Abstract
The aim of this systematic review was to answer the question: What are the treatments available for bisphosphonate-related osteonecrosis of the jaws (BRONJ) and their outcomes? A literature search of PubMed, Cochrane Library, and Web of Science databases was conducted in accordance with the PRISMA statement, search phrases were (‘jaw osteonecrosis’ OR ‘bisphosphonate-related osteonecrosis’ OR ‘bisphosphonate osteonecrosis’) AND (‘treatment’ OR ‘outcomes’). Ninety-seven articles published between 2003 and February 2014 were reviewed. The studies reported 4879 cases of BRONJ. The mean age of the patients was 66.5 ± 4.7 years. The male to female ratio was 1:2. The mean duration of bisphosphonate (BP) administration was 38.2 ± 15.7 months. The quality of the publications was good, with some moderate and poor. Minimally invasive surgical treatment was the treatment most used. Medical treatment was also used. Adjunctive treatments included laser, growth factors, hyperbaric oxygen and ozone. The articles provided a broad range of outcome variables to assess the treatment of BRONJ and the outcomes of each treatment. Considerable heterogeneity was found regarding study design, sample size, and treatment modalities. Clinical trials with larger samples are required to provide sufficient information for each treatment modality to predict the outcomes of each treatment.
Bisphosphonates (BPs) are a class of drugs used across a wide range of disciplines including endocrinology, oncology, orthopaedics, and dentistry. They are commonly prescribed for bone diseases such as osteoporosis, Paget’s disease of bone, hypercalcaemia of malignancy, osteolytic bone metastases, and osteolytic lesions of multiple myeloma. Their use has resulted in a statistically significant reduction in skeletal complications, including pathological fractures, spinal cord compression, and hypercalcaemia of malignant disease, and has reduced the need for subsequent radiotherapy or surgery to bone.
BPs are synthetic analogues of the naturally occurring pyrophosphate molecule. They are broadly classified on the basis of whether or not they contain a nitrogen atom, with nitrogen-containing bisphosphonates (N-BPs) being more potent than non-N-BPs. They differ from one another in the substitution of the active side chains on their phosphorous–carbon phosphorous structural backbone.
The mechanism of action of BPs is the inhibition of bone resorption by suppressing osteoclast activation and inducing osteoclast apoptosis. The efficacy of BPs has been established in several studies. However, their use may have side effects. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been characterized as a main side effect of BP therapy. The first descriptions of BRONJ were reported in 2003. Since then, numerous reports on the development of osteonecrosis of the jaw in patients treated with BPs have been published.
BRONJ lesions may remain silent until the occurrence of a triggering event, such as an invasive dental procedure, infection, or mechanical trauma to the jawbone, as well as the concomitant use of immunosuppressive and chemotherapy drugs. According to a recent position paper from the American Association of Oral and Maxillofacial Surgeons (AAOMS), risk factors for the development of BRONJ can be grouped into drug-related, local, demographic and systematic, genetic, and preventive. The clinical manifestations of BRONJ vary from necrotic bone exposure (ranging from a few millimetres in size to larger areas, which can be asymptomatic for weeks, months, or years ), simple swellings of the soft tissues, and abscesses, to more complex cases presenting with fistulas and diffuse pain.
There are two major theories regarding the pathophysiology of BRONJ. One is the osteoclast-based, ‘inside-out’ theory, in which inhibition of osteoclastic activity and marked suppression of bone turnover, together with the spread of physiological micro-damage and possibly local infection, leads to bone death within the jaw, with subsequent exposure. As such, the bone exposure would be a late event. The second, ‘outside-in’ theory suggests a break in the oral mucosa leads to ingress of bacteria and local infection, which, coupled with poor bone remodelling, leads to bone death. BRONJ may result from a combination of these two mechanisms, and hypovascularity may also play an important role. Although there have been reports relating no obvious co-morbidity factors, it is reasonable to believe that co-factors play a relevant role in the development of these lesions.
The management of BRONJ has centred on efforts to eliminate or reduce the severity of symptoms, to slow or prevent the progression of disease, and to eradicate diseased bone. There is currently no gold standard for the treatment of BRONJ. Several treatment options have been described in relation to the AAOMS staging of BRONJ. No agreement on a surgical versus non-surgical approach to therapy has been reached in the treatment of BRONJ. Some recommendations focus on prevention and a conservative approach.
Treatment strategies include the administration of antibiotics, oral antibacterial mouth rinse, cessation of BPs if possible, pain control, surgical debridement or resection for long-term palliation of infection and pain, sequential removal of sequestrum (extensive involvement may necessitate a large area of debridement to include a segmental mandibulectomy and partial maxillectomy ), mandibular reconstruction with the fibula flap, and covering the exposed areas with tissue flaps. Hyperbaric oxygen (HBO) therapy, fluorescence-guided bone resection, and low-intensity laser therapy have also been studied as therapeutic tools.
