Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but severely debilitating drug-induced bone disorder in the jawbone region. The first MRONJ was reported in 2003 after bisphosphonates (BPs) exposure. Recently, other drugs such as receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor denosumab and antiangiogenic agents were also associated with MRONJ. The purpose of this study was to evaluate the incidence and risk factors for MRONJ related to BPs and/or denosumab in cancer patients in real-world clinical settings using data from the OneFlorida Clinical Research Consortium. We queried the electronic health records of participants with prescriptions of intravenous (IV) BPs or denosumab between January 1, 2012 and September 1, 2021 in the OneFlorida Consortium. Time to MRONJ diagnosis was evaluated using Kaplan Meier method and Cox regression analysis was performed to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for MRONJ. A total of 5,689 participants had one or more prescriptions of IV BP or denosumab within this study period and were included in this study. Among these participants, 52 (0.9%) had a diagnosis of MRONJ. The overall rate of MRONJ was 0.73%, 0.86%, and 3.50% in the cancer patients treated with IV BPs, denosumab, and sequential IV BPs and denosumab, respectively. The risk of MRONJ was similar in participants treated with denosumab alone compared to those treated with IV BPs alone (HR: 1.25, 95% CI: 0.66-2.34, p = 0.49). The patients with sequential prescription of IV BP and denosumab were at much higher risk for MRONJ, with adjusted HR of 4.49, 95% CI of 1.96-10.28, p = 0.0004. In conclusion, in real-world clinical settings, the rates of MRONJ associated with IV BPs and denosumab were similar, while the sequential treatment of these two drug classes was associated with a much higher risk of MRONJ.
Keywords: Medication-related osteonecrosis of the jaw, bisphosphonates, denosumab, OneFlorida Research Consortium, drug-induced adverse event
Introduction
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but severely debilitating drug-related bone disorder. According to the American Association of Oral Maxillofacial Surgeons (AAOMS), MRONJ is defined as persistent exposure of maxillofacial bones without resolution for more than 8 weeks. It’s manifested as mucosal swelling, loose teeth, altered sensations, pathologic fractures, and even oral-antral/oral-nasal communication in late stages(1). As a severe adverse reaction, MRONJ was first reported to be associated with intravenous (IV) bisphosphonates (BPs) in 2003 (2). Recently, other antiresorptive medications, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor denosumab, antiangiogenic medications (such as bevacizumab, sorafenib, pazopanib, and axitinib), (2,3), medications targeting mammalian target of rapamycin (mTOR) (such as everolimus), and tumor necrosis factor-alpha (TNF-alpha) inhibitor adalimumab were also reported to be associated with MRONJ (2,4). Based on these, AAOMS updated the term “Bisphosphonate-related osteonecrosis of the jaw (BRONJ)” to “Medication-related osteonecrosis of the jaw (MRONJ)” in 2014 (3,5).
While the risk of MRONJ is estimated to be 0.001%-0.4% (1.04 to 69 per 100,000 patient-years) among patients treated for osteoporosis using antiresorptive therapy(6,7), this risk among cancer patients exposed to IV BPs is at least 10 times higher, ranging from 0.4% to 6.9% (69 to 12,222 per 100,000 patient-years) (7–11).
Recent reports indicate that RANKL inhibitor denosumab is associated with higher risk for MRONJ than IV BPs in cancer patients, ranging from 1.9 to 10% (10,12,13). A long-term extension of two phase 3 international clinical trials and a couple of retrospective cohort studies from Europe and Japan showed that patients sequentially treated with IV BPs and denosumab had even higher risks of MRONJ (5.5%-15.5%) (10,13–15). However, whether this is true in cancer patients treated in real-world clinical settings in the United States is not clear. To this end, this retrospective cohort study was designed and conducted to evaluate the incidence and risk factors of MRONJ related to IV BPs and/or denosumab in cancer patients in real-world clinical settings using the data from the OneFlorida Clinical Research Consortium.
Methods
OneFlorida Clinical Research Consortium
The OneFlorida Clinical Research Consortium is a cooperative research team that provides health care for half of Floridians through 11 unique health systems, 4,100 physicians, 1240 clinic/practice settings and 22 hospitals among all 67 Florida counties(16). The OneFlorida Data Trust is the informatics infrastructure that supports health researches in OneFlorida, which currently includes information on collated electronic health records (EHR), administrative claims, and other individual-level health-related data on a broad-based, unselected population of 15 million people in Florida. The OneFlorida Data are limited to the Health Insurance Portability and Accountability Act (HIPAA), which restrict to dates and locations to protect the health information of patients.
