Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review

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 ).

Table 1
Staging of and treatment strategies for bisphosphonate-related osteonecrosis of the jaw (BRONJ) according to the American Association of Oral and Maxillofacial Surgeons (AAOMS).
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

IV, intravenous; BP, bisphosphonate.

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 ).

Fig. 1
Flow chart of the search strategy and study selection used in this systematic review.

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 ).

Table 2
Summary of the publications included in the systematic review: study design, total number of patients, mean patient age, duration of administration of bisphosphonates, quality of publications, and treatment modalities.
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
BP, bisphosphonate; CS, case series; RCT, randomized clinical trial; CR, clinical report; NR, not reported; PRP, platelet-rich plasma; BMP2, bone morphogenetic protein 2.

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 ).

Table 3
Characteristics of patients diagnosed with BRONJ.
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, bisphosphonate-related osteonecrosis of the jaws; BP, bisphosphonate; IV, intravenous.

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 ).

Table 4
Outcome of each treatment modality.
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 .

Table 5
Summary of treatment modalities and the outcome variables measured with the mean follow-up of each treatment.
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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Jan 17, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review
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