Comparing the Surgical Response of Bisphosphonate-Related Versus Denosumab-Related Osteonecrosis of the Jaws
Benjamin Palla, DMD,* Egon Burian, MD, DMD,y Andrew Deek, DDS,z Christopher Scott, DMD,x John Anderson, MD, DDS,k
Nicholas Callahan, MD, DMD, MPH,{ and Eric R. Carlson, DMD, MD, EdM#
Purpose: The pathophysiology and treatment of medication-related osteonecrosis of the jaws (MRONJ) remain unclear after nearly two decades of recorded observation and discussion. The purpose of this study was to assess outcomes of surgical resection of MRONJ in patients exposed to denosumab.
Materials and Methods: A literature review was performed in conjunction with experts at the Univer- sity of Illinois at Chicago Library. The primary outcome of interest was surgical success defined by main- tenance of complete mucosal closure without bone exposure and infection after surgical resection. Secondary interests included demographics, MRONJ stage, location of the focus of osteonecrosis, and the primary underlying disease necessitating antiresorptive treatment. Statistical analysis was performed by c2, analysis of variance, or t test (P < .05 and b = 0.2 or a power of 0.8).
Results: A total of 70 articles were identified and 14 met inclusion criteria. Twenty patients were included (13 women; 7 men); age 61.8 years 12.9 (range 19 to 77); and MRONJ stage I (40.0%), II (35.0%), and III (25.0%). Most cases occurred in the mandible (65.0%), followed by the maxilla (30.0%). The success rate of surgical intervention for MRONJ secondary to denosumab was in 16 of 20 (80.0%) pa- tients. Stage I MRONJ lesions achieved mucosal closure in 100% of patients, stage II in 71.4%, and stage III in 60.0%. The surgical success rate was 83.3% in the maxilla and 76.9% in the mandible.
Conclusions: The surgical success rate for MRONJ secondary to denosumab was 80.0%, similar to that reported in bisphosphonates of 85 to 95%; however, more evidence must be reported and analyzed.
© 2020 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 79:1045-1052, 2021
*Resident, Department of Oral and Maxillofacial Surgery, University of Illinois at Chicago, Chicago, IL.
yResident, Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany.
zResident, Department of Oral and Maxillofacial Surgery, University of Tennessee Knoxville, Knoxville, TN.
xResident, Department of Oral and Maxillofacial Surgery, University of Tennessee Knoxville, Knoxville, TN.
kResident, Department of Oral and Maxillofacial Surgery, University of Illinois at Chicago, Chicago, IL.
{Assitant Professor, Department of Oral and Maxillofacial Surgery, University of Illinois at Chicago, Chicago, IL.
#Professor and Kelly L. Krahwinkel Endowed Chairman, Department of Oral and Maxillofacial Surgery, University of Tennessee Knoxville, Knoxville, TN.
Conflict of Interest Disclosures: Dr. Carlson receives royalties from Wiley Blackwell and Elsevier. None of the other authors have any relevant financial relationship(s) with a commercial interest.
Address correspondence and reprint requests to Dr Palla: Depart- ment of Oral and Maxillofacial Surgery, University of Illinois at Chi- cago, College of Dentistry, 801 S. Paulina St., Room 110, Chicago, IL 60612-7211; e-mail: [email protected]
Received October 12 2020
Accepted November 18 2020
© 2020 American Association of Oral and Maxillofacial Surgeons 0278-2391/20/31407-5
https://doi.org/10.1016/j.joms.2020.11.017
1045
Medication-related osteonecrosis of the jaws (MRONJ) is a fascinating disease that was initially described in 2003 by 2 clinician researchers.1,2 The disease was pri- marily noted in patients exposed to 2 intravenous bi- sphosphonates, zoledronate and pamidronate, antiresorptive medications used at that time in the management of metastatic breast cancer and multiple myeloma. Marx1 reviewed 36 cases of painful bone exposure in a letter to the editor published in the Jour- nal of Oral and Maxillofacial Surgery in September 2003. In this letter, Marx1 reported that debridement of the focus of osteonecrosis could not be effectively undertaken and might be responsible for further expo- sure of bone.
In 2004, Ruggiero et al3 retrospectively reviewed os- teonecrosis of the jaws in 63 patients exposed to bi- sphosphonate medications. Like Marx’s1 recommendation to avoid surgical removal of the focus of osteonecrosis, Ruggiero et al3 indicated that the sur- gical management of their 63 patients was extremely challenging. They reported the lack of success of surgi- cal debridement in eradicating the disease, with the observation of difficulty in realizing a surgical margin with viable bleeding bone as part of a debridement pro- cedure. The authors therefore recommended surgical treatment only for symptomatic patients.