Source population and study population
The inclusion criteria for this study were adult cancer patients with prescriptions of one or more MRONJ-related drugs including IV BPs (zoledronate or pamidronate) or RANKL inhibitor (denosumab, Xgeva®) since the beginning of OneFlorida data collection (January 1, 2012) until the last data refresh before the date of query (September 1, 2021). Patients treated with denosumab under the brand name of Prolia® were not included due to its osteoporosis indication. Details of the data included encrypted patient IDs, demographic information of patients, diagnosis information, and prescription and events data. This study was approved by the University of Florida Institutional Review Board (IRB) (IRB#202102843).
Categorization of MRONJ Cases
MRONJ cases were identified with an algorithm based upon the International Classification of Diseases, 9th version (ICD-9) diagnosis code 733.45 (Aseptic necrosis of bone, jaw) and 10th version (ICD-10) diagnosis code M87.180 (Osteonecrosis due to drugs, jaw). Both ICD codes have been used in previous ONJ studies to evaluate potential ONJ cases (17–26). Dental surgery information were identified with Current Procedure Terminology (CPT) code of 41899 or Current Dental Terminology (CDT) procedure codes of D7111, D7140, D7210, D7220, D7230, D7240, D7241, D7250, D7251. Since the medications of interest were used mainly in patients with cancer, we have categorized each patient into different cancer conditions. The cancer diagnoses were based on Global Burden of Disease Study 2016 (GBD 2016) ICD cancer diagnosis codes(27).
Statistical Analyses
Categorical variables were summarized with frequencies and percentages, while continuous variables were summarized with means and standard deviations. The incidence of MRONJ was summarized for each drug and drug class in all cancer participants. The baseline characteristics of patients treated with IV BPs alone, denosumab alone, sequential treatment of IV BP and denosumab were compared using ANOVA for continuous variables and chi-square test for categorical variables. The time-to-MRONJ was calculated as the interval from the time of prescription of IV BPs or denosumab to the occurrence of MRONJ. In the participants treated with sequential IV BPs and denosumab, the time of the first antiresorptive was used to calculate the time-to-MRONJ. The participants who did not have a diagnosis of ONJ were censored at the end of study period (September 1, 2021). Kaplan-Meier method was used to compare time-to-MRONJ across different drug classes. Log-rank test was used to compare time-to-MRONJ among the three drug classes: IV BPs alone, denosumab alone, IV BP / denosumab. Cox proportional hazard model was used to estimate the hazard ratios (HRs) and 95% confidence interval (CI) for MRONJ among different drugs (IV BPs, denosumab, sequential use of IV BPs and denosumab). Step-wise regression was used to determine the covariates for the adjusted Cox regression analysis. Covariates considered in the adjusted model included age, sex and race/ethnicity, and comorbidities. Since other drug classes such as antiangiogenic agents (bevacizumab, sunitinib, sorafenib, pazopanib, axitinib, cabozantinib), m-TOR inhibitor (everolimus, temsirolimus), and TNF-alpha inhibitor (adalimumab) were also associated with MRONJ (2–4,28), prior exposure to any of these drug classes were also evaluated as covariates in the multivariable analyses. P < 0.05 was considered statistically significant. All statistical analysis was performed in SAS v9.4 (Cary, NC) or R version 4.1.1.
Results
Included in this analysis were the 5,689 OneFlorida participants with at least one prescription of IV BPs or denosumab and had diagnosis codes available. Among these participants, 2,752 participants were treated with IV BPs including 2,004 with zoledronate and 630 with pamidronate, 2,680 patients were on denosumab, and 257 patients had sequential treatment of IV BPs and denosumab. The demographic information of all 5,689 participants were summarized in Table 1. The overall mean age of participants was 65 years and 71.1% of participants were females. In terms of race/ethnicity, 71.6% were non-Hispanic whites, 17.2% were non-Hispanic blacks, and 5.3% were Hispanics. Almost half of these participants had hyperlipidemia and about a quarter of these were obese, and 28% had diabetes. The top three cancer types were breast cancer (25%), lung cancer (13%) and multiple myeloma (11%). There were statistically significant differences in age, sex, race/ethnicity, cancer type, and comorbidities evaluated among patients treated with IV BPs alone, denosumab alone, and those with sequential IV BPs and denosumab (Table 1).
