- Email: [email protected]
Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw
YIJOM-3597; No of Pages 6
Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2017.01.023, available online at http://www.sciencedirect.com
Clinical Paper Clinical Pathology
Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw
S. Caldroney, N. Ghazali, D. Dyalram, J. E. Lubek Oral–Head and Neck Surgery/Microvascular Surgery, University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA
S. Caldroney, N. Ghazali, D. Dyalram, J.E. Lubek: Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw. Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx. ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. A retrospective review of all patients with stage 3 medication-related osteonecrosis of the jaw (MRONJ), treated by surgical resection and immediate vascularized bone reconstruction at a tertiary care medical center, was performed. Eleven patients were included, seven female and four male; their mean age was 65.8 years (range 56–73 years). Mean follow-up was 25 months. Ten patients had received intravenous bisphosphonates. The most common pathology was breast cancer (4/11). Pain (n = 8) and pathological fracture (n = 7) were the most common presenting symptoms. Microvascular free flaps consisted of seven fibula osteocutaneous flaps and four scapula osteocutaneous free flaps. All patients reported resolution of symptoms, with complete bone union identified radiographically (100%). Complications occurred in three patients (27%). One patient required removal of hardware at 8 months postoperative. Dental implant rehabilitation was completed in two patients. Ten patients are tolerating an oral diet. Ten patients are alive without evidence of MRONJ at any of the surgical sites. One patient died 28 months after surgery from progression of metastatic disease. Advanced MRONJ can be successfully treated in patients using vascularized tissue transfer, including those patients with significant peripheral vascular disease. Dental rehabilitation is a viable option for advanced MRONJ patients treated by vascularized flap reconstruction.
0901-5027/000001+06
Key words: MRONJ; osteonecrosis; vascularized tissue transfer; mandible. Accepted for publication 31 January 2017
ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
YIJOM-3597; No of Pages 6
2
Caldroney et al.
Medication-related osteonecrosis of the jaw (MRONJ), previously known as bisphosphonate-related osteonecrosis of the jaw (BRONJ), is a recognized complication of anti-resorptive and anti-angiogenic bone-related therapies. The name change is justified to accommodate the growing number of osteonecrosis cases associated with other anti-resorptive (denosumab) and anti-angiogenic medications.1 The first reports of MRONJ were published more than a decade ago; however the pathophysiology has not yet been fully elucidated.2,3. MRONJ is especially associated with oncology-dose parenteral anti-resorptive therapy with bisphosphonates and the receptor activator of nuclear kappa B ligand (RANKL) inhibitor medication denosumab.4 Denosumab is an anti-resorptive agent that exists as a fully humanized antibody against RANKL and inhibits osteoclast function and associated bone resorption.5,6 It is also effective in decreasing systemic events related to metastatic bone disease from solid tumors.7,8 Bisphosphonates, especially the nitrogencontaining subset such as zoledronate and pamidronate, similarly decrease bone resorption. This leads to osteoclast cytoskeleton disruption, intracellular vesicular trafficking impairment, increased osteoclast apoptosis, and decreased osteoclast function.9 Bisphosphonates physiochemically bind to exposed hydroxyapatite and incorporate into the bone matrix with a half-life of many years. However unlike bisphosphonate medications, the incorporation and long-term effects of denosumab on bone remodeling and its half-life in the bone matrix are not well defined.9 The incidence of MRONJ is greatest in the oncology patient population (1% to 15%), where high doses are used at frequent intervals.4 The incidence of MRONJ in the osteoporosis patient population is significantly lower (0.001% to 0.01%) and is only marginally higher than the incidence in the general population.4 A prospective study, published in 2015, found that 22 of 80 patients (28%) receiving intravenous (IV) bisphosphonates for malignant neoplasms developed BRONJ.10 MRONJ is defined clinically in patients on current or previous treatment with anti-resorptive or anti-angiogenic medication, where the presence of exposed necrotic bone is evident through a fistula persisting over 8 weeks within the maxillofacial region that has not been irradiated previously.1 Established MRONJ can manifest within a wide spectrum of clinical presentations in the affected jaw (Table 1).
Table 1. Medication-related osteonecrosis of the jaw—staging system.a MRONJ staging Stage 0 Stage 1 Stage 2 Stage 3
Definition No clinical evidence of necrotic bone, radiographic changes only, non-specific symptoms Exposedb and necrotic bone, fistulae that probe into bone, no evidence of infection Exposedb and necrotic bone, fistulae that probe into bone, infection, pain, erythema purulent drainage Exposedb and necrotic bone with associated infection, pain including one or more of the following: bone necrosis/exposure beyond the alveolar bone, pathological jaw fracture, extraoral fistula, oro-antral/nasal communication, osteolysis extending to the inferior border of the mandible or sinus floor
MRONJ, medication-related osteonecrosis of the jaw. a Adapted from the Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg 2014: 72: 1938–1956.
Within the MRONJ continuum, stage 3 is the most advanced, where the exposed, necrotic bone and fistula occurs with evidence of infection, and with at least one of the following criteria: (1) exposed necrotic bone extending beyond the alveolar bone; (2) pathological fracture; (3) extraoral fistula; (4) oro-antral or oronasal communication; and (5) osteolysis extending to the inferior border of the mandible or sinus floor.1 Stage 3 MRONJ is debilitating and significant morbidity is experienced, particularly with repeated bouts of infection and when pathological fracture is present. The problems experienced include chronic unpleasant symptoms (e.g., pain, swelling, halitosis, purulent discharge, sinonasal symptoms), neurosensory deficit, loosening of teeth, masticatory dysfunction, and overall decreased quality of life. Despite a lack of high-quality evidence in regard to treatment, there is a general perception favoring conservative treatment over surgical therapy.11 Limited surgery in the form of localized debridement or sequestrectomy is advocated with the aim of simply softening sharp bony edges to promote soft tissue healing over the exposed bone rather than eliminating the entire area of necrotic bone.11,12 Aggressive radical surgery is offered only to symptomatic patients with extensive osteonecrosis, including those who have failed conservative treatment, with the aim of long-term palliation of infection and pain.1,13–15 Some authors have reported that surgical approaches result in superior treatment outcomes than conservative therapy regimens, with success rates of 80–90% and 10–62%, respectively.16 Nevertheless, an aggressive surgical treatment approach with wide bone resection and immediate reconstruction with microvascular free tissue transfer is considered controversial.