Other treatment modalities that increase bone wound healing using growth and differentiation factors are being studied, as well as transplantation of intra-lesional autologous bone marrow stem cells. More recently, teriparatide (N-terminal 34-amino acid recombinant human parathyroid hormone) has been reported for the medical treatment of BRONJ. Pentoxifylline and α-tocopherol in addition to antimicrobial therapy has been shown to decrease the area of bone exposure and symptoms in BRONJ patients. The use of ozone in combination with antibiotics and surgery for patients with exposed bone lesions has also been the subject of a clinical investigation and found to resolve pain, secretions, and halitosis.
The main objective of this study was to conduct a systematic review of the literature to determine the treatment strategies available for BRONJ, describing the outcome variables measured for each treatment modality and the success of the treatment expressed by the outcome.
Materials and methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied for this review. PRISMA comprises a 27-item checklist and a four-phase flow diagram that relates to the title, abstract, introduction, methods, results, and discussion sections of articles, and funding. They were developed based on recommendations regarding what should be included in an accurate and complete report of systematic reviews and meta-analyses.
The systematic search covered the time period 2003 (the year of the initial description of BRONJ) to 28 February 2014. All publications identified in the literature search were retrieved from online journals and selected on the basis of the inclusion criteria.
Inclusion and exclusion criteria
The following inclusion criteria were applied: (1) academic publications; the review included any published studies (cross-sectional surveys, cohort, and case–control studies), clinical trials, case series, and retrospective studies; (2) publication in the English language confirming the diagnosis of BRONJ in accordance with the AAOMS or American Society of Bone and Mineral Research (ASBMR) definitions; (3) studies on humans; (4) participants of any age and gender with a clinical diagnosis of BRONJ; (5) any form of treatment; (6) outcomes variables should be mentioned in the publication; (7) outcome of the treatment.
The following exclusion criteria were applied: (1) single case reports of BRONJ; (2) experimental laboratory studies; (3) case series with fewer than five patients; (4) literature reviews, letters, editorials, doctoral theses, and abstracts.
Disease definition
The disease definition, as proposed by AAOMS and ASBMR, includes the persistence of exposed necrotic bone in the oral cavity for 8 weeks, despite adequate treatment, in a patient with current or a previous history of BP use, without local evidence of malignancy, and no prior radiotherapy to the affected region.
A clinical staging system has been proposed to classify patients with established BRONJ, with appropriate treatment for each stage ( Table 1 ).
| BRONJ stage | Clinical conditions | Treatment strategies |
|---|---|---|
| At risk | No apparent necrotic bone in patients who have been treated with either oral or IV bisphosphonates | No treatment indicated Patient education |
| Stage 0 | No clinical evidence of necrotic bone, but non-specific clinical findings and symptoms | Systemic management, including the use of pain medication and antibiotics |
| Stage 1 | Exposed and necrotic bone in asymptomatic patients without evidence of infection | Oral anti-bacterial mouth rinse Clinical follow-up on a quarterly basis Patient education and review of indications for continued BP use |
| Stage 2 | Exposed and necrotic bone associated with infection as evidenced by pain and erythema in the region of exposed bone, with or without purulent drainage | Symptomatic treatment with oral antibiotics Oral anti-bacterial mouth rinse Pain control Superficial debridement to relieve soft tissue irritation |
| Stage 3 | Exposed necrotic bone in patients with pain and erythema and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone, such as the inferior border and ramus in the mandible, or maxillary sinus or zygoma in the maxilla, resulting in pathological fracture, extraoral fistula, or oral–antral/oral–nasal communication, or osteolysis extending to the inferior border of the mandible or to the maxillary sinus floor | Oral anti-bacterial mouth rinse Antibiotic therapy and pain control Debridement/surgical resection for prolonged relief of pain and infection |
Electronic database search
Three databases – PubMed, the Cochrane Library, and Web of Science – were electronically searched. The heading sequence (‘jaw osteonecrosis’ OR ‘bisphosphonate-related osteonecrosis’ OR ‘bisphosphonate osteonecrosis’) AND (‘treatment’ OR ‘outcomes’) was searched as text word. The results of the database searches were combined and duplicate articles were excluded. All references were gathered and screened for eligibility.
In the first round search, abstracts were reviewed and all articles containing the key words were retained. Articles that were not in English were excluded. Complete versions were then obtained for all articles that that met the inclusion criteria.
In the second round search and evaluation, a manual search was done of the reference lists of all the articles retained after the first round for appropriate studies relevant to the review topic. A search of the unpublished literature was not performed. Literature reviews and systematic reviews were also considered, with the objective of identifying cases already reported. All of the articles were read in full for final selection.
In the third round search, each of the publications was critically appraised for assessment of validity, and the following data were extracted from the accepted articles and recorded in a standardized spread sheet: reference and year, study design, number of patients in the study, mean age of patients, gender of patients, location of the lesions, primary cause of the BRONJ, types of BP used, route of administration of the BP used, range of duration of use of BP triggering factors, co-morbidities, treatment methods, outcome variables measured, follow-up period, and outcomes of the different treatments.
