- Email: [email protected]
Effectiveness of treatments for medication-related osteonecrosis of the jaw
ORIGINAL CONTRIBUTIONS
ARTICLE 3
Effectiveness of treatments for medication-related osteonecrosis of the jaw A systematic review and meta-analysis Mohamed El-Rabbany, DDS, MSc; Adam Sgro; David K. Lam, MD, DDS, PhD; Prakeshkumar S. Shah, MSc, MBBS, MD, DCH; Amir Azarpazhooh, DDS, MSc, PhD
M
edication-related osteonecrosis of the jaw (MRONJ) is defined as exposed bone, in a susceptible patient who does not have a history of head and neck radiation, that fails to heal over a period of 8 weeks in the absence of any evidence of obvious metastatic disease.1,2 Despite being relatively uncommon, with a prevalence of up to 0.01% in patients receiving oral bisphosphonates, 12% in patients receiving intravenous bisphosphonates, and 16% in patients receiving a combination of bisphosphonates and antiangiogenics, MRONJ presents major repercussions for both a patient’s quality of life and health care resources.1,3,4 Patients with MRONJ often have signs and symptoms that include pain, swelling, exposed bony sequestrum, fistulae, erythematous or ulcerated soft tissue, or pathologic fractures.1 Because MRONJ occurs more commonly in the mandible This article has an accompanying online continuing education activity available at: http://jada.ada.org/ce/home. Copyright ª 2017 American Dental Association. All rights reserved.
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ABSTRACT Background. The effectiveness of management strategies used for the treatment of medication-related osteonecrosis of the jaw (MRONJ) remains poorly understood. The authors evaluated systematically the effectiveness of the various treatment modalities used for MRONJ. Types of Studies Reviewed. The authors conducted a comprehensive search of MEDLINE, Embase, the Cochrane Library, and Scopus to identify randomized controlled trials, nonrandomized controlled trials, and prospective cohort studies to evaluate comparatively the effectiveness of management strategies for the treatment of MRONJ. The authors conducted the identification of eligible studies in duplicate and synthesized the extracted data by means of a metaanalysis, when feasible. Results. The authors found 13 studies with a medium-to-high risk of bias that met the inclusion criteria of this review. The authors found that, compared with medical treatment of local antimicrobials with or without systemic antimicrobials, the study investigators associated surgical treatment with higher odds of complete resolution of the condition (2 studies; 76 participants; unadjusted odds ratio, 3.55; 95% confidence interval, 1.12 to 11.19). The effectiveness of other therapies, such as bisphosphonate drug holidays, teriparatide, and hyperbaric oxygen, was uncertain. Conclusions and Practical Implications. On the basis of the results of an unadjusted analysis, the results of the studies that were deemed to be medium to low quality and to have medium-to-low statistical power suggested that there are higher odds of resolving MRONJ with surgical treatment compared with medical treatment. High-quality research is required for conclusive statements to be made regarding treatment strategies for management of MRONJ. Key Words. Osteonecrosis; medication-related osteonecrosis of the jaw; bisphosphonate-associated osteonecrosis of the jaw; osteonecrosis of the jaw; oral and maxillofacial surgery; bone. JADA 2017:148(8):584-594 http://dx.doi.org/10.1016/j.adaj.2017.04.002
ORIGINAL CONTRIBUTIONS
than in the maxilla, owing to mandibular bone’s relatively low vascularity, the dominant hypothesis for the cause of MRONJ is a combination of injury or insult to the bone, along with a diminished ability to heal.1 Management of MRONJ has remained a controversial topic within the oral and maxillofacial surgery community. To date, therapeutic management has focused largely on symptomatic treatment, divided into the categories of surgical therapy and nonsurgical therapy. Examples of nonsurgical therapies include, but are not limited to, long-term use of local antimicrobials, systemic antimicrobials, or both; cessation of antiresorptive or antiangiogenic therapy; hyperbaric oxygen therapy; lowintensity laser therapy; teriparatide; ozone; pentoxifylline; and tocopherol. Similarly, surgical treatment options for the management of MRONJ range from conservative to aggressive, such as curettage, sequestrectomy, and resection as a final resort.1,2 Given the paucity of evidence to support the use of these various therapies to manage and treat MRONJ, we determined that the purpose of this study would be to evaluate the effectiveness of the various treatment modalities used. We registered the protocol of this study a priori with PROSPERO (International Prospective Register of Systematic Reviews, Centre for Reviews and Dissemination, University of York, York, United Kingdom: http://www.crd.york.ac.uk/PROSPERO/ display_record.asp?ID¼CRD42016051939). METHODS
Objectives. Our objective for this systematic review was to evaluate the effectiveness of the various therapies used to manage and treat patients with MRONJ to resolve the condition. We used the recommendations outlined by the Cochrane Handbook for Systematic Reviews of Interventions5 to produce the methods for this systematic review. Eligibility criteria. We used the following criteria to consider studies for inclusion in this review. - Types of studies: We determined that prospective cohort studies, nonrandomized trials, and randomized controlled trials whose investigators had evaluated the effectiveness of various MRONJ therapies to resolve the condition, as defined in “types of outcome measures” below, were eligible for this study. We excluded retrospective cohort studies, case-control studies, crosssectional studies, case series, case studies, reviews, and studies that did not involve humans. - Types of participants: We included studies that involved patients older than 18 years who had a diagnosis of MRONJ. We used the following diagnostic guidelines, set by the American Association of Oral and Maxillofacial Surgeons2 regarding MRONJ in eligible patients: current or previous treatment with antiresorptive or antiangiogenic agents, exposed bone or bone that could
be probed through an intraoral or extraoral fistula or fistulae in the maxillofacial region that had persisted for more than 8 weeks, and no history of radiation therapy in the jaws or obvious metastatic disease in the jaws. - Types of interventions: We set no limitations for the interventions used to manage MRONJ. - Types of outcome measures: We considered studies whose investigators had evaluated the following outcomes of interest: complete resolution (defined as an absence of clinical signs and symptoms of MRONJ), changes in bony exposure and mucosal coverage, changes in radiographic lesion size, recurrence of the condition, the presence of pain, neurosensory changes, and quality of life. Search methods for the identification of studies. We applied our search strategy for this review (eTable 1; available online at the end of this article) on June 9, 2016, to the following electronic databases, which we accessed through the University of Toronto: MEDLINE (Ovid MEDLINE, from 1960 to Week 4, May 2016; Ovid MEDLINE In-Process and Other Non-Indexed Citations), Embase (Ovid’s Embase Classic and Embase, 1960 to Week 22, 2016), and the Cochrane Library. In addition, we added the Scopus database and the first 200 hits from Google Scholar to the search to identify gray literature, unpublished literature, or both. Once we identified articles for inclusion, we reviewed the reference lists of the included articles to identify any articles that we may have missed in the search. We made no language exclusions for this review, and we translated all of the articles not published in English. Study selection and data extraction. Two reviewers (M.E.-R., A.S.) independently conducted study selection and data extraction. After removing duplicate results from the initial yield of the search, each reviewer independently reviewed the titles and abstracts of these studies to identify potentially eligible results. Next, they combined their results, and after removing duplicate studies, each of the 2 reviewers reviewed the full texts of the selected studies to determine final eligibility. The 2 reviewers resolved disagreements regarding eligibility by means of seeking consensus, consultation, or both with a senior reviewer (A.A.); after this stage of review, they presented the measure of agreement as a k statistic, which is a chance-corrected measure of agreement. Risk of bias in individual studies. We assessed the methodological quality of the eligible studies using the information in the original publications and using either the Cochrane Risk of Bias Tool6 for randomized controlled trials or the Newcastle-Ottawa Scale7 for all other studies. Two authors (M.E.-R., A.S.) independently
ABBREVIATION KEY. BID: Twice daily. BP: Bisphosphonate. HBO: Hyperbaric oxygen. IV: Intravenous. MRONJ: Medication-related osteonecrosis of the jaw. NA: Not applicable.
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Records identified through database searching (n = 3,026)
Records identified through other sources (n = 200)
Records after duplicates removed (n = 2,155)
Records excluded (n = 2,104)
Full-text articles assessed for eligibility (n = 51)
we considered a P value of .05 or less to be significant. We planned to combine unadjusted and adjusted data from the available studies. As we conducted the metaanalyses of the adjusted data, we planned to combine the data irrespective of the variability in the factors adjusted in each study. Publication bias across studies. To identify publication bias, we planned to use funnel plots for all metaanalyses of 10 or more included studies. RESULTS
Full-text articles excluded, with reasons (n = 38)
Articles included in qualitative synthesis (n = 13)
Articles included in quantitative synthesis (n = 2)
Figure 1. Flow chart outlining the study selection process.