The aim of this study was to evaluate the outcomes of surgical resection and vascularized reconstruction in a cohort of advanced MRONJ patients at a single institution. The primary outcome measures included the presence of primary bone union and the recurrence of MRONJ. The secondary outcome measure was pain control and functional outcomes as they related to patient quality of life. Materials and methods
Institutional review board approval was obtained for the study. A retrospective review of the departmental reconstruction database was undertaken. All patients with stage 3 MRONJ treated by surgical resection and vascularized bone reconstruction, performed in the Department of Oral and Maxillofacial Surgery, University of Maryland from September 2010 to December 2015, were identified. A chart review of the subjects selected was completed to obtain demographic data, presenting clinical features, anti-resorptive medication history, risk habits, predisposing factors, site of MRONJ, surgical details including the type of resection and flap selection, perioperative complications, length of hospital stay, follow-up details including the length of follow-up, speech/swallowing outcomes, and recurrence of MRONJ. Functional status was determined using the Eastern Cooperative Oncology Group performance status (ECOG-PS) functional scale, which was noted preoperatively and at the 6-week follow-up. All patients received a computed tomography (CT) scan at least 8 weeks postoperatively to evaluate the outcomes of reconstruction. The three-dimensional (3D) digital images were retrieved from the hospital records using the eUnity diagnostic imaging system (Client Outlook Inc., Waterloo, ON, Canada) and
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
YIJOM-3597; No of Pages 6
Surgical resection and reconstruction in MRONJ viewed on a standard flat-screen monitor. The length of the defect restored was measured using both the pathological specimen and the eUnity system measurement tools on post-reconstruction CT imaging. The primary outcome measure of bony union was determined by reviewing the 8week postoperative CT scan for evidence of bony union at the resection site, determined by the presence of direct bone-tobone contact, without evidence of osteolytic lesions. The presence of recurrent MRONJ was determined by reviewing the last entry in the chart documenting the absence of exposed bone and a normal panoramic radiograph during the most recent follow-up visit. The secondary outcome measure was based on documented pain symptoms and the ECOG-PS,17 obtained preoperatively and at 6 weeks postoperative. All reconstructions were performed with the assistance of preoperative virtual surgical 3D planning (3D Systems, Colorado, USA) using patient-specific CT scans of the facial bones. Results
A total of 11 patients were included in this study; seven were female (64%) and four were male (36%). These patients underwent immediate microvascular free flap reconstruction at the time of ablative surgery or resection for MRONJ. The mean age at the time of surgery was 65.8 years (range 56–73 years). The majority of patients were treated with IV medications (10/11 IV, 1/11 oral). The most common class of drug was the bisphosphonates (10/ 11), followed by denosumab (2/11). Two patients received a bisphosphonate and denosumab. Patient baseline disease included metastatic breast cancer (4/11), multiple myeloma (3/11), osteoporosis (3/11), and prostate cancer (1/11). All patients were classified with stage 3 MRONJ. A total of seven patients (64%) presented with a pathological fracture and six patients presented with an orocutaneous fistula (55%). Pain was present on initial consultation in eight patients (73%). Eight patients required multiple courses of intravenous antibiotics preoperatively. Microvascular free flaps consisted of seven fibula osteocutaneous flaps (64%) and four scapula free flaps (36%). A scapula flap was selected in those patients with significant vascular disease not deemed suitable candidates for a fibula donor site, as identified on clinical examination and lower extremity vascular imaging studies.
The average length of the restored defects was 8.36 cm (range 5–14 cm). The average length of hospital stay was 9.6 days (range 7–15 days). One patient required a hemimandibulectomy with condylar disarticulation and was placed into intermaxillary wire fixation for a period of 6 weeks. All patients were pain-free after reconstruction (100%). ECOG-PS status was consistent with preoperative baseline (range 0–2) and was not negatively affected significantly postoperative. Three patients developed wound-related complications (27%). Complications included postoperative wound infection (n = 2), wound dehiscence (n = 2), and plate exposure (n = 2) requiring local wound care measures. One patient with hardware exposure underwent late hardware removal at 8 months postoperative without complication. One wound infection required a return to the operating room in conjunction with intravenous antibiotics. Complete bone union was noted in all 11 patients, with bone-to-bone contact noted radiographically (100%). There were no recurrences of MRONJ noted at the surgical site, although one patient did develop early stage MRONJ in the maxilla, treated with local wound care measures. Dental implant rehabilitation was completed in two patients (18%). Ten patients are tolerating an oral diet. One patient requires a percutaneous endoscopic gastrostomy (PEG) tube to supplement nutrition, although tolerating thin and thick liquids by mouth. Ten patients are alive without symptoms or evidence of MRONJ at any of the surgical sites. One patient died 28 months after surgery from progression of metastatic disease. The patient had resolution of the oral symptoms and complete bone healing at the osteotomy sites. The mean follow-up for the patients in this study was 25 months (range 6–69 months) (Table 2). Discussion
The definitive management of MRONJ, particularly in the advanced stage of the disease, remains divisive. It has been established that medical therapy is ineffective for the treatment of stage 3 disease, in which patients present with fistulae, pathological fractures, or bony destruction extending to the inferior border of the mandible.1 Radical surgical treatment has to be considered when (1) MRONJ seems to involve a large area of the jaw, (2) the disease is not resolved by conservative approach, (3) the donor site is well perfused, and (4) the preoperative exclusion of bone metastases at the donor site is
3
performed.18 The arguments against this approach are the concerns that surgical trauma inflicted on the bone could result in the progression of osteonecrosis and/or development of osteomyelitis in the remaining bone, the difficulty obtaining a viable surgical resection margin, and ultimately that bony union may be problematic considering the diffuse uptake of bisphosphonate by the entire jaw bone.19,20 Marx et al. suggested the possibility of free flap reconstruction in cases of significant soft tissue loss, but advocated against osseous microsurgical reconstruction given the higher surgical risk, and reported good outcomes with this management strategy of resection and titanium plating despite leaving a bony discontinuity.19,21 A concern against this argument is the management of a hardware failure, requiring a second surgery to manage the discontinuity, especially as many of these patients are living longer with stable metastatic disease. One could potentially avoid this issue with a composite bone and soft tissue flap reconstruction. Previously, a reconstruction bar alone was recommended over free vascularized bone because of trepidation regarding supposed unreliable bone healing seeing that the donor bone was also exposed to the generalized diffuse uptake of anti-resorptive and anti-angiogenic medications.1,2,21 In 2011, Pautke et al. reported for the first time the development of a bisphosphonate-related osteonecrosis in a microvascular iliac bone graft that was performed after a partial mandibulectomy due to BRONJ stage 3.16 The theoretical risk of potentially transferring malignancy with the donor bone in the case of multiple myeloma and when secondary metastatic bone disease is present has also been considered.19 In a review of 31 published cases of stage 3 MRONJ treated by surgical resection and vascularized bone reconstruction, the reported rate of non-union and recurrence of MRONJ at the resection margin was 6.5%.22 This contradicts some of the original concerns about unpredictable bone healing, progression/recurrence of MRONJ at the resection site, and the transferring of malignant disease. In the current series, all patients had bony union (100%) and there were no cases of progression or recurrence of MRONJ in the transplanted bony flap or at the resection site. Furthermore, the two patients who completed dental implant rehabilitation did not have any issues with dental implant osseointegration. The present authors routinely order either a whole body positron emission tomography
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
Caldroney et al.