Statistical analysis
The duration of BP exposure was defined as the time in months from the date of first BP infusion to the last recorded infusion.
A qualitative data analysis was performed with the aim of summarizing the results of the studies included. The mean age of patients with osteonecrosis of the jaw and the ratio of male to female patients were calculated to determine whether any particular stratum had a greater predisposition to develop osteonecrosis of the jaw than another. The existence of potential risk factors for osteonecrosis of the jaw was examined: the mean dose and range, the duration of treatment, and the proportions of patients receiving immunosuppressant therapy (e.g., corticosteroids), with other comorbidities, and with a history of dental trauma, infection, or surgical procedures.
The quality of accepted publications was assessed based on a modification of the ASBMR, by the reporting of 12 parameters for all patients diagnosed with BRONJ: age, sex, primary cause of the disease, name of the bisphosphonate used, duration or treatment, mode of administration, affected site, medical history (concomitant medications, comorbidities), triggering factors, treatment, outcome variable measured, and treatment outcome. The quality of each publication was classified as good (10–12 variables reported), moderate (5–9 variables reported), or poor (1–4 variables reported).
Results
The results of the literature search are presented in a flow chart, showing study selection according to the PRISMA statement (2009) ( Fig. 1 ). The initial search strategy yielded 1355 titles/abstracts from the databases analyzed: 1085 from PubMed, 235 from Web of Science, and 35 from the Cochrane Library; five additional articles were identified through a hand search of the relevant reference lists, bringing the number of accepted articles to 1360. After title and abstract screening and/or paper analyses, 300 potentially relevant articles were identified for article retrieval and full-text review. Two hundred papers were included in the qualitative synthesis and finally 103 papers were excluded after a preliminary review, due to non-compliance with the inclusion/exclusion criteria, lack of outcome, not being related to the proposed research question, or being irrelevant ( Fig. 1 ).
The remaining 97 articles were included in the final review. These articles described 4879 cases of BRONJ. With regard to the quality of the publications, 79 were classified as good (81.4%), 16 as moderate (16.5%), and two publications as poor (2.1%). Of the 97 accepted publications, 35 (36.1%) were case series, 3 (3.1%) were clinical trials, 18 (18.6%) were prospective studies, 37 (38.1%) were retrospective studies, and 4 (4.1%) were clinical reports ( Table 2 ).
| Reference | Study design | Number of patients | Age, years | Duration of BP administration, months | Quality of publication | Treatment |
|---|---|---|---|---|---|---|
| Thumbigere-Math 2009 | Retrospective | 26 | 64 | 45.8 | Good | Medical and minimally invasive surgery |
| Thumbigere-Math 2012 | Retrospective | 18 | 60 | 44.3 | Good | |
| Anavi-Lev 2013 | CS | 52 | 70.7 | 40 | Good | |
| Holzinger 2013 | Prospective | 88 | NR | NR | Moderate | |
| Saussez 2009 | Retrospective | 34 | 62 | 34.5 | Good | |
| Montebugnoli 2007 | CS | 16 | 61.2 | 17.9 | Good | |
| Dannemann 2006 | CS | 14 | 65 | NR | Good | |
| Beninati 2013 | Prospective | 51 | 68 | 41 | Good | |
| Alons 2009 | Retrospective | 7 | 66.9 | 55.2 | Good | |
| Lazarovici 2009 | CS | 101 | 63.5 | 48.5 | Good | |
| Junquera 2009 | CS | 21 | 65.1 | 25 | Good | |
| Stanton 2009 | Retrospective | 33 | 64.5 | NR | Good | |
| Estilo 2008 | Retrospective | 28 | NR | 34.1 | Good | |
| Dimitrakopoulos 2006 | Retrospective | 11 | 61 | 6 | Good | |
| Fortuna 2012 | Prospective | 26 | 68.4 | 23.3 | Good | |
| Abu-Id 2008 | Retrospective | 78 | 65.6 | 12 | Good | |
| Pozzi 2007 | Retrospective | 35 | 70 | 36 | Good | |
| Williamson 2010 | Prospective | 40 | 64 | NR | Good | |
| Longobardi 2007 | CS | 18 | 55 | 42.3 | Good | |
| Wutzl 2012 | Prospective | 58 | 68.3 | 35.5 | Good | |
| O’Ryan 2012 | Retrospective | 30 | 77 | 52.8 | Good | |
| Scoletta 2010 | Prospective | 37 | 68 | 25.5 | Good | |
| Nomura 2013 | CS | 13 | 71.2 | 29.6 | Good | |
| Jabbour 2012 | CS | 14 | 69 | 37.5 | Good | |
| Mücke 2011 | Prospective | 108 | 68.5 | NR | Moderate | Medical, minimally invasive and major surgery |