Table 1.
Patient Characteristics
| Characteristics | Total (n=5,689) | IV Bisphosphonates (n = 2,752) | Denosumab (n=2,680) | IV BP/Denosumab (n=257) | P value |
|---|---|---|---|---|---|
| Age (Years) (Mean ± SD) | 65.1 ± 18.0 | 61.9 ± 16.8 | 68.4 ± 18.4 | 64.2 ± 19.3 | <0.0001 |
| Female sex, n (%) | 4045 (71.1%) | 1651 (60.0%) | 2207 (82.3%) | 187 (72.8%) | <0.0001 |
| Race | <0.0001 | ||||
| White/Non-Hispanic | 4075 (71.6%) | 1817 (66.0%) | 2069 (77.2%) | 189 (73.5%) | |
| Black/Non-Hispanic | 977 (17.2%) | 623 (22.6%) | 314 (11.7%) | 40 (14.6%) | |
| Hispanic | 304 (5.3%) | 163 (5.9%) | 126 (4.7%) | 15 (5.8%) | |
| Other | 333 (5.9%) | 149 (5.4%) | 171 (6.4%) | 13 (5.1%) | |
| Comorbidity | |||||
| Diabetes | 1595 (28.0%) | 795 (28.9%) | 716 (26.7%) | 84 (32.7%) | 0.048 |
| Hyperlipidemia | 2855 (50.2) | 1260 (45.8%) | 1463 (54.6%) | 132 (51.4%) | <0.0001 |
| Obesity | 1423 (25.0%) | 777 (28.2%) | 582 (21.7%) | 64 (24.9%) | <0.0001 |
| Cancer type | |||||
| Multiple Myeloma | 644 (11.3%) | 554 (20.1%) | 61 (2.3%) | 29 (11.3%) | <0.0001 |
| Breast cancer | 1429 (25.1%) | 496 (18.0%) | 842 (31.4%) | 91 (35.4%) | <0.0001 |
| Prostate cancer | 482 (8.5%) | 232 (8.4%) | 218 (8.1%) | 32 (12.4%) | 0.059 |
| Lung cancer | 728 (12.8%) | 474 (17.2%) | 228 (8.5%) | 26 (10.1%) | <0.0001 |
| Renal cancer | 144 (2.5%) | 89 (3.2%) | 44 (1.6%) | 11 (4.3%) | 0.0002 |
| Bladder cancer | 136 (2.4%) | 98 (3.6%) | 34 (1.3%) | 4 (1.6%) | <0.0001 |
| Cervical cancer | 67 (1.2%) | 42 (1.5%) | 21 (0.8%) | 4 (1.6%) | 0.034 |
| Bone cancer | 366 (6.4%) | 239 (8.7%) | 98 (3.7%) | 29 (11.3%) | <0.0001 |
| Dental surgery | 45 (0.79%) | 17 (0.62%) | 24 (0.90%) | 4 (1.56%) | 0.19 |
Continuous variables were summarized as mean and standard deviation, and categorical variables were summarized as numbers and percentages.
The average follow-up time in the study was 2.46 years. A total of 52 (0.91%) patients were diagnosed with MRONJ during the study period. The mortality rate was 50% and 31% in the MRONJ patients and non-MRONJ patients, respectively (p = 0.0034).
The MRONJ event rate was 0.73% and 0.86% among patients treated with IV BPs and denosumab, respectively. The MRONJ event rate was highest in those with sequential prescriptions of IV BPs and denosumab (3.5%, 9/257) (Table 2). Out of the 9 patients who developed MRONJ after the sequential treatments, 7 started out with IV BPs then switched to denosumab later. The median time to MRONJ was 10.4, 11.1 and 13.5 months for participants treated with IV BPs, denosumab, and sequential IV BPs and denosumab, respectively. The characteristics of the 52 MRONJ patients were summarized in Table 3. There were no statistical differences between the MRONJ patients in the three treatment groups (data not shown).
Table 2.