graded the studies as having a “low,” “unclear,” or “high” risk of bias, according to each set of the domains for both the Newcastle-Ottawa Scale7 or the Cochrane Risk of Bias Tool,6 and they resolved any disagreements either by seeking consensus or consultation with a third author (A.A.). Data synthesis. We made attempts to combine studies that had similar comparisons and outcome measures by means of meta-analyses (and metaregressions for nonrandomized studies to control for potential confounding variables, when possible8) using RevMan 5.3 software (Nordic Cochrane Centre, The Cochrane Collaboration). For groups of studies whose results we deemed to be clinically homogenous, we pooled the data via the inverse-variance method with a random-effects model for continuous variables and via the Mantel-Haenszel test method with a random-effects model for discrete variables. We reported outcomes as risk ratios for discrete variables or mean differences for continuous variables. We displayed statistical heterogeneity in each forest plot by calculating an I2 value, for which we considered a value greater than 50% to have a high level of statistical heterogeneity.9 For all test results,
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Figure 1 shows a flow chart of the study selection; the initial search strategy yielded 3,226 results. After we removed duplicates, 2,155 unique articles remained. Next, the 2 reviewers’ independent reviews of titles and abstracts yielded 51 articles,10-60 and after the 2 reviewers completed independent full-text reviews, we found that a total of 13 articles10-22 met the inclusion criteria for this review. Agreement between the 2 reviewers was associated with a k statistic of 0.84. eTable 223-60 (available online at the end of this article) lists the 38 studies23-60 that we excluded at the full-text review stage and the reasons for exclusion. In our review of the 13 included articles, we found that investigators had evaluated the following therapies used for the treatment of MRONJ: nonsurgical versus surgical therapy,10-13 conservative versus aggressive surgical therapy,11,14 antiresorptive drug continuation versus discontinuation,15-17 early versus delayed surgery,18 supplemental hyperbaric oxygen therapy versus control,19 spiramycin versus amoxicillin and clavulanate,20 mucoperiosteal flap repair versus mylohyoid flap repair,21 and teriparatide versus plasma rich in growth factors.22 Investigators had conducted all of the 13 studies in hospital settings. One study was a randomized controlled trial,19 1 was a nonrandomized trial,20 and the remaining 11 were prospective cohort studies.10-18,21,22 The mean number of included patients in these studies was 52, with sample sizes ranging from 9 to 195. Table 110-22 provides details regarding the methodologies and summarizes the outcome values. Of the 12 prospective cohort and nonrandomized studies,10-18,20-22 we determined that 7 studies11,12,14-17,21 had a medium risk of bias and 5 studies10,13,18,20,22 had a high risk of bias. Table 210-18,20-22 provides a breakdown of the components of the Newcastle-Ottawa Scale,7 which we used to determine the risk of bias for these studies. We found that the randomized controlled trial19 had a high risk of bias, as per the results of our evaluation using the Cochrane Risk of Bias Tool.6 Although we determined that the study19 had a low risk of bias when we evaluated allocation concealment and selective outcome reporting, we found that the study’s investigators fell short in adequately blinding participants or health care providers, controlling for the number of patient dropouts from the study, and conducting data
ORIGINAL CONTRIBUTIONS
analyses in an intention-to-treat manner. In addition, the investigators’ reporting of random sequence generation methodology as well as the masking of outcome assessors was unclear. Given the lack of consensus regarding the treatment of MRONJ, we found that the results of the studies included in this review did have heterogeneity related to the treatments and the outcomes evaluated. With the exception of comparing surgical and nonsurgical therapy, we made no attempts to conduct data synthesis owing to the unavailability of necessary data. Table 110-22 provides a detailed overview of these findings. Surgical versus nonsurgical therapy. The investigators of 4 of the included studies10-13 (n ¼ 223) evaluated surgical therapy versus nonsurgical therapy for the treatment of MRONJ. Of these, the investigators of 2 studies11,12 reported the superiority of surgical therapy compared with nonsurgical therapy; the investigators of 1 study reported a greater likelihood of condition resolution,11 and the investigators of another study reported fewer recurrences of the treated lesions.12 Figure 2 shows the results of the meta-analysis of the 2 included studies11,13 that had sufficient data for synthesis; these results support the findings of the aforementioned studies whose investigators had reported significant differences. Compared with medical treatment of local antimicrobials with or without systemic antimicrobials, we found that surgical treatment was associated with higher odds of complete resolution of the condition (2 studies; 76 participants; unadjusted odds ratio [OR], 3.55; 95% confidence interval [CI], 1.12 to 11.19; P ¼ .03). Conservative versus aggressive surgical therapy. The investigators of 2 studies (n ¼ 79) evaluated conservative surgery versus aggressive surgery, defined as debridement and resection, respectively.11,14 The investigators of 1 of these studies14 reported that the time to remission was significantly lower in their aggressive surgical therapy cohort (P < .001) compared with no significant differences reported in the study by Lesclous and colleagues11 (unadjusted OR, 0.77; 95% CI, 0.15 to 3.86). Bisphosphonate drug holiday. The investigators of 3 studies15-17 (n ¼ 113) evaluated the effects of cessation of bisphosphonate therapy on the resolution of MRONJ, of which the investigators of only 1 study16 reported a significant effect of a drug holiday on the outcome of surgical therapy, indicating significantly greater rates of improvement in the drug holiday cohort (P < .05).16 The investigators of all 3 of these studies did not make available the details regarding the length of time the patients had stopped taking bisphosphonates before the intervention. Early versus delayed surgery. The investigators of 1 study18 (n ¼ 17) compared the effectiveness of early surgery with that of delayed surgery. They reported no
differences in the rate of complete resolution between the 2 groups. Supplemental hyperbaric oxygen therapy. The investigators of 1 study19 (n ¼ 46) compared the effectiveness of supplemental hyperbaric oxygen in addition to usual care. They reported significantly higher increases in mucosal coverage (unadjusted OR, 3.45; 95% CI, 1.02 to 11.66; P ¼ .03) but not in full mucosal healing. Spiramycin versus amoxicillin and clavulanate. The investigators of 1 study20 (n ¼ 12) compared the effectiveness of spiramycin with that of amoxicillin and clavulanate. They found faster rates of condition resolution in the spiramycin group (P ¼ .015). Mucoperiosteal versus mylohyoid flaps. The investigators of 1 study21 (n ¼ 195) compared the effectiveness of mucoperiosteal with that of mylohyoid flaps for mandibular coverage after debridement. They found that the mylohyoid group had significantly lower rates of recurrence (P ¼ .023). Teriparatide versus plasma rich in growth factors. The investigators of 1 study22 (n ¼ 9) compared the effectiveness of teriparatide with that of plasma rich in growth factors. They reported no difference in the rate of complete resolution between the 2 groups. DISCUSSION
The purpose of this study was to review the evidence supporting the various therapies used to treat MRONJ. Through our review of the highest quality articles we found whose authors addressed this topic, we found that surgical therapy, compared with medical therapy, may result in higher rates of resolution of MRONJ. Nevertheless, it is apparent that the results of more high-quality research studies are required for investigators to make conclusive statements regarding many of the treatment strategies for managing MRONJ. The investigators of studies comparing medical therapy with surgical therapy reported that surgical therapy was associated with a higher rate of resolving the condition. Despite the fact that we found that the 2 studies11,12 whose investigators reported that surgical therapy resulted in significantly improved treatment outcomes had a medium risk of bias, only Mucke and colleagues12 attempted to control for potential confounding variables between the 2 cohorts in their study.11,12 Second, although the results of a metaanalysis of the available data suggested significantly improved rates of success with surgical therapy compared with those of nonsurgical treatment, owing to the unavailability of necessary data, we were unable to control for potential confounding variables. Given that the investigators of cohort studies (unlike the investigators of randomized controlled trials) are unable to control for confounding variables without making statistical corrections, the most correct way for us to synthesize the data would have been through a meta-
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ORIGINAL CONTRIBUTIONS
TABLE 1
Summary of the characteristics and results of the included studies evaluating success of treatment of MRONJ.* TREATMENT
STUDY
TYPE OF STUDY
POPULATION
CONTROL TREATMENT
INTERVENTION
OUTCOME
Elad and colleagues,10 2006
Prospective cohort
Mean (SD†) age: 62.7 (10.8) y Sex (% female): 72% Oral BP‡: n ¼ 5 IV§ BP: n ¼ 52 Malignancy: 93% MRONJ stage: NA¶
n ¼ 12 Nonsurgical therapy: antibiotics with or without topical agents (chlorhexidine, saline) with or without HBO# therapy
n ¼ 27 Nonsurgical plus surgical therapy: superficial debridment, curettage, extensive surgery
No significant differences in rates of improvement between the 2 groups (unadjusted OR**, 0.4; 95% CI,†† 0.09 to 1.73).
Scoletta and colleagues,13 2010
Prospective cohort
Mean (SD) age: 68.0 (13.0) y Sex (% female): 70% Oral BP: n ¼ 3 IV BP: n ¼ 34 Malignancy: 89% MRONJ stage: NA
n ¼ 24 Nonsurgical therapy: chlorhexidine with or without antibiotics
n ¼ 13 Nonsurgical plus surgical therapy: debridement or resection
No significant differences in rates of complete healing between the 2 groups (unadjusted OR, 4.67; 95% CI, 1.02 to 21.03).
Mucke and colleagues,12 2011
Prospective cohort
Mean age: NA Sex (% female): NA Oral BP: n ¼ 14 IV BP: n ¼ 94 Malignancy: 84% MRONJ stage 1: n ¼ 18 MRONJ stage 2: n ¼ 46 MRONJ stage 3: n ¼ 44
n¼6 Nonsurgical therapy: hexetidine antiseptic rinse and antibiotics
n ¼ 102 Nonsurgical plus surgical therapy: sequestrectomy, debridement, and marginal or segmental resection
The surgical group had a lower likelihood for recurrences (OR, 3.9; 95% CI, 1.75 to 8.66; P ¼ .001).
Lesclous and Nonsurgical colleagues,11 Versus Conservative 2014 Versus Aggressive Surgical Therapy
Prospective cohort
Mean (SD) age: 69.6 (2.3) y Sex (% female): 69% Oral BP: n ¼ 8 IV BP: n ¼ 31 Malignancy: 82% MRONJ stage: NA
n¼8 Nonsurgical therapy: systemic antibiotics and local antiseptics
n1 ¼ 8 Conservative surgical therapy: nonsurgical plus decortication and fibrin glue coverage
Surgical groups showed significantly higher rates of resolution compared with nonsurgical groups (unadjusted OR, 2.47; 95% CI, 0.43 to 14.21). No significant differences between conservative and aggressive surgery (unadjusted OR, 0.77; 95% CI, 0.15 to 3.86).
Nonsurgical Versus Surgical Therapy
n2 ¼ 23 Aggressive surgical therapy: as listed previously, plus bone resection Lee and Conservative colleagues,14 Versus Aggressive 2014 Surgical Therapy
Prospective cohort
Mean (SD) age: 69 (11) y Sex (% female): 60% Oral BP: n ¼ 19 IV BP: n ¼ 21 Malignancy: 53% MRONJ stage 1: n ¼ 4 MRONJ stage 2: n ¼ 28 MRONJ stage 3: n ¼ 8
n ¼ 30 Conservative therapy: antibiotics, antiseptic irrigation, with or without debridement
n ¼ 10 Aggressive therapy: surgical resection
Time to achieving complete remission was significantly lower in the aggressive surgery group (P < .001).
* MRONJ: Medication-related osteonecrosis of the jaw. † SD: Standard deviation. ‡ BP: Bisphosphonate. § IV: Intravenous. ¶ NA: Not applicable. # HBO: Hyperbaric oxygen. ** OR: Odds ratio. †† CI: Confidence interval. ‡‡ BID: Twice daily.
regression to allow for the control of any potential confounding variables8; unfortunately, we were limited by the availability of data, and therefore, we were unable to accomplish this analysis. Third, the results of the 2 studies whose investigators did not report significant differences between the 2 groups were associated with a high risk of bias.10,13 Considering these
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findings, we suggest, contrary to recommendations for the prevention of MRONJ,2 that surgical intervention does not result in high rates of recurrence and, in fact, may result in better treatment outcomes compared with nonsurgical interventions. Nevertheless, researchers should conduct additional well-controlled studies to confirm these findings.
ORIGINAL CONTRIBUTIONS
TABLE 1 (CONTINUED)
TREATMENT
STUDY
TYPE OF STUDY
POPULATION
CONTROL TREATMENT
INTERVENTION
OUTCOME
n ¼ 25 Cessation of BP therapy
Cessation of BP therapy did not influence treatment outcome.
n ¼ 13 Continuation of BP therapy before surgical therapy
n ¼ 28 Cessation of BP therapy before surgical therapy
Cessation of BP therapy before surgical therapy resulted in a significantly higher rate of improvement (P < .05).
Mean (SD) age: 72 (9) y Sex (% female): 64% Oral BP: n ¼ 0 IV BP: n ¼ 39 Malignancy: 100% MRONJ stage 2: n ¼ 23 sites MRONJ stage 3: n ¼ 24 sites
n ¼ 24 Continuation of BP therapy; all patients received partial resections of affected areas
n ¼ 15 Cessation of BP therapy. All patients received partial resections of affected areas
Cessation of BP therapy did not influence resolution (unadjusted OR, 1.70; 95% CI, 0.49 to 5.90).
Prospective cohort
Mean age: 63.6 y Sex (% female): 35% Oral BP: n ¼ 0 IV BP: n ¼ 17 Malignancy: 100% MRONJ stage 1: n ¼ 17
n ¼ 17 Duration of nonsurgical therapy: chlorhexidine rinse 3 times daily and chlorhexidine gel once daily
Randomized controlled trial
Mean age: 66.2 y Sex (% female): 57% Oral BP: NA IV BP: NA Malignancy: 85% MRONJ stage: NA
n ¼ 21 Usual care: antiseptic rinses, surgery, antibiotics, and surgical debridement per the discretion of the surgeon
n ¼ 25 Usual care plus 40 HBO treatments at 2.0 atmospheres for 2 h twice per d
Significantly higher rates of improvement in the HBO group (P ¼ .03; unadjusted OR, 3.45; 95% CI, 1.02 to 11.66). No significant differences in complete gingival healing or changes to quality of life.
Gasparini and Nonrandomized colleagues,20 controlled study 2010
Mean age: 70.5 y Sex (% female): 64% Oral BP: NA IV BP: NA Malignancy: NA MRONJ stage: NA
n¼6 Spiramycin BID‡‡ for 15-d periods every 45 d, for a total of 6 mo
n¼6 Amoxicillin and clavulanate BID for 15-d periods every 45 d, for a total of 6 mo
Considering a combination of pain, bony exposure, neurosensory deficits, and presence of purulence, the spiramycin showed significantly faster healing (P ¼ .015).
Mucoperiosteal Versus Mylohyoid Flap
Mucke and colleagues,21 2016
Prospective cohort
Mean (SD) age: 66.3 (12.6) y Sex (% female): NA Oral BP: NA IV BP: NA Malignancy: 87% MRONJ stage 1: n ¼ 32 MRONJ stage 2: n ¼ 85 MRONJ stage 3: n ¼ 78
n ¼ 169 Surgical debridement followed by closure with local mucoperiosteal flap
n ¼ 26 Surgical debridement followed by closure with mylohyoid flap
The mylohyoid group had significantly fewer recurrences compared with the mucoperiosteal group (P ¼ .023).
