Реконструкция пашины фибулы для максимально вспомогательного этапа 3 Связанный с лекарствами остеонекроз челюсти с точки зрения получателей и доноров: предварительное исследование с использованием одного центра.

Introduction

Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication induced by the administration of antiresorptive medications, antiangiogenic agents, or immune modulators for the treatment of bone metastases, multiple myeloma, osteoporosis, and other diseases [ 1 ]. Clinical manifestations mainly include gingival swelling, pyorrhea, pain, oral or extraoral fistula, exposed bone, and pathological fractures, which not only affect patients’ masticatory function but also necessitate the temporary cessation of primary disease treatment, severely reducing quality of life [ 2 ].

Studies have found that MRONJ lesions occur more commonly in the mandible than the maxilla at a 3:1 ratio [ 1 ]. This lower incidence in the maxilla often shifts research focus to the mandible. Anatomically, the proximity of the maxilla to the maxillary sinus makes it susceptible to the spread of infection, potentially leading to maxillary sinusitis. Hershberger et al. reported that 64% of maxillary MRONJ cases exhibited sinus opacification, and 28% were diagnosed with maxillary sinusitis [ 3 ]. If unchecked, such infections may spread to adjacent sinuses or systemically. Therefore, despite its lower incidence, attention to maxillary MRONJ is imperative.

Currently, the extent of surgical interventions for maxillary stage 3 MRONJ varies, including resection alone, or reconstruction with pedicled or vascularized soft tissue flaps, among others [ 4 – 6 ]. According to the 2022 American Association of Oral and Maxillofacial Surgeons (AAOMS) position paper, maxillary stage 3 MRONJ is defined as the exposed necrotic bone or fistula that probes to bone, accompanied by infection, and one or more of the following: (1) exposed necrotic bone extending beyond the alveolar bone; (2) pathologic fracture; (3) extraoral fistula; (4) oroantral/oral-nasal communication; (5) osteolysis extending to the maxillary sinus [ 1 ]. For extensive lesions, radical resection is crucial for completely removing necrotic bone to prevent recurrence. However, the use of fibula flap for reconstruction remains controversial [ 7 ]. The fibula flap can effectively reconstruct maxillary defects and assist in tension-free wound closure with a skin paddle, but it may be affected by antiresorptive medications.

Atypical femoral fracture (AFF) is a serious complication of antiresorptive medications, defined as a femoral fracture triggered by a minor trauma and occurring between the lower end of the lesser trochanter and just above the femoral condyle [ 8 ]. It remains uncertain whether these medications severely impact the fibula or tibia, increasing the risk of fibula flap necrosis or fracture, or causing tibia fracture due to the inability to withstand additional stress [ 9 , 10 ]. These considerations raise concerns about the feasibility of fibula flap, warranting further clinical investigation.

In this study, patients with maxillary stage 3 MRONJ underwent fibula flap reconstruction following radical resection. The objective was to assess the surgical outcomes and functional recovery of fibula flap reconstruction for maxillary stage 3 MRONJ. To our knowledge, this is one of the largest studies to date, providing a comprehensive evaluation of prognosis from both recipient and donor site perspectives.

Materials and methods

Patients and methods

This retrospective observational study included patients with maxillary stage 3 MRONJ who underwent fibula flap reconstruction at the Department of Oral and Maxillofacial Surgery, Fujian Medical University Union Hospital, between 2023 and 2024 (Fig. 1 ). Inclusion criteria were: (1) patients receiving current or previous antiresorptive treatment; (2) patients with lesions persisting for more than 8 weeks; (3) patients with no history of radiation therapy or metastatic disease to the jaws; (4) patients with controlled and stable primary disease. Exclusion criteria were: (1) patients with lesions located in the mandible; (2) patients who underwent non-fibula flap reconstruction; (3) patients with lesions not classified as stage 3; (4) patients deemed unfit for surgery. All surgeries were performed by the same surgical team. This study was conducted in accordance with the tenets of the Declaration of Helsinki and approved by the Ethical Committee of Fujian Medical University Union Hospital (2024KY095).