Patient
Sex
Age, years
Medication
Pathology
1
F
56
Zoledronate
Metastatic breast
2
F
65
Zoledronate
Osteoporosis
3
F
60
Osteoporosis
4
F
61
Pamidronate Alendronate Alendronate
Osteoporosis
5
F
65
Zoledronate
Metastatic breast
6
F
64
Metastatic breast
7
M
68
Denosumab and zoledronate Zoledronate
Multiple myeloma
8
M
67
Zoledronate
Multiple myeloma
9 10
M F
73 72
Zoledronate Zoledronate
Prostate Metastatic breast
11
M
73
Pamidronate Denosumab
Multiple myeloma
Initial symptoms
Free flap
Length of bone (cm)
Defect location and osteotomiesa
Adverse events
Bone union
Dental implants
Follow-up (months)
Fracture Pain Fracture Fistula Pain Fracture Fistula Fracture Pain Fracture Pain Fracture Pain Fracture
Scapula
6.67
Right mandible (2)
None
Yes
No
44
Fibula
5
Left mandible (2)
None
Yes
No
69
Fibula
7.85
None
Yes
Yes
44
Fibula
11.7
Symphysis/left mandible (3) Subtotal mandibleb (3)
None
Yes
Yes
36
Fibula
6.1
Right mandible (2)
None
Yes
No
28 DWD
Fibula
7
Right mandible (2)
None
Yes
No
6
Scapula
10
Subtotal mandibleb (3)
Yes
No
6
Fistula Pain
Scapula
6.45
Right mandible (2)
Yes
No
10
Fistula Fistula Pain Fistula Pain
Scapula Fibula
9.29 8
Subtotal mandibleb (3) Subtotal mandibleb (4)
Yes Yes
No No
17 11
Fibula
14
Right mandible w/condylar disarticulation (2)
Infection Dehiscence Infection Hardware exposure Plate removal None Dehiscence Hardware exposure None
Yes
No
6
F, female; M, male; DWD, died with disease. a Osteotomies (n): the number of osteotomies, native bone and flap inclusive. b Subtotal mandible: right/left mandibular body including symphysis.
YIJOM-3597; No of Pages 6
4
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
Table 2. Flap reconstruction for patients with medication-related osteonecrosis of the jaw.
YIJOM-3597; No of Pages 6
Surgical resection and reconstruction in MRONJ (PET)-CT scan or technetium bone scan to rule out pre-existing metastatic disease at the potential donor site. Intraoperative assessment of the resected surgical margin and the establishment of a viable healthy bone margin can become a difficult task in the face of MRONJ. At the current time there is no one proven test that can guarantee with 100% accuracy the achievement of this goal. The authors rely on preoperative imaging, both CT scan and magnetic resonance imaging (MRI), to evaluate the cortical bone and marrow signal, respectively. This, in conjunction with intraoperative clinical assessment of healthy bleeding bone, is the method of choice for margin evaluation. When performing reconstructions with healthy vascularized tissue, one can also be generous with the length of mandible removed to include a larger segmental resection and removal of any questionable poor quality dentition. The recruitment of a healthy soft tissue component to aid in tension-free wound closure also assists with healing, as it minimizes wound breakdown. All of these factors are likely to have contributed to the successful bone union at the osteotomies reported in this current series. Although techniques such as auto-fluorescence have been advocated to evaluate the marrow signal and improve the establishment of an adequate viable surgical margin, this technology has not been employed by the current authors.23 Several authors have advocated against microvascular mandible reconstruction after BRONJ because the candidates are a high surgical risk cancer population with a limited life-expectancy. Patients with reasonable life-expectancy with regard to their malignant disease should be considered for microvascular tissue transfer after aggressive resection of the affected region15. There are increasing amounts of level 4 evidence of successful outcomes of resection and vascularized bone reconstruction for advanced stage MRONJ.15,16,22,24–30 Microvascular free flap restoration of MRONJ defects offers several advantages over multistage soft tissue and hard tissue reconstruction. These advantages include the ability to perform a single-stage surgery with a composite vascularized graft, to reconstruct large oral cavity defects, and to restore facial form and function including dental rehabilitation, in a clean-contaminated wound exposed to oral flora and saliva. The consideration of such extensive surgery should be assessed on an individual patient case basis, evaluating risk factors such as
significant medical co-morbidities, advanced age, peripheral vascular disease, or anomalous lower extremity vasculature. While the reliability of vascularized fibula reconstruction has been described in the previously published reports, and despite the favorable experiences with fibula and iliac crest, data indicating whether other osteocutaneous free flaps are equally successful are lacking. To date there have been 45 cases of refractory MRONJ treated with microvascular flaps. Thirty-eight patients underwent reconstruction with a free fibula flap and five with an osteocutaneous iliac crest free flap. In the series of Hanasono et al., two soft tissue free flaps were reported. One patient was deemed not to be a candidate for a bony free flap at the time of mandibulectomy and underwent reconstruction using a titanium plate with a soft tissue free flap. This patient had significant edema and advanced peripheral vascular disease of the legs, precluding use of the fibula.29 In the current series, four patients had significant peripheral vascular disease and were not candidates for a fibula osteocutaneous free flap. These four patients were successfully reconstructed with a scapula free flap, thus proving the scapula flap to be a viable option in severe peripheral vascular disease and large segmental mandibular defects. The present case series is rare in describing the use of scapula osteocutaneous free flaps in the management of MRONJ. At the authors’ institution, the patient is the main driver behind the decision to perform radical surgical treatment. These patients are often in pain and highly motivated to proceed with resection. Most are treated with conservative therapy as advocated; however some patients are no longer able to experience a good quality of life and are considered candidates for surgical resection and immediate reconstruction. It is also important to mention that only patients with stable metastatic disease or remission should be considered for such extensive methods of reconstruction. As stated previously, preoperative work-up should include a whole body PET-CT or technetium bone scan to screen for any occult active metastatic disease, particularly at potential donor sites, as recommended by Seth et al.26 In addition, close communication with the medical oncologist is critical in determining patient suitability for surgery based on current status and overall prognosis. The limitations of this study include its retrospective nature and small patient sample. Currently only the study by Hana-
5
sono et al. has included a larger sample size (n = 13), and as mentioned previously, two of the patients in that series underwent reconstruction only with soft tissue flaps29. A weakness of all the reported series on vascularized tissue transfer for the management of MRONJ, the current study included, is with regard to the management of advanced MRONJ of the maxilla. Conclusions cannot be drawn on the outcomes of flap reconstruction for maxillary MRONJ as all patients in the current series had disease treated within the mandible exclusively. Often the maxillary bone is diffusely diseased and of poorer quality, with difficulty in locating adequate bone to fixate the flap reconstruction. Patients undergoing the removal of maxillary bone can often have fistulae closed with local advancement flaps, and dental obturators can generally be used to reconstruct partial defects. Further study of maxillary MRONJ is required. The current findings suggest that advanced mandibular MRONJ may be treated predictably in selected patients using microvascular free fibula flaps, or, in cases where peripheral vascular disease is identified, the scapula osteocutaneous free flap as an effective alternative. Surgical resection with immediate vascularized reconstruction can provide for significant improvements in quality of life, including the possibility of successful dental implant rehabilitation in the MRONJ patient. The risk of both surgical and medical complications in this cohort of patients is not different as compared to other patient populations undergoing similar reconstructive procedures. Funding
Not applicable. Competing interests
None. Ethical approval
This study was approved by the Institutional Review Board for Ethical Human Research at the University of Maryland, Baltimore, Maryland, USA. Patient consent
Not applicable. References 1. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F.
