A 63-year-old woman with bisphosphonate-related osteonecrosis of the mandible demonstrated pathologic fractures and bony erosion.
Specimen from segmental mandibulectomy (A) and the surgical defect (B).
A rapid prototype model was created (A) to help guide fibula free flap reconstruction such that the patient’s mandibular shape and occlusion were restored (B).
Complete healing of the fibula osteocutaneous free flap was achieved.
A 57-year-old man with a history of bisphosphonate-related osteonecrosis of the mandible who had undergone segmental mandibulectomy and titanium plate reconstruction at an outside facility and then presented with a fractured plate.
Left mandibular surgical defect (A) following removal of the fractured titanium plate (B).
Computer-assisted design software (A) and rapid prototype modeling (B) were used to help guide fibula free flap reconstruction of the mandible, which had malaligned left and right segments following fracture of the titanium reconstruction plate placed after initial mandibulectomy.
Anterior (A), left lateral (B), and intraoral (C) postoperative results of surgery.
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Hanasono MM, Militsakh ON, Richmon JD, Rosenthal EL, Wax MK. Mandibulectomy and Free Flap Reconstruction for Bisphosphonate-Related Osteonecrosis of the Jaws. JAMA Otolaryngol Head Neck Surg. 2013;139(11):1135–1142. doi:10.1001/jamaoto.2013.4474
Bisphosphonate-related osteonecrosis of the jaws is an increasingly recognized complication of intravenous and oral bisphosphonate therapy. Our experience suggests that mandibulectomy and free flap reconstruction is an effective treatment for patients with stage 3 and recalcitrant stage 2 disease.
To analyze indications for segmental mandibulectomy and microvascular free flap reconstruction for bisphosphonate-related osteonecrosis of the jaws and surgical outcomes following this procedure.
Design, Setting, and Participants
In a multi-institutional case series study conducted in academic tertiary care centers, 13 patients underwent segmental mandibulectomy and microvascular free flap reconstruction, including 8 patients with stage 3 disease and 5 patients with recalcitrant stage 2 disease. All patients had persistent or progressive disease despite conservative oral care and antibiotic treatment.
Segmental mandibulectomy and microvascular free flap reconstruction.
Main Outcomes and Measures
Treatment efficacy and postoperative complications.
There was 1 total flap loss due to infection. The patient with a flap loss ultimately underwent a successful fibula osteocutaneous free flap reconstruction after serial irrigation and debridement. The overall complication rate was 46% (n = 6). All complications occurred in patients with stage 3 disease. Ultimately, all patients achieved a successful reconstruction, with no recurrences. All patients tolerated a soft or regular diet postoperatively.
Conclusions and Relevance
Bisphosphonate-related osteonecrosis of the jaws is an increasingly recognized complication of intravenous and oral bisphosphonate therapy that can occasionally progress to involve full-thickness mandibular destruction, pathologic fracture, and fistulization, as well as chronic pain and infection. Mandibulectomy and free flap reconstruction is an effective treatment for patients with stage 3 and recalcitrant stage 2 bisphosphonate-related osteonecrosis of the jaws. High rates of chronic infection and underlying medical comorbidities may predispose to a substantial perioperative complication rate.
Recently, we have experienced an increasing number of referrals for surgical resection and reconstruction of necrotic maxillary and mandibular bone in patients receiving bisphosphonate drugs. Bisphosphonate-related osteonecrosis of the jaws (BRONJ) was first reported in 2003, and since then many reports1-3 have appeared in the oral maxillofacial and dental literature. Although most patients who develop this disease process have received intravenous bisphosphonate therapy for metastatic carcinoma affecting the skeleton or multiple myeloma, patients receiving oral bisphosphonates for osteoporosis have also developed this complication.
Most patients who develop BRONJ receive conservative treatment by stopping the administration of the bisphosphonate and by using topical antibiotic therapy, dental care, and local wound debridement. Rarely is more extensive surgery required. There is, however, a subset of patients who are refractory to conservative or minor surgical procedures and progress to having advanced osteonecrosis, including the development of pathologic fractures and draining fistulae. In these patients, mandibulectomy is generally considered the next form of intervention. However, the natural history of highly aggressive BRONJ is unknown; it remains unclear whether the disease can be arrested by segmental resection and vascularized reconstruction.
We report our experience following segmental mandibulectomy with microvascular free flap reconstruction in patients with advanced BRONJ. Our experience suggests that patients with osteoradionecrosis (ORN) secondary to radiotherapy or combined chemotherapy and radiotherapy have measurably worse outcomes with their mandibular reconstruction compared with patients who undergo segmental mandibulectomy for oncologic reasons.4,5 We therefore also sought to examine whether patients with BRONJ experienced more recipient-site morbidity.