Preoperative management

Single-photon emission computed tomography (SPECT) was performed to exclude malignant tumor fibula metastasis. A specialty consultation with the relevant departments was required to exclude the primary disease being in a progressive stage. Bilateral lower extremity arterial and venous color Doppler ultrasound was performed to assess the presence of the anterior and posterior tibial arteries and veins, and the peroneal artery and vein, as well as any abnormalities or thrombosis. Intravenous cefuroxime sodium and ornidazole were administered to treat infection. A specific duration for drug holiday is not strictly required [ 11 ].

Surgical procedure

The operation was divided into two groups. One group underwent partial maxillectomy, thorough removal of necrotic bone, and excision of inflammatory mucosa, using a lower lip-splitting approach. The facial vein, facial artery, and superior thyroid artery were preserved for anastomosis. The maxillary sinus was packed with iodoform gauze, which was brought out through the nasal cavity. The oroantral communication was closed with a buccal fat pad (BFP).

In the other group, fibula flap was prepared by conventional methods. Fibula was harvested to repair the maxillary defect. Anastomosis was performed between the peroneal artery and the facial artery/superior thyroid artery, and between the peroneal vein and the facial vein. The defect in the maxillary mucosa was meticulously closed using a skin paddle.

Postoperative management

The color, texture, temperature, dermatoglyphs, and degree of swelling of the flap were closely observed. Starting on the second postoperative day, a liquid diet was administered via a nasogastric tube. By the end of the second week, the nasogastric tube was removed, and the patient initiated oral intake of liquids, gradually transitioning to a semi-liquid diet and subsequently to soft foods. Daily oral wound cleansing was performed to maintain oral hygiene. Iodoform gauze was gradually removed at 5 days post-surgery. Intravenous antibiotics were administered to prevent infection. Postoperatively, the affected limb was elevated, and toe joint exercises were performed. Gradual progression to bedside activities and crutch walking was recommended, with activity intensity adjusted based on daily activity levels. Prompt treatment was undertaken in case of any other complications that developed in patients. Antiresorptive medications were discontinued for 3 to 6 months postoperatively.

Observation indexes

(1) Demographic and clinical characteristics: Age, sex, primary diseases, type of drugs, route of drugs, drug administration frequency, cumulative dose, drug holiday, history of chemotherapy, history of diabetes, history of steroid hormone use, trigger factors, past therapy history, anatomic location, symptoms and signs, and occurrences of maxillary sinusitis. Maxillary deficiency was classified based on Brown’s classification [ 12 ].

(2) Postoperative and long-term data of the recipient site: Postoperative complications were classified according to the Clavien-Dindo classification [ 13 ]. The Speech Handicap Index (SHI) questionnaire, Eating Assessment Tool-10 (EAT-10) questionnaire, survival of fibula flaps, incidence of fibula flap fractures, recurrence of MRONJ, and patient survival status after 6 months post-surgery. Recurrence was defined as the dehiscence or infection of the surgical site, or bone exposure, lasting more than 8 weeks postoperatively [ 2 , 14 ]. The SHI was used to assess the recovery of speech function, which has a scale of 0-120, with a lower score indicating a better speech function [ 15 ]. The EAT-10 was used to assess the recovery of swallowing function, which has a scale of 0–40, with a lower score indicating a better swallowing function [ 16 ].

(3) Postoperative and long-term data of the donor site: Postoperative complications were classified according to the Clavien-Dindo classification. The short-form McGill Pain Questionnaire (SF-MPQ), American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, and incidence of tibia fractures after 6 months post-surgery. The SF-MPQ was used to assess chronic pain in the lower limb surgical site, which has a scale of 0–45, with a lower score indicating a less pain [ 17 ]. The AOFAS ankle-hindfoot score was used to assess the ankle joint function, which has a scale of 0-100, with a higher score indicating a better ankle joint function [ 18 ]. The assessment of prodromal symptoms of tibia fracture is facilitated by the status of chronic pain and ankle joint function.

Statistical analysis

All data were presented as mean ± standard deviation after normal distribution was confirmed by the Shapiro-Wilk test. All statistical analyses were performed using SPSS (IBM SPSS Statistics 27.0).