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
YIJOM-3597; No of Pages 6
6
Caldroney et al.
American Association of Oral and Maxillofacial Surgeons: American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw— 2014 update. J Oral Maxillofac Surg 2014;72:1938–56. 2. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115–7. 3. Ruggiero 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;62:527–34. 4. Khan A, Morrison A, Cheung A, Hashem W, Compston J. Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015. Osteoporos Int 2016;27. 853–839. 5. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C. FREEDOM Trial: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65. 6. Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Man Z, Mellstrom D, Radominski SC, Reginster JY, Resch H, Roman Ivorra JA, Roux C, Vittinghoff E, Austin M, Daizadeh N, Bradley MN, Grauer A, Cummings SR, Bone HG. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 2012:694–701. [7] Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessi C. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813–22. [8] Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Vinegar M, Fan M, jiang Q, Dansey R, jun S, Braun A. Denosumab compared with zoledronic acid for the treatment of bne metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132–9. 9. Lewiecki EM. Denosumab update. Curr Opin Rheumatol 2009;21:369–73. –. 10. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G. Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008; 44:857–69.
11. Carlson ER, Basile JD. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2009;67(5 Suppl): 85–95. 12. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis. An American Academy of Oral Medicine position paper. J Am Dent Assoc 2005;136:1658–68. –. 13. Ruggiero SL, Dodson TB, Assail LA, Landesberg R, Marx RE, Mehrotra B. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws 2009 update. J oral Maxillofac Surg 2009;67(5 Suppl): 2–12. 14. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479–91. 15. Mu¨cke T, Haarmann S, Wolff KD, Ho¨lzle F. Bisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstruction. J Craniomaxillofac Surg 2009;37: 291–7. 16. Pautke C, Otto S, Reu S, Kolk A, Ehrenfeld M, Stu¨rzenbaum S, Wolff KD. Bisphosphonate related osteonecrosis of the jaw—manifestation in a microvascular iliac bone flap. Oral Oncol 2011;47:425–9. 17. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Co-operative Oncology Group. Am J Clin Oncol 1983;5:649–55. 18. Sacco R, Sacco G, Acocella A, Sale S, Sacco N, Baldoni E. A systematic review of microsurgical reconstruction of the jaws using vascularized fibula flap technique in patients with bisphosphonate-related osteonecrosis. J Appl Oral Sci 2011;19:293–300. 19. Marx RE. Reconstruction of defects caused by bisphosphonate-induced osteonecrosis of the jaws. J Oral Maxillofac Surg 2009; 67(5 Suppl):107–19. 20. Nocini PF, Saia G, Bettini G, Ragazzo M, Blandamura S, Chiarini L, Bedogni A. Vascularized fibula flap reconstruction of the mandible in bisphosphonate-related osteonecrosis. Eur J Surg Oncol 2009;35:373–9. 21. Marx 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: 1567–75. 22. Vercruysse Jr H, Backer T, Mommaerts M. Outcomes of osseous free flap reconstruction in stage III bisphosphonate-related osteonecrosis of the jaw: systematic review and a
23.
24.
25.
26.
27.
28.
29.
30.
new case series. J Craniomaxillofac Surg 2014;42:377–86. Ristow O, Pautke C. Auto-fluorescence of the bone and its use for delineation of bone necrosis. Int J Oral Maxillofac Surg 2014; 43:1391–3. Engroff SL, Kim DD. Treating bisphosphonate osteonecrosis of the jaws: is there a role for resection and vascularized reconstruction. J Oral Maxillofac Surg 2007;65: 2374–85. Ferrari S, Bianchi B, Savi A, Poli T, Multinu A, Balestreri A, Ferri A. Fibula free flap with endosseous implants for reconstructing a resected mandible in bisphosphonate osteonecrosis. J Oral Maxillofac Surg 2008;66: 999–1003. Seth R, Futran ND, Alam DS, Knott PD. Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonaterelated osteonecrosis of the jaws. Laryngoscope 2010;120:2165–71. Bedogni A, Saia G, Bettini G, Tronchet A, Totola A, Bedogni G, Ferronato G, Nocini PF, Blandamura S. Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis. Oral Oncol 2011;47:420–4. Ghazali N, Collyer JC, Tighe J. Hemimandibulectomy and vascularized fibula flap in bisphosphonate-induced mandibular osteonecrosis with polycythaemia rubra vera. Int J Oral Maxillofac Surg 2013;42: 120–3. 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: 1135–42. Spinelli G, Torresetti M, Lazzeri D, Zhang YX, Arcuri F, Agostini T, Grassetti L. Microsurgical reconstruction after bisphosphonate-related osteonecrosis of the jaw: our experience with fibula free flap. J Craniofac Surg 2014;25:788–92.