Teriparatide Versus Plasma Rich in Growth Factors
Pelaz and colleagues,22 2014
Prospective cohort
Mean (SD) age: 73.1 (9.9) y Sex (% female): 100% Oral BP: n ¼ 9 IV BP: n ¼ 0 Malignancy: 0% MRONJ stage 3: n ¼ 9
n¼5 Sequestration and curettage followed by application of plasma rich in growth factors
n¼4 Teriparatide hormone therapy once daily
No significant differences in rates of partial or complete healing between the 2 groups.
Prospective Van den Wyngaert and cohort 17 colleagues, 2009
n¼8 Mean age: 63 y Sex (% female): 73% Continuation of BP therapy Oral BP: n = 0 IV BP: n ¼ 33 Malignancy: 100% MRONJ stage 1: n ¼ 9 MRONJ stage 2: n ¼ 21 MRONJ stage 3: n ¼ 3
Wutzl and colleagues,16 2012
Prospective cohort
Mean (SD) age: 68.3 (10.7) y Sex (% female): 61% Oral BP: n ¼ 1 IV BP: n ¼ 40 Malignancy: 88% MRONJ stage 1: n ¼ 10 MRONJ stage 2: n ¼ 24 MRONJ stage 3: n ¼ 7
Bodem and colleagues,15 2016
Prospective cohort
Duration of Nonsurgical Therapy
Bodem and colleagues,18 2015
Hyperbaric Oxygen
Freiberger and colleagues,19 2012
Spiramycin Versus Amoxicillin and Clavulanate
Bisphosphonate Drug Holiday
NA
Duration of nonsurgical treatment did not significantly affect the treatment outcome.
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TABLE 2
Risk of bias of the prospective cohort studies and the nonrandomized trial included in the review, evaluated using the Newcastle-Ottawa Scale.*,† STUDY
REPRESENTATIVENESS OF EXPOSED COHORT
SELECTION OF NONEXPOSED COHORT
ASCERTAINMENT OF PROVIDED TREATMENT
ABSENCE OF OUTCOMES OF INTEREST AT START OF STUDY
Elad and Colleagues,10 Unclear: distribution of 2006 stage not reported
Unclear: no mention of what may affect Low decision for surgery
Low
Van den Wyngaertand Unclear: no details Colleagues,17 2009 regarding population of recruitment
Low
Low
Low
Gasparini and Colleagues,20 2010
Unclear: differences between included and excluded patients not reported
Unclear: no baseline comparisons between the 2 groups
Low
Low
Scoletta and Colleagues,13 2010
Unclear: distribution of stage not reported
High: surgical treatment was performed on unresponsive patients
Low
Low
Mucke and Colleagues,12 2011
Unclear: sex and age of patients not reported
High: surgical treatment based on severity of symptoms
Low
Low
Wutzl and Colleagues,16 2012
Low
Low
Low
Low
Lee and Colleagues,14 2014
Unclear: no details regarding population of recruitment
Low
Low
Low
Lesclous and Colleagues,11 2014
Low
High: patients receiving aggressive surgery were more likely to have a more advanced stage of MRONJ‡ than patients in other groups
Low
Low
Pelaz and Colleagues,22 2014
High: only female patients included
High: teriparatide group more likely to have sicker patients than other groups
Low
Low
Bodem and Colleagues,18 2015
Unclear: no details regarding population or recruitment
Unclear: no mention of what may affect Low time to surgery
Low
Bodem and Colleagues,15 2016
Low
Low
Low
Low
Mucke and Colleagues,21 2016
Unclear: sex of patients and Unclear: no mention of what may affect Low antiresorptive medications decision for treatment used not reported
Low
* Source: Wells and colleagues.7 † Each item was evaluated to have a low, unclear, or high risk of bias. ‡ MRONJ: Medication-related osteonecrosis of the jaw.
Despite the fact that we rated the 2 studies whose investigators evaluated debridement versus resection as having an overall medium risk of bias, the investigators of both of these studies made no attempts to control for any potential confounding variables that may have existed between the 2 studies.11,14 Therefore, we believe that researchers should conduct additional studies to make conclusive differentiations between the effects of conservative and aggressive surgical therapy. Because the investigators of all 3 of the studies that evaluated the effects of a bisphosphonate drug holiday had reported evidence of their attempts to control for confounding variables between the evaluated cohorts, we rated these studies as having a medium risk of bias.15-17 Nevertheless, we found that the effects of a bisphosphonate drug holiday remain inconclusive, owing to the mixed results, the methodological heterogeneity of the studies, and the unavailability of the necessary data
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required for quantitative data synthesis. Therefore, we believe that researchers should conduct additional wellcontrolled studies to further evaluate the effectiveness of a bisphosphonate drug holiday. Of the remaining 5 studies,18-22 we found that the 1 study with the lowest risk of bias was the study whose investigators had evaluated the effects of a mylohyoid flap for tension-free closure after surgical debridement.21 Because of this study’s overall medium risk of bias and the investigators’ efforts to control for any potential confounding variables that may have existed between the 2 groups, we suggest that, on the basis of our review of the results of this study and as hypothesized by investigators of other previously published studies,61,62 the toxic effects of bisphosphonates may extend to the surrounding mucosa as well as to the underlying bone, as found in the relative inferiority of an oral mucosal flap in achieving coverage. Nonetheless, we believe that more
ORIGINAL CONTRIBUTIONS
TABLE 2 (CONTINUED)
COMPARABILITY OF THE COHORTS
ADEQUACY OF ASSESSMENT
LENGTH OF FOLLOW-UP
INCOMPLETE OUTCOME DATA
OVERALL RISK OF BIAS
High: no control of potential confounding variables
Low
High: follow-up period was a minimum of 2 mo
High: high dropout rate (32%)
High
Low
Low
High: follow-up period was a minimum of 2 mo
Unclear: no mention of dropouts
Medium
High: no control of potential confounding variables
Unclear: blinding of outcome assessors not reported
Low
Unclear: no mention of dropouts
High
High: no control of potential confounding variables
Unclear: blinding of outcome assessors not reported
Low
Unclear: no mention of dropouts
High
Low
Low
Low
Unclear: no mention of dropouts
Medium
Unclear: confounding factors not reported
Low
Low
Unclear: no mention of dropouts
Medium
High: no control of potential confounding variables
Low
Low
Unclear: no mention of dropouts
Medium
High: no control of potential confounding variables
Low
Low
Unclear: no mention of dropouts
Medium
High: no control of potential confounding variables
Low
Low
Unclear: no mention of dropouts
High
Unclear: confounding variables not reported
Low
Unclear: no follow-up period stated
Unclear: no mention of dropouts
High
Unclear: confounding variables not reported
Low
Low
Unclear: no mention of dropouts
Medium
Low
Low
Low
Unclear: no mention of dropouts
Medium
study results are required to confirm the use of mylohyoid flaps for successful mucosal coverage of MRONJ lesions in the mandible. Considering that we deemed that each of the other 4 studies18-20,22 had a high risk of bias, clinicians should interpret the results of these studies cautiously. Of these studies, only the investigators of the 1 randomized controlled trial that was included in this review19 suggested that the effectiveness of supplemental hyperbaric oxygen therapy was associated with increasing rates of improvement in the treatment group. Although these results appear promising, it is important for researchers to evaluate these results by conducting other wellcontrolled studies. On the basis of the results of this systematic review, we believe it is clear that, although much progress has been made to better understand how to treat this complex condition, much still is required in the way of highquality research. For the purposes of this systematic review, we included only prospective studies, thereby ensuring that the included studies were free of the
limitations that limit retrospective studies, such as temporal biases and issues associated with missing data.63 Nevertheless, we found that the results of the included studies had their own limitations, and we found that none of the included studies had a low risk of bias (although some risks, such as the presence of baseline differences between the cohorts studied, sometimes are unavoidable, owing to the fact that most surgeons will work within the bounds of existing treatment guidelines, such as those proposed by the American Association of Oral and Maxillofacial Surgeons2). Therefore, we believe it is imperative, in addition to the continuation of the study of this condition, that investigators make efforts to maximize the quality of the results of their studies. Considering the state of the evidence related to the treatment of MRONJ and although treatment suggestions may exist, few study results associated with highquality evidence are available to support most proposed treatment practices. Although, on the basis of the results of our review, we were able to report on the possible effectiveness of surgical intervention over nonsurgical
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ORIGINAL CONTRIBUTIONS
Surgical Study or Subgroup
Events
Nonsurgical
Total
Events
Total
Weight
Odds Ratio
Odds Ratio
M-H, Random, 95% CI
M-H, Random, 95% CI
Scoletta and colleagues,13 2010
10
13
10
24
56.9%
Lesclous and colleagues,11 2014
14
31
2
8
43.1%
2.47 (0.43 to 14.21)
32
100.0%
3.55 (1.12 to 11.19)
Total (95% CI)
44
4.67 (1.02 to 21.43)
Total events 2 2 2 Heterogeneity: τ = 0.00; χ1 = 0.29, P = .59; I = 0%
Test for overall effect: z = 2.16 (P = .03)
0.01
0.1 Favors nonsurgical
1
10
100
Favors surgical
Figure 2. Forest plot comparing surgical therapy with nonsurgical therapy on complete resolution of medication-related osteonecrosis of the jaw. CI: Confidence interval. M-H: Mantel-Haenszel.