Event rates of MRONJ
| Drug Class | Medication | Total | MRONJ | Rate | Rate for class | Medium time to MRONJ (months) |
|---|---|---|---|---|---|---|
| IV BP | Zoledronate | 2004 | 15 | 0.75% | 0.73% | 10.4 (0.04-36.4) |
| Pamidronate | 630 | 5 | 0.79% | |||
| Pamidronate/Zoledronate | 118 | 0 | 0.00% | |||
|
| ||||||
| RANKL inhibitor | Denosumab | 2680 | 23 | 0.86% | 0.86% | 11.1 (2.8-32.0) |
|
| ||||||
| IV BP/RANKL inhibitor | Zoledronate/Denosumab | 231 | 7 | 3.03% | 3.50% | 13.5 (8.1-21.4) |
| Pamidronate/Denosumab | 14 | 1 | 7.14% | |||
| Zoledronate/Pamidronate/Denosumab | 12 | 1 | 8.33% | |||
IQR: interquartile range.
Table 3.
Characteristics of MRONJ Patients
| Characteristics | Total (n=52) | IV Bisphosphonates (n = 20) | Denosumab (n = 23) | IV BP/Denosumab (n = 9) |
|---|---|---|---|---|
| Age (Years) (Mean ± SD) | 62.0 ± 10.4 | 58.9 ± 11.9 | 62.4 ± 8.8 | 67.8 ± 8.9 |
| Female sex, n (%) | 39 (75%) | 15 (75%) | 16 (69.6%) | 8 (88.9%) |
| Race | ||||
| White/Non-Hispanic | 41 (71.6%) | 14 (70.0%) | 20 (87.0%) | 7 (77.8%) |
| Black/Non-Hispanic | 8 (15.4%) | 5 (25.0%) | 2 (8.7%) | 1 (11.1%) |
| Hispanic | 2 (3.8%) | 0 | 1 (4.4%) | 1 (11.1%) |
| Other | 1 (1.9%) | 1 (5.0%) | 0 | 0 |
| Comorbidity | ||||
| Diabetes | 13 (25.0%) | 5 (25.0%) | 5 (21.7%) | 3 (33.3%) |
| Hyperlipidemia | 26 (50.0%) | 7 (35.0%) | 14 (60.9%) | 5 (55.6%) |
| Obesity | 14 (26.9%) | 7 (35.0%) | 4 (17.4%) | 3 (33.3%) |
| Exposure to other medications related to MRONJ | ||||
| Antiangiogenic meds | 4 (7.7%) | 1 (5.0%) | 1 (4.4%) | 2 (22.2%) |
| mTOR inhibitors | 5 (9.6%) | 1 (5.0%) | 3 (13.0%) | 1 (11.1%) |
| Dental surgery | 3 (5.8%) | 0 | 2 (8.7%) | 1 (11.1%) |
The Kaplan-Meier curve for time to MRONJ was presented in Figure 1. While there was no significant difference between the time to MRONJ in patients treated with IV BPs and denosumab (Log-rank p = 0.57), there was a significant difference in time to MRONJ between patients treated with IV BP and those treated with sequential IV BPs and denosumab (Log-rank p = 0.0019).
Figure 1.
Kaplan-Meier curve for MRONJ
Age, sex, race/ethnicity, and comorbidities were not associated with risk of MRONJ (p > 0.20). Dental surgery was associated with over eight times higher risk for MRONJ. Three of the 52 patients (5.8%) who developed MRONJ had dental surgery after the initiation of antiresorptive treatment and prior to MRONJ diagnosis, compared to 42/5637 (0.75%) patients who did not have MRONJ. The adjusted HR for dental surgery was 8.57 with 95% CI of 2.61-28.11, p = 0.0004 (Table 4). Prior exposure of m-TOR inhibitors was associated with higher risk of MRONJ, 4.4% (5/108) in those with m-TOR inhibitor treatment vs. those without (0.84% (47/5529), p < 0.0001). The adjusted HR of m-TOR inhibitor exposure for the risk of MRONJ was 3.53 (1.33-9.34) (p = 0.011). There were no evidence that prior exposure of antiangiogenic agents (p = 0.15) or TNF-alpha inhibitor (p = 0.99) were associated with MRONJ. After adjusting for age, sex, race, dental surgery, and prior m-TOR inhibitor exposure, the risk of MRONJ in those treated with denosumab alone was similar to those treated with IV BPs alone, with adjusted HR of 1.25 (0.66-2.34) (p = 0.49). However, the risk of MRONJ was over four times higher in patients treated with sequential IV BP and denosumab vs. those treated with IV BPs alone, with adjusted HR of 4.49 (1.96-10.28), p = 0.0004 (Figure 2). The final Cox regression model was summarized in Table 4.