Address: Joshua E. Lubek Oral–Head and Neck Surgery/Microvascular Surgery Department of Oral and Maxillofacial Surgery 650 West Baltimore St Rm 1401 University of Maryland Baltimore MD 21201 USA Tel: +1 410 706 7060 Fax: +1 410 706 4199 E-mail: [email protected]
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2017.01.023, available online at http://www.sciencedirect.com
Clinical Paper Clinical Pathology
Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw
S. Caldroney, N. Ghazali, D. Dyalram, J. E. Lubek Oral–Head and Neck Surgery/Microvascular Surgery, University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA
S. Caldroney, N. Ghazali, D. Dyalram, J.E. Lubek: Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw. Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx. ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. A retrospective review of all patients with stage 3 medication-related osteonecrosis of the jaw (MRONJ), treated by surgical resection and immediate vascularized bone reconstruction at a tertiary care medical center, was performed. Eleven patients were included, seven female and four male; their mean age was 65.8 years (range 56–73 years). Mean follow-up was 25 months. Ten patients had received intravenous bisphosphonates. The most common pathology was breast cancer (4/11). Pain (n = 8) and pathological fracture (n = 7) were the most common presenting symptoms. Microvascular free flaps consisted of seven fibula osteocutaneous flaps and four scapula osteocutaneous free flaps. All patients reported resolution of symptoms, with complete bone union identified radiographically (100%). Complications occurred in three patients (27%). One patient required removal of hardware at 8 months postoperative. Dental implant rehabilitation was completed in two patients. Ten patients are tolerating an oral diet. Ten patients are alive without evidence of MRONJ at any of the surgical sites. One patient died 28 months after surgery from progression of metastatic disease. Advanced MRONJ can be successfully treated in patients using vascularized tissue transfer, including those patients with significant peripheral vascular disease. Dental rehabilitation is a viable option for advanced MRONJ patients treated by vascularized flap reconstruction.
0901-5027/000001+06
Key words: MRONJ; osteonecrosis; vascularized tissue transfer; mandible. Accepted for publication 31 January 2017
ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
YIJOM-3597; No of Pages 6
2
Caldroney et al.
Medication-related osteonecrosis of the jaw (MRONJ), previously known as bisphosphonate-related osteonecrosis of the jaw (BRONJ), is a recognized complication of anti-resorptive and anti-angiogenic bone-related therapies. The name change is justified to accommodate the growing number of osteonecrosis cases associated with other anti-resorptive (denosumab) and anti-angiogenic medications.1 The first reports of MRONJ were published more than a decade ago; however the pathophysiology has not yet been fully elucidated.2,3. MRONJ is especially associated with oncology-dose parenteral anti-resorptive therapy with bisphosphonates and the receptor activator of nuclear kappa B ligand (RANKL) inhibitor medication denosumab.4 Denosumab is an anti-resorptive agent that exists as a fully humanized antibody against RANKL and inhibits osteoclast function and associated bone resorption.5,6 It is also effective in decreasing systemic events related to metastatic bone disease from solid tumors.7,8 Bisphosphonates, especially the nitrogencontaining subset such as zoledronate and pamidronate, similarly decrease bone resorption. This leads to osteoclast cytoskeleton disruption, intracellular vesicular trafficking impairment, increased osteoclast apoptosis, and decreased osteoclast function.9 Bisphosphonates physiochemically bind to exposed hydroxyapatite and incorporate into the bone matrix with a half-life of many years. However unlike bisphosphonate medications, the incorporation and long-term effects of denosumab on bone remodeling and its half-life in the bone matrix are not well defined.9 The incidence of MRONJ is greatest in the oncology patient population (1% to 15%), where high doses are used at frequent intervals.4 The incidence of MRONJ in the osteoporosis patient population is significantly lower (0.001% to 0.01%) and is only marginally higher than the incidence in the general population.4 A prospective study, published in 2015, found that 22 of 80 patients (28%) receiving intravenous (IV) bisphosphonates for malignant neoplasms developed BRONJ.10 MRONJ is defined clinically in patients on current or previous treatment with anti-resorptive or anti-angiogenic medication, where the presence of exposed necrotic bone is evident through a fistula persisting over 8 weeks within the maxillofacial region that has not been irradiated previously.1 Established MRONJ can manifest within a wide spectrum of clinical presentations in the affected jaw (Table 1).
Table 1. Medication-related osteonecrosis of the jaw—staging system.a MRONJ staging Stage 0 Stage 1 Stage 2 Stage 3
Definition No clinical evidence of necrotic bone, radiographic changes only, non-specific symptoms Exposedb and necrotic bone, fistulae that probe into bone, no evidence of infection Exposedb and necrotic bone, fistulae that probe into bone, infection, pain, erythema purulent drainage Exposedb and necrotic bone with associated infection, pain including one or more of the following: bone necrosis/exposure beyond the alveolar bone, pathological jaw fracture, extraoral fistula, oro-antral/nasal communication, osteolysis extending to the inferior border of the mandible or sinus floor
MRONJ, medication-related osteonecrosis of the jaw. a Adapted from the Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg 2014: 72: 1938–1956.
Within the MRONJ continuum, stage 3 is the most advanced, where the exposed, necrotic bone and fistula occurs with evidence of infection, and with at least one of the following criteria: (1) exposed necrotic bone extending beyond the alveolar bone; (2) pathological fracture; (3) extraoral fistula; (4) oro-antral or oronasal communication; and (5) osteolysis extending to the inferior border of the mandible or sinus floor.1 Stage 3 MRONJ is debilitating and significant morbidity is experienced, particularly with repeated bouts of infection and when pathological fracture is present. The problems experienced include chronic unpleasant symptoms (e.g., pain, swelling, halitosis, purulent discharge, sinonasal symptoms), neurosensory deficit, loosening of teeth, masticatory dysfunction, and overall decreased quality of life. Despite a lack of high-quality evidence in regard to treatment, there is a general perception favoring conservative treatment over surgical therapy.11 Limited surgery in the form of localized debridement or sequestrectomy is advocated with the aim of simply softening sharp bony edges to promote soft tissue healing over the exposed bone rather than eliminating the entire area of necrotic bone.11,12 Aggressive radical surgery is offered only to symptomatic patients with extensive osteonecrosis, including those who have failed conservative treatment, with the aim of long-term palliation of infection and pain.1,13–15 Some authors have reported that surgical approaches result in superior treatment outcomes than conservative therapy regimens, with success rates of 80–90% and 10–62%, respectively.16 Nevertheless, an aggressive surgical treatment approach with wide bone resection and immediate reconstruction with microvascular free tissue transfer is considered controversial.