therapy and suggest the promising effectiveness of local flaps such as mylohyoid flaps for mucosal coverage in mandibular lesions, investigators have yet to study many other proposed therapies, such as low-level laser therapy, ozone, pentoxifylline, or the discontinuation of other drugs such as denosumab, in a prospective manner.1,2 Considering the as-yet relative shortage of results of high-quality studies to which clinicians can refer to evaluate many of the therapies that have been proposed within the body of literature, steps for the future will be for clinical researchers to work closely with clinicians and scientists in wet laboratories to determine effective means for managing MRONJ. CONCLUSIONS
Although clinicians and researchers have made progress toward understanding MRONJ better, it remains a largely understudied condition. Through the results of this systematic review, we identified that surgical interventions for the management of MRONJ may be a more effective method than investigators previously have hypothesized; however, we found that this information was reported by investigators of studies that had a medium-to-high risk of bias and were associated with low statistical power. Researchers should conduct additional high-quality studies before making conclusive suggestions regarding optimal permutations for the treatment of this condition. n SUPPLEMENTAL DATA
Supplemental data related to this article can be found at: http://dx.doi.org/10.1016/j.adaj.2017.04.002. Dr. El-Rabbany is a resident and a doctoral student, Oral and Maxillofacial Surgery, University of Toronto, Toronto, Ontario, Canada. Mr. Sgro is an undergraduate student, University of Toronto, Toronto, Ontario, Canada. Dr. Lam was an assistant professor, the discipline head, and the graduate program director, Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada, when this article was written. He now is a professor and the chair, Department of Oral & Maxillofacial Surgery, Stony Brook School of Dental Medicine, Stony Brook, NY, a professor, Department of Surgery, Stony Brook School of Medicine,
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Stony Brook, NY, and the chief, Oral & Maxillofacial Surgery, Stony Brook University Hospital, Stony Brook, NY. Dr. Shah is a professor, Institute of Health, Policy, Management and Evaluation, and a professor, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Dr. Azarpazhooh is an associate professor, Dental Public Health and Endodontics, Faculty of Dentistry, University of Toronto, 710F-481 University Ave., Toronto, Ontario, M5G2P1, Canada, e-mail amir. [email protected]. Address correspondence to Dr. Azarpazhooh. Disclosure. None of the authors reported any disclosures. This study was supported by grants from the Canadian Association of Oral and Maxillofacial Surgeons and the Alpha Omega Foundation of Canada. 1. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30(1):3-23. 2. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw: 2014 update. J Oral Maxillofac Surg. 2014;72(10): 1938-1956. 3. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol. 2005;23(34):8580-8587. 4. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22(10):1479-1491. 5. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken, NJ: Wiley; 2008. 6. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. 7. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses; 2000, 2014. The Ottawa Hospital Research Institute. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed April 18, 2017. 8. Thompson SG, Higgins J. How should meta-regression analyses be undertaken and interpreted? Stat Med. 2002;21(11, special issue):1559-1573. 9. Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med. 2002;21(11, special issue):1539-1558. 10. Elad S, Yarom N, Hamed W, Ayalon S, Yahalom R, Regev E. Osteomylelitis and necrosis of the jaw in patients treated with bisphosphonates: a comparative study focused on multiple myeloma. Clin Lab Haematol. 2006;28(6):393-398. 11. Lesclous P, Grabar S, Abi Najm S, et al. Relevance of surgical management of patients affected by bisphosphonate-associated osteonecrosis of the jaws: a prospective clinical and radiological study. Clin Oral Investig. 2014;18(2):391-399. 12. Mucke T, Koschinski J, Deppe H, et al. Outcome of treatment and parameters influencing recurrence in patients with
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bisphosphonate-related osteonecrosis of the jaws. J Cancer Res Clin Oncol. 2011;137(5):907-913. 13. Scoletta M, Arduino PG, Dalmasso P, Broccoletti R, Mozzati M. Treatment outcomes in patients with bisphosphonate-related osteonecrosis of the jaws: a prospective study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;110(1):46-53. 14. Lee LW, Hsiao SH, Chen LK. Clinical treatment outcomes for 40 patients with bisphosphonates-related osteonecrosis of the jaws. J Formos Med Assoc. 2014;113(3):166-172. 15. Bodem JP, Schaal C, Kargus S, et al. Surgical management of bisphosphonate-related osteonecrosis of the jaw stages II and III. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;121(4):367-372. 16. Wutzl A, Pohl S, Sulzbacher I, et al. Factors influencing surgical treatment of bisphosphonate-related osteonecrosis of the jaws. Head Neck. 2012;34(2):194-200. 17. Van den Wyngaert T, Claeys T, Huizing MT, Vermorken JB, Fossion E. Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol. 2009;20(2):331-336. 18. Bodem JP, Kargus S, Engel M, Hoffmann J, Freudlsperger C. Value of nonsurgical therapeutic management of stage I bisphosphonate-related osteonecrosis of the jaw. J Craniomaxillofac Surg. 2015;43(7):1139-1143. 19. Freiberger JJ, Padilla-Burgos R, McGraw T, et al. What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. J Oral Maxillofac Surg. 2012;70(7): 1573-1583. 20. Gasparini G, Saponaro G, Di Nardo F, et al. Clinical experience with spiramycin in bisphosphonate-associated osteonecrosis of the jaw. Int J Immunopathol Pharmacol. 2010;23(2):619-626. 21. Mucke T, Koerdt S, Jung M, et al. The role of mylohyoid flap in the treatment of bisphosphonate-related osteonecrosis of the jaws. J Craniomaxillofac Surg. 2016;44(4):369-373. 22. Pelaz A, Junquera L, Gallego L, Garcia-Consuegra L, Junquera S, Gomez C. Alternative treatments for oral bisphosphonate-related osteonecrosis of the jaws: a pilot study comparing fibrin rich in growth factors and teriparatide. Med Oral Patol Oral Cir Bucal. 2014;19(4):e320-e326. 23. Agrillo A, Filiaci F, Ramieri V, et al. Bisphosphonate-related osteonecrosis of the jaw (BRONJ): 5 year experience in the treatment of 131 cases with ozone therapy. Eur Rev Med Pharmacol Sci. 2012;16(12):1741-1747. 24. Al Hadi H, Smerdon GR, Fox SW. Hyperbaric oxygen therapy accelerates osteoblast differentiation and promotes bone formation. J Dent. 2015;43(3):382-388. 25. Alsehimy MM. Efficacy of a nonsurgical treatment regimen in patients with bisphosphonate-related osteonecrosis of the jaws in Saudi Arabia. SAGE Open Med. 2014;2:2050312114522995. 26. Bast F, Gross A, Hecht L, Schrom T. Etiology and treatment of osteonecrosis of the mandible. Contemp Oncol (Pozn). 2013;17(3):281-285. 27. Bedogni A, Saia G, Bettini G, et al. Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis. Oral Oncol. 2011;47(5):420-424. 28. Bocanegra-Pérez S, Vicente-Barrero M, Knezevic M, et al. Use of platelet-rich plasma in the treatment of bisphosphonate-related osteonecrosis of the jaw. Int J Oral Maxillofac Surg. 2012;41(11):1410-1415. 29. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G. Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol. 2008; 44(9):857-869. 30. Carlson ER, Basile JD. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2009;67(5):85-95. 31. Carlson ER. Management of antiresorptive osteonecrosis of the jaws with primary surgical resection. J Oral Maxillofac Surg. 2014;72(4):655-657. 32. Cetiner S, Sucak GT, Kahraman SA, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with zoledronic acid. J Bone Miner Metab. 2009;27(4):435-443. 33. Eckardt AM, Lemound J, Lindhorst D, Rana M, Gellrich NC. Surgical management of bisphosphonate-related osteonecrosis of the jaw in oncologic patients: a challenging problem. Anticancer Res. 2011;31(6): 2313-2318. 34. Ferlito S, Puzzo S, Palermo F, Verzi P. Treatment of bisphosphonaterelated osteonecrosis of the jaws: presentation of a protocol and an
observational longitudinal study of an Italian series of cases. Br J Oral Maxillofac Surg. 2012;50(5):425-429. 35. Hallmer F, Bjornland T, Nicklasson A, Becktor JP, Andersson G. Osteonecrosis of the jaw in patients treated with oral and intravenous bisphosphonates: experience in Sweden. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;118(2):202-208. 36. Harper RP, Fung E. Resolution of bisphosphonate-associated osteonecrosis of the mandible: possible application for intermittent low-dose parathyroid hormone [rhPTH(1-34)]. J Oral Maxillofac Surg. 2007;65(3): 573-580. 37. Hinson AM, Siegel ER, Stack BC Jr. Temporal correlation between bisphosphonate termination and symptom resolution in osteonecrosis of the jaw: a pooled case report analysis. J Oral Maxillofac Surg. 2015;73(1):53-62. 38. Ikeda T, Kuraguchi J, Kogashiwa Y, et al. Successful treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) patients with sitafloxacin: new strategies for the treatment of BRONJ. Bone. 2015;73: 217-222. 39. Kim KM, Park W, Oh SY, et al. Distinctive role of 6-month teriparatide treatment on intractable bisphosphonate-related osteonecrosis of the jaw. Osteoporos Int. 2014;25(5):1625-1632. 40. Kim YH, Lee HK, Song SI, Lee JK. Drug holiday as a prognostic factor of medication-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg. 2014;40(5):206-210. 41. Lazarovici TS, Yahalom R, Taicher S, Elad S, Hardan I, Yarom N. Bisphosphonate-related osteonecrosis of the jaws: a single-center study of 101 patients. J Oral Maxillofac Surg. 2009;67(4):850-855. 42. Lemound J, Eckardt A, Kokemüller H, et al. Bisphosphonateassociated osteonecrosis of the mandible: reliable soft tissue reconstruction using a local myofascial flap. Clin Oral Investig. 2012;16(4): 1143-1152. 43. Martins MA, Martins MD, Lascala CA, et al. Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: a preliminary study. Oral Oncol. 2012;48(1):79-84. 44. Mucke T, Jung M, Koerdt S, et al. Free flap reconstruction for patients with bisphosphonate related osteonecrosis of the jaws after mandibulectomy. J Craniomaxillofac Surg. 2016;44(2):142-147. 45. Pautke C, Bauer F, Tischer T, et al. Fluorescence-guided bone resection in bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg. 2009;67(3):471-476. 46. Pautke C, Bauer F, Otto S, et al. Fluorescence-guided bone resection in bisphosphonate-related osteonecrosis of the jaws: first clinical results of a prospective pilot study. J Oral Maxillofac Surg. 2011;69(1):84-91. 47. Ripamonti CI, Cislaghi E, Mariani L, Maniezzo M. Efficacy and safety of medical ozone (O[3]) delivered in oil suspension applications for the treatment of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: preliminary results of a phase I-II study. Oral Oncol. 2011;47(3):185-190. 48. Ripamonti CI, Maniezzo M, Boldini S, Pessi MA, Mariani L, Cislaghi E. Efficacy and tolerability of medical ozone gas insufflations in patients with osteonecrosis of the jaw treated with bisphosphonates, preliminary data: medical ozone gas insufflation in treating ONJ lesions. J Bone Oncol. 2012;1(3):81-87. 49. Schubert M, Klatte I, Linek W, et al. The Saxon Bisphosphonate Register: therapy and prevention of bisphosphonate-related osteonecrosis of the jaws. Oral Oncol. 2012;48(4):349-354. 50. Scoletta M, Arduino PG, Reggio L, Dalmasso P, Mozzati M. Effect of low-level laser irradiation on bisphosphonate-induced osteonecrosis of the jaws: preliminary results of a prospective study. Photomed Laser Surg. 2010; 28(2):179-184. 51. Shintani T, Hayashido Y, Mukasa H, et al. Comparison of the prognosis of bisphosphonate-related osteonecrosis of the jaw caused by oral and intravenous bisphosphonates. Int J Oral Maxillofac Surg. 2015; 44(7):840-844. 52. Stockmann P, Vairaktaris E, Wehrhan F, et al. Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support Care Cancer. 2010;18(4):449-460. 53. Thumbigere-Math V, Sabino MC, Gopalakrishnan R, et al. Bisphosphonate-related osteonecrosis of the jaw: clinical features, risk factors, management, and treatment outcomes of 26 patients. J Oral Maxillofac Surg. 2009;67(9):1904-1913.
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54. Vescovi P, Merigo E, Meleti M, Fornaini C, Nammour S, Manfredi M. Nd:YAG laser biostimulation of bisphosphonate-associated necrosis of the jawbone with and without surgical treatment. Br J Oral Maxillofac Surg. 2007;45(8):628-632. 55. Vescovi P, Manfredi M, Merigo E, et al. Surgical approach with Er: YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med Sci. 2010;25(1):101-113. 56. Vescovi P, Merigo E, Meleti M, Manfredi M, Fornaini C, Nammour S. Surgical approach and laser applications in BRONJ osteoporotic and cancer patients. J Osteoporos. 2012;2012:585434. 57. Vescovi P, Merigo E, Meleti M, et al. Conservative surgical management of stage I bisphosphonate-related osteonecrosis of the jaw. Int J Dent. 2014;2014:107690. 58. Wilde F, Heufelder M, Winter K, et al. The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis
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of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111(2): 153-163. 59. Williamson RA. Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg. 2010;39(3): 251-255. 60. Wutzl A, Biedermann E, Wanschitz F, et al. Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head Neck. 2008;30(9): 1224-1230. 61. Landesberg R, Cozin M, Cremers S, et al. Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg. 2008;66(5): 839-847. 62. Reid IR, Bolland MJ, Grey AB. Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone. 2007;41(3):318-320. 63. Hess DR. Retrospective studies and chart reviews. Respir Care. 2004; 49(10):1171-1174.
ORIGINAL CONTRIBUTIONS
eTABLE 1
Sample detailed search strategy used for MEDLINE. 1.
exp “Bisphosphonate-Associated Osteonecrosis of the Jaw”/
2.
(BRONJ or MRONJ or ARONJ or BION or BONJ or BIONJ).ti,ab.
3.
((bisphosphonate or medication or denosumab or antiangiogenic? or angiogenic? or antiresorptive? or resorptive?) adj5 osteonecrosis).mp.
4.
or/1-3
5.
exp Jaw/or exp Jaw Diseases/
6.
(jaw$ or mand$ or maxilla$ or alveolar).mp.
7.
or/5-6
8.
exp Therapeutics/
9.
treat$.mp.
