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Primary Surgical Therapy for Osteonecrosis of the Jaw Secondary to Bisphosphonate Therapy

2006; Elsevier BV; Volume: 81; Issue: 8 Linguagem: Inglês

10.4065/81.8.1100

1942-5546

Deepak Kademani, Sreenivas Koka, Martha Q. Lacy, S. Vincent Rajkumar,

Cancer Diagnosis and Treatment

Bisphosphonate chemotherapy is commonly used in the treatment of bone diseases such as osteoporosis, Paget disease, and multiple myeloma and to limit bone pain and hypercalcemia associated with malignant metastatic bone lesions. The introduction of bisphosphonate therapy has improved the quality of life in a vast majority of patients, showing clear medical efficacy. However, since 2003 a growing number of reports have described necrotic bone lesions (osteonecrosis of the jaw [ONJ]) affecting maxillofacial bones in patients who have received chemotherapy with intravenous bisphosphonate therapy. Unfortunately, the development of ONJ has been refractory to conventional treatment modalities. Several treatment options have been proposed for ONJ, most of which focus primarily on conservative management with local irrigation and empirical long-term antibiotic therapy. However, results of treatment have been associated with high failure rates, progression of disease, and continued decline in patients' quality of life. We describe 2 patients in whom primary surgical salvage was performed successfully for ONJ. Our experience indicates that with appropriate technique, primary surgical treatment may offer benefit to selected patients with ONJ. Bisphosphonate chemotherapy is commonly used in the treatment of bone diseases such as osteoporosis, Paget disease, and multiple myeloma and to limit bone pain and hypercalcemia associated with malignant metastatic bone lesions. The introduction of bisphosphonate therapy has improved the quality of life in a vast majority of patients, showing clear medical efficacy. However, since 2003 a growing number of reports have described necrotic bone lesions (osteonecrosis of the jaw [ONJ]) affecting maxillofacial bones in patients who have received chemotherapy with intravenous bisphosphonate therapy. Unfortunately, the development of ONJ has been refractory to conventional treatment modalities. Several treatment options have been proposed for ONJ, most of which focus primarily on conservative management with local irrigation and empirical long-term antibiotic therapy. However, results of treatment have been associated with high failure rates, progression of disease, and continued decline in patients' quality of life. We describe 2 patients in whom primary surgical salvage was performed successfully for ONJ. Our experience indicates that with appropriate technique, primary surgical treatment may offer benefit to selected patients with ONJ. A series of recent reports suggests that long-term bisphosphonate therapy (BPT), most commonly administered intravenously (IV) as adjunctive therapy to cancer patients, is associated with osteonecrosis of the jaw (ONJ).1Bamias A Kastritis E Bamia C et al.Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors.J Clin Oncol. 2005; 23: 8580-8587Crossref PubMed Scopus (979) Google Scholar, 2Durie BG Katz M Crowley J Osteonecrosis of the jaw and bisphosphonates [letter].N Engl J Med. 2005; 353: 99-100Crossref PubMed Scopus (660) Google Scholar, 3Marx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic [letter].J Oral Maxillofac Surg. 2003; 61: 1115-1117Abstract Full Text Full Text PDF PubMed Scopus (2146) Google Scholar, 4Marx RE Sawatari Y Fortin M Broumand V Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment.J Oral Maxillofac Surg. 2005; 63: 1567-1575Abstract Full Text Full Text PDF PubMed Scopus (1273) Google Scholar, 5Pogrel MA Bisphosphonates and bone necrosis [letter].J Oral Maxillofac Surg. 2004; 62: 391-392Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 6Ruggiero SL Mehrotra B Rosenberg TJ Engroff SL Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.J Oral Maxillofac Surg. 2004; 62: 527-534Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar, 7Sanna G Zampino MG Pelosi G Nole F Goldhirsch A Jaw avascular bone necrosis associated with long-term use of bisphosphonates [letter].Ann Oncol. 2005 Jul; 16 (Epub 2005 Apr 22.): 1207-1208Crossref PubMed Scopus (44) Google Scholar, 8Vannucchi AM Ficarra G Antonioli E Bosi A Osteonecrosis of the jaw associated with zoledronate therapy in a patient with multiple myeloma.Br J Haematol. 