The American Association of Oral and Maxillofacial Surgeons (AAOMS) published its first position paper on this form of osteonecrosis of the jaws in 2007 and applied the nomenclature bisphosphonate-related os- teonecrosis of the jaws.4 A case definition, as well as staging, for bisphosphonate-related osteonecrosis of the jaws was offered. In 2009, the AAOMS issued their update and reiterated staging criteria and nonsurgical recommendations for stage 1 and 2 disease with debridement/resection for stage 3 disease for long- term palliation of infection and pain.5 Superficial debridement was thought to represent palliative treat- ment for stage 2 disease to relieve soft tissue irritation. In 2014, the AAOMS issued their update of this diag- nosis and offered new nomenclature, MRONJ, owing to the increasing number of cases of osteonecrosis of the jaws associated with medications other than bi- sphosphonate medications, including other antire- sorptive drugs such as denosumab (receptor activator of nuclear factor kB ligand inhibitor), and antiangiogenic drugs such as sunitinib, sorafenib, bev- acizumab, and sirolimus.6 Despite the change in nomenclature of this disease in recognition of diverse pharmacologic associations, the position paper re- mained firm on treatment strategies, only recommend- ing debridement/resection for stage 3 disease and only for long-term palliation of infection and pain without mention of or the ability to cure the disease.
Based on the recommendations of Marx1and Rosen- berg and Ruggiero,2 nonsurgical management of
MRONJ became commonplace in oral and maxillofacial surgery practices. These recommendations continue to be promulgated in the literature. Many authors continue to define success as maintaining or improving MRONJ stage and not as achieving and maintaining full mucosal closure over the bone. In fact, we now know that nonsurgical treatment will achieve mucosal closure in fewer than 20% of cases.7-11 Surgical intervention on the other hand has the ability of achieve mucosal closure with high rates of success.12-15 A growing amount of literature continues to show that surgical intervention, in the appropriate patient, can achieve and maintain full mucosal closure. Howev- er, these recent conclusions have been exclusive to pa- tients only taking bisphosphonates.16 In fact, in most large institutional reviews, a previous history of deno- sumab administration is often listed as an exclusion cri- terion. No prior publications have performed a literature review to determine the surgical success
rate with MRONJ secondary to denosumab.
The purpose of this present study is to answer the following research question: Among patients with MRONJ exposed to denosumab, what is the response to surgical intervention and what factors are associ- ated with mucosal closure? This literature review iden- tified cases of MRONJ secondary to denosumab to determine the surgical success rate of maintenance of mucosal closure without exposed bone and infec- tion after surgical resection of the jaws.
Materials and Methods
STUDY DESIGN
To address the research question, the investigators de- signed a scoping review to identify all patients who un- derwent surgical intervention for MRONJ secondary to denosumab. Institutional review board exemption was granted for this project by the University of Illinois at Chicago Office for the Protection of Research Subjects (Protocol #2020-0406) and the University of Tennessee Health Science Center (institutional review board #4634). The literature review was guided by experts at the University of Illinois at Chicago Library. A scoping review was performed in conjunction with available guidelines.17 An initial limited search was conducted to analyze text words in titles and abstracts of relevant articles. Terms were indexed, and controlled vocabulary terms (medical subject headings) were used when avail- able and appropriate.
STUDY SAMPLE
Literature searches were conducted through PubMed on 9 September 2020. The search used key words for osteonecrosis, denosumab, and surgical resection. Searches were linked by OR operators and
intersections of concepts linked consecutively with AND statements. Appendix 1 contains the search algo- rithm used. A hand search of bibliographies was per- formed to identify any additional studies.
Records were excluded if one of the following criteria pertained: 1) article language not English or German; 2) study of nonhuman/nonanimal individ- uals; 3) patients without diagnosis of MRONJ; 4) article without patient cases; 5) Patients did not have surgical intervention; 6) surgical MRONJ cases without denosumab; 7) Individual demographics un- obtainable; and 8) concomitant use of bisphospho- nates at the time of surgery.
Inclusion criteria were the following: 1) diagnosis of MRONJ; 2) patients with documented history or cur- rent use of denosumab; 3) surgical treatment was per- formed (defined by utilization of flap for bony exposure followed by a) debridement b) marginal resection, or c) segmental resections); and 4) patient description included at least age, sex, and surgical outcome. No publication date limitations were applied to identify all relevant cases.