Results

Demographic and clinical features

In total, seven patients (three males, four females; mean age 61.29 ± 6.87 years) were included (Fig. 1 ). Two had multiple myeloma, and five had bone metastases (three with lung cancer, two with breast cancer). Zoledronate was the most common antiresorptive medication (5/7), followed by denosumab (3/7) and ibandronate (2/7). Three patients received more than one type of antiresorptive medication. Zoledronate and ibandronate were administered intravenously, while denosumab was administered subcutaneously. The typical dosing frequency was once every four weeks. Due to the higher single-dose amount of denosumab, the total dose for patients who used denosumab was significantly higher. At the time of admission, the average drug holiday was 13.28 ± 15.46 weeks. Six patients had a history of tooth extraction, including one who underwent extraction after unsuccessful root canal treatment (RCT), while one patient had no identifiable trigger factors. The chief complaints included pain, swelling, and pyorrhea, with most patients exhibiting signs of necrotic bone exposure (5/7). Following the onset of symptoms and signs, antibiotic therapy was administered to all patients, with two undergoing debridement, which subsequently resulted in recurrence, and one receiving hyperbaric oxygen (HBO) therapy. Radiographic findings for all patients indicated ipsilateral maxillary sinusitis. According to Brown’s classification, six patients had type IIb defect, while one patient had type IId defect (Table 1 ).

Postoperative complications and long-term outcomes of recipient site

All vascularized fibula flaps survived, with primary healing achieved in all cases. There were no instances of fibula flap fractures or non-union. Six months after surgery, the mean postoperative speech function score was 28.00 ± 12.03, and the mean postoperative swallowing function score was 2.86 ± 2.79. No recurrence of MRONJ was observed in the fibula graft or other regions of the jaw. All patients were alive at the last follow-up (Table 2 ).

Postoperative complications and long-term outcomes of donor site

According to the Clavien-Dindo classification, two patients (No. 1, 3) developed delayed healing and were classified as grade I-d. Regular dressing changes were performed, resulting in complete wound healing within two months postoperatively. Six months after surgery, the mean postoperative pain score was 2.71 ± 2.29, and the mean postoperative ankle joint function score was 94.43 ± 4.35. No patients had tibial fracture or prodromal symptoms of tibial fracture (Table 2 ).

Case presentation

A 64-year-old male patient (No. 3) presented with a chief complaint of pain and pyorrhea of the right upper gums, persisting for a year following tooth extractions. He was diagnosed with bone metastases from lung cancer and had been receiving targeted therapy and denosumab. Necrotic bone exposure, along with redness and swelling of the surrounding mucosa, was observed (Fig. 2 A). CT and panoramic radiographs revealed an extensive osteolytic lesion in the right maxilla, with osteolysis extending to the sinus floor and associated maxillary sinusitis (Fig. 2 B, C). SPECT showed abnormal radioactive concentration in the right maxilla, with no increased uptake of 99mTc-methylene diphosphonate (99mTc-MDP) in the fibula (Fig. 2 D).

During the operation, a partial maxillectomy was performed to completely remove the necrotic bone, and a fibula flap was harvested to reconstruct the maxillary defect (Fig. 3 ). Postoperatively, the patient’s symptoms were significantly relieved. Panoramic radiographs showed proper alignment of the fibula with the maxillary bone ends (Fig. 4 A). The soft tissue healed well, and the fibula flap survived (Fig. 4 B). The incision on the lower leg had delayed healing but recovered after regular dressing changes (Fig. 4 C). Six months postoperatively, there was no recurrence of MRONJ or any serious complications. The patient’s speech, swallowing, and ankle joint functions were acceptable.

Discussion

Growing evidence suggests that conservative treatment for stage 3 MRONJ only alleviates symptoms and is unlikely to achieve a cure [ 19 ]. Early surgical intervention is considered beneficial for halting disease progression and preventing symptom recurrence [ 1 , 19 ]. However, the extent of surgical treatment remains inconclusive, and fibula flap reconstruction is controversial, particularly for maxillary MRONJ due to its low incidence and limited research [ 20 – 22 ]. This study presents a summary of seven cases of maxillary stage 3 MRONJ reconstructed with fibula flaps to provide insights for colleagues in the field.