10. exp Hyperbaric Oxygenation/or hyperbaric oxygen.mp. 11. free flap.mp. or exp Free Tissue Flaps/ 12. resect$.mp. 13. exp Debridement/or debride*.mp. 14. exp Curettage/or curett*.mp. 15. sequestrectomy.mp. 16. saucerization.mp. 17.
or/8-16
18. 4 and 7 and 17
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ORIGINAL CONTRIBUTIONS
eTABLE 2
List of excluded studies, with reasons for exclusion. STUDY Harper and Fung,36 2007
REASON FOR EXCLUSION Case study
Vescovi and Colleagues,54 2007
Case series, with only descriptive statistics
Boonyapakorn and Colleagues,29 2008
No treatment data
Wutzl and Colleagues,60 2008
Case series, with only descriptive statistics
Carlson and Basile,30 2009
Case series, with only descriptive statistics
Cetiner and Colleagues,32 2009
Case series, with only descriptive statistics
Lazarovici and Colleagues,41 2009
Retrospective study
Pautke and Colleagues,45 2009
Case series, with only descriptive statistics
Thumbigere-Math and Colleagues,53 2009 Case series, with only descriptive statistics Scoletta and Colleagues,50 2010
Case series, with only descriptive statistics
Stockmann and Colleagues,52 2010
Case series, with only descriptive statistics
Vescovi and Colleagues,55 2010
Retrospective study
Williamson,59 2010
Case series, with only descriptive statistics
Bedogni and Colleagues,27 2011
Case series, with only descriptive statistics
Eckardt and Colleagues,33 2011
Retrospective study
Pautke and Colleagues,46 2011
Case series, with only descriptive statistics
Ripamonti and Colleagues,47 2011
Case series, with only descriptive statistics
Wilde and Colleagues,58 2011
Case series, with only descriptive statistics
Agrillo and Colleagues,23 2012
Retrospective study
Bocanegra-Perez and Colleagues,28 2012
Case series, with only descriptive statistics
Ferlito and Colleagues,34 2012
Case series, with only descriptive statistics
Lemound and Colleagues,42 2012
Case series, with only descriptive statistics
Martins and Colleagues,43 2012
Retrospective study
Ripamonti and Colleagues,48 2012
Case series, with only descriptive statistics
Schubert and Colleagues,49 2012
Case series, with only descriptive statistics
Vescovi and Colleagues,56 2012
Retrospective study
Bast and Colleagues,26 2013
Case series, with only descriptive statistics
Alsehimy,25 2014
Case series, with only descriptive statistics
Carlson,31 2014
Literature review
Hallmer and Colleagues,35 2014
Retrospective study
Kim, Lee, and Colleagues,40 2014
Retrospective study
Kim, Park, and Colleagues,39 2014
Retrospective study
Vescovi and Colleagues,57 2014
Retrospective study
Al Hadi and Colleagues,24 2015
Study that did not involve human participants
Hinson and Colleagues,37 2015
Retrospective study
Ikeda and Colleagues,38 2015
Case series, with only descriptive statistics
Shintani and Colleagues,51 2015
Case series, with only descriptive statistics
Mucke and Colleagues,44 2016
Case series, with only descriptive statistics
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ARTICLE 3
Effectiveness of treatments for medication-related osteonecrosis of the jaw A systematic review and meta-analysis Mohamed El-Rabbany, DDS, MSc; Adam Sgro; David K. Lam, MD, DDS, PhD; Prakeshkumar S. Shah, MSc, MBBS, MD, DCH; Amir Azarpazhooh, DDS, MSc, PhD
M
edication-related osteonecrosis of the jaw (MRONJ) is defined as exposed bone, in a susceptible patient who does not have a history of head and neck radiation, that fails to heal over a period of 8 weeks in the absence of any evidence of obvious metastatic disease.1,2 Despite being relatively uncommon, with a prevalence of up to 0.01% in patients receiving oral bisphosphonates, 12% in patients receiving intravenous bisphosphonates, and 16% in patients receiving a combination of bisphosphonates and antiangiogenics, MRONJ presents major repercussions for both a patient’s quality of life and health care resources.1,3,4 Patients with MRONJ often have signs and symptoms that include pain, swelling, exposed bony sequestrum, fistulae, erythematous or ulcerated soft tissue, or pathologic fractures.1 Because MRONJ occurs more commonly in the mandible This article has an accompanying online continuing education activity available at: http://jada.ada.org/ce/home. Copyright ª 2017 American Dental Association. All rights reserved.
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ABSTRACT Background. The effectiveness of management strategies used for the treatment of medication-related osteonecrosis of the jaw (MRONJ) remains poorly understood. The authors evaluated systematically the effectiveness of the various treatment modalities used for MRONJ. Types of Studies Reviewed. The authors conducted a comprehensive search of MEDLINE, Embase, the Cochrane Library, and Scopus to identify randomized controlled trials, nonrandomized controlled trials, and prospective cohort studies to evaluate comparatively the effectiveness of management strategies for the treatment of MRONJ. The authors conducted the identification of eligible studies in duplicate and synthesized the extracted data by means of a metaanalysis, when feasible. Results. The authors found 13 studies with a medium-to-high risk of bias that met the inclusion criteria of this review. The authors found that, compared with medical treatment of local antimicrobials with or without systemic antimicrobials, the study investigators associated surgical treatment with higher odds of complete resolution of the condition (2 studies; 76 participants; unadjusted odds ratio, 3.55; 95% confidence interval, 1.12 to 11.19). The effectiveness of other therapies, such as bisphosphonate drug holidays, teriparatide, and hyperbaric oxygen, was uncertain. Conclusions and Practical Implications. On the basis of the results of an unadjusted analysis, the results of the studies that were deemed to be medium to low quality and to have medium-to-low statistical power suggested that there are higher odds of resolving MRONJ with surgical treatment compared with medical treatment. High-quality research is required for conclusive statements to be made regarding treatment strategies for management of MRONJ. Key Words. Osteonecrosis; medication-related osteonecrosis of the jaw; bisphosphonate-associated osteonecrosis of the jaw; osteonecrosis of the jaw; oral and maxillofacial surgery; bone. JADA 2017:148(8):584-594 http://dx.doi.org/10.1016/j.adaj.2017.04.002
ORIGINAL CONTRIBUTIONS
than in the maxilla, owing to mandibular bone’s relatively low vascularity, the dominant hypothesis for the cause of MRONJ is a combination of injury or insult to the bone, along with a diminished ability to heal.1 Management of MRONJ has remained a controversial topic within the oral and maxillofacial surgery community. To date, therapeutic management has focused largely on symptomatic treatment, divided into the categories of surgical therapy and nonsurgical therapy. Examples of nonsurgical therapies include, but are not limited to, long-term use of local antimicrobials, systemic antimicrobials, or both; cessation of antiresorptive or antiangiogenic therapy; hyperbaric oxygen therapy; lowintensity laser therapy; teriparatide; ozone; pentoxifylline; and tocopherol. Similarly, surgical treatment options for the management of MRONJ range from conservative to aggressive, such as curettage, sequestrectomy, and resection as a final resort.1,2 Given the paucity of evidence to support the use of these various therapies to manage and treat MRONJ, we determined that the purpose of this study would be to evaluate the effectiveness of the various treatment modalities used. We registered the protocol of this study a priori with PROSPERO (International Prospective Register of Systematic Reviews, Centre for Reviews and Dissemination, University of York, York, United Kingdom: http://www.crd.york.ac.uk/PROSPERO/ display_record.asp?ID¼CRD42016051939). METHODS
Objectives. Our objective for this systematic review was to evaluate the effectiveness of the various therapies used to manage and treat patients with MRONJ to resolve the condition. We used the recommendations outlined by the Cochrane Handbook for Systematic Reviews of Interventions5 to produce the methods for this systematic review. Eligibility criteria. We used the following criteria to consider studies for inclusion in this review. - Types of studies: We determined that prospective cohort studies, nonrandomized trials, and randomized controlled trials whose investigators had evaluated the effectiveness of various MRONJ therapies to resolve the condition, as defined in “types of outcome measures” below, were eligible for this study. We excluded retrospective cohort studies, case-control studies, crosssectional studies, case series, case studies, reviews, and studies that did not involve humans. - Types of participants: We included studies that involved patients older than 18 years who had a diagnosis of MRONJ. We used the following diagnostic guidelines, set by the American Association of Oral and Maxillofacial Surgeons2 regarding MRONJ in eligible patients: current or previous treatment with antiresorptive or antiangiogenic agents, exposed bone or bone that could
be probed through an intraoral or extraoral fistula or fistulae in the maxillofacial region that had persisted for more than 8 weeks, and no history of radiation therapy in the jaws or obvious metastatic disease in the jaws. - Types of interventions: We set no limitations for the interventions used to manage MRONJ. - Types of outcome measures: We considered studies whose investigators had evaluated the following outcomes of interest: complete resolution (defined as an absence of clinical signs and symptoms of MRONJ), changes in bony exposure and mucosal coverage, changes in radiographic lesion size, recurrence of the condition, the presence of pain, neurosensory changes, and quality of life. Search methods for the identification of studies. We applied our search strategy for this review (eTable 1; available online at the end of this article) on June 9, 2016, to the following electronic databases, which we accessed through the University of Toronto: MEDLINE (Ovid MEDLINE, from 1960 to Week 4, May 2016; Ovid MEDLINE In-Process and Other Non-Indexed Citations), Embase (Ovid’s Embase Classic and Embase, 1960 to Week 22, 2016), and the Cochrane Library. In addition, we added the Scopus database and the first 200 hits from Google Scholar to the search to identify gray literature, unpublished literature, or both. Once we identified articles for inclusion, we reviewed the reference lists of the included articles to identify any articles that we may have missed in the search. We made no language exclusions for this review, and we translated all of the articles not published in English. Study selection and data extraction. Two reviewers (M.E.-R., A.S.) independently conducted study selection and data extraction. After removing duplicate results from the initial yield of the search, each reviewer independently reviewed the titles and abstracts of these studies to identify potentially eligible results. Next, they combined their results, and after removing duplicate studies, each of the 2 reviewers reviewed the full texts of the selected studies to determine final eligibility. The 2 reviewers resolved disagreements regarding eligibility by means of seeking consensus, consultation, or both with a senior reviewer (A.A.); after this stage of review, they presented the measure of agreement as a k statistic, which is a chance-corrected measure of agreement. Risk of bias in individual studies. We assessed the methodological quality of the eligible studies using the information in the original publications and using either the Cochrane Risk of Bias Tool6 for randomized controlled trials or the Newcastle-Ottawa Scale7 for all other studies. Two authors (M.E.-R., A.S.) independently
ABBREVIATION KEY. BID: Twice daily. BP: Bisphosphonate. HBO: Hyperbaric oxygen. IV: Intravenous. MRONJ: Medication-related osteonecrosis of the jaw. NA: Not applicable.