2005; 128: 738Crossref PubMed Scopus (100) Google Scholar, 9Zarychanski R Elphee E Walton P Johnston J Osteonecrosis of the jaw associated with pamidronate therapy.Am J Hematol. 2006; 81: 73-75Crossref PubMed Scopus (79) Google Scholar, 10Ficarra G Beninati F Rubino I et al.Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment.J Clin Periodontol. 2005; 32: 1123-1128Crossref PubMed Scopus (160) Google Scholar, 11Purcell PM Boyd IW Bisphosphonates and osteonecrosis of the jaw.Med J Australia. 2005; 182: 417-418PubMed Google Scholar Patients with multiple myeloma, breast cancer, or prostate cancer receive IV BPT to mitigate hypercalcemia resulting from chemotherapy. The reports of ONJ are associated with pamidronate, zoledronate, or a combination of these 2 agents. Although patients taking bisphosphonates orally have developed ONJ, in the large majority of reported cases, those who experienced ONJ received IV BPT. Typically, patients with ONJ present with painful exposed bone, often a result of dental extraction or trauma. However, in contrast to osteoradionecrosis, which is observed mainly in the mandible, ONJ often occurs in the maxilla as well as the mandible. A link between IV BPT and ONJ was first proposed by Marx3Marx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic [letter].J Oral Maxillofac Surg. 2003; 61: 1115-1117Abstract Full Text Full Text PDF PubMed Scopus (2146) Google Scholar in a letter published in 2003, followed by a report by Marx et al4Marx RE Sawatari Y Fortin M Broumand V Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment.J Oral Maxillofac Surg. 2005; 63: 1567-1575Abstract Full Text Full Text PDF PubMed Scopus (1273) Google Scholar describing ONJ in 119 patients. In the interim, Ruggiero et al6Ruggiero SL Mehrotra B Rosenberg TJ Engroff SL Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.J Oral Maxillofac Surg. 2004; 62: 527-534Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar published descriptive data on 63 cases of BPT-induced ONJ. When combined with other reports, BPT-associated ONJ is clearly of concern to cancer patients whose quality of life is already severely compromised and in whom ONJ causes additional discomfort and dysfunction. To date, prospective data regarding the putative incidence of ONJ in patients receiving BPT are limited to a single publication by Bamias et al,1Bamias A Kastritis E Bamia C et al.Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors.J Clin Oncol. 2005; 23: 8580-8587Crossref PubMed Scopus (979) Google Scholar who reported that 17 (6.7%) of 252 cancer patients receiving BPT developed ONJ. Hypercalcemic cancer patients undergoing chemotherapy have a compromised wound-healing response, and many already are experiencing pain and discomfort. In these patients, ONJ is most often observed in areas in which bone is exposed and where coverage of exposed bone by mucosa is difficult to achieve. Reduced blood supply, decreased bone turnover, and bacterial insult from oral microbes are routinely cited as the main reasons for ONJ. No clear guidelines exist for the management of ONJ, and most treatment regimens are disappointingly palliative (eg, empirical long-term antibiotic therapy and local irrigations), with the apparent intent being to limit pain rather than to prevent or resolve developed ONJ. In this article, we present the rationale for a novel protocol for surgical salvage of bisphosphonate-induced ONJ and report preliminary results that suggest that our protocol may be used both to treat and to prevent ONJ. A 73-year-old man was referred from the hematology service at the Mayo Clinic in Rochester, Minn, to the Division of Oral and Maxillofacial Surgery for evaluation of bone exposure and pain in the right posterior mandibular alveolus. The patient's primary disease process was multiple myeloma, for which he had undergone stem cell transplantation in March 2003 and subsequent systemic BPT with zoledronate (Zometa, Novartis, East Hanover, NJ). In March 2005, he consulted his local general dental practitioner because of pain associated with tooth No. 28. Thetooth was deemed nonrestorable and was extracted with use of local anesthesia without complication. Bone and soft tissue healing ensued, which appeared to be progressing well until 6 weeks posttreatment, when the patient began to experience increasing pain and noted an area of bone exposure in the