A review of patients who were referred for microvascular free flap reconstruction following segmental mandibulectomy for BRONJ at Oregon Health & Science University, University of Alabama at Birmingham, and The University of Texas MD Anderson Cancer Center between January 1, 2007, and December 31, 2012, was performed. Institutional review board approval or a waiver was obtained at each center before the study. The degree of BRONJ was classified according to the staging system proposed by Ruggiero et al6 (Table 1).
Thirteen patients (mean age, 66.6 years) were referred to us for treatment following the development of BRONJ. Eleven of these patients (85%) had received zoledronic acid and the remainder had received pamidronate disodium. Patients included a mix of those who were classified as having stage 2 BRONJ but had persistent symptoms following local debridement; those individuals were classified as having stage 3 disease. All patients had previously received antibiotics, and treatment was maintained with antiseptic oral rinses. Preoperative or intraoperative cultures were obtained in 5 of the 13 patients (38%) and included Haemophilus species (patient 1), Staphylococcus aureus (patient 2), Peptostreptococcus species (patient 5), Eikenella corrodens (patient 10), and α-hemolytic streptococci and Pseudomonas aeruginosa (patient 12). Table 2 summarizes the patients’ clinical presentation as well as their cancer diagnoses and medical comorbidities.
Table 3 summarizes the resections as well as the microvascular reconstructions performed for the patients in this series. Patient 2 had a staged reconstruction, with fibula free flap reconstruction performed 3 months after a segmental resection (described below in the Case Reports section). Another patient was deemed not to be a candidate for bony free flap at the time of mandibulectomy and underwent reconstruction using a titanium plate with soft-tissue free flap. This patient had significant edema and advanced peripheral vascular disease of the legs, precluding use of the fibula. The defect was anticipated to be angle to angle, so an alternative type of bony flap would not have been adequate to reconstruct the defect and the patient was not considered a good candidate for a long multi–free flap procedure because of his medical condition.
Six of the 13 patients (46%) developed 1 or more complications. Three patients (23%) developed a purulent infection. All complications occurred in patients with stage 3 disease. In one patient, infection led to pedicle thrombosis and fibula free flap loss, and in another case, infection led to hardware exposure (in the patient receiving a titanium plate with soft-tissue free flap reconstruction), necessitating a second soft-tissue free flap for wound coverage. All reconstructions were ultimately successful (the patient with flap loss eventually underwent successful reconstruction with a second fibula osteocutaneous free flap after serial irrigation and debridement). There were no cases of malunion. No patient developed recurrent BRONJ. All patients resumed a soft or regular diet without supplemental tube feeding. No patient was tracheostomy dependent.
The length of time that patients were bisphosphonate-free prior to resection and free flap reconstruction is reported in Table 3. The median time since bisphosphonates were discontinued for patients who developed recipient-site complications was 12.0 months, and the median time since bisphosphonates were discontinued for patients who did not develop recipient-site complications was 12.5 months (P = .97; Mann-Whitney test).
Patient 1 was a 63-year-old woman with a history of multiple myeloma who developed bisphosphonate-associated necrosis of the mandible 6 months after treatment with pamidronate. The bisphosphonate treatment had been stopped 5 months prior to presentation, but she continued to experience persistent pain and intermittent infections with intraoral drainage requiring oral and intravenous antibiotics. A computed tomographic scan was performed that demonstrated stage 3 BRONJ, including pathologic fractures (Figure 1). A segmental mandibulectomy from the right angle to the left parasymphysis was performed (Figure 2). Preoperative computer-assisted design planning of the reconstruction was performed, and a rapid prototype model was created to guide the reconstruction and assist with bending of the titanium plate (Figure 3). Postoperatively, the patient experienced a hematoma of the right aspect of her neck that required evacuation, but she otherwise healed without complication (Figure 4).
Patient 2 was a 57-year-old man with a history of multiple myeloma. He had undergone an autologous stem cell transplant; however, his multiple myeloma recurred and was treated with zoledronic acid for 24 months. The patient developed stage 2 BRONJ that was treated for 3 years with local debridement and intermittent antibiotics. He then was referred to an oral surgeon who performed a segmental mandibulectomy from the right parasymphysis to the left angle and reconstructed the jaw with a titanium plate. A delayed free flap reconstruction was recommended in 6 months; however, the patient presented to us after 3 months with a fractured plate (Figure 5). Computer-assisted design was used to plan the reconstruction, and a rapid prototype model was created to guide the operation, which was particularly helpful because the mandibular segments were malaligned following the plate fracture (Figure 6 and Figure 7). His postoperative recovery was uncomplicated, and his occlusion was restored (Figure 8). Osseointegrated implants are planned.
