Introduction
Medication-related osteonecrosis of the jaws (MRONJ) is an adverse drug reaction characterized by the progressive destruction and necrosis of the bone in patients treated with drugs for which an increased risk of MRONJ has been described [ 1 , 2 ]. These drugs include antiresorptive medications such as bisphosphonates and denosumab (a monoclonal antibody), but also some antiangiogenic drugs and immune modulators [ 3 ]. Antiresorptive drugs suppress with different mechanisms of the activity of osteoclasts, reducing the risks of skeletal complications in patients with bone loss. For this reason, they are used in patients affected by osteoporosis, bone metastasis from solid tumor, multiple myeloma, and other conditions such as Paget’s disease of bone or giant cell tumor of the bone [ 4 ]. Antiresorptive drugs significantly reduce the risk of fracture or other bone complications for these patients [ 5 – 9 ], but their use is associated with the possible development of MRONJ.
MRONJ is a relatively rare disease and estimates of its incidence are often variable and not accurate. However, different studies agree that incidence and prevalence of MRONJ in oncologic patients are higher than in the osteoporotic ones. The incidence of MRONJ in osteoporotic patients ranges from 1.04 to 69 per 100,000 patient-years, whereas in oncologic patients it ranges from 0 to 90 per 100,000 patient-years [ 10 ]. According to the Italian position paper on MRONJ, cancer patients with bone metastasis or multiple myeloma taking antiresorptive drugs present an incidence of MRONJ ranging between 1 and 20%. The risk of MRONJ in osteoporotic patients, instead, is below 1% [ 11 ]. These differences are due to the higher dose and different route of administrations (usually intravenous) requested for subjects affected by bone metastasis or multiple myeloma [ 3 , 10 , 12 ] ( Figure 1 ).
MRONJ can also considerably reduce the quality of life of cancer patients, stressing the importance of a correct and early diagnosis for an optimum treatment [ 13 , 14 ]. MRONJ is a clinical diagnosis based on the presence of exposed bone in the maxillofacial region of patients with current or previous treatment with ONJ-related drugs [ 3 ]. Radiographic features of MRONJ are relatively nonspecific. However, different imaging modalities can be useful as an adjunctive aid in the diagnosis and evaluation of MRONJ patients. Among them, we can include intraoral radiographs, panoramic radiograph, computed tomography (CT), cone beam computed tomography (CBCT), magnetic resonance imaging (MRI), bone scintigraphy (BS), and positron emission tomography (PET) [ 10 , 15 ]. As regards plain radiographs, CT, CBCT, and MRI, they may be useful in the identification of the disease and in delineating its extent. They may identify nonspecific changes in the bone such as areas of focal sclerosis, areas of osteolysis, thickened lamina dura, reactive periostal bone, and sequestration [ 10 ]. However, they are morphologic imaging techniques that can detect only a macroscopic anatomic change.
BS and PET, instead, are functional imaging modalities able to identify areas of altered bone metabolism through an increased tracer uptake, even without an anatomic change. They can detect minimal and subclinical changes in bones, showing a high sensitivity for detecting early disease [ 10 , 16 ]. Both techniques are widely used in oncology, especially in the diagnosis of bone metastasis and in the follow up of their treatment with antiresorptive drugs [ 17 , 18 ]. For these reasons, cancer patients at high risk of developing MRONJ often possess BS and/or PET that may show an alteration of the jaws, thus helping in an early diagnosis of MRONJ.
The aim of this study is to evaluate the effective role of BS and PET in the early diagnosis of MRONJ and their possible use in the identification of patients at risk for MRONJ development.
Materials and methods
To address the aim of the study, a retrospective cohort study design was used. To enroll patients, a research was conducted in the electronic database of “Momax” (Oral Medicine and Maxillofacial) project of the Department of Oral Sciences and Maxillofacial Surgery. Inclusion criteria consisted of adult patients with the following features: medical examination performed at the “Policlinico Umberto I” of Rome by an oral pathology specialist in a period ranging from January 2015 to February 2023; previous or ongoing treatment with ONJ-related drugs; BS and/or PET performed to evaluate bone lesions caused by multiple myeloma or bone metastases from solid tumors.
All patients who had performed nuclear medicine imaging studies solely before the beginning of therapy with ONJ-related drugs or after the clinical diagnosis of MRONJ were excluded. Exclusion criteria consisted also of patients with previous treatment with radiotherapy of the head-neck district and with insufficient follow-up to evaluate MRONJ development.
Medical records filled after specialistic examination of all patients included in the study were examined. All data regarding sex, age at first visit, underlying disease who led to the beginning of therapy with ONJ-related drugs, drug administration, date of execution of PET or BS, date of clinical diagnosis of MRONJ, and MRONJ staging according to the AAOMS system [ 3 ] were collected.
