The outcomes of conservative and surgical treatment of stage 2 bisphosphonate-related osteonecrosis of the jaws: a case series

Abstract

The purpose of the current retrospective chart review is to describe the outcomes of conservative or surgical treatment of stage 2 bisphosphonate-related osteonecrosis of the jaws (BRONJ). 14 charts (mean patient age 69.07 ± 10.37 years) describing 19 BRONJ stage 2 sites were identified. According to the treatment protocol, all patients received conservative treatment. Surgical treatment was delivered only to sites that did not respond to conservative treatment. Conservative treatment alone was delivered to 11 sites in 8 patients (mean postoperative follow-up 17.6 ± 9.4 months). Surgical treatment was delivered to 8 sites in 6 patients (mean postoperative follow-up 10.0 ± 6.1 months). Bisphosphonate exposure ranged from 1 to 8 years. In most cases, tooth extractions and wearing dentures were reported as triggers for BRONJ. At the last follow-up, BRONJ stage 0 was noted in 7 sites that received conservative treatment and 5 sites that received surgical treatment. Within the limitations of the current chart review, the results showed that although conservative treatment for BRONJ stage 2 can provide favourable outcomes, surgical treatment represents a suitable alternative in non-responsive cases.

Bisphosphonates and denosumab are drugs that have a strong influence on bone remodelling. Bisphosphonates inhibit osteoclast recruitment, differentiation and induce osteoclast apoptosis.

Bisphosphonates also have direct effects on other cells. They appear to prevent apoptosis of osteoblasts and osteocytes, and inhibit the growth of epithelial cells. Oral bisphosphonates have been increasingly used in the management of osteoporosis, Paget’s disease and osteogenesis imperfecta. The use of intravenous bisphosphonates is also common in the context of cancer therapy such as multiple myeloma and bone metastasis from solid tumours. Bisphosphonates associated with cancer therapy preserve bone integrity and reduce the risk of skeletal complications. They have direct antitumor effects by reducing the release of cancer growth factor, and inhibiting cancer cell adhesion and invasion.

There is growing evidence supporting the link between bisphosphonate-related osteonecrosis of the jaws (BRONJ) and the administration of bisphosphonates. It was estimated that up to 12% of patients treated with intravenous bisphosphonates for cancer develop BRONJ following dental intervention. BRONJ among patients taking oral bisphosphonates was estimated at 0.1%. Spontaneous development of BRONJ with no history of dental treatment or trauma to the oral cavity was also observed.

BRONJ stages and treatment alternatives are described in the current guidelines. Accordingly, treatment for stages 0 and 1 is conservative and treatment for stage 3 is surgical resection of the necrotic bone. According to these guidelines, management of established BRONJ stage 2, which is typically associated with exposed bone, erythema, ulceration of the soft tissues and pain with or without purulent drainage, is conservative, but recent case series showed positive outcomes after surgical therapy. The present retrospective chart review aimed to describe the outcomes of BRONJ stage 2 in a cohort of patients who received conservative therapy alone or followed by surgical treatment.

Materials and methods

This study was approved by the McGill University Health Center Research Ethics Board. All patients diagnosed and treated for BRONJ stage 2 between July 2008 and July 2011 were identified. The inclusion criteria were: male and female patients aged 18 years and older; patients receiving oral and/or intravenous bisphosphonates; patients diagnosed with BRONJ stage 2 at the time of admission to the Oral and Maxillofacial Surgery Clinic; patients treated according to the protocol for BRONJ stage 2 at the Montreal General Hospital; and patients with minimum 6-month follow-up.

Patients with history of radiation to the head and neck area were excluded from the study. According to the treatment protocol for BRONJ stage 2 at the Montreal General Hospital, all patients received conservative therapy. Conservative treatment focused on reinforcing oral hygiene, regular dental follow-up, mouthrinse administration (chlorhexidine 0.12%, twice per day) and superficial necrotic bone debridement with topical anaesthesia. Patients who did not show signs of improvement after 8 weeks of conservative treatment associated with appropriate antibiotic coverage and when the area of radiolucency measured more than 1 cm in thickness on panoramic X-ray were offered surgical treatment after discussion with their treating specialist.