Table 4.
Final Cox regression model for the development of MRONJ
| Parameter | Adjusted Hazard Ratio | 95% CI | P |
|---|---|---|---|
| Age >=65 year | 0.91 | 0.52-1.60 | 0.74 |
| Female sex | 1.22 | 0.64-2.32 | 0.55 |
| Race (black vs. white) | 0.74 | 0.34-1.62 | 0.46 |
| Race (Hispanic/other vs. white) | 0.49 | 0.15-1.59 | 0.23 |
| Prior exposure to mTOR inhibitors | 3.53 | 1.33-9.34 | 0.011 |
| Dental surgery | 8.57 | 2.61-28.11 | 0.0004 |
| Denosumab vs. IV BP | 1.25 | 0.66-2.34 | 0.49 |
| IV BP/Denosumab vs. IV BP | 4.49 | 1.96-10.28 | 0.0004 |
Figure 2. Adjusted hazard ratios for MRONJ.
The reference group is the patients treated with IV BPs. Cox regression analysis was adjusted for m-TOR inhibitor exposure. The adjusted hazard ratios were plotted on a log2 scale.
Discussion
In the real-world clinical data of OneFlorida consortium, we estimated the overall incidence of MRONJ in cancer patients to be 0.73%, 0.86%, and 3.5% for IV BPs alone, denosumab alone, and sequential treatment of IV BPs and denosumab, respectively. We found similar risk of MRONJ in patients treated with IV BPs compared to those treated with denosumab, but patients treated with sequential IV BPs and denosumab were at over four times higher risk for MRONJ.
BPs and denosumab are two major classes of antiresorptive agents used in cancer patients and osteoporosis patients to strengthen bone or prevent bone loss. BPs are antiresorptive medications that have been used for more than 40 years(29). IV BPs are effective in managing cancer-related conditions such as hypercalcemia of malignancy and skeletal-related events associated with bone metastases in solid tumors and multiple myeloma (11). IV BPs such as zoledronate and pamidronate bind to bone mineral and inhibit mature osteoclast function by being taken up by osteoclasts at sites of bone resorption and disrupting protein prenylation in osteoclasts (30). The half-life of IV BPs in bone is very long, ranging from 1 to 10 years (2,31,32) and the bone-remodeling effects last for a long time even after discontinuation of the treatment.
Denosumab is a fully humanized monoclonal antibody against RANK ligand and inhibits osteoclast function and associated bone resorption by blocking RANKL. Denosumab was first approved by the US Food and Drug Administration (FDA) in 2010 in preventing postmenopausal women from osteoporosis and for the prevention of skeletal-related events in patients with bone metastases from solid tumors (33). Denosumab does not bind to the bone and has much shorter half-life (~32 days)(34) than IV BPs, therefore the bone remodeling effects of denosumab diminish much faster compared to that of IV BPs.
Our study confirmed previous reports that advancing age is not significantly associated with higher odds for ONJ (35). The current study also found no evidence that race/ethnicity and sex were associated with IV BPs or denosumab related MRONJ in cancer patients. Dentoalveolar procedures are the most common identifiable risk factor for developing MRONJ(36,37). In our analysis, we found that dental surgery is associated eight times higher risk for MRONJ.
We found that the rate of MRONJ were similar between IV BPs (0.73%) and denosumab (0.86%) in cancer patients in real world clinical settings. This finding was consistent with reports in the literature that the risk for MRONJ in cancer patients ranges from 0.7-6.7% for those exposed to zoledronate(38–40) and 0.7 – 1.9% in those exposed to denosumab(40), and the risk for MRONJ in cancer patients were comparable between these two drugs (29,40–42).