Whole-body BS was performed approximately 2 h after injection of Technetium-99m bound to methylene or hydroxymethylene diphosphonate. Radiotracer uptake was detected using a single-head gamma camera. As regards PET, it was performed 1 h after injection of fluorodeoxyglucose ( 18 F FDG). A high-resolution PET scanner which also incorporated a CT scanner was used. The jaws of each patient were divided into four areas (right maxillary, left maxillary, left mandible, and right mandible). A specialist in nuclear medicine with 15 years of experience and blinded to MRONJ development reviewed BS and PET for pathological tracer uptake. Visual interpretation was performed and the findings were related to the eventual development of MRONJ. If a patient had performed multiple BS or PET, the older scan with a pathological uptake was analyzed. When nuclear medicine imaging techniques did not show any pathological uptake, the most recent scan preceding the clinical diagnosis of MRONJ was used.
True positives, true negatives, false positives, and false negatives were determined and used to calculate sensitivity, specificity, positive, and negative predictive values. The odds ratio and the latency from the finding of pathological tracer uptake in BS or PET to the clinical diagnosis of MRONJ were also calculated. Statistical analysis was conducted using GraphPad Prism (version 9.5.1 for Windows, GraphPad Software, San Diego, California USA, www.graphpad.com). All values were determined with a 95% confidence level. As regards BS, the statistical significance of the sample was calculated by Yates’s chi-squared test, whereas Fisher’s exact test was used for PET. A p -value less than 0.05 was considered statistically significant.
Informed consent: Informed consent was obtained according to Helsinki Declaration.
Ethical approval: The study was approved by the Council of the Department of Oral Sciences and Maxillofacial Surgery at “Sapienza” University of Rome (Prot. N.5 of 20/02/2024).
Results
A total of 51 patients fulfilled the inclusion criteria. Thirty-one patients had performed BS and 20 patients had performed PET. The median age of the 31 patients who had performed BS was 67.35 years. They were 11 males and 20 females. All of them had taken ONJ-related drugs in order to treat bone metastasis from a solid tumor. The most frequent tumor was breast cancer (64.5% of the patients), followed by prostate cancer (19.4%), lung cancer (9.7%), and kidney cancer (6.4%). Around 14 patients (45.2%) received denosumab by injection, 11 patients (35.5%) received zoledronate intravenously, and 6 patients (19.3%) received both denosumab and zoledronate at different times.
A total of 124 areas were reviewed. Forty-one regions showed pathological tracer uptake. Among them, 30 areas developed MRONJ whereas 11 areas did not develop osteonecrosis despite the positive BS. Among the 83 areas without pathological tracer uptake, only 6 sites developed MRONJ. MRONJ stage 2 was diagnosed in 21 of 31 patients (67.7%), MRONJ stage 3 in 5 patients (16.1%), and MRONJ stage 1 in 3 patients (9.7%). One patient (3.2%) developed MRONJ stage 0 that evolved into stage 1 during the follow up of the disease. Another patient did not develop MRONJ despite the positive BS ( Table 1 ).
Table 1
Summary data of BS
| MRONJ development | No MRONJ development | TOT | |
| Positive BS | 30 | 11 | 41 |
| Negative BS | 6 | 77 | 83 |
| TOT | 36 | 88 | 124 |
Sensitivity and specificity of BS for MRONJ prediction were, respectively, 83.3 and 87.5%. Positive and negative predictive values were, respectively, 73.2 and 92.8%. The odds ratio was 35. Yates’s chi-squared test showed the statistical significance of the sample ( p < 0.0001). The median latency from the finding of pathological tracer uptake in BS to the clinical diagnosis of MRONJ was 15.96 months with a standard deviation of 11.04 months, showing a great variability.
Twenty patients (5 males and 15 females) with a median age of 68.15 years had performed PET. They took ONJ-related drugs in order to treat bone metastasis from a solid tumor or multiple myeloma. Even in this case the most frequent tumor was breast cancer (60.0% of the patients), followed by lung cancer (20.0%). The remaining patients showed more heterogeneity: one patient (5%) had multiple myeloma, one patient (5%) had prostate cancer, and two patients (10%) were affected by tumors that more rarely spread to the bone (bladder cancer and a rare form of angiosarcoma). Fifteen patients (75.0%) received denosumab by injection, three patients (15.0%) received zoledronate intravenously, and two patients (10.0%) received both denosumab and zoledronate at different times.
A total of 80 areas were reviewed. Ten regions showed pathological tracer uptake. Among them, seven areas developed MRONJ. Among the 70 areas without pathological tracer uptake, 14 sites developed MRONJ. MRONJ stage 1 was diagnosed in 12 of 20 patients (60.0%), MRONJ stage 2 in 4 patients (20.0%), and MRONJ stage 3 in 2 patients (10.0%). One patient (5.0%) did not develop MRONJ despite the positive PET. Another patient did not show pathological tracer uptake and did not develop MRONJ during the follow up ( Table 2 ).