| Mortensen 2007 | CS | 7 | 66 | NR | Good | |
| O’Ryan 2009 | Retrospective | 59 | 61.4 | NR | Good | |
| Elad 2006 | CR | 57 | 62.7 | NR | Good | |
| Stockmann 2010 | Prospective | 50 | 69.5 | 31 | Good | |
| Ibrahim 2008 | Retrospective | 8 | 66.5 | 14.6 | Good | |
| Kim 2012 | Retrospective | 21 | 64.3 | 30 | Good | |
| Yarom 2007 | Retrospective | 11 | 69.7 | 49.2 | Good | |
| Hong 2010 | Retrospective | 24 | 72.1 | 43.1 | Good | |
| Lerman 2013 | Retrospective | 120 | 63 | 36 | Good | |
| Maurer 2011 | Retrospective | 21 | 69 | 47.4 | Good | |
| Hansen 2013 | CR | 37 | NR | NR | Poor | |
| Hoefert 2011 | Retrospective | 47 | 66.1 | 41.9 | Good | Medical |
| Marx 2005 | CS | 119 | NR | NR | Good | |
| Van den Wyngaert 2009 | CR | 33 | 58 | 27 | Good | |
| Moretti 2011 | Prospective | 34 | 69.0 | 39 | Good | |
| Alsehimy 2014 | Prospective | 96 | 66.5 | NR | Good | |
| Lazarovici 2010 | CS | 27 | 70 | NR | Good | |
| Nicolatou-Galitis 2011 | Prospective | 63 | 63.6 | 37.1 | Good | |
| Epstein 2010 | CS | 6 | 75 | 74.6 | Good | |
| Vescovi 2011 | Retrospective | 567 | 67.2 | NR | Good | Minimally invasive surgery |
| Graziani 2012 | Retrospective | 347 | 67 | 23 | Good | |
| Mercer 2013 | Retrospective | 91 | 69.8 | 60 | Good | |
| Kos 2010 | Retrospective | 18 | 67.0 | 34.9 | Good | |
| Wutzl 2006 | CS | 17 | 64.8 | 32 | Good | |
| Ferlito 2012 | CS | 94 | 66 | 24 | Moderate | |
| Schubert 2012 | Prospective | 258 | NR | NR | Moderate | |
| Rugani 2010 | CS | 5 | 75.4 | 36 | Good | Laser |
| Romeo 2011 | CS | 12 | 62 | NR | Moderate | |
| Angiero 2009 | Retrospective | 49 | 69.7 | 14.8 | Good | |
| Stübinger 2009 | CR | 8 | 59.1 | 53 | Good | |
| Vescovi 2014 | Retrospective | 63 | NR | NR | Moderate | |
| Vescovi 2012 | CS | 151 | 66.6 | 48.2 | Good | |
| Vescovi 2007 | CS | 19 | 71 | NR | Moderate | |
| Manfredi 2011 | Retrospective | 25 | 70.4 | 55.9 | Good | |
| Atalay 2011 | Retrospective | 20 | 55.4 | 32.4 | Good | |
| Scoletta 2010 | Prospective | 20 | 71.3 | 42.9 | Good | |
| Rugani 2013 | CS | 12 | 63.9 | NR | Moderate | |
| Vescovi 2010 | Retrospective | 91 | 67 | NR | Moderate | |
| Vescovi 2008 | CS | 28 | 70.3 | NR | Moderate | |
| Martins 2012 | Retrospective | 22 | 58.09 | 24.68 | Good | |
| Curi 2011 | CS | 25 | 60.7 | NR | Good | Growth factor (PRP or BMP2) |
| Mozzati 2012 | Retrospective | 32 | 69.7 | 37 | Good | |
| Bocanegra-Perez 2012 | Prospective | 8 | 66.3 | 1 | Good | |
| Coviello 2012 | CS | 7 | 75.57 | 66 | Good | |
| Cicciu 2012 | CS | 20 | NR | NR | Poor | |
| Ripamonti 2011 | RCT | 10 | 65 | NR | Moderate | Ozone |
| Agrillo 2007 | CS | 58 | 64 | NR | Moderate | |
| Ripamonti 2012 | RCT | 24 | 62.5 | NR | Good | |
| Agrillo 2012 | Retrospective | 131 | 60 | NR | Good | |
| Boonyapakorn 2008 | Prospective | 22 | 61.1 | NR | Good | Discontinuation of BP |
| Urade 2011 | Retrospective | 263 | 68.1 | NR | Good | |
| Park 2010 | CS | 5 | 72.6 | 79.2 | Good | |
| Watters 2013 | CS | 109 | 64 | NR | Good | |
| Wilde 2011 | Retrospective | 24 | NR | NR | Good | |
| Chiu 2010 | CS | 12 | 69.7 | 67.2 | Good | Hyperbaric oxygen |
| Freiberger 2012 | RCT | 22 | 66.1 | NR | Moderate | |
| Freiberger 2007 | CS | 16 | NR | 18 | Moderate | |
| Kwon 2012 | CS | 6 | 77.5 | 55.2 | Good | Teriparatide |
| Narvaez 2013 | CS | 7 | 72 | 55.2 | Good | |
| Kim 2014 | Retrospective | 15 | 77.1 | 45.6 | Good | |
| Pautke 2011 | Prospective | 15 | 63.2 | 44.4 | Good | Guided debridement |
| Fleisher 2008 | CS | 10 | NR | NR | Moderate | |
| Seth 2010 | Retrospective | 11 | 61.3 | NR | Good | Major surgery |
| Carlson 2009 | Prospective | 82 | NR | NR | Moderate | |
| Badros 2006 | Retrospective | 22 | 61 | NR | Good | |
| Bedogni 2011 | Prospective | 30 | 66 | NR | Good | |
| Jacobsen 2012 | Retrospective | 110 | 67 | NR | Good | |
| Voss 2012 | Retrospective | 21 | 68.5 | 40.1 | Good | |
| Hanasono 2013 | CS | 13 | 66.6 | NR | Good | |
| Nocini 2009 | CS | 7 | 61 | NR | Good | |
| Lemound 2012 | CS | 20 | 68 | 34.8 | Good | |
| Blus 2013 | CS | 8 | 71.3 | 32 | Good | |
| Total | 4879 | 66.5 ± 4.7 | 38.2 ± 15.7 | |||
Age and gender
A total of 4879 patients were identified and treated in the 97 publications; the mean age of these patients was 66.5 ± 4.7 years. In the 4481 cases in which the sex distribution was reported, 1471 were male patients (32.8%) and 3010 were female patients (67.2%), showing a female predilection with a female to male ratio of 2:1 among all reported cases ( Table 3 ).
