Radiographic Findings in Bisphosphonate-Treated Patients With Stage 0 Disease in the Absence of Bone Exposure

doi:10.1016/j.joms.2010.05.003

Journal of Oral and Maxillofacial Surgery

Volume 68, Issue 9, September 2010, Pages 2232-2240

https://doi.org/10.1016/j.joms.2010.05.003 Get rights and content

Purpose

Radiographic features in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) are well described, but less is known in bisphosphonate-exposed individuals with stage 0 disease (clinical symptoms without exposed necrotic bone) considered at risk for BRONJ. We sought to characterize radiographic findings in a subgroup of patients with concerning clinical symptoms and bisphosphonate exposure to identify imaging features that may presage development of BRONJ.

Materials and Methods

A dental symptom survey was returned by 8,572 Kaiser Permanente Health Plan members receiving chronic oral bisphosphonate therapy, and 1,005 patients reporting pertinent dental symptoms or complications after dental procedures were examined. Those without BRONJ but with concerning symptoms were referred for clinical evaluation, including imaging. Among the subset who received maxillofacial imaging, we identified those with stage 0 disease and abnormal radiographic features.

Results

There were a total of 30 patients without exposed bone but with concerning symptoms who received maxillofacial imaging (panoramic radiography or computed tomography) in the context of clinical care. Among these 30 patients, 10 had stage 0 disease with similar radiographic features of regional or diffuse osteosclerosis in clinically symptomatic areas, most with extension beyond the involved site. Other findings in these 10 patients included density confluence of cortical and cancellous bone, prominence of the inferior alveolar nerve canal, markedly thickened and sclerotic lamina dura, uniform periradicular radiolucencies, cortical disruption, lack of bone fill after extraction, and a persisting alveolar socket. None had exposed bone develop during 1-year follow-up. The remaining 20 patients had normal or localized radiographic findings consistent with odontogenic pathology.

Conclusion

In 10 of 30 symptomatic patients referred for clinical evaluation and imaging, a consistent finding was conspicuous osteosclerosis in clinically symptomatic areas characteristic of stage 0 disease. These data support the need to better understand radiographic features associated with bisphosphonate exposure and to determine whether osteosclerosis is a specific finding indicative of the risk for progression to BRONJ.

Section snippets

Materials and Methods

The Predicting Risk of Osteonecrosis with Bisphosphonate Exposure (PROBE) Study was conducted by Kaiser Permanente Northern California in 2007 to ascertain the prevalence of BRONJ among adult members with a history of chronic oral bisphosphonate therapy, excluding those with known exposure to intravenous bisphosphonates.¹⁰ Among 8,572 mailed survey respondents, 2,159 individuals reporting osteonecrosis, exposed bone, gingival sores, moderate periodontal disease, persistent dental symptoms, or

Results

Among the 1,005 patients undergoing clinical examination (excluding BRONJ, osteomyelitis, or implant complications),¹⁰ there were a total of 30 individuals with findings concerning for development of BRONJ (persisting bone pain, delayed healing after extraction, infection or periodontal fistula not related to caries, or unexplained tooth mobility), who underwent radiographic imaging during clinical follow-up. Within this subset, 10 patients had radiographic evidence of regional or diffuse

Discussion

A wide spectrum of radiographic features have recently been reported in BRONJ, with the emergence of typical patterns now readily identifiable in affected patients.18, 19, 20, 21, 22, 23, 24 These include osteosclerosis, thickened and disorganized medullary trabeculation, cortical disruption, increased thickness of the lamina dura and IAN canal margins, periosteal bone formation, and sequestration.18, 19, 20, 21, 22, 23, 24 In our cohort of stage 0 patients with radiographic abnormalities, a

Acknowledgments

The authors sincerely appreciate the Maxillofacial Surgery Clinics at Kaiser Permanente Oakland, South Sacramento, and Santa Clara for their support of the study visits and for providing follow-up care of patients who had concerning symptoms or findings. They also thank Jingrong Yang, Malini Chandra, Rita Hui, and Lindsay Kwong for their assistance in data extraction.