Table 2
Summary data of PET
| MRONJ development | No MRONJ development | TOT | |
| Positive PET | 7 | 3 | 10 |
| Negative PET | 14 | 56 | 70 |
| TOT | 21 | 59 | 80 |
Sensitivity of PET was 33.3%, specificity was 94.9%, and positive and negative predictive values were 70.0 and 80.0%, respectively. The odds ratio was 9.333. Fisher’s exact test showed the statistical significance of the sample ( p = 0.0025). The median latency from the finding of pathological tracer uptake in PET to the clinical diagnosis of MRONJ was 6.83 months with a standard deviation of 6.49 months. Even in this case there was a great variability.
Discussion
Different authors proved that BS is able to identify cases of already diagnosed MRONJ as areas with an increased uptake of Technetium-99m [ 19 , 20 ]. Other authors focused on the possible use of pathological tracer uptake as a sign for an early diagnosis of MRONJ. Lesclous et al. reported that strong radionuclide uptake was detected in 5 of 14 patients several months before clinical diagnosis of MRONJ. In the other nine patients, the increased uptake followed tooth extraction [ 21 ]. O’Ryan et al. identified 59 cases of intravenous MRONJ. Of the 35 patients who had performed BS before development of MRONJ, 23 (65.7%) had positive tracer uptake in areas that developed MRONJ during the follow up. The latency from the pathological tracer uptake to the clinical diagnosis of MRONJ was 14.4 months on average [ 22 ]. Thomas et al. studied 30 patients with metastatic prostate cancer treated with bisphosphonates. Their BS performed after the beginning of the therapy was evaluated for pathological tracer uptake of the jaws and the results were compared to development of MRONJ. In this way, they calculated sensitivity (67%), specificity (79%), positive (44%), and negative (91%) predictive values of BS in the early diagnosis of MRONJ [ 23 ]. The results of this study confirm the data reported in the literature. BS showed high sensitivity (83.3%) and specificity (87.5%) in the early diagnosis of MRONJ, with a good positive predictive value (73.2%) and optimum negative predictive value (92.8%). The risk of developing MRONJ was 35-fold increased when BS was positive ( Figure 2) .
PET can be used as a substitute for BS in the evaluation of bone metastasis. Different authors demonstrated that the technique is useful for detecting areas of altered bone metabolism, allowing to identify cases of already diagnosed MRONJ [ 24 – 26 ]. A very low number of studies focus on the use of PET before the clinical diagnosis of MRONJ and on its use for an early diagnosis. Fujimoto et al. investigated a total of 11 patients who had undergone 18 F-FDG PET/CT scan over 6 months before diagnosing MRONJ, establishing a protocol that is very similar to the one of the present study. They found good values of sensitivity (80.0%), specificity (72.4%), positive (60.0%), and negative (87.5%) predictive values [ 27 ]. Watanabe et al. evaluated a total of 53 patients who underwent 18 F-FDG PET/CT for oncologic surveillance. Twelve of the 53 patients developed MRONJ after PET was performed. Analyzing the tracer uptake in the jaws, the authors described a higher standardized uptake value in MRONJ patients compared to the control group. Moreover, they calculated sensitivity (75%) and specificity (98%) of PET [ 28 ]. Belcher et al., instead, performed a retrospective chart review of 20 patients whose PET scans were acquired within 1 year of MRONJ diagnosis. They found diametrically opposite results, determining low values of sensitivity (43%) and specificity (19%) [ 29 ] ( Tables 3 and 4 ).
Table 3
Summary data of patients with BS
| #Patient | Sex | Age | Pathology | Medication | Latency from pathological tracer uptake to clinical diagnosis | MRONJ stage |
| 1 | M | 87 | Prostate cancer | Zoledronate | 2 months | 2 |
| 2 | M | 73 | Kidney cancer | Zoledronate | 20 months | 2 |
| 3 | F | 71 | Breast cancer | Zoledronate and denosumab | 14 months | 2 |
| 4 | M | 76 | Prostate cancer | Zoledronate | No uptake | 2 |
| 5 | F | 63 | Breast cancer | Denosumab | No uptake | 2 |
| 6 | M | 73 | Lung cancer | Denosumab | 9 months | 1 |
| 7 | F | 85 | Breast cancer | Denosumab | 2 months | 2 |
| 8 | F | 70 | Breast cancer | Zoledronate | No uptake | 3 |
| 9 | F | 76 | Breast cancer | Zoledronate | 0 months | 2 |
| 10 | F | 61 | Breast cancer | Zoledronate | 1 month | 3 |
| 11 | F | 53 | Breast cancer | Zoledronate and denosumab | No uptake | 1 |
| 12 | M | 76 | Prostate cancer | Zoledronate | 6 months | 2 |
| 13 | F | 57 | Breast cancer | Denosumab | 24 months | 1 |
| 14 | F | 54 | Breast cancer | Denosumab | 24 months | 2 |
| 15 | F | 74 | Breast cancer | Denosumab | No MRONJ | NO |
| 16 | F | 58 | Breast cancer | Zoledronate | 27 months | 2 |
| 17 | F | 57 | Breast cancer | Zoledronate and denosumab | 7 months | 2 |
| 18 | F | 64 | Breast cancer | Denosumab | 1 month | 3 |