| Characteristics | Details | Number | Percentage (%) |
|---|---|---|---|
| Gender | Male | 1471 | 32.8 |
| Female | 3010 | 67.2 | |
| Location | Maxilla | 1320 | 28.5 |
| Mandible | 3011 | 65.1 | |
| Both | 296 | 6.4 | |
| Primary cause of the disease | Multiple myeloma | 1434 | 31.2 |
| Breast cancer | 1359 | 29.5 | |
| Osteoporosis | 903 | 19.6 | |
| Prostate cancer | 442 | 9.6 | |
| Other cancers | 348 | 7.6 | |
| Metastasis | 116 | 2.5 | |
| Type of BP administered | Zoledronate | 2427 | 58.9 |
| Pamidronate | 571 | 13.9 | |
| Alendronate | 523 | 12.7 | |
| Ibandronate | 128 | 3.1 | |
| Combination | 469 | 11.4 | |
| Route of administration of BP | IV | 3245 | 83.2 |
| Oral | 656 | 16.8 | |
| Triggering factors | Extraction | 1974 | 61.7 |
| Dental implant | 123 | 3.9 | |
| Dental surgery | 230 | 7.2 | |
| Periodontal disease | 159 | 5.0 | |
| Prosthetic trauma | 237 | 7.4 | |
| Spontaneous | 475 | 14.8 | |
| Comorbidities | Diabetes | 298 | 11.2 |
| Corticosteroids | 658 | 24.6 | |
| Hypertension | 225 | 8.4 | |
| Thrombosis | 108 | 4.0 | |
| Smoking | 215 | 8.0 | |
| Chemotherapy | 1062 | 39.7 | |
| None | 108 | 4.1 | |
BRONJ characteristics
Eighty-nine publications described the site of BRONJ in 4627 patients receiving BPs; the site was not reported for only eight publications. BRONJ lesions were located most commonly in the mandible (3011 patients; 65.1%), followed by the maxilla (1320 patients; 28.5%) or both jaws (296 patients; 6.4%) ( Table 3 ).
Primary cause of disease
BP therapy was started in 4602 cases for the following indications: multiple myeloma (1434 cases; 31.2%), breast cancer (1359 cases; 29.5%), osteoporosis (903 cases; 19.6%), prostate cancer (442 cases; 9.6%), metastasis (116 cases; 2.5%), and other cancers including lung, renal, and bladder carcinoma (348 cases; 7.6%). Most patients (60.7%) had multiple myeloma or metastatic breast cancer ( Table 3 ).
Characteristics of bisphosphonate treatment
The bisphosphonate prescribed was specified for 4118 patients with BRONJ. Overall, 2427 (58.9%) patients received zoledronate, 571 (13.9%) patients received pamidronate, 523 (12.7%) patients received alendronate, 128 (3.1%) patients received ibandronate, and 469 (11.4%) patients received a combination of BPs ( Table 3 ).
BP treatment was principally intravenous (IV) in 3245 patients (83.2%), while 656 patients (16.8%) received oral BPs ( Table 3 ).
Duration of treatment
There was variability in the duration of BP therapy, which ranged from 1 to 79.2 months, with a mean duration of 38.2 ± 15.7 months.
Triggering factors and comorbidities
The most important triggering factors for the development of BRONJ were described for 3198 cases in the articles included. Tooth extraction was the principal cause (1974 patients; 61.7%), followed by trauma from manipulation of dental implants (123 cases; 3.9%). A history of dental surgery was reported for 230 patients (7.2%), periodontal diseases in 159 patients (5.0%), and prosthesis-induced trauma in 237 patients (7.4%). A large proportion of BRONJ lesions appeared spontaneously (475 patients; 14.8%) ( Table 3 ).