The aim of this study was to evaluate the outcomes of surgical resection and vascularized reconstruction in a cohort of advanced MRONJ patients at a single institution. The primary outcome measures included the presence of primary bone union and the recurrence of MRONJ. The secondary outcome measure was pain control and functional outcomes as they related to patient quality of life. Materials and methods
Institutional review board approval was obtained for the study. A retrospective review of the departmental reconstruction database was undertaken. All patients with stage 3 MRONJ treated by surgical resection and vascularized bone reconstruction, performed in the Department of Oral and Maxillofacial Surgery, University of Maryland from September 2010 to December 2015, were identified. A chart review of the subjects selected was completed to obtain demographic data, presenting clinical features, anti-resorptive medication history, risk habits, predisposing factors, site of MRONJ, surgical details including the type of resection and flap selection, perioperative complications, length of hospital stay, follow-up details including the length of follow-up, speech/swallowing outcomes, and recurrence of MRONJ. Functional status was determined using the Eastern Cooperative Oncology Group performance status (ECOG-PS) functional scale, which was noted preoperatively and at the 6-week follow-up. All patients received a computed tomography (CT) scan at least 8 weeks postoperatively to evaluate the outcomes of reconstruction. The three-dimensional (3D) digital images were retrieved from the hospital records using the eUnity diagnostic imaging system (Client Outlook Inc., Waterloo, ON, Canada) and
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
YIJOM-3597; No of Pages 6
Surgical resection and reconstruction in MRONJ viewed on a standard flat-screen monitor. The length of the defect restored was measured using both the pathological specimen and the eUnity system measurement tools on post-reconstruction CT imaging. The primary outcome measure of bony union was determined by reviewing the 8week postoperative CT scan for evidence of bony union at the resection site, determined by the presence of direct bone-tobone contact, without evidence of osteolytic lesions. The presence of recurrent MRONJ was determined by reviewing the last entry in the chart documenting the absence of exposed bone and a normal panoramic radiograph during the most recent follow-up visit. The secondary outcome measure was based on documented pain symptoms and the ECOG-PS,17 obtained preoperatively and at 6 weeks postoperative. All reconstructions were performed with the assistance of preoperative virtual surgical 3D planning (3D Systems, Colorado, USA) using patient-specific CT scans of the facial bones. Results
A total of 11 patients were included in this study; seven were female (64%) and four were male (36%). These patients underwent immediate microvascular free flap reconstruction at the time of ablative surgery or resection for MRONJ. The mean age at the time of surgery was 65.8 years (range 56–73 years). The majority of patients were treated with IV medications (10/11 IV, 1/11 oral). The most common class of drug was the bisphosphonates (10/ 11), followed by denosumab (2/11). Two patients received a bisphosphonate and denosumab. Patient baseline disease included metastatic breast cancer (4/11), multiple myeloma (3/11), osteoporosis (3/11), and prostate cancer (1/11). All patients were classified with stage 3 MRONJ. A total of seven patients (64%) presented with a pathological fracture and six patients presented with an orocutaneous fistula (55%). Pain was present on initial consultation in eight patients (73%). Eight patients required multiple courses of intravenous antibiotics preoperatively. Microvascular free flaps consisted of seven fibula osteocutaneous flaps (64%) and four scapula free flaps (36%). A scapula flap was selected in those patients with significant vascular disease not deemed suitable candidates for a fibula donor site, as identified on clinical examination and lower extremity vascular imaging studies.
The average length of the restored defects was 8.36 cm (range 5–14 cm). The average length of hospital stay was 9.6 days (range 7–15 days). One patient required a hemimandibulectomy with condylar disarticulation and was placed into intermaxillary wire fixation for a period of 6 weeks. All patients were pain-free after reconstruction (100%). ECOG-PS status was consistent with preoperative baseline (range 0–2) and was not negatively affected significantly postoperative. Three patients developed wound-related complications (27%). Complications included postoperative wound infection (n = 2), wound dehiscence (n = 2), and plate exposure (n = 2) requiring local wound care measures. One patient with hardware exposure underwent late hardware removal at 8 months postoperative without complication. One wound infection required a return to the operating room in conjunction with intravenous antibiotics. Complete bone union was noted in all 11 patients, with bone-to-bone contact noted radiographically (100%). There were no recurrences of MRONJ noted at the surgical site, although one patient did develop early stage MRONJ in the maxilla, treated with local wound care measures. Dental implant rehabilitation was completed in two patients (18%). Ten patients are tolerating an oral diet. One patient requires a percutaneous endoscopic gastrostomy (PEG) tube to supplement nutrition, although tolerating thin and thick liquids by mouth. Ten patients are alive without symptoms or evidence of MRONJ at any of the surgical sites. One patient died 28 months after surgery from progression of metastatic disease. The patient had resolution of the oral symptoms and complete bone healing at the osteotomy sites. The mean follow-up for the patients in this study was 25 months (range 6–69 months) (Table 2). Discussion
The definitive management of MRONJ, particularly in the advanced stage of the disease, remains divisive. It has been established that medical therapy is ineffective for the treatment of stage 3 disease, in which patients present with fistulae, pathological fractures, or bony destruction extending to the inferior border of the mandible.1 Radical surgical treatment has to be considered when (1) MRONJ seems to involve a large area of the jaw, (2) the disease is not resolved by conservative approach, (3) the donor site is well perfused, and (4) the preoperative exclusion of bone metastases at the donor site is
3
performed.18 The arguments against this approach are the concerns that surgical trauma inflicted on the bone could result in the progression of osteonecrosis and/or development of osteomyelitis in the remaining bone, the difficulty obtaining a viable surgical resection margin, and ultimately that bony union may be problematic considering the diffuse uptake of bisphosphonate by the entire jaw bone.19,20 Marx et al. suggested the possibility of free flap reconstruction in cases of significant soft tissue loss, but advocated against osseous microsurgical reconstruction given the higher surgical risk, and reported good outcomes with this management strategy of resection and titanium plating despite leaving a bony discontinuity.19,21 A concern against this argument is the management of a hardware failure, requiring a second surgery to manage the discontinuity, especially as many of these patients are living longer with stable metastatic disease. One could potentially avoid this issue with a composite bone and soft tissue flap reconstruction. Previously, a reconstruction bar alone was recommended over free vascularized bone because of trepidation regarding supposed unreliable bone healing seeing that the donor bone was also exposed to the generalized diffuse uptake of anti-resorptive and anti-angiogenic medications.1,2,21 In 2011, Pautke et al. reported for the first time the development of a bisphosphonate-related osteonecrosis in a microvascular iliac bone graft that was performed after a partial mandibulectomy due to BRONJ stage 3.16 The theoretical risk of potentially transferring malignancy with the donor bone in the case of multiple myeloma and when secondary metastatic bone disease is present has also been considered.19 In a review of 31 published cases of stage 3 MRONJ treated by surgical resection and vascularized bone reconstruction, the reported rate of non-union and recurrence of MRONJ at the resection margin was 6.5%.22 This contradicts some of the original concerns about unpredictable bone healing, progression/recurrence of MRONJ at the resection site, and the transferring of malignant disease. In the current series, all patients had bony union (100%) and there were no cases of progression or recurrence of MRONJ in the transplanted bony flap or at the resection site. Furthermore, the two patients who completed dental implant rehabilitation did not have any issues with dental implant osseointegration. The present authors routinely order either a whole body positron emission tomography
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
Caldroney et al.