| 19 | F | 62 | Breast cancer | Denosumab | 12 months | 2 |
| 20 | M | 84 | Lung cancer | Denosumab | 29 months | 3 |
| 21 | M | 74 | Lung cancer | Denosumab | 13 months | 3 |
| 22 | M | 62 | Prostate cancer | Denosumab | 21 months | 2 |
| 23 | M | 62 | Prostate cancer | Denosumab | 23 months | 2 |
| 24 | F | 61 | Breast cancer | Zoledronate and denosumab | 11 months | 2 |
| 25 | M | 75 | Prostate cancer | Denosumab | No uptake | 2 |
| 26 | F | 66 | Breast cancer | Zoledronate and denosumab | 28 months | 2 |
| 27 | F | 54 | Breast cancer | Zoledronate and denosumab | 12 months | 2 |
| 28 | F | 68 | Breast cancer | Denosumab | 22 months | 0 |
| 29 | F | 63 | Breast cancer | Zoledronate | 20 months | 2 |
| 30 | F | 61 | Breast cancer | Zoledronate | 41 months | 2 |
| 31 | M | 68 | Kidney cancer | Zoledronate | 30 months | 2 |
Table 4
Summary data of 31 patients with BS
| Sex | 11 males (35.5%) and 20 females (64.5%) |
| Median age | 67.35 years |
| Pathology | 20 breast cancer (64.5%), 6 prostate cancer (19.4%), 3 lung cancer (9.7%), and 2 kidney cancer (6.4%) |
| Medication | 14 denosumab (45.2%), 11 zoledronate (35.5%), 6 both denosumab and zoledronate (19.3%) |
| Median latency from pathological tracer uptake to clinical diagnosis | 15.96 months |
| MRONJ stage | 21 stage 2 (67.7%), 5 stage 3 (16.1%), 3 stage 1 (3.2%), 1 stage 0 (9.7%), 1 no MRONJ (3.2%) |
Our results regarding PET, although preliminary, are encouraging. We obtained good positive (70.0%) and negative (80.0%) values and a really high specificity (94.9%). The risk of developing MRONJ was 9.333-fold increased when PET was positive. Quite the opposite, sensitivity was low (33.3%), because different areas who developed MRONJ had negative PET scans. This result could be explained by different factors, such as the variable and high amount of time from the acquisition of the scan to the diagnosis of MRONJ. Moreover, the uptake of 18 F-FDG seems to occur only in areas where osteonecrosis is associated with an inflammatory-infectious process, so the initial stages of MRONJ with low inflammatory component could result negative [ 30 – 32 ] ( Tables 5 and 6 ).
Table 5
Summary data of patients with PET
| #Patient | Sex | Age | Pathology | Medication | Latency from pathological tracer uptake to clinical diagnosis | MRONJ stage |
| 1 | M | 65 | Lung cancer | Denosumab | No uptake | 1 |
| 2 | M | 52 | Lung cancer | Denosumab | No uptake and no MRONJ | NO |
| 3 | F | 62 | Breast cancer | Denosumab | 1 month | 2 |
| 4 | F | 69 | Multiple myeloma | Zoledronate | No uptake | 1 |
| 5 | M | 69 | Bladder cancer | Denosumab | 5 months | 2 |
| 6 | F | 76 | Breast cancer | Denosumab | No uptake | 2 |
| 7 | F | 77 | Breast cancer | Denosumab | No uptake | 1 |
| 8 | F | 58 | Lung cancer | Denosumab | No uptake | 1 |
| 9 | F | 70 | Breast cancer | Zoledronate and denosumab | No uptake | 3 |
| 10 | F | 73 | Breast cancer | Denosumab | No uptake | 1 |
| 11 | F | 76 | Breast cancer | Denosumab | 11 months | 1 |
| 12 | F | 67 | Breast cancer | Zoledronate | 2 months | 1 |
| 13 | M | 66 | Prostate cancer | Zoledronate and denosumab | No uptake | 3 |
| 14 | F | 71 | Breast cancer | Denosumab | 4 months | 1 |
| 15 | F | 59 | Breast cancer | Denosumab | No uptake | 1 |
| 16 | F | 58 | Angiosarcoma | Denosumab | No MRONJ | NO |
| 17 | F | 75 | Breast cancer | Denosumab | No uptake | 2 |
| 18 | F | 78 | Breast cancer | Denosumab | 18 months | 1 |
| 19 | F | 69 | Breast cancer | Zoledronate | No uptake | 1 |
| 20 | M | 73 | Lung cancer | Denosumab | No uptake | 1 |
Table 6
Summary data of 20 patients with PET
| Sex | 5 males (25%) and 15 females (75%) |
| Median age | 68.15 years |
| Pathology | 12 breast cancer (60.0%), 4 lung cancer (20.0%), 1 multiple myeloma (5.0%), 1 prostate cancer (5.0%), 2 tumors that rarely spread to the bone (10.0%) |
| Medication | 15 denosumab (75.0%), 3 zoledronate (15.0%), 2 both denosumab and zoledronate (10.0%) |
| Median latency from pathological tracer uptake to clinical diagnosis | 6.83 months |
| MRONJ stage | 12 stage 1 (60.0%), 4 stage 2 (20.0%), 2 stage 3 (10.0%), 2 no MRONJ (10.0%) |
Despite the promising results, there are several limitations of this study. Because of the low prevalence of MRONJ, a relatively smart number of patients, especially who had performed PET, were included. The retrospective nature of this study also causes a high variability of the median latency from the finding of pathological tracer uptake in BS or PET to the clinical diagnosis of MRONJ, whose results should be considered with caution. A prospective study is needed to allow a better assessment. Furthermore, giving the specialistic nature of “Momax” project, the oral health status of the patients prior to our first visit and MRONJ diagnosis was often unknown. For this reason, the possibility that the positive uptake reflected dental or periodontal disease preceding MRONJ development cannot be excluded.