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ORIGINAL CONTRIBUTIONS
Records identified through database searching (n = 3,026)
Records identified through other sources (n = 200)
Records after duplicates removed (n = 2,155)
Records excluded (n = 2,104)
Full-text articles assessed for eligibility (n = 51)
we considered a P value of .05 or less to be significant. We planned to combine unadjusted and adjusted data from the available studies. As we conducted the metaanalyses of the adjusted data, we planned to combine the data irrespective of the variability in the factors adjusted in each study. Publication bias across studies. To identify publication bias, we planned to use funnel plots for all metaanalyses of 10 or more included studies. RESULTS
Full-text articles excluded, with reasons (n = 38)
Articles included in qualitative synthesis (n = 13)
Articles included in quantitative synthesis (n = 2)
Figure 1. Flow chart outlining the study selection process.
graded the studies as having a “low,” “unclear,” or “high” risk of bias, according to each set of the domains for both the Newcastle-Ottawa Scale7 or the Cochrane Risk of Bias Tool,6 and they resolved any disagreements either by seeking consensus or consultation with a third author (A.A.). Data synthesis. We made attempts to combine studies that had similar comparisons and outcome measures by means of meta-analyses (and metaregressions for nonrandomized studies to control for potential confounding variables, when possible8) using RevMan 5.3 software (Nordic Cochrane Centre, The Cochrane Collaboration). For groups of studies whose results we deemed to be clinically homogenous, we pooled the data via the inverse-variance method with a random-effects model for continuous variables and via the Mantel-Haenszel test method with a random-effects model for discrete variables. We reported outcomes as risk ratios for discrete variables or mean differences for continuous variables. We displayed statistical heterogeneity in each forest plot by calculating an I2 value, for which we considered a value greater than 50% to have a high level of statistical heterogeneity.9 For all test results,
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Figure 1 shows a flow chart of the study selection; the initial search strategy yielded 3,226 results. After we removed duplicates, 2,155 unique articles remained. Next, the 2 reviewers’ independent reviews of titles and abstracts yielded 51 articles,10-60 and after the 2 reviewers completed independent full-text reviews, we found that a total of 13 articles10-22 met the inclusion criteria for this review. Agreement between the 2 reviewers was associated with a k statistic of 0.84. eTable 223-60 (available online at the end of this article) lists the 38 studies23-60 that we excluded at the full-text review stage and the reasons for exclusion. In our review of the 13 included articles, we found that investigators had evaluated the following therapies used for the treatment of MRONJ: nonsurgical versus surgical therapy,10-13 conservative versus aggressive surgical therapy,11,14 antiresorptive drug continuation versus discontinuation,15-17 early versus delayed surgery,18 supplemental hyperbaric oxygen therapy versus control,19 spiramycin versus amoxicillin and clavulanate,20 mucoperiosteal flap repair versus mylohyoid flap repair,21 and teriparatide versus plasma rich in growth factors.22 Investigators had conducted all of the 13 studies in hospital settings. One study was a randomized controlled trial,19 1 was a nonrandomized trial,20 and the remaining 11 were prospective cohort studies.10-18,21,22 The mean number of included patients in these studies was 52, with sample sizes ranging from 9 to 195. Table 110-22 provides details regarding the methodologies and summarizes the outcome values. Of the 12 prospective cohort and nonrandomized studies,10-18,20-22 we determined that 7 studies11,12,14-17,21 had a medium risk of bias and 5 studies10,13,18,20,22 had a high risk of bias. Table 210-18,20-22 provides a breakdown of the components of the Newcastle-Ottawa Scale,7 which we used to determine the risk of bias for these studies. We found that the randomized controlled trial19 had a high risk of bias, as per the results of our evaluation using the Cochrane Risk of Bias Tool.6 Although we determined that the study19 had a low risk of bias when we evaluated allocation concealment and selective outcome reporting, we found that the study’s investigators fell short in adequately blinding participants or health care providers, controlling for the number of patient dropouts from the study, and conducting data
ORIGINAL CONTRIBUTIONS
analyses in an intention-to-treat manner. In addition, the investigators’ reporting of random sequence generation methodology as well as the masking of outcome assessors was unclear. Given the lack of consensus regarding the treatment of MRONJ, we found that the results of the studies included in this review did have heterogeneity related to the treatments and the outcomes evaluated. With the exception of comparing surgical and nonsurgical therapy, we made no attempts to conduct data synthesis owing to the unavailability of necessary data. Table 110-22 provides a detailed overview of these findings. Surgical versus nonsurgical therapy. The investigators of 4 of the included studies10-13 (n ¼ 223) evaluated surgical therapy versus nonsurgical therapy for the treatment of MRONJ. Of these, the investigators of 2 studies11,12 reported the superiority of surgical therapy compared with nonsurgical therapy; the investigators of 1 study reported a greater likelihood of condition resolution,11 and the investigators of another study reported fewer recurrences of the treated lesions.12 Figure 2 shows the results of the meta-analysis of the 2 included studies11,13 that had sufficient data for synthesis; these results support the findings of the aforementioned studies whose investigators had reported significant differences. Compared with medical treatment of local antimicrobials with or without systemic antimicrobials, we found that surgical treatment was associated with higher odds of complete resolution of the condition (2 studies; 76 participants; unadjusted odds ratio [OR], 3.55; 95% confidence interval [CI], 1.12 to 11.19; P ¼ .03). Conservative versus aggressive surgical therapy. The investigators of 2 studies (n ¼ 79) evaluated conservative surgery versus aggressive surgery, defined as debridement and resection, respectively.11,14 The investigators of 1 of these studies14 reported that the time to remission was significantly lower in their aggressive surgical therapy cohort (P < .001) compared with no significant differences reported in the study by Lesclous and colleagues11 (unadjusted OR, 0.77; 95% CI, 0.15 to 3.86). Bisphosphonate drug holiday. The investigators of 3 studies15-17 (n ¼ 113) evaluated the effects of cessation of bisphosphonate therapy on the resolution of MRONJ, of which the investigators of only 1 study16 reported a significant effect of a drug holiday on the outcome of surgical therapy, indicating significantly greater rates of improvement in the drug holiday cohort (P < .05).16 The investigators of all 3 of these studies did not make available the details regarding the length of time the patients had stopped taking bisphosphonates before the intervention. Early versus delayed surgery. The investigators of 1 study18 (n ¼ 17) compared the effectiveness of early surgery with that of delayed surgery. They reported no
differences in the rate of complete resolution between the 2 groups. Supplemental hyperbaric oxygen therapy. The investigators of 1 study19 (n ¼ 46) compared the effectiveness of supplemental hyperbaric oxygen in addition to usual care. They reported significantly higher increases in mucosal coverage (unadjusted OR, 3.45; 95% CI, 1.02 to 11.66; P ¼ .03) but not in full mucosal healing. Spiramycin versus amoxicillin and clavulanate. The investigators of 1 study20 (n ¼ 12) compared the effectiveness of spiramycin with that of amoxicillin and clavulanate. They found faster rates of condition resolution in the spiramycin group (P ¼ .015). Mucoperiosteal versus mylohyoid flaps. The investigators of 1 study21 (n ¼ 195) compared the effectiveness of mucoperiosteal with that of mylohyoid flaps for mandibular coverage after debridement. They found that the mylohyoid group had significantly lower rates of recurrence (P ¼ .023). Teriparatide versus plasma rich in growth factors. The investigators of 1 study22 (n ¼ 9) compared the effectiveness of teriparatide with that of plasma rich in growth factors. They reported no difference in the rate of complete resolution between the 2 groups. DISCUSSION
The purpose of this study was to review the evidence supporting the various therapies used to treat MRONJ. Through our review of the highest quality articles we found whose authors addressed this topic, we found that surgical therapy, compared with medical therapy, may result in higher rates of resolution of MRONJ. Nevertheless, it is apparent that the results of more high-quality research studies are required for investigators to make conclusive statements regarding many of the treatment strategies for managing MRONJ. The investigators of studies comparing medical therapy with surgical therapy reported that surgical therapy was associated with a higher rate of resolving the condition. Despite the fact that we found that the 2 studies11,12 whose investigators reported that surgical therapy resulted in significantly improved treatment outcomes had a medium risk of bias, only Mucke and colleagues12 attempted to control for potential confounding variables between the 2 cohorts in their study.11,12 Second, although the results of a metaanalysis of the available data suggested significantly improved rates of success with surgical therapy compared with those of nonsurgical treatment, owing to the unavailability of necessary data, we were unable to control for potential confounding variables. Given that the investigators of cohort studies (unlike the investigators of randomized controlled trials) are unable to control for confounding variables without making statistical corrections, the most correct way for us to synthesize the data would have been through a meta-
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TABLE 1
Summary of the characteristics and results of the included studies evaluating success of treatment of MRONJ.* TREATMENT
STUDY
TYPE OF STUDY
POPULATION
CONTROL TREATMENT
INTERVENTION
OUTCOME
Elad and colleagues,10 2006
Prospective cohort
Mean (SD†) age: 62.7 (10.8) y Sex (% female): 72% Oral BP‡: n ¼ 5 IV§ BP: n ¼ 52 Malignancy: 93% MRONJ stage: NA¶
n ¼ 12 Nonsurgical therapy: antibiotics with or without topical agents (chlorhexidine, saline) with or without HBO# therapy
n ¼ 27 Nonsurgical plus surgical therapy: superficial debridment, curettage, extensive surgery
No significant differences in rates of improvement between the 2 groups (unadjusted OR**, 0.4; 95% CI,†† 0.09 to 1.73).
Scoletta and colleagues,13 2010
Prospective cohort
Mean (SD) age: 68.0 (13.0) y Sex (% female): 70% Oral BP: n ¼ 3 IV BP: n ¼ 34 Malignancy: 89% MRONJ stage: NA
n ¼ 24 Nonsurgical therapy: chlorhexidine with or without antibiotics
n ¼ 13 Nonsurgical plus surgical therapy: debridement or resection
No significant differences in rates of complete healing between the 2 groups (unadjusted OR, 4.67; 95% CI, 1.02 to 21.03).
Mucke and colleagues,12 2011
Prospective cohort
Mean age: NA Sex (% female): NA Oral BP: n ¼ 14 IV BP: n ¼ 94 Malignancy: 84% MRONJ stage 1: n ¼ 18 MRONJ stage 2: n ¼ 46 MRONJ stage 3: n ¼ 44
n¼6 Nonsurgical therapy: hexetidine antiseptic rinse and antibiotics
n ¼ 102 Nonsurgical plus surgical therapy: sequestrectomy, debridement, and marginal or segmental resection
The surgical group had a lower likelihood for recurrences (OR, 3.9; 95% CI, 1.75 to 8.66; P ¼ .001).
Lesclous and Nonsurgical colleagues,11 Versus Conservative 2014 Versus Aggressive Surgical Therapy
Prospective cohort
Mean (SD) age: 69.6 (2.3) y Sex (% female): 69% Oral BP: n ¼ 8 IV BP: n ¼ 31 Malignancy: 82% MRONJ stage: NA
n¼8 Nonsurgical therapy: systemic antibiotics and local antiseptics
n1 ¼ 8 Conservative surgical therapy: nonsurgical plus decortication and fibrin glue coverage
Surgical groups showed significantly higher rates of resolution compared with nonsurgical groups (unadjusted OR, 2.47; 95% CI, 0.43 to 14.21). No significant differences between conservative and aggressive surgery (unadjusted OR, 0.77; 95% CI, 0.15 to 3.86).
Nonsurgical Versus Surgical Therapy
n2 ¼ 23 Aggressive surgical therapy: as listed previously, plus bone resection Lee and Conservative colleagues,14 Versus Aggressive 2014 Surgical Therapy
Prospective cohort
Mean (SD) age: 69 (11) y Sex (% female): 60% Oral BP: n ¼ 19 IV BP: n ¼ 21 Malignancy: 53% MRONJ stage 1: n ¼ 4 MRONJ stage 2: n ¼ 28 MRONJ stage 3: n ¼ 8
n ¼ 30 Conservative therapy: antibiotics, antiseptic irrigation, with or without debridement
n ¼ 10 Aggressive therapy: surgical resection
Time to achieving complete remission was significantly lower in the aggressive surgery group (P < .001).
* MRONJ: Medication-related osteonecrosis of the jaw. † SD: Standard deviation. ‡ BP: Bisphosphonate. § IV: Intravenous. ¶ NA: Not applicable. # HBO: Hyperbaric oxygen. ** OR: Odds ratio. †† CI: Confidence interval. ‡‡ BID: Twice daily.
regression to allow for the control of any potential confounding variables8; unfortunately, we were limited by the availability of data, and therefore, we were unable to accomplish this analysis. Third, the results of the 2 studies whose investigators did not report significant differences between the 2 groups were associated with a high risk of bias.10,13 Considering these
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findings, we suggest, contrary to recommendations for the prevention of MRONJ,2 that surgical intervention does not result in high rates of recurrence and, in fact, may result in better treatment outcomes compared with nonsurgical interventions. Nevertheless, researchers should conduct additional well-controlled studies to confirm these findings.
ORIGINAL CONTRIBUTIONS
TABLE 1 (CONTINUED)
TREATMENT
STUDY
TYPE OF STUDY
POPULATION
CONTROL TREATMENT
INTERVENTION
OUTCOME
n ¼ 25 Cessation of BP therapy
Cessation of BP therapy did not influence treatment outcome.
n ¼ 13 Continuation of BP therapy before surgical therapy
n ¼ 28 Cessation of BP therapy before surgical therapy
Cessation of BP therapy before surgical therapy resulted in a significantly higher rate of improvement (P < .05).