Many studies have indicated that invasive procedures, such as tooth extraction, RCT, and dental implantation, are trigger factors for MRONJ [ 14 ]. Additionally, diabetes, chemotherapy, and steroid hormone therapy increase the risk of developing MRONJ [ 1 ]. However, Soutome et al. concluded that the incidence of MRONJ was significantly lower in the tooth extraction group compared to the non-extraction group, suggesting that preserving teeth that require extraction poses a risk for developing MRONJ, whereas tooth extraction itself does not [ 23 ]. In this study, six patients had a history of tooth extraction; five complained of loose tooth prior to extraction, and one had tooth pain leading to extraction after unsuccessful RCT. However, it remains uncertain whether MRONJ was precipitated by the tooth extraction or by the pre-existing periodontitis or apical periodontitis, necessitating further investigation.

Nisi et al. indicated that maxillary lesions are associated with more severe MRONJ staging, potentially due to the difficulty in detecting lesions before necrotic bone exposure [ 24 ]. Clinical manifestations are nonspecific and often misdiagnosed as simple maxillary sinusitis, a characteristic of stage 3 MRONJ. By the time intraoral fistulas or necrotic bone exposure occur, the disease is already advanced [ 24 , 25 ]. Park et al. found that combining oral surgery with functional endoscopic sinus surgery exhibited a higher percentage of resolution compared to oral surgery alone for maxillary stage 3 MRONJ [ 26 ]. This may be due to maxillary sinusitis acting as an infection source, exacerbating MRONJ progression and diminishing treatment outcomes if not effectively controlled. The BFP has been shown to be effective for the closure of oroantral fistulas [ 27 ]. In this study, following radical resection, iodoform gauze was packed into the maxillary sinus to control inflammation, and BFP was used to close the oroantral communication, reducing the likelihood of recurrence.

Various surgical treatments for maxillary stage 3 MRONJ have been reported, including resection alone or the insertion of bioactive materials [ 28 ]. Terenzi et al. preferred the use of local and pedicled flaps [ 29 ]. In cases of extensive tissue loss, vascularized soft tissue flaps like the anterolateral thigh flap can provide substantial coverage [ 6 ]. In this study, the defects of six patients were classified as Brown’s classification IIb, while the defect of one patient was classified as Brown’s classification IId, resulting in functional impairments and midfacial collapse [ 30 ]. Brown et al. pointed out the fibula flap as the ideal choice for defects within these classifications [ 12 ]. The fibula flap contributes to restoring speech, swallowing, and mastication functions [ 30 , 31 ]. Moreover, the skin paddle facilitates tension-free wound closure, reducing the risk of wound dehiscence and recurrence [ 6 ].

Currently, research on fibula flap reconstruction for maxillary stage 3 MRONJ is limited [ 20 – 22 ]. Bedogni et al. described a maxillary stage 3 MRONJ patient who underwent fibula flap reconstruction, resulting in flap failure and salivary duct fistula post-surgery. Subsequent flap removal and salivary fistula repair led to healing [ 20 , 32 ]. Sotsuka et al. reported a bilateral maxillary stage 3 MRONJ patient who underwent fibula flap reconstruction, achieving postoperative flap survival and soft tissue healing [ 21 ]. Sweeny et al. included three maxillary MRONJ patients who underwent fibula flap reconstruction; however, their specific outcomes were not detailed [ 22 ]. In this study, all seven patients experienced flap survival with no recurrence of MRONJ. The mean speech function score was 28.00 ± 12.03, and mean swallowing function score was 2.86 ± 2.79. Compared to previous studies, the restoration of speech and swallowing functions was acceptable [ 30 , 33 ]. Lombardo et al. conducted an average follow-up of six years on patients who received dental implants following fibula flap reconstruction, achieving excellent implant survival and success [ 34 ]. This suggests that the ultimate objective of fibula flap reconstruction is occlusal reconstruction. Given that no patients in this study completed dental rehabilitation, the assessment of masticatory function remains incomplete. This necessitates longer follow-up periods to optimize patient outcomes.