Conclusions
BS and PET can identify bone alterations earlier and with more precision compared to traditional radiological procedures. They are used to identify and to assess response to treatment of bone metastasis in cancer patients, which are also at high risk of developing MRONJ. Representing the whole body of the patients, they could discover pathological alterations of the jaws and allow an early diagnosis of MRONJ. Despite the limitations, this study shows that BS and PET with pathological tracer uptake in the jaws are associated with an increased risk of developing MRONJ. On the contrary, if the exams are negative development of MRONJ in the future has a low probability. For these reasons, they may be accurate techniques for an early prediction of MRONJ. For daily clinical practice, our results suggest nuclear medicine specialists to search for pathological tracer uptake in the jaws when they examine BS or PET of patients taking ONJ-related drugs. Moreover, the clinician should also ask the patient if he has performed BS or PET in the past, in order to use them as a valid aid in the early diagnosis of MRONJ.
Funding information: The authors of this study did not receive funding.
Author contributions: P.D.: writer-investigator; M.M.: editing; T.G.: supervisor; P.G.: editing-supervisor; M.L.: writer-investigator; D.V.A.: methodology; R.U.: supervisor.
Conflict of interest: Gaspare Palaia serves as Guest Editor in one of the Special Issues in Open Medicine, but this fact hasnt affected peer-review process. The authors of this study have no conflict of interest.
Data availability statement: The data are available at the Department of Oral and Maxillofacial Sciences of Sapienza University of Rome.
References
[1] Di Fede O, Panzarella V, Mauceri R, Fusco V, Bedogni A, Lo Muzio L, et al. The dental management of patients at risk of medication-related osteonecrosis of the jaw: new paradigm of primary prevention. Biomed Res Int. 2018 Sep;2018:2684924. 10.1155/2018/2684924 PMC6164200 30306086 Di Fede O Panzarella V Mauceri R Fusco V Bedogni A Lo Muzio L The dental management of patients at risk of medication-related osteonecrosis of the jaw: new paradigm of primary prevention Biomed Res Int 2018 Sep 2018 2684924 30306086 10.1155/2018/2684924 PMC6164200
[2] Campisi G, Mauceri R, Bertoldo F, Bettini G, Biasotto M, Colella G, et al. Medication-related osteonecrosis of jaws (MRONJ) prevention and diagnosis: Italian consensus update 2020. Int J Environ Res Public Health. 2020 Aug;17(16):5998. 10.3390/ijerph17165998 PMC7460511 32824826 Campisi G Mauceri R Bertoldo F Bettini G Biasotto M Colella G Medication-related osteonecrosis of jaws (MRONJ) prevention and diagnosis: Italian consensus update 2020 Int J Environ Res Public Health 2020 Aug 17 16 5998 32824826 10.3390/ijerph17165998 PMC7460511
[3] 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. 2022 May;80(5):920–43. 10.1016/j.joms.2022.02.008 35300956 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 2022 May 80 5 920 43 35300956 10.1016/j.joms.2022.02.008
[4] Nicolatou-Galitis O, Schiødt M, Mendes RA, Ripamonti C, Hope S, Drudge-Coates L, et al. Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment. Oral Surg Oral Med Oral Pathol Oral Radiol. 2019 Feb;127(2):117–35. 10.1016/j.oooo.2018.09.008 30393090 Nicolatou-Galitis O Schiødt M Mendes RA Ripamonti C Hope S Drudge-Coates L Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment Oral Surg Oral Med Oral Pathol Oral Radiol 2019 Feb 127 2 117 35 30393090 10.1016/j.oooo.2018.09.008
[5] Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008 Sep;83(9):1032–45. 10.4065/83.9.1032 PMC2667901 18775204 Drake MT Clarke BL Khosla S Bisphosphonates: mechanism of action and role in clinical practice Mayo Clin Proc 2008 Sep 83 9 1032 45 18775204 10.4065/83.9.1032 PMC2667901
[6] Watts NB. Bisphosphonate treatment of osteoporosis. Clin Geriatr Med. 2003 May;19(2):395–414. 10.1016/s0749-0690(02)00069-1 12916293 Watts NB Bisphosphonate treatment of osteoporosis Clin Geriatr Med 2003 May 19 2 395 414 12916293 10.1016/s0749-0690(02)00069-1