With regard to concomitant diseases and medications, 2674 patients had comorbidities. Diabetes mellitus was observed in 298 patients (11.2%) and hypertension in 225 patients (8.4%); 1062 (39.7%) patients were under chemotherapy, 215 (8.0%) patients were smokers, 108 (4.0%) patients had thrombocoagulopathies, 658 (24.6%) were taking corticosteroids, and 108 (4.1%) were free from any concomitant diseases. The incidence of BRONJ was associated with chemotherapy (39.7%) of the patients compared to corticosteroid therapy (24.6%) ( Table 3 ).
Management of osteonecrosis of the jaw
Regarding the management of the BRONJ lesions, the studies reported discontinuation of BP administration (5.1%) in addition to treatment by medical therapy (50%) or minimally invasive surgical therapy (45.9%); 22.4% of patients underwent major surgical procedures, such as segmental resection of the jaw bones.
Various adjunctive treatments such as hyperbaric oxygen (HBO) therapy, laser therapy, ozone therapy, teriparatide, fluorescence-guided debridement, treatment with growth factors (platelet-rich plasma (PRP) or bone morphogenetic protein 2 (BMP2)), and ultrasonic therapy were also mentioned.
Medical treatment of BRONJ was reported in 49 publications and minimally invasive surgical treatment in 44 publications. Major surgical intervention was reported in 22 publications, including the use of surgical flaps in two publications and ultrasonic therapy in one. Laser therapy was reported in 14 publications, ozone therapy in four publications, PRP in five publications, BMP2 in one, HBO in three publications, and teriparatide in three publications. Fluorescence or tetracycline guided debridement was reported in two publications.
Seven hundred and fifteen patients were treated by medical and minimally invasive surgical treatment, 422 patients were treated by medical, minimally invasive and major surgical treatment, 286 patients were treated by medical treatment only, 767 patients were treated by minimally invasive surgical treatment, 252 patients were treated by major surgical treatment, 25 patients were treated by guided debridement, 322 patients were treated with laser therapy, 92 patients were treated with growth factors, 161 patients were treated with ozone therapy, 361 patients stopped BP treatment in addition to other treatment modalities, 45 patients were treated with HBO, and 27 patients were treated with teriparatide ( Table 4 ).
| Treatment | Outcome, number of patients (%) | Total number of patients (%) | ||||||
|---|---|---|---|---|---|---|---|---|
| Complete healing | Partial healing | Stable lesion | Progressive lesion | Regressive lesion | Recurrent lesion | Non-healing lesion | ||
| Medical and minimally invasive surgery | 278 (38.9) | 125 (17.5) | 94 (13.1) | 52 (7.3) | 64 (9.0) | 5 (0.7) | 97 (13.6) | 715 (20.6) |
| Medical, minimally invasive and major surgery | 169 (40.0) | 105 (24.9) | 34 (8.1) | 19 (4.5) | 5 (1.2) | 47 (11.1) | 43 (10.2) | 422 (12.1) |
| Medical treatment | 129 (45.1) | 52 (18.2) | 23 (8.0) | 8 (2.8) | 52 (18.2) | 20 (7.0) | 2 (0.7) | 286 (8.2) |
| Minimally invasive surgery | 301 (39.2) | 0 (0) | 152 (19.8) | 61 (8.0) | 231 (30.1) | 0 (0) | 22 (2.9) | 767 (22.1) |
| Major surgery | 207 (82.1) | 11 (4.4) | 8 (3.2) | 5 (2.0) | 0 (0) | 11 (4.4) | 10 (4.0) | 252 (7.3) |
| Guided debridement | 12 (48) | 10 (40) | 0 (0) | 1 (4) | 0 (0) | 0 (0) | 2 (8) | 25 (0.7) |
| Laser therapy | 146 (45.3) | 18 (5.6) | 81 (25.2) | 5 (1.6) | 33 (10.2) | 2 (0.6) | 37 (11.5) | 322 (9.3) |
| Growth factors | 75 (81.5) | 2 (2.2) | 6 (6.5) | 0 (0) | 8 (8.7) | 1 (1.1) | 0 (0) | 92 (2.6) |
| Ozone therapy | 93 (57.8) | 27 (16.8) | 5 (3.1) | 0 (0) | 28 (17.4) | 0 (0) | 8 (5.0) | 161 (4.6) |
| Discontinuation of bisphosphonates | 127 (35.2) | 27 (7.5) | 142 (39.3) | 50 (13.9) | 3 (0.8) | 5 (1.4) | 7 (1.9) | 361 (10.4) |
| Hyperbaric oxygen | 12 (26.7) | 8 (17.8) | 2 (4.4) | 6 (13.3) | 17 (37.8) | 0 (0) | 0 (0) | 45 (1.3) |
| Teriparatide | 22 (81.5) | 5 (18.5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 27 (0.8) |
| Total | 1571 (45.2) | 390 (11.2) | 547 (15.7) | 207 (6.0) | 441 (12.7) | 91 (2.6) | 228 (6.6) | 3475 |
Follow-up and treatment outcomes
After the initial BRONJ treatment, follow-up periods, which were reported in only 80 publications, ranged from 4 weeks to 50 months, with a mean of 12.9 ± 9.9 months.