Mean (SD) age: 72 (9) y Sex (% female): 64% Oral BP: n ¼ 0 IV BP: n ¼ 39 Malignancy: 100% MRONJ stage 2: n ¼ 23 sites MRONJ stage 3: n ¼ 24 sites
n ¼ 24 Continuation of BP therapy; all patients received partial resections of affected areas
n ¼ 15 Cessation of BP therapy. All patients received partial resections of affected areas
Cessation of BP therapy did not influence resolution (unadjusted OR, 1.70; 95% CI, 0.49 to 5.90).
Prospective cohort
Mean age: 63.6 y Sex (% female): 35% Oral BP: n ¼ 0 IV BP: n ¼ 17 Malignancy: 100% MRONJ stage 1: n ¼ 17
n ¼ 17 Duration of nonsurgical therapy: chlorhexidine rinse 3 times daily and chlorhexidine gel once daily
Randomized controlled trial
Mean age: 66.2 y Sex (% female): 57% Oral BP: NA IV BP: NA Malignancy: 85% MRONJ stage: NA
n ¼ 21 Usual care: antiseptic rinses, surgery, antibiotics, and surgical debridement per the discretion of the surgeon
n ¼ 25 Usual care plus 40 HBO treatments at 2.0 atmospheres for 2 h twice per d
Significantly higher rates of improvement in the HBO group (P ¼ .03; unadjusted OR, 3.45; 95% CI, 1.02 to 11.66). No significant differences in complete gingival healing or changes to quality of life.
Gasparini and Nonrandomized colleagues,20 controlled study 2010
Mean age: 70.5 y Sex (% female): 64% Oral BP: NA IV BP: NA Malignancy: NA MRONJ stage: NA
n¼6 Spiramycin BID‡‡ for 15-d periods every 45 d, for a total of 6 mo
n¼6 Amoxicillin and clavulanate BID for 15-d periods every 45 d, for a total of 6 mo
Considering a combination of pain, bony exposure, neurosensory deficits, and presence of purulence, the spiramycin showed significantly faster healing (P ¼ .015).
Mucoperiosteal Versus Mylohyoid Flap
Mucke and colleagues,21 2016
Prospective cohort
Mean (SD) age: 66.3 (12.6) y Sex (% female): NA Oral BP: NA IV BP: NA Malignancy: 87% MRONJ stage 1: n ¼ 32 MRONJ stage 2: n ¼ 85 MRONJ stage 3: n ¼ 78
n ¼ 169 Surgical debridement followed by closure with local mucoperiosteal flap
n ¼ 26 Surgical debridement followed by closure with mylohyoid flap
The mylohyoid group had significantly fewer recurrences compared with the mucoperiosteal group (P ¼ .023).
Teriparatide Versus Plasma Rich in Growth Factors
Pelaz and colleagues,22 2014
Prospective cohort
Mean (SD) age: 73.1 (9.9) y Sex (% female): 100% Oral BP: n ¼ 9 IV BP: n ¼ 0 Malignancy: 0% MRONJ stage 3: n ¼ 9
n¼5 Sequestration and curettage followed by application of plasma rich in growth factors
n¼4 Teriparatide hormone therapy once daily
No significant differences in rates of partial or complete healing between the 2 groups.
Prospective Van den Wyngaert and cohort 17 colleagues, 2009
n¼8 Mean age: 63 y Sex (% female): 73% Continuation of BP therapy Oral BP: n = 0 IV BP: n ¼ 33 Malignancy: 100% MRONJ stage 1: n ¼ 9 MRONJ stage 2: n ¼ 21 MRONJ stage 3: n ¼ 3
Wutzl and colleagues,16 2012
Prospective cohort
Mean (SD) age: 68.3 (10.7) y Sex (% female): 61% Oral BP: n ¼ 1 IV BP: n ¼ 40 Malignancy: 88% MRONJ stage 1: n ¼ 10 MRONJ stage 2: n ¼ 24 MRONJ stage 3: n ¼ 7
Bodem and colleagues,15 2016
Prospective cohort
Duration of Nonsurgical Therapy
Bodem and colleagues,18 2015
Hyperbaric Oxygen
Freiberger and colleagues,19 2012
Spiramycin Versus Amoxicillin and Clavulanate
Bisphosphonate Drug Holiday
NA
Duration of nonsurgical treatment did not significantly affect the treatment outcome.
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TABLE 2
Risk of bias of the prospective cohort studies and the nonrandomized trial included in the review, evaluated using the Newcastle-Ottawa Scale.*,† STUDY
REPRESENTATIVENESS OF EXPOSED COHORT
SELECTION OF NONEXPOSED COHORT
ASCERTAINMENT OF PROVIDED TREATMENT
ABSENCE OF OUTCOMES OF INTEREST AT START OF STUDY
Elad and Colleagues,10 Unclear: distribution of 2006 stage not reported
Unclear: no mention of what may affect Low decision for surgery
Low
Van den Wyngaertand Unclear: no details Colleagues,17 2009 regarding population of recruitment
Low
Low
Low
Gasparini and Colleagues,20 2010
Unclear: differences between included and excluded patients not reported
Unclear: no baseline comparisons between the 2 groups
Low
Low
Scoletta and Colleagues,13 2010
Unclear: distribution of stage not reported
High: surgical treatment was performed on unresponsive patients
Low
Low
Mucke and Colleagues,12 2011
Unclear: sex and age of patients not reported
High: surgical treatment based on severity of symptoms
Low
Low
Wutzl and Colleagues,16 2012
Low
Low
Low
Low
Lee and Colleagues,14 2014
Unclear: no details regarding population of recruitment
Low
Low
Low
Lesclous and Colleagues,11 2014
Low
High: patients receiving aggressive surgery were more likely to have a more advanced stage of MRONJ‡ than patients in other groups
Low
Low
Pelaz and Colleagues,22 2014
High: only female patients included
High: teriparatide group more likely to have sicker patients than other groups
Low
Low
Bodem and Colleagues,18 2015
Unclear: no details regarding population or recruitment
Unclear: no mention of what may affect Low time to surgery
Low
Bodem and Colleagues,15 2016
Low
Low
Low
Low
Mucke and Colleagues,21 2016
Unclear: sex of patients and Unclear: no mention of what may affect Low antiresorptive medications decision for treatment used not reported
Low
* Source: Wells and colleagues.7 † Each item was evaluated to have a low, unclear, or high risk of bias. ‡ MRONJ: Medication-related osteonecrosis of the jaw.
Despite the fact that we rated the 2 studies whose investigators evaluated debridement versus resection as having an overall medium risk of bias, the investigators of both of these studies made no attempts to control for any potential confounding variables that may have existed between the 2 studies.11,14 Therefore, we believe that researchers should conduct additional studies to make conclusive differentiations between the effects of conservative and aggressive surgical therapy. Because the investigators of all 3 of the studies that evaluated the effects of a bisphosphonate drug holiday had reported evidence of their attempts to control for confounding variables between the evaluated cohorts, we rated these studies as having a medium risk of bias.15-17 Nevertheless, we found that the effects of a bisphosphonate drug holiday remain inconclusive, owing to the mixed results, the methodological heterogeneity of the studies, and the unavailability of the necessary data
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required for quantitative data synthesis. Therefore, we believe that researchers should conduct additional wellcontrolled studies to further evaluate the effectiveness of a bisphosphonate drug holiday. Of the remaining 5 studies,18-22 we found that the 1 study with the lowest risk of bias was the study whose investigators had evaluated the effects of a mylohyoid flap for tension-free closure after surgical debridement.21 Because of this study’s overall medium risk of bias and the investigators’ efforts to control for any potential confounding variables that may have existed between the 2 groups, we suggest that, on the basis of our review of the results of this study and as hypothesized by investigators of other previously published studies,61,62 the toxic effects of bisphosphonates may extend to the surrounding mucosa as well as to the underlying bone, as found in the relative inferiority of an oral mucosal flap in achieving coverage. Nonetheless, we believe that more
ORIGINAL CONTRIBUTIONS
TABLE 2 (CONTINUED)
COMPARABILITY OF THE COHORTS
ADEQUACY OF ASSESSMENT
LENGTH OF FOLLOW-UP
INCOMPLETE OUTCOME DATA
OVERALL RISK OF BIAS
High: no control of potential confounding variables
Low
High: follow-up period was a minimum of 2 mo
High: high dropout rate (32%)
High
Low
Low
High: follow-up period was a minimum of 2 mo
Unclear: no mention of dropouts
Medium
High: no control of potential confounding variables
Unclear: blinding of outcome assessors not reported
Low
Unclear: no mention of dropouts
High
High: no control of potential confounding variables
Unclear: blinding of outcome assessors not reported
Low
Unclear: no mention of dropouts
High
Low
Low
Low
Unclear: no mention of dropouts
Medium
Unclear: confounding factors not reported
Low
Low
Unclear: no mention of dropouts
Medium
High: no control of potential confounding variables
Low
Low
Unclear: no mention of dropouts
Medium
High: no control of potential confounding variables
Low
Low
Unclear: no mention of dropouts
Medium
High: no control of potential confounding variables
Low
Low
Unclear: no mention of dropouts
High
Unclear: confounding variables not reported
Low
Unclear: no follow-up period stated
Unclear: no mention of dropouts
High
Unclear: confounding variables not reported
Low
Low
Unclear: no mention of dropouts
Medium
Low
Low
Low
Unclear: no mention of dropouts
Medium
study results are required to confirm the use of mylohyoid flaps for successful mucosal coverage of MRONJ lesions in the mandible. Considering that we deemed that each of the other 4 studies18-20,22 had a high risk of bias, clinicians should interpret the results of these studies cautiously. Of these studies, only the investigators of the 1 randomized controlled trial that was included in this review19 suggested that the effectiveness of supplemental hyperbaric oxygen therapy was associated with increasing rates of improvement in the treatment group. Although these results appear promising, it is important for researchers to evaluate these results by conducting other wellcontrolled studies. On the basis of the results of this systematic review, we believe it is clear that, although much progress has been made to better understand how to treat this complex condition, much still is required in the way of highquality research. For the purposes of this systematic review, we included only prospective studies, thereby ensuring that the included studies were free of the
limitations that limit retrospective studies, such as temporal biases and issues associated with missing data.63 Nevertheless, we found that the results of the included studies had their own limitations, and we found that none of the included studies had a low risk of bias (although some risks, such as the presence of baseline differences between the cohorts studied, sometimes are unavoidable, owing to the fact that most surgeons will work within the bounds of existing treatment guidelines, such as those proposed by the American Association of Oral and Maxillofacial Surgeons2). Therefore, we believe it is imperative, in addition to the continuation of the study of this condition, that investigators make efforts to maximize the quality of the results of their studies. Considering the state of the evidence related to the treatment of MRONJ and although treatment suggestions may exist, few study results associated with highquality evidence are available to support most proposed treatment practices. Although, on the basis of the results of our review, we were able to report on the possible effectiveness of surgical intervention over nonsurgical
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ORIGINAL CONTRIBUTIONS
Surgical Study or Subgroup
Events
Nonsurgical
Total
Events
Total
Weight
Odds Ratio
Odds Ratio
M-H, Random, 95% CI
M-H, Random, 95% CI
Scoletta and colleagues,13 2010
10
13
10
24
56.9%
Lesclous and colleagues,11 2014
14
31
2
8
43.1%
2.47 (0.43 to 14.21)
32
100.0%
3.55 (1.12 to 11.19)
Total (95% CI)
44
4.67 (1.02 to 21.43)
Total events 2 2 2 Heterogeneity: τ = 0.00; χ1 = 0.29, P = .59; I = 0%
Test for overall effect: z = 2.16 (P = .03)
0.01
0.1 Favors nonsurgical
1
10
100
Favors surgical
Figure 2. Forest plot comparing surgical therapy with nonsurgical therapy on complete resolution of medication-related osteonecrosis of the jaw. CI: Confidence interval. M-H: Mantel-Haenszel.