We also found that in patients who were treated with sequential IV BPs and denosumab had the highest incidence of MRONJ (3.5%) compared with IV BPs or denosumab treatment alone. This result was consistent with a few reports (14,15,43) that switching from zoledronate to denosumab was associated with increased risk for developing MRONJ in cancer patients. The mechanisms for such increased risk are not known, but it is likely due to different mechanisms of these two drug classes and the long half-life of IV BPs in the bone. Based on this finding, caution is needed for patients with a prior exposure to IV BPs and need to be treated with denosumab given the increased risk for MRONJ.
We recognize that there are a few limitations in using a large EHR system such as OneFlorida consortium. Firstly, our study is a retrospective observational study of an EHR system that was not necessarily designed for research. As such, not all patients who were treated with antiresorptive agents were intentionally monitored by dentists. Therefore, we might have underestimated the rates of MRONJ. Secondly, some important risk factors such as cumulative dose of medications, dental health such as periodontitis information are not available. Thirdly, since OneFlorida data started collecting data in September of 2012, we were not able to ascertain drug exposure before that time. There would be likelihood that some MRONJ patients had been exposed with medications earlier than the starting date of the study period and this information was not recorded in our system. Nevertheless, we believe large EHR databases are valuable sources to identify risk factors for rare drug induced adverse events such as MRONJ. Finally, even though we found higher risk of MRONJ in patients treated sequentially of IV BPs and denosumab, we did not have information on the reason for such switch.
In conclusion, we found that IV BPs and RANKL inhibitor denosumab are associated with comparable risk of MRONJ in cancer patients in real-world clinical settings, while the sequential treatment of IV BPs and denosumab was associated with over four times higher risk of MRONJ. Despite the risk of MRONJ, both BPs and denosumab provide significant clinical benefits in cancer patients. It is imperative to develop personalized treatment strategies to give the right antiresorptive to the right patient at the outset in order to prevent MRONJ among high-risk patients and improve patient safety and their quality of life.
Acknowledgement
Research reported in this publication was supported in part by NIH grant R56DE030538. The OneFlorida Clinical Data Network was funded by the Patient-Centered Outcomes Research Institute #CDRN-1501-26692, in part by the OneFlorida Cancer Control Alliance, funded by the Florida Department of Health’s James and Esther King Biomedical Research Program #4KB16, and in part by the University of Florida Clinical and Translational Science Institute, which is supported in part by the NIH National Center for Advancing Translational Sciences under award number UL1TR001427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Patient-Centered Outcomes Research Institute (PCORI), its Board of Governors or Methodology, the OneFlorida Clinical Research Consortium, the University of Florida’s Clinical and Translational Science Institute, the Florida Department of Health, or the National Institutes of Health.
Footnotes
Author Disclosure Statements
The authors declare no conflict of interest.
References:
- 1.Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws AeAoOaMS. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. Mar 2007;65(3):369–76. [DOI] [PubMed] [Google Scholar]
- 2.Hamadeh IS, Ngwa BA, Gong Y. Drug induced osteonecrosis of the jaw. Cancer Treat Rev. May 2015;41(5):455–64. Epub 2015/04/21. [DOI] [PubMed] [Google Scholar]
- 3.Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. Oct 2014;72(10):1938–56. Epub 2014/05/05. [DOI] [PubMed] [Google Scholar]
- 4.Cassoni A, Romeo U, Terenzi V, Della Monaca M, Rajabtork Zadeh O, Raponi I, et al. Adalimumab: Another Medication Related to Osteonecrosis of the Jaws? Case Rep Dent. 2016;2016:2856926. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Yang G, Singh S, Chen Y, Hamadeh IS, Langaee T, McDonough CW, et al. Pharmacogenomics of osteonecrosis of the jaw. Bone. Jul 2019;124:75–82. Epub 2019/04/22. [DOI] [PubMed] [Google Scholar]