Outcome measures
A total of seven outcome variables were used in the studies. The most frequently measured outcome was mucosal healing (47 publications; 48.5%), followed by bone exposure (30 publications; 30.9%), pain (31 publications; 31.9%), changes in signs and symptoms (28 publications; 28.9%), improvement in stage (14 publications; 14.4%), reduction in lesion size and number (12 publications; 12.4%), and finally infection control (seven publications; 7.2%).
The outcome of the treatment was classified as (1) complete healing, defined as complete regrowth of the oral mucosa over previously exposed bone; (2) partial healing, defined as either a decrease in lesion size (largest linear dimension) or the number of lesions, and/or cessation of pain or signs of infection; (3) stable disease, defined as no improvement in clinical signs or symptoms; (4) progressive disease, defined as an increase in the size or number of lesions, or increased pain and severity of infection; (5) regressive disease, defined as a decrease in the size or number of lesions, or decreased pain and severity of infection; and (6) negligible or no healing when there was no sign of improvement.
The outcomes of the treatment modalities of the BRONJ were assessed in 3475 patients. Outcomes of the different treatment modalities were compared ( Table 4 ).
Medical and minimally invasive surgical treatment
Seven hundred and fifteen patients were treated by medical and conservative surgical treatment; 278 patients (38.9%) showed complete healing, 125 (17.5%) showed partial healing, 94 (13.1%) had stable lesions, 52 (7.3%) had progressive lesions, 64 (9.0%) had regressive lesions, only five (0.7%) had recurrent lesions, and 97 patients (13.6%) had lesions with negligible or no healing.
Medical, minimally invasive and major surgical treatment
Four hundred and twenty-two patients were treated by medical, conservative and surgical treatment; 169 patients (40.0%) showed complete healing, 105 (24.9%) showed partial healing, 34 (8.1%) had stable lesions, 19 (4.5%) had progressive lesions, five (1.2%) had regressive lesions, 47 (11.1%) had recurrent lesions, and 43 patients (10.2%) had lesions with negligible or no healing.
Medical treatment only
Two hundred and eighty-six patients were treated medically; 129 patients (45.1%) showed complete healing, 52 (18.2%) showed partial healing, 23 (8.0%) had stable lesions, eight (2.8%) had progressive lesions, 52 (18.2%) had regressive lesions, 20 (7.0%) had recurrent lesions, and two patients (0.7%) had lesions with negligible or no healing.
Minimally invasive surgical treatment
Seven hundred and seventy-six patients were treated with conservative surgery; 301 patients (39.2%) showed complete healing, no patients (0%) showed partial healing, 152 (19.8%) had stable lesions, 61 (8.0%) had progressive lesions, 231 (30.1%) had regressive lesions, no patients (0%) had recurrent lesions, and 22 patients (2.9%) had lesions with negligible or no healing.
Major surgical treatment
Two hundred and fifty-two patients were treated with major surgery; 207 patients (82.1%) showed complete healing, 11 (4.4%) showed partial healing, eight (3.2%) had stable lesions, five (2.0%) had progressive lesions, no patients (0%) had regressive lesions, 11 (4.4%) had recurrent lesions, and 10 patients (4.0%) had lesions with negligible or no healing.
Guided debridement
Twenty-five patients were treated with guided debridement; 12 patients (48%) showed complete healing, 10 (40%) showed partial healing, no patients (0%) had stable lesions, one (4%) had progressive lesions, no patients (0%) had regressive lesions, no patients (0%) had recurrent lesions, and two patients (8%) had lesions with negligible or no healing.
Laser treatment
Three hundred and twenty-two patients were treated with laser therapy; 146 patients (45.3%) showed complete healing, 18 (5.6%) showed partial healing, 81 (25.2%) had stable lesions, five (1.6%) had progressive lesions, 33 (10.2%) had regressive lesions, two (0.6%) had recurrent lesions, and 37 patients (11.5%) had lesions with negligible or no healing.
Growth factor (PRP and BMP2) treatment
Ninety-two patients were treated with growth factors; 75 patients (81.5%) showed complete healing, two (2.2%) showed partial healing, six (6.5%) had stable lesions, no patients (0%) had progressive lesions, eight (8.7%) had regressive lesions, one (1.1%) had recurrent lesions, and no patients (0%) had lesions with negligible or no healing.
Ozone treatment
One hundred and sixty-one patients were treated with ozone therapy; 93 patients (57.8%) showed complete healing, 27 (16.8%) showed partial healing, five (3.1%) had stable lesions, no patients (0%) had progressive lesions, 28 (17.4%) had regressive lesions, no patients (0%) had recurrent lesions, and eight patients (5.0%) had lesions with negligible or no healing.