[7] Body JJ, Diel IJ, Lichinitzer M, Lazarev A, Pecherstorfer M, Bell R, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer. 2004 Mar;90(6):1133–7. 10.1038/sj.bjc.6601663 PMC2409647 15026791 Body JJ Diel IJ Lichinitzer M Lazarev A Pecherstorfer M Bell R Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies Br J Cancer 2004 Mar 90 6 1133 7 15026791 10.1038/sj.bjc.6601663 PMC2409647
[8] Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug;361(8):756–65. 10.1056/NEJMoa0809493 19671655 Cummings SR San Martin J McClung MR Siris ES Eastell R Reid IR FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis N Engl J Med 2009 Aug 361 8 756 65 19671655 10.1056/NEJMoa0809493
[9] 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. 2010 Dec;28(35):5132–9. 10.1200/JCO.2010.29.7101 21060033 Stopeck AT Lipton A Body JJ Steger GG Tonkin K de Boer RH 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 2010 Dec 28 35 5132 9 21060033 10.1200/JCO.2010.29.7101
[10] Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, et al. International task force on osteonecrosis of the jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Min Res. 2015 Jan;30(1):3–23. 10.1002/jbmr.2405 25414052 Khan AA Morrison A Hanley DA Felsenberg D McCauley LK O’Ryan F International task force on osteonecrosis of the jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus J Bone Min Res 2015 Jan 30 1 3 23 10.1002/jbmr.2405 25414052
[11] Bedogni A, Mauceri R, Fusco V, Bertoldo F, Bettini G, Di Fede O, et al. Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ). Oral Dis. 2024 Sep;30(6):3679–709. 10.1111/odi.14887 38317291 Bedogni A Mauceri R Fusco V Bertoldo F Bettini G Di Fede O Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ) Oral Dis 2024 Sep 30 6 3679 709 38317291 10.1111/odi.14887
[12] Boffano P, Agnone AM, Neirotti F, Bonfiglio R, Brucoli M, Ruslin M, et al. Epidemiology, etiopathogenesis, and management of MRONJ: a European multicenter study. J Stomatol Oral Maxillofac Surg. 2024 Sep;125(5S1):101931. 10.1016/j.jormas.2024.101931 38821192 Boffano P Agnone AM Neirotti F Bonfiglio R Brucoli M Ruslin M Epidemiology, etiopathogenesis, and management of MRONJ: a European multicenter study J Stomatol Oral Maxillofac Surg 2024 Sep 125 5S1 101931 38821192 10.1016/j.jormas.2024.101931
[13] Miksad RA, Lai KC, Dodson TB, Woo SB, Treister NS, Akinyemi O, et al. Quality of life implications of bisphosphonate-associated osteonecrosis of the jaw. Oncologist. 2011;16(1):121–32. 10.1634/theoncologist.2010-0183 PMC3228058 21212433 Miksad RA Lai KC Dodson TB Woo SB Treister NS Akinyemi O Quality of life implications of bisphosphonate-associated osteonecrosis of the jaw Oncologist 2011 16 1 121 32 21212433 10.1634/theoncologist.2010-0183 PMC3228058
[14] Tenore G, Mohsen A, Rossi AF, Palaia G, Rocchetti F, Cassoni A, et al. Does medication-related osteonecrosis of the jaw influence the quality of life of cancer patients? Biomedicines. 2020 Apr;8(4):95. 10.3390/biomedicines8040095 PMC7235831 32344782 Tenore G Mohsen A Rossi AF Palaia G Rocchetti F Cassoni A Does medication-related osteonecrosis of the jaw influence the quality of life of cancer patients? Biomedicines 2020 Apr 8 4 95 32344782 10.3390/biomedicines8040095 PMC7235831
[15] Tsuchimochi M, Kurabayashi T. Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (1), role of imaging in drug-related osteonecrosis of the jaw: an up-to-date review (secondary publication). Jpn Dent Sci Rev. 2019 Nov;55(1):1–4. 10.1016/j.jdsr.2018.11.004 PMC6348294 30705708 Tsuchimochi M Kurabayashi T Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (1), role of imaging in drug-related osteonecrosis of the jaw: an up-to-date review (secondary publication) Jpn Dent Sci Rev 2019 Nov 55 1 1 4 30705708 10.1016/j.jdsr.2018.11.004 PMC6348294