Patient
Sex
Age, years
Medication
Pathology
1
F
56
Zoledronate
Metastatic breast
2
F
65
Zoledronate
Osteoporosis
3
F
60
Osteoporosis
4
F
61
Pamidronate Alendronate Alendronate
Osteoporosis
5
F
65
Zoledronate
Metastatic breast
6
F
64
Metastatic breast
7
M
68
Denosumab and zoledronate Zoledronate
Multiple myeloma
8
M
67
Zoledronate
Multiple myeloma
9 10
M F
73 72
Zoledronate Zoledronate
Prostate Metastatic breast
11
M
73
Pamidronate Denosumab
Multiple myeloma
Initial symptoms
Free flap
Length of bone (cm)
Defect location and osteotomiesa
Adverse events
Bone union
Dental implants
Follow-up (months)
Fracture Pain Fracture Fistula Pain Fracture Fistula Fracture Pain Fracture Pain Fracture Pain Fracture
Scapula
6.67
Right mandible (2)
None
Yes
No
44
Fibula
5
Left mandible (2)
None
Yes
No
69
Fibula
7.85
None
Yes
Yes
44
Fibula
11.7
Symphysis/left mandible (3) Subtotal mandibleb (3)
None
Yes
Yes
36
Fibula
6.1
Right mandible (2)
None
Yes
No
28 DWD
Fibula
7
Right mandible (2)
None
Yes
No
6
Scapula
10
Subtotal mandibleb (3)
Yes
No
6
Fistula Pain
Scapula
6.45
Right mandible (2)
Yes
No
10
Fistula Fistula Pain Fistula Pain
Scapula Fibula
9.29 8
Subtotal mandibleb (3) Subtotal mandibleb (4)
Yes Yes
No No
17 11
Fibula
14
Right mandible w/condylar disarticulation (2)
Infection Dehiscence Infection Hardware exposure Plate removal None Dehiscence Hardware exposure None
Yes
No
6
F, female; M, male; DWD, died with disease. a Osteotomies (n): the number of osteotomies, native bone and flap inclusive. b Subtotal mandible: right/left mandibular body including symphysis.
YIJOM-3597; No of Pages 6
4
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
Table 2. Flap reconstruction for patients with medication-related osteonecrosis of the jaw.
YIJOM-3597; No of Pages 6
Surgical resection and reconstruction in MRONJ (PET)-CT scan or technetium bone scan to rule out pre-existing metastatic disease at the potential donor site. Intraoperative assessment of the resected surgical margin and the establishment of a viable healthy bone margin can become a difficult task in the face of MRONJ. At the current time there is no one proven test that can guarantee with 100% accuracy the achievement of this goal. The authors rely on preoperative imaging, both CT scan and magnetic resonance imaging (MRI), to evaluate the cortical bone and marrow signal, respectively. This, in conjunction with intraoperative clinical assessment of healthy bleeding bone, is the method of choice for margin evaluation. When performing reconstructions with healthy vascularized tissue, one can also be generous with the length of mandible removed to include a larger segmental resection and removal of any questionable poor quality dentition. The recruitment of a healthy soft tissue component to aid in tension-free wound closure also assists with healing, as it minimizes wound breakdown. All of these factors are likely to have contributed to the successful bone union at the osteotomies reported in this current series. Although techniques such as auto-fluorescence have been advocated to evaluate the marrow signal and improve the establishment of an adequate viable surgical margin, this technology has not been employed by the current authors.23 Several authors have advocated against microvascular mandible reconstruction after BRONJ because the candidates are a high surgical risk cancer population with a limited life-expectancy. Patients with reasonable life-expectancy with regard to their malignant disease should be considered for microvascular tissue transfer after aggressive resection of the affected region15. There are increasing amounts of level 4 evidence of successful outcomes of resection and vascularized bone reconstruction for advanced stage MRONJ.15,16,22,24–30 Microvascular free flap restoration of MRONJ defects offers several advantages over multistage soft tissue and hard tissue reconstruction. These advantages include the ability to perform a single-stage surgery with a composite vascularized graft, to reconstruct large oral cavity defects, and to restore facial form and function including dental rehabilitation, in a clean-contaminated wound exposed to oral flora and saliva. The consideration of such extensive surgery should be assessed on an individual patient case basis, evaluating risk factors such as
significant medical co-morbidities, advanced age, peripheral vascular disease, or anomalous lower extremity vasculature. While the reliability of vascularized fibula reconstruction has been described in the previously published reports, and despite the favorable experiences with fibula and iliac crest, data indicating whether other osteocutaneous free flaps are equally successful are lacking. To date there have been 45 cases of refractory MRONJ treated with microvascular flaps. Thirty-eight patients underwent reconstruction with a free fibula flap and five with an osteocutaneous iliac crest free flap. In the series of Hanasono et al., two soft tissue free flaps were reported. One patient was deemed not to be a candidate for a bony free flap at the time of mandibulectomy and underwent reconstruction using a titanium plate with a soft tissue free flap. This patient had significant edema and advanced peripheral vascular disease of the legs, precluding use of the fibula.29 In the current series, four patients had significant peripheral vascular disease and were not candidates for a fibula osteocutaneous free flap. These four patients were successfully reconstructed with a scapula free flap, thus proving the scapula flap to be a viable option in severe peripheral vascular disease and large segmental mandibular defects. The present case series is rare in describing the use of scapula osteocutaneous free flaps in the management of MRONJ. At the authors’ institution, the patient is the main driver behind the decision to perform radical surgical treatment. These patients are often in pain and highly motivated to proceed with resection. Most are treated with conservative therapy as advocated; however some patients are no longer able to experience a good quality of life and are considered candidates for surgical resection and immediate reconstruction. It is also important to mention that only patients with stable metastatic disease or remission should be considered for such extensive methods of reconstruction. As stated previously, preoperative work-up should include a whole body PET-CT or technetium bone scan to screen for any occult active metastatic disease, particularly at potential donor sites, as recommended by Seth et al.26 In addition, close communication with the medical oncologist is critical in determining patient suitability for surgery based on current status and overall prognosis. The limitations of this study include its retrospective nature and small patient sample. Currently only the study by Hana-
5
sono et al. has included a larger sample size (n = 13), and as mentioned previously, two of the patients in that series underwent reconstruction only with soft tissue flaps29. A weakness of all the reported series on vascularized tissue transfer for the management of MRONJ, the current study included, is with regard to the management of advanced MRONJ of the maxilla. Conclusions cannot be drawn on the outcomes of flap reconstruction for maxillary MRONJ as all patients in the current series had disease treated within the mandible exclusively. Often the maxillary bone is diffusely diseased and of poorer quality, with difficulty in locating adequate bone to fixate the flap reconstruction. Patients undergoing the removal of maxillary bone can often have fistulae closed with local advancement flaps, and dental obturators can generally be used to reconstruct partial defects. Further study of maxillary MRONJ is required. The current findings suggest that advanced mandibular MRONJ may be treated predictably in selected patients using microvascular free fibula flaps, or, in cases where peripheral vascular disease is identified, the scapula osteocutaneous free flap as an effective alternative. Surgical resection with immediate vascularized reconstruction can provide for significant improvements in quality of life, including the possibility of successful dental implant rehabilitation in the MRONJ patient. The risk of both surgical and medical complications in this cohort of patients is not different as compared to other patient populations undergoing similar reconstructive procedures. Funding
Not applicable. Competing interests
None. Ethical approval
This study was approved by the Institutional Review Board for Ethical Human Research at the University of Maryland, Baltimore, Maryland, USA. Patient consent
Not applicable. References 1. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F.