region of the previous extraction site. He was subsequently referred to the Mayo Clinic. His last dose of BPT was administered in October 2005. Medical comorbidities included hypothyroidism, for which he was taking levothyroxine. He denied any allergies to medications or other constitutional symptoms at the time of evaluation. Soon after mandibular ONJ (Figure 1) was identified, the patient was hospitalized and underwent limited surgical exposure of the bony sequestra with use of general anesthesia. All incisions were made with a scalpel rather than alternative incision techniques such as electrocauterization to provide optimal healing results. Once limited surgical exposure was created, a gentle subperiosteal dissection plane was established to identify the margins of the bony sequestra (Figure 2). The sequestra were removed, and theunderlying bone was débrided to ensure the presence of good vascularity. The surgical site was copiously irrigated with normal saline and closed in a tension-free fashion with the aid of periosteal-releasing incisions (Figure 3). On routine follow-up 1 month after surgery, the bone sequestration and pain had resolved. The patient resumed BPT and recently underwent a second stem cell transplantation without further jaw complications. Figure 4 shows the well-healed site of previous ONJ 4 months after surgical repair.FIGURE 2Case 1. Limited surgical exposure delineating the area of bone sequestration and poorly healed dental extraction site. This area was meticulously débrided to limit surgical trauma.View Large Image Figure ViewerDownload (PPT)FIGURE 3Case 1. After sufficient subperiosteal-releasing incisions were made to facilitate closure, the soft tissue overlying the bony defect was closed in a tension-free fashion. Complete soft tissue healing ensued without incident.View Large Image Figure ViewerDownload (PPT)FIGURE 4Case 1. Site of osteonecrosis of the jaw 4 months after primary surgical management.View Large Image Figure ViewerDownload (PPT) A 64-year-old woman was referred to our institution from an oral and maxillofacial surgeon for consultation regarding an area of developed ONJ in the left posterior mandibular body. In 2002, she fell and sustained several compression fractures of her thoracic vertebrae. Severe osteoporosis was subsequently diagnosed, and IV BPT (Aredia, Pamidronate, East Hanover, NJ) was initiated. The patient underwent dental extraction of a left mandibular molar (tooth No. 19) in early 2003, which did not heal. She returned to her general dental practitioner and underwent several local débridement procedures and multiple courses of empirical antibiotics. She continued to have a nonhealing area that became progressively more painful and refractory to treatment. In early 2005, an oral fistula tract developed involving adjacent tooth No. 20. In mid 2005, the patient was referred to a local oral and maxillofacial surgeon, who diagnosed ONJ and referred her to our institution for definitive care. On presentation, she clearly had established ONJ of the left mandibular body with a large mucosal dehiscence. No gross purulence was evident at presentation, but the site was exquisitely tender to examination. The patient underwent surgical débridement removal of tooth No. 20 and tension-free double-layered closure with a buccal fat pad local rotational flap. Healing was uneventful after the procedure. Her pain level and functional status improved substantially postoperatively. She continues to be symptom free of ONJ recurrence at 9 months posttreatment. Considerable speculation has centered on the mechanisms of ONJ development in individuals receiving BPT. Three principal theories of etiology have been offered: (1) bisphosphonates inhibit osteoclast activity, thereby reducing the rate of bone turnover, which results in compromised bone wound healing; (2) bone healing is compromised, but the lack of primary mucosal closure over areas of exposed bone is the key factor in the development of ONJ; and (3) bone healing is compromised, but factors specific to the oral cavity such as bacterial insult or exposure to saliva are key factors in the development of ONJ. Clearly, these theories are not mutually exclusive. In addition, although ONJ has been reported to be a consequence of BPT, the fact remains that a causative role cannot be proved definitively. It may well be that 1 or more cofactors (eg, chemotherapy) are required along with BPT to