Bisphosphonates are a proven effective drug class used in the setting of osteoporosis, Paget disease of the bone, and cancer therapy. Their initial use was limited to treating hypercalcemia-associated malignant neoplasm, but they are now used in patients with multiple myeloma, metastatic bone disease, and as an adjuvant antineoplastic therapy.7 Bisphosphonates cause apoptosis of mature osteoclasts and osteoclast progenitor cells and strongly inhibit osteoblastic activity.8 There also is reduced osteal vascularity secondary to the antiandrogenic properties of bisphosphonates.9 The net effect is an overall reduction in osteoclast activity with reduced bone resorption and turnover, but a reduced ability to heal also occurs. Since their introduction, there has been an increasing awareness of a correlation between bisphosphonate use and the appearance of destructive bone lesions of the mandible and maxilla.
Bisphosphonate-related osteonecrosis of the jaws is therefore a process of osteochemonecrosis, in contrast to the process of osteoradionecrosis in which radiation-induced endarteritis obliterans results in a hypocellular, hypoxic, and hypovascular microenvironment. Both intravenous (eg, pamidronate or zoledronic acid) and oral (alendronate sodium, ibandronate sodium, or risedronate sodium) bisphosphonates can cause osteonecrosis; however, the intravenous form is more commonly associated with the development of BRONJ.10 Moreover, the potency of a particular bisphosphonate depends on the side chains of the central carbon atom. The newer bisphosphonates with nitrogen side chains are much more potent than earlier generations. For example, zoledronic acid is 100 times more potent than pamidronate, and in fact 11 of the 13 patients (85%) in our study were receiving zoledronic acid.
The incidence of BRONJ has been reported as between 0.1% and 28%.11-14 The single prospective study15 published thus far found that 22 of 80 patients (28%) receiving intravenous bisphosphonates for malignant neoplasms developed BRONJ. Although BRONJ has been reported to occur spontaneously following bisphosphonate therapy, it is most commonly observed after dental procedures, especially dental extractions.2,16 Preventive care is thought to be critical in the management of bisphosphonate therapy.2,16 Dental evaluation before initiation of bisphosphonates is essential and must be followed with consistent surveillance and meticulous dental care. If possible, any necessary invasive dental procedures should be completed before the onset of bisphosphonate therapy.14,15
The extent of surgical resection necessary to adequately treat BRONJ is a subject of debate within the literature. It may range from local debridement and curettage to segmental resection requiring free tissue transfer for reconstruction. Determining adequate resection margins may be difficult. Marx17 recommended resection to a margin with some residual marrow, bleeding points within it, and bone of normal color. However, one should anticipate resection of more bone than what is clinically apparent because short resection margins have resulted in a continuation or extension of exposed bone. In fact, patients with minimal debridement may have retained osteomyelitic bone and have a progression of a persistent disease rather than an onset of new BRONJ in previously healthy bone. For example, when Nocini et al18 reviewed pathologic characteristics in a series of patients who underwent segmental resections, only one patient was found to have residual disease on his initial resection specimen and only that patient developed a recurrence of BRONJ within 6 months. All other patients in their series had a complete cure, which was assessed both clinically and radiologically. Similarly, Bedogni et al19 analyzed 32 jaws resected for BRONJ and found that the presence of osteomyelitis at the margin of the resection was highly predictive of BRONJ recurrence. In our study, we adhered to Marx’s17 guidelines for resection, and our results support use of aggressive resection to healthy bony margins. Furthermore, approaching these cases anticipating free tissue transfer allows the ablative surgeon to take wide margins.
Marx17 and Ruggiero et al3 do not recommend free bone flap reconstructions in patients with BRONJ. They claim that placement of a reconstruction plate alone usually provides resolution of symptoms and adequate function. Their concern is that donor site bone also will be affected by bisphosphonate treatment, as well as by likely chemotherapeutic agents, and may have unpredictable healing. They also caution surgeons not to use bone flaps in patients with multiple myeloma because the bone marrow may contain malignant cells. All donor sites in our series healed without complication, and thus far there have been no reports in the literature of diseased tissue being transferred to the head and neck during reconstruction. All patients demonstrated clinical and radiographic evidence of bony union. Our study expands on this experience and demonstrates a high free flap success rate with eventual resolution of BRONJ in all patients. However, given the theoretic risk of transferring diseased bone to the head and neck, it is appropriate to perform preoperative imaging studies of the donor site before free tissue transfer in patients with a history of bony neoplasia, as recommended by Seth et al.20
To our knowledge, the present study is the largest to date on free flap reconstruction of segmental mandibular defects in patients with BRONJ. Together with previously published reports, there have been 45 cases of refractory BRONJ treated with free bone flaps.18,20-24 The overall flap success rate is 98%, rivaling the best results in patients without BRONJ. In the most recent series prior to the present one, Seth et al20 demonstrated successful osteocutaneous fibula free flap reconstructions in 11 patients with a similar postoperative complication rate of 36%. Including the present study, complications reported in the literature18,20-24 include infection (n = 5), fistula (n = 3), hematoma (n = 2), pneumonia (n = 1), deep vein thrombosis (n = 1), and free flap loss (n = 1).