[16] Watanabe S, Nakajima K, Kinuya S. ☆Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (5), utility of bone scintigraphy and 18F-FDG PET/CT in early detection and risk assessment of medication-related osteonecrosis of the jaw (secondary publication). Jpn Dent Sci Rev. 2019 Nov;55(1):76–9. 10.1016/j.jdsr.2018.12.002 PMC6431786 30956739 Watanabe S Nakajima K Kinuya S ☆ Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (5), utility of bone scintigraphy and 18 F-FDG PET/CT in early detection and risk assessment of medication-related osteonecrosis of the jaw (secondary publication) Jpn Dent Sci Rev 2019 Nov 55 1 76 9 30956739 10.1016/j.jdsr.2018.12.002 PMC6431786
[17] Krasnow AZ, Hellman RS, Timins ME, Collier BD, Anderson T, Isitman AT. Diagnostic bone scanning in oncology. Semin Nucl Med. 1997 Apr;27(2):107–41. 10.1016/s0001-2998(97)80043-8 9144855 Krasnow AZ Hellman RS Timins ME Collier BD Anderson T Isitman AT Diagnostic bone scanning in oncology Semin Nucl Med 1997 Apr 27 2 107 41 9144855 10.1016/s0001-2998(97)80043-8
[18] Juweid ME, Cheson BD. Positron-emission tomography and assessment of cancer therapy. N Engl J Med. 2006 Feb;354(5):496–507. 10.1056/NEJMra050276 16452561 Juweid ME Cheson BD Positron-emission tomography and assessment of cancer therapy N Engl J Med 2006 Feb 354 5 496 507 16452561 10.1056/NEJMra050276
[19] Hong CM, Ahn BC, Choi SY, Kim DH, Lee SW, Kwon TG, et al. Implications of three-phase bone scintigraphy for the diagnosis of bisphosphonate-related osteonecrosis of the jaw. Nucl Med Mol Imaging. 2012 Sep;46(3):162–8. 10.1007/s13139-012-0144-x PMC4043030 24900055 Hong CM Ahn BC Choi SY Kim DH Lee SW Kwon TG Implications of three-phase bone scintigraphy for the diagnosis of bisphosphonate-related osteonecrosis of the jaw Nucl Med Mol Imaging 2012 Sep 46 3 162 8 24900055 10.1007/s13139-012-0144-x PMC4043030
[20] Chiandussi S, Biasotto M, Dore F, Cavalli F, Cova MA, Di Lenarda R. Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws. Dentomaxillofac Radiol. 2006 Jul;35(4):236–43. 10.1259/dmfr/27458726 16798918 Chiandussi S Biasotto M Dore F Cavalli F Cova MA Di Lenarda R Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws Dentomaxillofac Radiol 2006 Jul 35 4 236 43 16798918 10.1259/dmfr/27458726
[21] Lesclous P, Abi Najm S, Carrel JP, Baroukh B, Lombardi T, Willi JP, et al. Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation? Bone. 2009 Nov;45(5):843–52. 10.1016/j.bone.2009.07.011 19631301 Lesclous P Abi Najm S Carrel JP Baroukh B Lombardi T Willi JP Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation? Bone 2009 Nov 45 5 843 52 19631301 10.1016/j.bone.2009.07.011
[22] O’Ryan FS, Khoury S, Liao W, Han MM, Hui RL, Baer D, et al. Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator. J Oral Maxillofac Surg. 2009 Jul;67(7):1363–72. 10.1016/j.joms.2009.03.005 19531404 O’Ryan FS Khoury S Liao W Han MM Hui RL Baer D Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator J Oral Maxillofac Surg 2009 Jul 67 7 1363 72 19531404 10.1016/j.joms.2009.03.005
[23] Thomas C, Spanidis M, Engel C, Roos FC, Frees S, Neisius A, et al. Bone scintigraphy predicts bisphosphonate-induced osteonecrosis of the jaw (BRONJ) in patients with metastatic castration-resistant prostate cancer (mCRPC). Clin Oral Investig. 2016 May;20(4):753–8. 10.1007/s00784-015-1563-8 26307268 Thomas C Spanidis M Engel C Roos FC Frees S Neisius A Bone scintigraphy predicts bisphosphonate-induced osteonecrosis of the jaw (BRONJ) in patients with metastatic castration-resistant prostate cancer (mCRPC) Clin Oral Investig 2016 May 20 4 753 8 10.1007/s00784-015-1563-8 26307268
[24] Fleisher KE, Raad RA, Rakheja R, Gupta V, Chan KC, Friedman KP, et al. Fluorodeoxyglucose positron emission tomography with computed tomography detects greater metabolic changes that are not represented by plain radiography for patients with osteonecrosis of the jaw. J Oral Maxillofac Surg. 2014 Oct;72(10):1957–65. 10.1016/j.joms.2014.04.017 25053572 Fleisher KE Raad RA Rakheja R Gupta V Chan KC Friedman KP Fluorodeoxyglucose positron emission tomography with computed tomography detects greater metabolic changes that are not represented by plain radiography for patients with osteonecrosis of the jaw J Oral Maxillofac Surg 2014 Oct 72 10 1957 65 25053572 10.1016/j.joms.2014.04.017