STUDY VARIABLES
All included studies were read in full. The primary outcome of interest was surgical success or failure, with success being defined as achievement and main- tenance of full mucosal closure over the resected bone. Other variables of interest included demographics (age, sex), MRONJ stage (stage 0, I, II,
III) as defined by the AAOMS,6 the location of the MRONJ lesion (mandible, maxilla, or both), and the primary disease for which denosumab was prescribed.
DATA COLLECTION, MANAGEMENT, AND ANALYSIS
Abstracts of all articles were analyzed with inclusion and exclusion criteria. Data extraction was performed by at least 2 authors and compared for agreement. Any discrepancies were discussed with the senior authors (N.C & E.C). MRONJ staging of each patient was pro- vided in the articles or determined by clinical photos, radiographs, and clinical description in alignment with the 2014 AAOMS Position Paper.6 Surgical success was defined as achievement and maintenance of full mucosal closure after surgical resection of bone. Descriptive statistics (mean, frequency, range) were computed for each study variable. Statistical analysis to measure the association between variables of inter-
est was performed by c2, analysis of variance, or t test
(P < .05 and b = 0.2 or a power of 0.8).
Results
Our literature review of the literature identified 66 articles (Table 1). In addition, we located 4 articles through hand search. Of these 70 articles, 14 articles met inclusion criteria, and data extraction was per- formed. From these 14 articles, 20 patients were iden- tified and included in the study (Table 2).18-31
Identification Records identified through
database searching Additional records identified
through other sources
66 4
Records after duplicates
removed
70
Screening Records screened Records excluded
70 56 Total
6 Language
8 Animal models
6 Not MRONJ
11 No patient Cases
14 Nonsurgical treatment
6 Not denosumab
5 Individual data unavailable
Eligibility Full-text article assessed for
eligibility Full-text article excluded
14 0
Included Studies included
14
Abbreviation: MRONJ, medication-related osteonecrosis of the jaw.
Palla et al. Denosumab Versus Bisphosphonate. J Oral Maxillofac Surg 2021.
Of the included 20 patients, 7 were men and 13 were women (Table 3). Average age was 61.8 years (SD 12.9; range 19 to 77). MRONJ stage included stage I (40.0%), stage II (35.0%), and stage III (25.0%). Most cases occurred in the mandible (65.0%), followed by the maxilla (30.0%), and 1 case had MRONJ present in both the maxilla and mandible (5.0%). Patients were most often prescribed denosu- mab for osteoporosis (45.0%) and metastatic bone dis- ease (50.0%) (prostate cancer [25.0%], breast cancer [20.0%], lung cancer [5.0%]), with 1 case of giant- cell tumor of bone (5.0%).
The analysis of the surgical success and surgical fail- ures was compared (Table 4). No statistically signifi- cant differences were noted between these groups. The success rate of surgical intervention for MRONJ secondary to denosumab was in 16 of 20 (80.0%) pa- tients. The surgical success rate for MRONJ stage I was in 8 of 8 patients (100%), stage II was in 5 of 7 pa- tients (71.4%), and stage III was in 3 of 5 patients (60.0%). The surgical success rate in the maxilla was in 5 of 6 patients (83.3%) and in the mandible was in 10 of 13 patients (76.9%).
The rate of success from surgical intervention for osteoporosis was in 9 of 9 patients (100.0%), for pros- tate cancer was in 3 of 4 patients (75.0%), and for breast cancer was in 3 of 4 patients (75.0%). Four pa- tients had a previous history of bisphosphonate use before denosumab; of which, all 4 had successful
surgical outcomes. Sixteen patients endorsed expo- sure only to denosumab; of which, the surgical rate of success was in 12 of 16 patients (75%).
Discussion
The purpose of this study was to determine the suc- cess rate of surgical intervention for MRONJ secondary to denosumab. The authors performed a literature re- view to identify subjects who underwent surgical resec- tion of MRONJ secondary to denosumab.