In our experience, postoperative recipient-site infection was common and, in one case, serious enough to cause flap loss. This mirrors our experience with treating ORN. Available preoperative cultures in 5 of our patients indicate that infection of necrotic bone is caused by various aerobic and anaerobic bacteria that are typically found in dental and other head and neck infections. The rate of complications in ORN and BRONJ may, in part, be elevated by the high prevalence of diabetes mellitus and vascular disease in our patient cohort, with only 2 of the 13 patients not having one of these diseases. One might speculate that progression to advanced BRONJ is more likely in patients with comorbidities known to affect wound healing, resistance to infection, and blood circulation, although further analysis of a much larger patient sample will be needed to evaluate this hypothesis.
In all cases, we recommend use of perioperative antibiotics, culture directed if possible. Our limited data suggest that bacterial infection that accompanies BRONJ is due to mixed aerobic and anaerobic organisms that are typically involved in dental abscesses and ORN. Another strategy to prevent infectious complications in heavily contaminated wounds is to delay reconstruction by temporary placement of a reconstruction plate with or without soft-tissue reconstruction, which was used in patient 2 in our series. However, because the rate of plate-related complications such as hardware fracture or extrusion can be high, and delayed reconstruction can be very challenging in terms of dissection through previously operated tissues as well as restoring proper occlusion, we hesitate to advocate this strategy. If delay is considered, it is likely best for the patient to limit the time between mandibulectomy and vascularized bone reconstruction, although there is admittedly little experience in the literature to support this recommendation.
It has been established that medical therapy is ineffective for treatment of stage 3 disease, in which patients present with fistulae, pathologic fractures, or bony destruction extending to the inferior border of the mandible6; however, our experience suggests that patients with recalcitrant stage 2 BRONJ are also appropriate candidates for surgical therapy. A prospective trial by Moretti et al25 found that professional hygiene treatment along with nonsurgical therapy resulted in a significant improvement in pain scores and decrease in area of bone exposure. However, 82% of the patients demonstrated visible persistence of disease. Other studies2,15,25 have found that, although conservative medical therapy may effectively stabilize BRONJ in most patients, 3% to 10% of patients become refractory to nonsurgical therapy and ultimately require surgical debridement of nonvital bone for relief of their symptoms. Five of the 12 patients in our study had recalcitrant stage 2 disease. Vascularized bone flaps were tolerated, with no postoperative complications in this group, and led to resolution of BRONJ. In contrast, the complication rate for patients with stage 3 disease was very high (71%), including all 3 patients who developed recipient-site infections. Perhaps earlier treatment of select patients with recalcitrant stage 2 disease with free tissue transfer would prevent progression to stage 3 and decrease the overall complication rate.
Our results confirm previous findings that segmental mandibulectomy and microvascular free flap reconstruction is an effective reconstructive option in patients with stage 3 and recalcitrant stage 2 BRONJ. Based on our experience and the growing body of evidence in the literature, the success rate for this treatment is high. However, complications are not infrequent, possibly resulting from chronic infection and/or the high rate of medical comorbidities in this patient population.
Submitted for Publication: December 4, 2012; final revision received January 25, 2013; accepted April 15, 2013.
Corresponding Author: Matthew M. Hanasono, MD, Department of Plastic Surgery, Unit 443, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (firstname.lastname@example.org).
Published Online: September 19, 2013. doi:10.1001/jamaoto.2013.4474.
Author Contributions: Drs Hanasono and Wax had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Hanasono, Militsakh, Wax.
Acquisition of data: Hanasono, Richmon, Rosenthal, Wax.
Analysis and interpretation of data: Hanasono, Militsakh, Richmon, Wax.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Hanasono.
Administrative, technical, or material support: Hanasono, Wax.
Study supervision: Richmon, Rosenthal, Wax.
Conflict of Interest Disclosures: None reported.
Previous Presentation: This study was presented in poster format at the American Head and Neck Society 2013 Annual Meeting; April 10-11, 2013; Orlando, Florida.
Additional Information: Drs Hanasono, Militsakh, Richmon, Rosenthal, and Wax produced this work as a collaborative effort of the American Head and Neck Society Reconstructive Committee.
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