Some studies have questioned the potential involvement of the fibula in primary diseases such as metastatic malignant tumors or multiple myeloma infiltration [ 35 ]. Consequently, it is recommended to routinely perform preoperative 18 F-fluoride positron emission tomography-computed tomography (PET-CT) or SPECT to rule out fibular involvement [ 36 , 37 ]. Additionally, the fibula is susceptible to the effects of antiresorptive medications. AFF is a serious complication of these medications, primarily due to the inhibition of bone remodeling and angiogenesis, as well as the lateral cortex being subjected to higher tensile stresses [ 38 ]. Radiologic features of AFF include a transverse morphology and a thickened cortex, among others [ 8 , 39 ]. Murray et al. reported a case of bilateral atraumatic distal fibula fractures in a patient treated with alendronate for low bone mineral density, with radiological features similar to AFF [ 9 ]. Raguse et al. reported a patient who suffered two successive tibia fractures after fibula flap reconstruction for mandibular stage 3 MRONJ [ 10 ]. Although these case reports have certain confounding factors, such as the absence of surgical detail and postoperative management, they underscore the need for vigilance. In our study, none of the seven patients exhibited fibula graft necrosis or fractures. The mean pain score was 2.71 ± 2.29, and the mean ankle function score was 94.43 ± 4.35, indicating no prodromal symptoms of tibia fracture. Two patients had delayed wound healing, possibly due to advanced age or malnutrition. For donor site defects of significant size, consideration may be given to performing a full-thickness skin graft or one-stage Pelnac reconstruction, the latter of which has been shown to provide good cosmetic outcomes and lower donor-site morbidity [ 40 ]. Wu et al. collected AOFAS ankle-hindfoot scores from 31 patients who underwent fibula flap reconstruction for non-MRONJ causes, with an average score of 94.03 ± 6.81 at least two years postoperatively, showing no significant difference compared to the average score obtained in this study [ 41 ]. These findings suggest that, while antiresorptive medications exert systemic skeletal effects, the fibula and tibia appear to be less adversely impacted compared to the jaw, which has a high bone turnover rate. Additionally, the femur, subjected to excessive mechanical loading, is more prone to complications, unlike the fibula, which is not predisposed to serious functional impairments.

This study has several limitations. First, the single-center design limits the generalizability of the findings, as the patient population may not fully represent the broader demographic. Second, the small sample size reduces the statistical power of the study, potentially affecting the reliability of the outcomes. Third, the limited follow-up period restricts our ability to fully assess the effectiveness of fibula flap reconstruction for maxillary stage 3 MRONJ. Further multi-center studies with larger sample sizes and longer follow-up periods are needed. Nevertheless, in contrast with other studies reporting the outcomes of fibula flap reconstruction for maxillary stage 3 MRONJ, our study is one of the largest studies and offers distinctive insights into outcomes from both recipient and donor site perspectives.

Conclusion

In the field of oral and maxillofacial surgery, the application of fibula flap reconstruction for maxillary defects is neither new nor particularly challenging, yet its use in maxillary stage 3 MRONJ remains controversial. Based on this study, fibula flap reconstruction is a feasible method for maxillary stage 3 MRONJ, and we have achieved satisfactory surgical outcomes and functional recovery of both recipient and donor sites in our follow-up. Preoperative exclusion of metastatic disease to the fibula and vascular variations, along with achieving a tension-free, secure closure of the wound during the procedure, are important for optimizing outcomes. However, further clinical studies with longer follow-up periods and larger sample sizes are needed to provide more knowledge. Additionally, exploring how the classification of the primary disease can influence treatment decisions could potentially lead to more personalized and effective strategies for managing maxillary stage 3 MRONJ.

Acknowledgements

Not applicable.

Abbreviations

Medication-related osteonecrosis of the jaw

Atypical femoral fracture

Single photon emission computed tomography

Buccal fat pad

Speech Handicap Index

Eating Assessment Tool-10

Short-form McGill Pain Questionnaire

Root canal treatment

Hyperbaric oxygen

99mTc-methylene diphosphonate

Positron emission tomography-computed tomography

Author contributions

YL and JW designed the study, analyzed the results, and drafted the manuscript. YL and CM revised the manuscript. CW, ML and QO collected clinical data. YH and WC guided the research direction, and reviewed the final manuscript. All authors read and approved the final manuscript.

Funding

No financial support with regards to this body of work.

Data availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the Ethical Committee of Fujian Medical University Union Hospital (2024KY095). Informed consent was waived because of the anonymity of the data and the retrospective nature of our study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yuhan Lin and Jin Wang contributed equally to this work.

Contributor Information

Yue He, Email: william5218@126.com.

Weihui Chen, Email: whchen@fjmu.edu.cn.

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Associated Data

Data Availability Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.