The surgical success rate of MRONJ secondary to de- nosumab in this review was in 16 of 20 patients (80.0%). Our review identified the current evidence base of surgical success of MRONJ secondary to deno- sumab consist only of 14 case reports and case series. In comparison, the evidence for surgical intervention related to bisphosphonates is provided by multiple, large prospective and retrospective cohort studies. The following studies have focused on surgical inter- vention of MRONJ secondary to bisphosphonates: Pautke et al12reported 85% success rate in 20 patients, Stockmann et al14 reported 89% success rate in 39 pa- tients, Carlson and Baslie15 previously reported a 91.6% success rate in 95 sites, Vosset al13 reported 95.2% success rate in 21 patients, providing a range of 85 to 95.2% success. Although bisphosphonate and denosumab response to surgical intervention ap- pears to be commensurate between bisphosphonates
Article Patient Age Sex MRONJ Stage Location Primary Disease BP History Surgical Outcome
Bagan 1 59 F II Maxilla Osteoporosis N Success
Diniz-Frietas 2 77 F I Mandible Osteoporosis Y Success
Diz 3 73 M I Mandible Prostate Cancer N Success
Maluf 4 69 M II Mandible Lung Cancer N Failure
Maluf 5 44 F II Mandible Breast Cancer N Failure
Matsumoto 6 71 F III Maxilla Breast Cancer N Success
Moysich 7 65 F I Mandible Breast Cancer N Success
Nørholt 8 66 F III Both Breast Cancer N Success
Nørholt 9 59 F II Maxilla Osteoporosis N Success
Nørholt 10 75 F II Mandible Osteoporosis N Success
Nørholt 11 69 M II Mandible Prostate Cancer N Success
Otto 12 58 F I Mandible Osteoporosis Y Success
Otto 13 68 F I Mandible Osteoporosis N Success
O’Halloran 14 60 M III Mandible Prostate Cancer N Success
O’Halloran 15 72 M III Maxilla Prostate Cancer N Failure
Pichardo 16 74 M III Mandible Prostate Cancer N Failure
Rachner 17 75 F I Mandible Osteoporosis Y Success
Saad 18 64 F I Maxilla Osteoporosis Y Success
Sahin 19 63 F I Maxilla Osteoporosis N Success
Uday 20 19 M II Mandible Giant Cell N Success
Abbreviations: BP, bisphosphonates; MRONJ, medication-related osteonecrosis of the jaw; N, no; Y, yes.
Palla et al. Denosumab Versus Bisphosphonate. J Oral Maxillofac Surg 2021.
Study Population
Age (yr) Mean 61.8 (SD 12.9; range 19 to 77)
Gender 7 men; 13 women
MRONJ stage
Stage I 8 (40.0%)
Stage II 7 (35.0%)
Stage III 5 (25.0%)
Location
Mandible 13 (65.0%)
Maxilla 6 (30.0%)
Both 1 (5.0%)
Primary disease
Osteoporosis 9 (45.0%)
Prostate cancer 5 (25.0%)
Lung cancer 1 (5.0%)
Giant cell 1 (5.0%)
BP history
Yes 4 (20.0%)
Surgical outcome
Failure 4 (20.0%)
Abbreviations: BP, bisphosphonate; MRONJ, medication- related osteonecrosis of the jaw; SD, standard deviation.
Palla et al. Denosumab Versus Bisphosphonate. J Oral Maxillofac Surg 2021.
and denosumab, the evidence base for denosumab is weak. We can only speculate on the similarity of the surgical response, especially with such varied mecha- nisms of action and half-life.
This initial study did display a predilection of MRONJ occurrence in women, consistent with previ- ous research with both bisphosphonates and denosu- mab.6,32,33 In addition, most MRONJ lesions in this study occurred in the mandible.6,32,33 In this review, we also noted higher rates of surgical success in the earlier stages of MRONJ (stage I 100%; stage II 71.4%; stage III 60.0%). This was shown by Graziani et al34in patients taking bisphosphonates.
The authors are aware of only 1 prior institutional review of MRONJ cases secondary to denosumab.32 This study reviewed patients from 2 German institu- tions and found that for those patients treated with sur- gical intervention, 71.7% achieved mucosal closure.
As surgical resection establishes an increasing role in the treatment of MRONJ, we sought to understand if dif- ferences might be expected between denosumab and bi- sphosphonates. These drugs have similar abilities to affect bone density and disease progression but function through separate mechanisms. Bisphosphonates are small chemical compounds with a half-life measured in
years. Denosumab is an enormous antibody by compar- ison, with a half-life of 25 to 29 days.35
The bisphosphonate family is composed of a variety of small chemical compounds, with a common phosphate-carbon-phosphate molecular core. These chemicals covalently bind to the hydroxyapatite ma- trix of bone and may remain present and active for de- cades.28 In the acidic environment created by resorbing osteoclasts, the bisphosphonates are released from bone, cross the osteoclast membrane, and inhibit their function.
Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kB ligand.20 It functions in the same manner as innate osteoprote- gerin. It inhibits osteoclast precursors from fusing and maturing into osteoclasts, and it prevents mature osteoclasts from normal activation and function. In addition, denosumab affects immunologic func- tioning, by preventing the chemotaxis of monocytes and macrophages. Denosumab was approved by the Food and Drug Administration in 2010, with the first cases of MRONJ due to denosumab reported the same year.36,37
Zebaze et al38reported denosumab reduced bone re- modeling more rapidly and more completely when compared with bisphosphonates. Cases of MRONJ have reflected this, some being reported after a single dose of denosumab.27 A recent case series also showed patients with osteoporosis developed MRONJ after an average of 3 doses of denosumab.18 Even a meta- analysis of 7 randomized control trials found denosu- mab had an increased risk of MRONJ when compared with bisphosphonates, but the results were not statis- tically significant.39
Similarly, a recent prospective study calculated the rate of MRONJ in a population of 1.3 million.40 Rates of MRONJ were 0.043% with oral bisphosphonates, 1.03% with IV bisphosphonates, and 3.64% with deno- sumab. Similarly, the mean duration of treatment was
70.5 months in oral bisphosphonates, 30 months in intravenous bisphosphonates, and only 15 months with denosumab.40
It remains to be determined if the potency of deno- sumab may be correlated with a lower success rate from surgical therapy. Even if the clinical characteris- tics of osteonecrosis is similar, the response to surgical intervention may be distinct.
This review contains limitations that must be taken into consideration. First, we performed a scoping re- view that has coalesced articles with low levels of ev- idence (case reports, case series). These are often researcher initiated and biased. Still this is the first collection of such cases from the literature. Of the 20 cases we identified, basic analysis also shows our population has similar characteristics to larger studies (predilection for the female gender, mandibular
Successful Failure P Value
Sample size 16 4
Age (yr) 61.5 (SD 13.0) 63.4 (SD 12.1)
Range 19 to 77 Range 44 to 74 .4514
Gender 12 women; 4 men 1 women; 3 men .0607 MRONJ stage
Stage I 8 0
Stage II 5 2
Stage III 3 2 .1677
Location
Mandible 10 3
Maxilla 5 1
Both 1 0 .8317
Primary disease
Osteoporosis 9 0
Prostate cancer 3 1
Breast cancer 3 1
Lung cancer 1 0
Giant cell 0 1 .1024 BP history
Yes 4 0
No 12 4 .2635
Abbreviations: BP, bisphosphonate; MRONJ, medication-related osteonecrosis of the jaw; SD, standard deviation.
Palla et al. Denosumab Versus Bisphosphonate. J Oral Maxillofac Surg 2021.
location, and increased success from treatment in earlier stages of disease).
Working in conjunction with the Data Management Coordinator at University of Illinois at Chicago, we per- formed a scoping review of this topic. A variety of evidence-based review types now exist, each with unique strengths and weaknesses and indications.41,42 A scoping review is appropriate to perform for a prelim- inary assessment of a topic, to display the volume of ev- idence or lack thereof, and to help guide future studies. This study displays a stark evidence gap, and future studies are imperative for accurate conclusions related to denosumab. Systematic reviews, which can often follow scoping reviews, are performed to assess the liter- ature in the form of a specific question, the strict meth- odology allowing authors to minimize bias through quality assessment, and make evidence-based treatment recommendations. A systematic review may be appro- priate in the future as more studies are published.
The study is limited by the current literature and the incidence of this disease. MRONJ is rare, and the occurrence secondary to denosumab is even less. Aljo- hani et al43gathered 643 cases of MRONJ in patients with osteoporosis, only 2.1% were secondary to deno- sumab. Furthermore, surgical intervention is still often avoided by many providers, and these interventions are reported even less. In cases that do undertake sur- gical intervention, often debate occurs as to what
procedures this constitutes. Sequestrectomy is vastly different from en bloc resection. Graziani et al34showed a significant increase in success rate when surgical resection was performed, as compared with local debridement.
Various authors may also define surgical success differently. Early reviews regarding the treatment of MRONJ often stated that nonsurgical management (ie systemic antibiotics and topical mouthrinse) led to treatment success in 85 to 95% of patients as well. However, if surgical success is defined as maintenance of mucosal closure without bone exposure and infec- tion, the review of these studies show that nonsurgical intervention may have only achieved mucosal closure in 0 to 20% of patients.
In conclusion, the surgical success rate of MRONJ sec- ondary to denosumab in this review was in 16 of 20 pa- tients (80.0%). This success rate is similar to that reported with bisphosphonates at 80 to 90%. The path- ophysiology of MRONJ remains unclear, and owing to the different mechanisms of bisphosphonates and deno- sumab, it remains unknown how they may differ.
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Appendix 1. SEARCH TERMS
Osteonecrosis
Medication-related osteonecrosis of the jaw
Denosumab
Prolia
Surgical Resection
Marginal resection
Ostectomy
Search Algorithm
Palla et al. Denosumab Versus Bisphosphonate. J Oral Maxillofac Surg 2021.B02