[25] Raje N, Woo SB, Hande K, Yap JT, Richardson PG, Vallet S, et al. Clinical, radiographic, and biochemical characterization of multiple myeloma patients with osteonecrosis of the jaw. Clin Cancer Res. 2008 Apr;14(8):2387–95. 10.1158/1078-0432.CCR-07-1430 18413829 Raje N Woo SB Hande K Yap JT Richardson PG Vallet S Clinical, radiographic, and biochemical characterization of multiple myeloma patients with osteonecrosis of the jaw Clin Cancer Res 2008 Apr 14 8 2387 95 18413829 10.1158/1078-0432.CCR-07-1430
[26] Catalano L, Del Vecchio S, Petruzziello F, Fonti R, Salvatore B, Martorelli C, et al. Sestamibi and FDG-PET scans to support diagnosis of jaw osteonecrosis. Ann Hematol. 2007 Jun;86(6):415–23. 10.1007/s00277-007-0263-0 17285274 Catalano L Del Vecchio S Petruzziello F Fonti R Salvatore B Martorelli C Sestamibi and FDG-PET scans to support diagnosis of jaw osteonecrosis Ann Hematol 2007 Jun 86 6 415 23 17285274 10.1007/s00277-007-0263-0
[27] Fujimoto K, Norikane T, Yamamoto Y, Mitamura K, Takami Y, Okuda H, et al. The feasibility of focal 18F-FDG uptake as a predictor of medication-related osteonecrosis of the jaw (MRONJ). J Nucl Med. 2020;61(Suppl. 1):1526. Fujimoto K Norikane T Yamamoto Y Mitamura K Takami Y Okuda H The feasibility of focal 18 F-FDG uptake as a predictor of medication-related osteonecrosis of the jaw (MRONJ) J Nucl Med 2020 61 Suppl. 1 1526
[28] Watanabe S, Nakajima K, Inokuchi M, Noguchi N, Kawashiri S, Mizokami A. The role of 18F-FDG PET/CT in early detection and risk assessment of medication-related osteonecrosis of the jaw. J Nucl Med. 2017;58(Suppl. 1):305. Watanabe S Nakajima K Inokuchi M Noguchi N Kawashiri S Mizokami A The role of 18 F-FDG PET/CT in early detection and risk assessment of medication-related osteonecrosis of the jaw J Nucl Med 2017 58 Suppl. 1 305
[29] Belcher R, Boyette J, Pierson T, Siegel E, Bartel TB, Aniasse E, et al. What is the role of positron emission tomography in osteonecrosis of the jaws? J Oral Maxillofac Surg. 2014 Feb;72(2):306–10. 10.1016/j.joms.2013.07.038 24075237 Belcher R Boyette J Pierson T Siegel E Bartel TB Aniasse E What is the role of positron emission tomography in osteonecrosis of the jaws? J Oral Maxillofac Surg 2014 Feb 72 2 306 10 24075237 10.1016/j.joms.2013.07.038
[30] Wilde F, Steinhoff K, Frerich B, Schulz T, Winter K, Hemprich A, et al. Positron-emission tomography imaging in the diagnosis of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Mar;107(3):412–9. 10.1016/j.tripleo.2008.09.019 19121962 Wilde F Steinhoff K Frerich B Schulz T Winter K Hemprich A Positron-emission tomography imaging in the diagnosis of bisphosphonate-related osteonecrosis of the jaw Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009 Mar 107 3 412 9 19121962 10.1016/j.tripleo.2008.09.019
[31] Kitagawa Y, Ohga N, Asaka T, Sato J, Hata H, Helman J, et al. Imaging modalities for drug-related osteonecrosis of the jaw (3), Positron emission tomography imaging for the diagnosis of medication-related osteonecrosis of the jaw. Jpn Dent Sci Rev. 2019 Nov;55(1):65–70. 10.1016/j.jdsr.2018.12.001 PMC6430078 30949253 Kitagawa Y Ohga N Asaka T Sato J Hata H Helman J Imaging modalities for drug-related osteonecrosis of the jaw (3), Positron emission tomography imaging for the diagnosis of medication-related osteonecrosis of the jaw Jpn Dent Sci Rev 2019 Nov 55 1 65 70 30949253 10.1016/j.jdsr.2018.12.001 PMC6430078
[32] Mohsen M, Migliau G, Pergolini D, Romeo U, Palaia G. Accident due to incorrect selection of diode laser technique in the treatment of oral venous malformation. Case Rep Dent. 2023 Dec;2023:8817274. 10.1155/2023/8817274 . PMID: 38106372; PMCID: PMC10723904. PMC10723904 38106372 Mohsen M Migliau G Pergolini D Romeo U Palaia G Accident due to incorrect selection of diode laser technique in the treatment of oral venous malformation Case Rep Dent 2023 Dec 2023 8817274 10.1155/2023/8817274 PMID: 38106372; PMCID: PMC10723904 38106372 PMC10723904