Temporary bisphosphonate discontinuation was also discussed with the treating specialist. Patients who accepted the surgical treatment underwent surgical debridement and sequestrectomy of the necrotic bone. As indicated by the treatment protocol for cases with large areas of necrotic bone, general anaesthesia was used. After induction of general anaesthesia, the face and neck were prepped and draped. The gingiva over the affected area was incised and full thickness flaps were elevated on the buccal and lingual aspects. The necrotic bone was removed using a high speed drill until bleeding bone was present in the surgical site. Care was taken to preserve vital structures when possible (e.g. inferior alveolar nerve). The site was irrigated and closed primarily with 3.0 vicryl sutures. When tension was noted in the flaps, releasing incisions and scoring of the periosteum were performed. All surgical procedures were performed by the same surgeon. The following parameters were extracted from the charts: age, gender, indication of bisphosphonate therapy, type and duration of bisphosphonate therapy, locations of BRONJ, co-medications, dental and medical history. BRONJ was diagnosed and staged according to the American Association of Oral and Maxillofacial Surgeons position paper (AAOMS). Descriptive analysis was used in the current case series.

Results

19 sites in 14 patients (males 4, females 10, mean age 69.07 ± 10.37 years) were identified ( Table 1 ). Exposure to bisphosphonates ranged from 1 to 8 years. The mean postoperative follow-up for both treatments was 12.67 ± 9.02 months. Intravenous bisphosphonates were prescribed to 11 patients for the treatment of: metastatic breast cancer ( n = 5); metastatic prostate cancer ( n = 2); kidney cancer ( n = 2); multiple myloma ( n = 1); and osteoporosis ( n = 1). Oral bisphosphonates were administered in 3 patients for the treatment of osteoporosis and osteopenia. The corticosteroid prednisone was used in 4 patients ( Table 1 ).

Table 1
Patient characteristics at the time of admission.
Patient Age (years) Gender Indication for bisphosphonate therapy Bisphosphonates Temporary bisphosphonate discontinuation Related co-medications Reported duration of bisphosphonate therapy (months) Reported trigger
1 75 F Osteoporosis Alendronate (PO) Not available Not available Not available Denture
2 51 F Osteoporosis Alendronate (PO) Yes Prednisone 36 Denture
3 60 F Kidney cancer Pamidronate (IV) Zoledronic acid (IV) Yes 6
10
Denture
4 79 F Multiple myeloma Zoledronic acid (IV) Yes Prednisone, melphalan 10 Tooth came out on its own
5 56 F Breast cancer Pamidronate (IV) Yes Capecitabine >84 Denture
6 78 M Prostate cancer Zoledronic acid (IV) No Prednisone 24 Remaining root extractions
7 69 M Kidney cancer Zoledronic acid (IV) Yes Sunitinib 24 Spontaneous
8 87 F Osteopenia Alendronate (PO) Yes Not available Tooth extractions
9 64 F Breast cancer Zoledronic acid (IV) Yes Exemestane 60 Not available
10 66 M Prostate cancer Zoledronic acid (IV) No Prednisone, docetaxel, vinorelbine, abiraterone acetate, sunitinib 12 Tooth extractions
11 68 F Breast cancer Zoledronic acid (IV) No Exemestane 72 Tooth extractions
12 79 M Osteoporosis Alendronate (IV) No 96 Tooth extractions
13 59 F Breast cancer Pamidronate (IV) Yes Tomoxilen, trastuzumab 17 Tooth extractions
14 76 F Breast cancer Zoledronic acid (IV) Yes Sunitinib 24 Tooth extractions

BRONJ was more frequent in the mandible than in the maxilla (4 in maxilla; 15 in mandible). In most cases, patients reported that the lesions were initiated in association with dental procedures such as tooth or root extractions ( n = 8) or wearing dentures ( n = 4). One patient reported spontaneous BRONJ. The trigger was not documented in 1 case.

During the course of BRONJ therapy, none of the treated sites progressed to stage 3 BRONJ. At the last follow-up, none of the patients died or had their health status apparently changed due to bisphosphonate therapy discontinuation ( Table 1 ).

Conservative treatment was delivered to 11 sites in 8 patients (mean postoperative follow-up 17.6 ± 9.4 months). At the 3-month follow-up, BRONJ stage 0 was not noted in any site ( Figs. 1 and 2 ). At the last follow-up, BRONJ stage 0 was present in 7 sites, stage 1 was present in 2 sites and stage 2 was present in 2 sites ( Table 2 ).

Fig. 1
BRONJ staging after conservative or surgical treatments.

Fig. 2
Cumulative rate of sustained BRONJ stage 0.