Discontinuation of BP treatment in addition to other treatment modalities
Three hundred and sixty-one patients stopped BP treatment; 127 patients (35.2%) showed complete healing, 27 (7.5%) showed partial healing, 142 (39.3%) had stable lesions, 50 (13.9%) had progressive lesions, three (0.8%) had regressive lesions, five (1.4%) had recurrent lesions, and seven patients (1.9%) had lesions with negligible or no healing.
Hyperbaric oxygen treatment
Forty-five patients were treated with HBO; 12 patients (26.7%) showed complete healing, eight (17.8%) showed partial healing, two (4.4%) had stable lesions, six (13.3%) had progressive lesions, 17 (37.8%) had regressive lesions, no patients (0%) had recurrent lesions, and no (0%) patients had lesions with negligible or no healing.
Teriparatide treatment
Twenty-seven patients were treated with teriparatide; 22 patients (81.5%) showed complete healing, five (18.5%) showed partial healing, no patients (0%) had stable lesions, no patients (0%) had progressive lesions, no patients (0%) had regressive lesions, no patients (0%) had recurrent lesions, and no patients (0%) had lesions with negligible or no healing.
The treatment of BRONJ and the outcome variables measured with the mean follow-up of each treatment are summarized in Table 5 .
| Treatment | Outcome variables measured | Follow-up, months |
|---|---|---|
| Medical and minimally invasive | Improved signs and symptoms, decrease in lesion size and number, elimination of pain, reduction in soft and hard tissue inflammation, no bone exposure or bone exposure less than 1–2 mm, no suppuration, improvement of stage, persistence of fistula, cessation of pus and extraoral manifestations, mucosal coverage, radiographic success (cessation of bony destruction), presence or recurrence of infection, BRONJ at stage 0 | 11.1 ± 6.6 |
| Medical, minimally invasive and major surgery | Closure of oro-antral fistula, stage improvement, healing of the lesion, extension of exposed bone areas, bone exposure, decrease in pain, healing of mucosa, improved signs and symptoms, asymptomatic lesions, patients free from symptoms, recurrence of BRONJ, recurrence of sinusitis | 11.6 ± 5.2 |
| Medical | No fistula, reduction of exposed bone, reduction in pain, closure of the mucosal defect, persistence of exposed bone or progressive necrosis, reduction in size of the lesion, size of necrotic lesions, resolution of BRONJ manifestations, cessation of pus or purulent secretion, mucosal inflammation, improvement in signs and symptoms | 16.4 ± 5.2 |
| Minimally invasive surgery | Improvement of the stage (transition to a less severe stage), deterioration of wound healing, recurrence rate of wound dehiscence, closure of lesion, pain reduction, complete healing of soft tissue, signs of inflammation, exposed bone, no symptoms of infection for a minimum of 3 months | 6.4 ± 3.6 |
| Laser | Effectiveness of surgical laser application, pain reduction, infection control, mucosal healing, no signs and symptoms, healing evaluated radiographically, complete removal of visible necrotic bone, absence of new exposed bone near surgical area, no signs of infection, stage improvement, size of the lesion, oedema, visual analogue score of pain, presence of pus, fistulas and halitosis, bone exposure | 10.7 ± 9.7 |
| Growth factor (PRP or BMP2) | Intact and healed mucosa, no exposed necrotic bone, no sign of infection or fistula, absence of pain, no radiographic signs of residual infection or evidence of bone sequestration, bleeding | 18.2 ± 18.3 |
| Ozone | Spontaneous expulsion or sequestrum of necrotic bone to be removed surgically, healed and re-epithelialized mucosa, presence or absence of oral mucosa redness around the lesion area, petechiae or bleeding, pain intensity, diminishing of symptoms | 9.9 ± 5.5 |
| Discontinuation of BP | Healing of the mucosa, pain relief, bleeding, stage improvement, resolution of symptoms, presence or absence of exposed necrotic bone, radiographic evidence of BRONJ, no fistulas, absence of swelling | 27.8 ± 29.2 |
| Hyperbaric oxygen (HBO) | Clinical evidence of symptom relief, pain reduction, absence of sequestrum, oral lesion size and number, regrowth of oral mucosa over exposed bone | 20 ± 5.7 |
| Teriparatide | Change in biochemical markers (osteocalcin and C terminal telopeptide cross-link type I collagen), clinical and radiographic healing, improvement of BRONJ stage | 4.5 ± 2.1 |
| Major surgery | Osseous union judged clinically and radiographically, without signs of residual infection, or exposed bone at the time of evaluation, postoperative complication, infection, recurrence of BRONJ, oral pain, exposed bone, mucosal healing, percentage of flap survival, percentage of complications at the donor and recipient site, symptom-free | 18 ± 5.2 |
| Guided debridement | Closure of mucosa, exposed bone, symptom-free | 1.5 ± 0.7 |
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