render a patient susceptible to ONJ. In essence, although BPT appears to be necessary, the rare occurrence of ONJ after oral BPT for osteoporosis makes it unclear whether BPT alone is sufficient to induce ONJ with compelling frequency. The outcomes of the cases reported herein suggest that of the 3 potential etiologies discussed previously, primary closure of the wound site is sufficient to treat and/or prevent ONJ. Some ONJ cases occur in patients with bone dehiscence, often along the thin mucosa covering the mylohyoid ridge or in the retromylohyoid region of the mandible. This area is routinely irritated by the movement of complete dentures in edentulous patients. In addition, many ONJ cases develop after dental extraction in which the extraction site is managed in a traditional manner, ie, the extraction socket is left to granulate and fill in with bone over time. In patients receiving IV BPT, this traditional approach does not overcome the compromised healing response associated with ONJ. However, we postulate that managing the site as described herein to achieve primary closure with or without local pedicle flaps ensures a sufficient blood supply and adequate protection for an effective bone-healing response to occur. Furthermore, this surgical salvage technique has been used by one of the authors (D.K.) to treat patients with established ONJ. In patients with large mucosal perforations or bony sequestra, similar to patients with established osteoradionecrosis, local vascularized pedicle flaps have been used to augment the surgical defect and to optimize bone and soft tissue healing. In sites amenable to local tissue transfer, the buccal fat pad flap is gently brought into the surgical defect while maintaining the vascular pedicle used to facilitate tension-free closure (Figure 5). When a major soft tissue defect is encountered, the buccal fat pad flap is used to cover the remaining bone and is left exposed to the oral cavity to mucosalize secondarily. When severe ONJ causing a pathological fracture is encountered, the affected portion of the mandible is resected and maintained without primary bony reconstruction because many of these patients have a guarded prognosis due to other malignancies or complex comorbid medical conditions that make them unsuitable candidates for sophisticated reconstructive efforts. Patients receive a single dose of intravenous broad-spectrum antibiotics intraoperatively, which is continued for 24 hours postoperatively. If during the operation, frank purulence is noted at the surgical site, a brief course (7-10 days) of empirical oral antibiotic therapy is also administered. All patients are followed up at 2 weeks postoperatively and then monthly to ensure that bony and soft tissue healing occur without complication. The relatively recent awareness of ONJ after administration of BPT accounts for the minimal information available regarding management of this painful condition. Clearly, pretreatment dental screening for patients likely to need BPT is warranted to ensure that compromised teeth are extracted with localized alveoloplasty as a preemptive measure. Indeed, this is the recommendation of the American Dental Association. However, if dental extractions are necessary during or after IV BPT, we believe that surgical salvage with the specific aim of gaining primary tension-free closure of the dental extraction site after alveoloplasty, with or without the use of local pedicle flaps, holds promise as a preventive option. A similar technique appears to offer potential benefit for those who present with existing ONJ. This approach may prevent the need for substantial resection and diminish further loss of quality of life in this debilitated population. However, we caution that more data are needed, and patients should be selected carefully for such therapy. In keeping with the general guidelines from the American Dental Association, general dental practitioners should appropriately optimize the oral health of patients who will be or are being treated with BPT. Invasive dental procedures such as routine extractions, deep periodontal therapy, and other forms of dentoalveolar surgery should be considered cautiously and should be performed with minimal soft and hard tissue trauma. Patients who require extensive dentoalveolar surgery or who have established ONJ should ideally be referred to a surgeon experienced in the management of these complex conditions.