcome at six months was favorable in 6 cases, with complete repair of the tissues overlying the osteonecrotic lesion (3 treated with topical, pharmacological, and surgical revision of the lesion under local anesthesia; 3 also with surgery under general anesthesia); in 16 patients the lesion was unchanged (5 treated with topical therapy only; 11 with topical and systemic pharmacological treatment); in 4 patients the lesion deteriorated (2 treated with outpatient surgery; 2 with resection under general anesthesia) and 4 died before evaluation (2 treated with

CONCLUSION
Bisphosphonate-related osteonecrosis of the jaws is a clinical and pathological entity that is not yet fully understood; the true incidence of this adverse effect is almost certainly underestimated.Many patients of our sample were sent from different Institution.For this reason it was not possible to subject all to the same imaging investigations and moreover, even to an untrained eye, evaluative discrepancies appear clearly between different radiologists.The most interesting findings of the current study are the lack of correlation between panoramic radiograph and osteonecrotic lesions, and the high grade of the plaque index and gingival index in patients of this series in spite of recommendations of maintaining a good oral hygiene to prevent oral diseases in patients at risk of BRONJ.In the expectation of results from research that may enable us to prevent osteonecrotic lesions, many works remain to be achieved to improve the education to oral health of physicians, dentists, dental hygienists and patients.

Figure 1 .
Figure 1.Fisher exact test on significance of panoramic radiograph (OPT) in diagnosing of BRONJ.

Table 1 .
Patients characteristics.BPs: Bisphosphonates; MM patients: patients affected by multiple myeloma; MTS: metastases of solid cancer.

Table 3 .
Data from oral examination.

Table 4 .
Number and stage of lesions in the different quadrants (Q1 upper right, Q2 upper left, Q3 lower left, Q4 lower right) of the maxilla and mandible.

Table 5 .
Trigger of BRONJ in the patients of our sample afflicted by: MM, multiple mieloma; MTS, metastases of solid cancer; CLL, Chronic lymphocytic leukemia; OST, osteoporosis; NHL, non Hodgkin's lymphoma; OST/PO, osteoporosis and osteosarcoma of palate.