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023
YIJOM-3597; No of Pages 6
6
Caldroney et al.
American Association of Oral and Maxillofacial Surgeons: American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw— 2014 update. J Oral Maxillofac Surg 2014;72:1938–56. 2. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115–7. 3. Ruggiero 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;62:527–34. 4. Khan A, Morrison A, Cheung A, Hashem W, Compston J. Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015. Osteoporos Int 2016;27. 853–839. 5. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C. FREEDOM Trial: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65. 6. Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Man Z, Mellstrom D, Radominski SC, Reginster JY, Resch H, Roman Ivorra JA, Roux C, Vittinghoff E, Austin M, Daizadeh N, Bradley MN, Grauer A, Cummings SR, Bone HG. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 2012:694–701. [7] Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessi C. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813–22. [8] Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Vinegar M, Fan M, jiang Q, Dansey R, jun S, Braun A. Denosumab compared with zoledronic acid for the treatment of bne metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132–9. 9. Lewiecki EM. Denosumab update. Curr Opin Rheumatol 2009;21:369–73. –. 10. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G. Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008; 44:857–69.
11. Carlson ER, Basile JD. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2009;67(5 Suppl): 85–95. 12. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis. An American Academy of Oral Medicine position paper. J Am Dent Assoc 2005;136:1658–68. –. 13. Ruggiero SL, Dodson TB, Assail LA, Landesberg R, Marx RE, Mehrotra B. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws 2009 update. J oral Maxillofac Surg 2009;67(5 Suppl): 2–12. 14. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479–91. 15. Mu¨cke T, Haarmann S, Wolff KD, Ho¨lzle F. Bisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstruction. J Craniomaxillofac Surg 2009;37: 291–7. 16. Pautke C, Otto S, Reu S, Kolk A, Ehrenfeld M, Stu¨rzenbaum S, Wolff KD. Bisphosphonate related osteonecrosis of the jaw—manifestation in a microvascular iliac bone flap. Oral Oncol 2011;47:425–9. 17. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Co-operative Oncology Group. Am J Clin Oncol 1983;5:649–55. 18. Sacco R, Sacco G, Acocella A, Sale S, Sacco N, Baldoni E. A systematic review of microsurgical reconstruction of the jaws using vascularized fibula flap technique in patients with bisphosphonate-related osteonecrosis. J Appl Oral Sci 2011;19:293–300. 19. Marx RE. Reconstruction of defects caused by bisphosphonate-induced osteonecrosis of the jaws. J Oral Maxillofac Surg 2009; 67(5 Suppl):107–19. 20. Nocini PF, Saia G, Bettini G, Ragazzo M, Blandamura S, Chiarini L, Bedogni A. Vascularized fibula flap reconstruction of the mandible in bisphosphonate-related osteonecrosis. Eur J Surg Oncol 2009;35:373–9. 21. Marx 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: 1567–75. 22. Vercruysse Jr H, Backer T, Mommaerts M. Outcomes of osseous free flap reconstruction in stage III bisphosphonate-related osteonecrosis of the jaw: systematic review and a
23.
24.
25.
26.
27.
28.
29.
30.
new case series. J Craniomaxillofac Surg 2014;42:377–86. Ristow O, Pautke C. Auto-fluorescence of the bone and its use for delineation of bone necrosis. Int J Oral Maxillofac Surg 2014; 43:1391–3. Engroff SL, Kim DD. Treating bisphosphonate osteonecrosis of the jaws: is there a role for resection and vascularized reconstruction. J Oral Maxillofac Surg 2007;65: 2374–85. Ferrari S, Bianchi B, Savi A, Poli T, Multinu A, Balestreri A, Ferri A. Fibula free flap with endosseous implants for reconstructing a resected mandible in bisphosphonate osteonecrosis. J Oral Maxillofac Surg 2008;66: 999–1003. Seth R, Futran ND, Alam DS, Knott PD. Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonaterelated osteonecrosis of the jaws. Laryngoscope 2010;120:2165–71. Bedogni A, Saia G, Bettini G, Tronchet A, Totola A, Bedogni G, Ferronato G, Nocini PF, Blandamura S. Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis. Oral Oncol 2011;47:420–4. Ghazali N, Collyer JC, Tighe J. Hemimandibulectomy and vascularized fibula flap in bisphosphonate-induced mandibular osteonecrosis with polycythaemia rubra vera. Int J Oral Maxillofac Surg 2013;42: 120–3. 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: 1135–42. Spinelli G, Torresetti M, Lazzeri D, Zhang YX, Arcuri F, Agostini T, Grassetti L. Microsurgical reconstruction after bisphosphonate-related osteonecrosis of the jaw: our experience with fibula free flap. J Craniofac Surg 2014;25:788–92.
Address: Joshua E. Lubek Oral–Head and Neck Surgery/Microvascular Surgery Department of Oral and Maxillofacial Surgery 650 West Baltimore St Rm 1401 University of Maryland Baltimore MD 21201 USA Tel: +1 410 706 7060 Fax: +1 410 706 4199 E-mail: [email protected]
Please cite this article in press as: Caldroney S, et al. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.01.023