- 6.Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. Jan 2015;30(1):3–23. [DOI] [PubMed] [Google Scholar]
- 7.Kawahara M, Kuroshima S, Sawase T. Clinical considerations for medication-related osteonecrosis of the jaw: a comprehensive literature review. Int J Implant Dent. May 14 2021;7(1):47. Epub 20210514. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. Dec 2010;28(35):5132–9. [DOI] [PubMed] [Google Scholar]
- 9.Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 03 2018;19(3):370–81. Epub 20180209. [DOI] [PubMed] [Google Scholar]
- 10.Loyson T, Van Cann T, Schöffski P, Clement PM, Bechter O, Spriet I, et al. Incidence of osteonecrosis of the jaw in patients with bone metastases treated sequentially with bisphosphonates and denosumab. Acta Clin Belg. Apr 2018;73(2):100–9. Epub 20170710. [DOI] [PubMed] [Google Scholar]
- 11.Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D. American Association of Oral and Maxillofacial Surgeons’ Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update. J Oral Maxillofac Surg. May 2022;80(5):920–43. Epub 20220221. [DOI] [PubMed] [Google Scholar]
- 12.Limones A, Sáez-Alcaide LM, Díaz-Parreño SA, Helm A, Bornstein MM, Molinero-Mourelle P. Medication-related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab VS. zoledronic acid: A systematic review and meta-analysis. Med Oral Patol Oral Cir Bucal. May 2020;25(3):e326–e36. Epub 2020/05/01. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Stopeck AT, Fizazi K, Body JJ, Brown JE, Carducci M, Diel I, et al. Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer. Jan 2016;24(1):447–55. Epub 20150903. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Higuchi T, Soga Y, Muro M, Kajizono M, Kitamura Y, Sendo T, et al. Replacing zoledronic acid with denosumab is a risk factor for developing osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol. 06 2018;125(6):547–51. Epub 20180306. [DOI] [PubMed] [Google Scholar]
- 15.Ikesue H, Doi K, Morimoto M, Hirabatake M, Muroi N, Yamamoto S, et al. Switching from zoledronic acid to denosumab increases the risk for developing medication-related osteonecrosis of the jaw in patients with bone metastases. Cancer Chemother Pharmacol. 06 2021;87(6):871–7. Epub 20210331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Shenkman E, Hurt M, Hogan W, Carrasquillo O, Smith S, Brickman A, et al. OneFlorida Clinical Research Consortium: Linking a Clinical and Translational Science Institute With a Community-Based Distributive Medical Education Model. Acad Med. Mar 2018;93(3):451–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Ehrenstein V, Gammelager H, Schiødt M, Nørholt SE, Neumann-Jensen B, Folkmar TB, et al. Evaluation of an ICD-10 algorithm to detect osteonecrosis of the jaw among cancer patients in the Danish National Registry of Patients. Pharmacoepidemiol Drug Saf. Jul 2015;24(7):693–700. Epub 2015/05/14. [DOI] [PubMed] [Google Scholar]
- 18.Wright NC, Curtis JR, Arora T, Smith WK, Kilgore ML, Saag KG, et al. The Validity of Claims-Based Algorithms to Identify Serious Hypersensitivity Reactions and Osteonecrosis of the Jaw. PLoS One. 2015;10(7):e0131601. Epub 2015/07/10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Gammelager H, Erichsen R, Antonsen S, Nørholt SE, Neumann-Jensen B, Ehrenstein V, et al. Positive predictive value of the International Classification of Diseases, 10th revision, codes to identify osteonecrosis of the jaw in patients with cancer. Cancer Epidemiol. Aug 2012;36(4):381–3. Epub 2012/04/24. [DOI] [PubMed] [Google Scholar]
- 20.Bergdahl J, Jarnbring F, Ehrenstein V, Gammelager H, Granath F, Kieler H, et al. Evaluation of an algorithm ascertaining cases of osteonecrosis of the jaw in the Swedish National Patient Register. Clin Epidemiol. 2013;5:1–7. Epub 2013/01/04. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Wang EP, Kaban LB, Strewler GJ, Raje N, Troulis MJ. Incidence of osteonecrosis of the jaw in patients with multiple myeloma and breast or prostate cancer on intravenous bisphosphonate therapy. J Oral Maxillofac Surg. Jul 2007;65(7):1328–31. [DOI] [PubMed] [Google Scholar]