therapy and suggest the promising effectiveness of local flaps such as mylohyoid flaps for mucosal coverage in mandibular lesions, investigators have yet to study many other proposed therapies, such as low-level laser therapy, ozone, pentoxifylline, or the discontinuation of other drugs such as denosumab, in a prospective manner.1,2 Considering the as-yet relative shortage of results of high-quality studies to which clinicians can refer to evaluate many of the therapies that have been proposed within the body of literature, steps for the future will be for clinical researchers to work closely with clinicians and scientists in wet laboratories to determine effective means for managing MRONJ. CONCLUSIONS
Although clinicians and researchers have made progress toward understanding MRONJ better, it remains a largely understudied condition. Through the results of this systematic review, we identified that surgical interventions for the management of MRONJ may be a more effective method than investigators previously have hypothesized; however, we found that this information was reported by investigators of studies that had a medium-to-high risk of bias and were associated with low statistical power. Researchers should conduct additional high-quality studies before making conclusive suggestions regarding optimal permutations for the treatment of this condition. n SUPPLEMENTAL DATA
Supplemental data related to this article can be found at: http://dx.doi.org/10.1016/j.adaj.2017.04.002. Dr. El-Rabbany is a resident and a doctoral student, Oral and Maxillofacial Surgery, University of Toronto, Toronto, Ontario, Canada. Mr. Sgro is an undergraduate student, University of Toronto, Toronto, Ontario, Canada. Dr. Lam was an assistant professor, the discipline head, and the graduate program director, Oral and Maxillofacial Surgery, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada, when this article was written. He now is a professor and the chair, Department of Oral & Maxillofacial Surgery, Stony Brook School of Dental Medicine, Stony Brook, NY, a professor, Department of Surgery, Stony Brook School of Medicine,
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Stony Brook, NY, and the chief, Oral & Maxillofacial Surgery, Stony Brook University Hospital, Stony Brook, NY. Dr. Shah is a professor, Institute of Health, Policy, Management and Evaluation, and a professor, Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Dr. Azarpazhooh is an associate professor, Dental Public Health and Endodontics, Faculty of Dentistry, University of Toronto, 710F-481 University Ave., Toronto, Ontario, M5G2P1, Canada, e-mail amir. [email protected]. Address correspondence to Dr. Azarpazhooh. Disclosure. None of the authors reported any disclosures. This study was supported by grants from the Canadian Association of Oral and Maxillofacial Surgeons and the Alpha Omega Foundation of Canada. 1. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30(1):3-23. 2. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw: 2014 update. J Oral Maxillofac Surg. 2014;72(10): 1938-1956. 3. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol. 2005;23(34):8580-8587. 4. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22(10):1479-1491. 5. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken, NJ: Wiley; 2008. 6. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. 7. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses; 2000, 2014. The Ottawa Hospital Research Institute. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed April 18, 2017. 8. Thompson SG, Higgins J. How should meta-regression analyses be undertaken and interpreted? Stat Med. 2002;21(11, special issue):1559-1573. 9. Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med. 2002;21(11, special issue):1539-1558. 10. Elad S, Yarom N, Hamed W, Ayalon S, Yahalom R, Regev E. Osteomylelitis and necrosis of the jaw in patients treated with bisphosphonates: a comparative study focused on multiple myeloma. Clin Lab Haematol. 2006;28(6):393-398. 11. Lesclous P, Grabar S, Abi Najm S, et al. Relevance of surgical management of patients affected by bisphosphonate-associated osteonecrosis of the jaws: a prospective clinical and radiological study. Clin Oral Investig. 2014;18(2):391-399. 12. Mucke T, Koschinski J, Deppe H, et al. Outcome of treatment and parameters influencing recurrence in patients with
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observational longitudinal study of an Italian series of cases. Br J Oral Maxillofac Surg. 2012;50(5):425-429. 35. Hallmer F, Bjornland T, Nicklasson A, Becktor JP, Andersson G. Osteonecrosis of the jaw in patients treated with oral and intravenous bisphosphonates: experience in Sweden. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;118(2):202-208. 36. Harper RP, Fung E. Resolution of bisphosphonate-associated osteonecrosis of the mandible: possible application for intermittent low-dose parathyroid hormone [rhPTH(1-34)]. J Oral Maxillofac Surg. 2007;65(3): 573-580. 37. Hinson AM, Siegel ER, Stack BC Jr. Temporal correlation between bisphosphonate termination and symptom resolution in osteonecrosis of the jaw: a pooled case report analysis. J Oral Maxillofac Surg. 2015;73(1):53-62. 38. Ikeda T, Kuraguchi J, Kogashiwa Y, et al. Successful treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) patients with sitafloxacin: new strategies for the treatment of BRONJ. Bone. 2015;73: 217-222. 39. Kim KM, Park W, Oh SY, et al. Distinctive role of 6-month teriparatide treatment on intractable bisphosphonate-related osteonecrosis of the jaw. Osteoporos Int. 2014;25(5):1625-1632. 40. Kim YH, Lee HK, Song SI, Lee JK. Drug holiday as a prognostic factor of medication-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg. 2014;40(5):206-210. 41. Lazarovici TS, Yahalom R, Taicher S, Elad S, Hardan I, Yarom N. Bisphosphonate-related osteonecrosis of the jaws: a single-center study of 101 patients. J Oral Maxillofac Surg. 2009;67(4):850-855. 42. Lemound J, Eckardt A, Kokemüller H, et al. Bisphosphonateassociated osteonecrosis of the mandible: reliable soft tissue reconstruction using a local myofascial flap. Clin Oral Investig. 2012;16(4): 1143-1152. 43. Martins MA, Martins MD, Lascala CA, et al. Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: a preliminary study. Oral Oncol. 2012;48(1):79-84. 44. Mucke T, Jung M, Koerdt S, et al. Free flap reconstruction for patients with bisphosphonate related osteonecrosis of the jaws after mandibulectomy. J Craniomaxillofac Surg. 2016;44(2):142-147. 45. Pautke C, Bauer F, Tischer T, et al. Fluorescence-guided bone resection in bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg. 2009;67(3):471-476. 46. Pautke C, Bauer F, Otto S, et al. Fluorescence-guided bone resection in bisphosphonate-related osteonecrosis of the jaws: first clinical results of a prospective pilot study. J Oral Maxillofac Surg. 2011;69(1):84-91. 47. Ripamonti CI, Cislaghi E, Mariani L, Maniezzo M. Efficacy and safety of medical ozone (O[3]) delivered in oil suspension applications for the treatment of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: preliminary results of a phase I-II study. Oral Oncol. 2011;47(3):185-190. 48. Ripamonti CI, Maniezzo M, Boldini S, Pessi MA, Mariani L, Cislaghi E. Efficacy and tolerability of medical ozone gas insufflations in patients with osteonecrosis of the jaw treated with bisphosphonates, preliminary data: medical ozone gas insufflation in treating ONJ lesions. J Bone Oncol. 2012;1(3):81-87. 49. Schubert M, Klatte I, Linek W, et al. The Saxon Bisphosphonate Register: therapy and prevention of bisphosphonate-related osteonecrosis of the jaws. Oral Oncol. 2012;48(4):349-354. 50. Scoletta M, Arduino PG, Reggio L, Dalmasso P, Mozzati M. Effect of low-level laser irradiation on bisphosphonate-induced osteonecrosis of the jaws: preliminary results of a prospective study. Photomed Laser Surg. 2010; 28(2):179-184. 51. Shintani T, Hayashido Y, Mukasa H, et al. Comparison of the prognosis of bisphosphonate-related osteonecrosis of the jaw caused by oral and intravenous bisphosphonates. Int J Oral Maxillofac Surg. 2015; 44(7):840-844. 52. Stockmann P, Vairaktaris E, Wehrhan F, et al. Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support Care Cancer. 2010;18(4):449-460. 53. Thumbigere-Math V, Sabino MC, Gopalakrishnan R, et al. Bisphosphonate-related osteonecrosis of the jaw: clinical features, risk factors, management, and treatment outcomes of 26 patients. J Oral Maxillofac Surg. 2009;67(9):1904-1913.
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of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111(2): 153-163. 59. Williamson RA. Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg. 2010;39(3): 251-255. 60. Wutzl A, Biedermann E, Wanschitz F, et al. Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head Neck. 2008;30(9): 1224-1230. 61. Landesberg R, Cozin M, Cremers S, et al. Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg. 2008;66(5): 839-847. 62. Reid IR, Bolland MJ, Grey AB. Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone. 2007;41(3):318-320. 63. Hess DR. Retrospective studies and chart reviews. Respir Care. 2004; 49(10):1171-1174.
ORIGINAL CONTRIBUTIONS
eTABLE 1
Sample detailed search strategy used for MEDLINE. 1.
exp “Bisphosphonate-Associated Osteonecrosis of the Jaw”/
2.
(BRONJ or MRONJ or ARONJ or BION or BONJ or BIONJ).ti,ab.
3.
((bisphosphonate or medication or denosumab or antiangiogenic? or angiogenic? or antiresorptive? or resorptive?) adj5 osteonecrosis).mp.
4.
or/1-3
5.
exp Jaw/or exp Jaw Diseases/
6.
(jaw$ or mand$ or maxilla$ or alveolar).mp.
7.
or/5-6
8.
exp Therapeutics/
9.
treat$.mp.
10. exp Hyperbaric Oxygenation/or hyperbaric oxygen.mp. 11. free flap.mp. or exp Free Tissue Flaps/ 12. resect$.mp. 13. exp Debridement/or debride*.mp. 14. exp Curettage/or curett*.mp. 15. sequestrectomy.mp. 16. saucerization.mp. 17.
or/8-16
18. 4 and 7 and 17
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ORIGINAL CONTRIBUTIONS
eTABLE 2
List of excluded studies, with reasons for exclusion. STUDY Harper and Fung,36 2007
REASON FOR EXCLUSION Case study
Vescovi and Colleagues,54 2007
Case series, with only descriptive statistics
Boonyapakorn and Colleagues,29 2008
No treatment data
Wutzl and Colleagues,60 2008
Case series, with only descriptive statistics
Carlson and Basile,30 2009
Case series, with only descriptive statistics
Cetiner and Colleagues,32 2009
Case series, with only descriptive statistics
Lazarovici and Colleagues,41 2009
Retrospective study
Pautke and Colleagues,45 2009
Case series, with only descriptive statistics
Thumbigere-Math and Colleagues,53 2009 Case series, with only descriptive statistics Scoletta and Colleagues,50 2010
Case series, with only descriptive statistics
Stockmann and Colleagues,52 2010
Case series, with only descriptive statistics
Vescovi and Colleagues,55 2010
Retrospective study
Williamson,59 2010
Case series, with only descriptive statistics
Bedogni and Colleagues,27 2011
Case series, with only descriptive statistics
Eckardt and Colleagues,33 2011
Retrospective study
Pautke and Colleagues,46 2011
Case series, with only descriptive statistics
Ripamonti and Colleagues,47 2011
Case series, with only descriptive statistics
Wilde and Colleagues,58 2011
Case series, with only descriptive statistics
Agrillo and Colleagues,23 2012
Retrospective study
Bocanegra-Perez and Colleagues,28 2012
Case series, with only descriptive statistics
Ferlito and Colleagues,34 2012
Case series, with only descriptive statistics
Lemound and Colleagues,42 2012
Case series, with only descriptive statistics
Martins and Colleagues,43 2012
Retrospective study
Ripamonti and Colleagues,48 2012
Case series, with only descriptive statistics
Schubert and Colleagues,49 2012
Case series, with only descriptive statistics
Vescovi and Colleagues,56 2012
Retrospective study
Bast and Colleagues,26 2013
Case series, with only descriptive statistics
Alsehimy,25 2014
Case series, with only descriptive statistics
Carlson,31 2014
Literature review
Hallmer and Colleagues,35 2014
Retrospective study
Kim, Lee, and Colleagues,40 2014
Retrospective study
Kim, Park, and Colleagues,39 2014
Retrospective study
Vescovi and Colleagues,57 2014
Retrospective study
Al Hadi and Colleagues,24 2015
Study that did not involve human participants
Hinson and Colleagues,37 2015
Retrospective study
Ikeda and Colleagues,38 2015
Case series, with only descriptive statistics
Shintani and Colleagues,51 2015
Case series, with only descriptive statistics
Mucke and Colleagues,44 2016
Case series, with only descriptive statistics
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