Table 2
The outcomes of conservative treatment of BRONJ at 3- and 6-month follow-up, and at last follow-up.
Patient Site of necrosis Conservative treatment BRONJ at 3-month follow-up BRONJ at 6 month follow-up BRONJ at the last follow-up (months)
1 Left maxilla Mouthwash (+)B (−)P (−)I (+)B (−)P (−)I (−)B (−)P (−)I (27)
1 Right posterior maxilla Mouthwash (+)B (−)P (−)I (−)B (−)P (−)I (−)B (−)P (−)I (27)
2 Left mandible Mouthwash Not available (+)B (−)P (−)I (−)B (+)P (−)I (24)
2 Right mandible Mouthwash Not available (+)B (+)P (−)I (−)B (+)P (−)I (24)
3 Left anterior maxilla Mouthwash (+)B (+)P (+)I (+)B (+)P (+)I (+)B (+)P (+)I (6)
4 Left posterior mandible Mouthwash Not available (+)B (+)P (+)I (+)B (+)P (+)I (7)
5 Mylohyoid ridge of left mandible Conservative debridement and mouthwash (+)B (+)P (+)I (−)B (−)P (−)I (−)B (−)P (−)I (8)
5 Mylohyoid ridge of right mandible Conservative debridement and mouthwash (+)B (+)P (+)I (−)B (−)P (−)I (−)B (−)P (−)I (8)
6 Left posterior mandibular Surgical incision and drainage (+)B (−)P (−)I (+)B (−)P (−)I (+)B (−)P (−)I (27)
7 Right posterior mandible Superficial debridement (+)B (−)P (+)I (+)B (−)P (−)I (+)B (−)P (−)I (10)
8 Left posterior mandible Mouthwash (+)B (−)P (+)I (+)B (−)P (+)I (−)B (−)P (−)I (25)
B: presence of bone exposure; P: presence of pain; I: presence of secondary infection.

Surgical intervention was delivered to 8 sites in 6 patients (mean postoperative follow-up 10.0 ± 6.1 months). The presence of bone necrosis in these patients was confirmed by the pathology report. At the 1-month follow-up, 6 sites were characterized by BRONJ stage 0 ( Figs. 1 and 2 ). At the last follow-up, BRONJ stage 0 was present in 5 sites, stage 1 was present in 1 site and stage 2 was present in 2 sites ( Table 3 ).

Table 3
The outcomes of surgical treatment of BRONJ at 1-, 3- and 6-month follow-up, and at last follow-up.
Patient Site of necrosis Duration between diagnosis and surgical treatment (months) Surgical treatment Antibiotic coverage BRONJ at 1 month follow-up BRONJ at 3 month follow-up BRONJ at 6 month follow-up BRONJ at the last follow-up (months)
9 Right mandible 36 Debridement/squestectomy Amoxicillin + Clavulanate (−)B (−)P (−)I (−)B (−)P (−)I (−)B (−)P (−)I (−)B (+)P (−)I (17)
9 Right maxilla 84 Debridement/squestectomy Amoxicillin + Clavulanate (−)B (−)P (−)I (−)B (−)P (−)I (−)B (−)P (−)I (−)B (−)P (−)I (17)
10 Right mandible 36 Debridement/squestectomy Amoxicillin + Clavulanate (−)B (−)P (+)I (+)B (+)P (+)I (+)B (+)P (+)I (+)B (−)P (+)I (15)
11 Anterior mandible 7 Debridement/squestectomy Amoxicillin + Clavulanate (−)B (+)P (−)I (+)B (−)P (−)I (+)B (−)P (−)I (+)B (−)P (−)I (13)
12 Left mandible 11 Debridement/squestectomy Penicillin VK (−)B (−)P (−)I (−)B (−)P (−)I (−)B (−)P (−)I (−)B (−)P (−)I (6)
12 Right mandible 11 Debridement/squestectomy Penicillin VK (+)B (+)P (+)I (+)B (+)P (+)I (−)B (−)P (−)I (−)B (+)P (−)I (6)
13 Left mandible 2 Debridement/squestectomy Amoxicillin + Clavulanate (−)B (−)P (−)I (−)B (−)P (−)I (−)B (−)P (−)I (−)B (−)P (−)I (6)
14 Left posterior mandible 3 Debridement/squestectomy Penicillin VK (+)B (−)P (−)I (+)B (−)P (−)I (+)B (−)P (+)I (+)B (−)P (+)I (6)
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Jan 26, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on The outcomes of conservative and surgical treatment of stage 2 bisphosphonate-related osteonecrosis of the jaws: a case series
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