- 22.Vlad SC, Felson DT, Miller DR. Can health care databases be used to identify incident cases of osteonecrosis? Arthritis Res Ther. 2009;11(3):R89. Epub 2009/06/17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Melville JC, Tursun R, Shum JW, Young S, Hanna IA, Marx RE. A technique for the treatment of oral-antral fistulas resulting from medication-related osteonecrosis of the maxilla: the combined buccal fat pad flap and radical sinusotomy. Oral Surg Oral Med Oral Pathol Oral Radiol. Sep 2016;122(3):287–91. Epub 2016/03/31. [DOI] [PubMed] [Google Scholar]
- 24.Gammelager H, Sværke C, Noerholt SE, Neumann-Jensen B, Xue F, Critchlow C, et al. Validity of an algorithm to identify osteonecrosis of the jaw in women with postmenopausal osteoporosis in the Danish National Registry of Patients. Clin Epidemiol. 2013;5:263–7. Epub 2013/08/01. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Kim HY, Kim JW, Kim SJ, Lee SH, Lee HS. Uncertainty of current algorithm for bisphosphonate-related osteonecrosis of the jaw in population-based studies: a systematic review. J Bone Miner Res. Mar 2017;32(3):584–91. Epub 2017/01/30. [DOI] [PubMed] [Google Scholar]
- 26.Facon T, Bensadoun RJ, Blanc JL, Confavreux C, Gourmet R, Maes JM, et al. [Osteonecrosis of the jaw and bisphophonates in oncology]. Bull Cancer. Apr 2008;95(4):413–8. [DOI] [PubMed] [Google Scholar]
- 27.Global Burden of Disease Study 2016 (GBD 2016) Cause of Death and Nonfatal Causes Mapped to ICD Codes. Seattle, United States: Institute for Health Metrics and Evaluation (IHME): Institute for Health Metrics and Evaluation (IHME); 2017. [Google Scholar]
- 28.Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws AeAoOaMS. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. Mar 2007;65(3):369–76. [DOI] [PubMed] [Google Scholar]
- 29.Russell RG. Bisphosphonates: the first 40 years. Bone. Jul 2011;49(1):2–19. [DOI] [PubMed] [Google Scholar]
- 30.Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. Jun 2008;19(6):733–59. [DOI] [PubMed] [Google Scholar]
- 31.Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Porras AG. Clinical pharmacology of alendronate sodium. Osteoporos Int. 1993;3 Suppl 3:S13–6. [DOI] [PubMed] [Google Scholar]
- 32.Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone. Feb 1996;18(2):75–85. [DOI] [PubMed] [Google Scholar]
- 33.O’Halloran M, Boyd NM, Smith A. Denosumab and osteonecrosis of the jaws - the pharmacology, pathogenesis and a report of two cases. Aust Dent J. Dec 2014;59(4):516–9. Epub 2014/09/27. [DOI] [PubMed] [Google Scholar]
- 34.Narayanan P. Denosumab: A comprehensive review. South Asian J Cancer. Oct 2013;2(4):272–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. May 2012;23(5):1341–7. Epub 2011/10/10. [DOI] [PubMed] [Google Scholar]
- 36.Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. May 2012;23(5):1341–7. Epub 20111010. [DOI] [PubMed] [Google Scholar]
- 37.Hallmer F, Andersson G, Götrick B, Warfvinge G, Anderud J, Bjørnland T. Prevalence, initiating factor, and treatment outcome of medication-related osteonecrosis of the jaw-a 4-year prospective study. Oral Surg Oral Med Oral Pathol Oral Radiol. Dec 2018;126(6):477–85. Epub 20180831. [DOI] [PubMed] [Google Scholar]
- 38.Qi WX, Tang LN, He AN, Yao Y, Shen Z. Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol. Apr 2014;19(2):403–10. Epub 20130420. [DOI] [PubMed] [Google Scholar]
- 39.Mauri D, Valachis A, Polyzos IP, Polyzos NP, Kamposioras K, Pesce LL. Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis. Breast Cancer Res Treat. Aug 2009;116(3):433–9. [DOI] [PubMed] [Google Scholar]
- 40.Scagliotti GV, Hirsh V, Siena S, Henry DH, Woll PJ, Manegold C, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol. Dec 2012;7(12):1823–9. [DOI] [PubMed] [Google Scholar]
- 41.Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. Mar 2011;377(9768):813–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. Mar 2011;29(9):1125–32. [DOI] [PubMed] [Google Scholar]
- 43.Srivastava A, Nogueras Gonzalez GM, Geng Y, Won AM, Cabanillas ME, Naing A, et al. Prevalence of medication related osteonecrosis of the jaw in patients treated with sequential antiresorptive drugs: systematic review and meta-analysis. Support Care Cancer. May 2021;29(5):2305–17. Epub 20201115. [DOI] [PMC free article] [PubMed] [Google Scholar]