J.C.L. has a household family member who receives research funding from GlaxoSmithKline and Johnson & Johnson. A non-household

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Cited by (102)

Depletion of macrophages deteriorates bisphosphonate-related osteonecrosis of the jaw-like lesions in mice
2023, Bone
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a potentially intractable disease with no definitive pathophysiology and no treatment and prevention strategies. This study aimed to investigate whether time-selective depletion of macrophages worsens BRONJ-like lesions in mice. A murine model of high-prevalence BRONJ-like lesions in combination with zoledronate/chemotherapeutic drug administration and tooth extraction was created according to the methods of our previous studies. Daily intra-oral submucosal administration of clodronate-loaded liposomes, which temporarily depletes systemic macrophages, was performed immediately after tooth extraction. Spleens, femora, tibiae, and maxillae were dissected 2 weeks after extraction to evaluate BRONJ-like lesions and systemic conditions by micro-computed tomography analysis, histomorphometric and immunofluorescent analyses, and serum chemistry with ELISA. Depletion of macrophages significantly decreased the numbers of local and systemic macrophages and osteoclasts on the bone surface, which markedly worsened osseous healing, with increased necrotic bone and empty lacunae in the existing alveolar bone and newly formed bone in the extraction sockets, and soft tissue healing, with decreased collagen production and increased infiltration of polymorphonuclear cells. Interestingly, the depletion of macrophages significantly shifted macrophage polarization to M1 macrophages through an increase in F4/80⁺CD38⁺ M1 macrophages and a decrease in F4/80⁺CD163⁺ M2 macrophages, with decreases in the total number of F4/80⁺ macrophages. These data demonstrated that severe inhibition of osteoclasts in bone tissue and polarization shifting of macrophages in soft tissue are essential factors associated with BRONJ.
Distinct immunopathology in the early stages between different antiresorptives-related osteonecrosis of the jaw-like lesions in mice
2020, Bone
There is limited information about denosumab-related osteonecrosis of the jaw (DRONJ), unlike bisphosphonate-related ONJ (BRONJ). The mode of action is clearly different between denosumab and bisphosphonates. DRONJ occurs mainly following tooth extraction in cancer patients treated with the combination of denosumab and other drugs including chemotherapy. However, DRONJ animal models similar to these clinical situations have not been developed. The aims of this study were to 1) create a new model of high-prevalence chemotherapy/anti-RANKL antibody-related ONJ-like lesions to mimic patients receiving a denosumab/chemotherapy combination; and 2) compare the histopathological and immunopathological findings in the early stages of BRONJ-like and anti-RANKL antibody-related ONJ-like lesions. Cyclophosphamide (CY) and anti-mouse RANKL monoclonal antibody (mAb) or zoledronate combination therapy (CY/mAb and CY/ZA, respectively) was performed to create ONJ-like lesions in female C57BL/6J mice. Both maxillary first molars were extracted at 3 weeks after drug administration. The animals were euthanized at either 2 or 4 weeks after tooth extraction. Increased necrotic bone and empty lacunae with decreased living bone and osteocyte numbers were common histopathological findings in CY/mAb- and CY/ZA-induced impaired wound healing at 4 weeks after tooth extraction, and they were diagnosed as ONJ-like lesions based on validation of BRONJ and DRONJ in humans. In areas of impaired healing at 2 weeks post-extraction, decreases in angiogenesis and F4/80⁺LYVE-1⁻ macrophages were noted as common immunopathological findings, although anti-angiogenesis was worse with CY/mAb than with CY/ZA. Interestingly, CY/mAb did not reduce F4/80⁺LYVE-1⁺ cells and normal lymphangiogenesis remained, whereas CY/ZA profoundly suppressed the larger size of F4/80⁺LYVE-1⁺ cells, similar to vessels with a concomitant decrease in lymphangiogenesis. Therefore, the distribution of the larger size of F4/80⁺LYVE-1⁺ cells differed in the early stages between different antiresorptive-induced ONJ-like lesions in conjunction with lymphangiogenesis, although the histopathological findings were similar. These findings suggest that the pathogenesis of BRONJ and DRONJ may differ due to the distributions of F4/80⁺LYVE-1⁺ tube-like-structured cells.
A comparison of the cone beam computed tomography findings in medication-related osteonecrosis of the jaws related to denosumab versus bisphosphonates: an observational pilot study
2020, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
The aim of this study was to compare the radiographic abnormalities on cone beam computed tomography (CBCT) in patients with medication-related osteonecrosis of the jaws (MRONJ) related to denosumab use versus bisphosphonate use.
The study included 34 consecutive patients with MRONJ who had a history of exclusive use of denosumab (n = 17) or bisphosphonates (n = 17) and had undergone CBCT for determination of extent of disease. Demographic data of the patients were collected. Differences in radiologic characteristics between patients with denosumab-related osteonecrosis of the jaws (DRONJ) and those with bisphosphonate-related osteonecrosis of the jaws (BRONJ) were scored and studied on CBCT.
In patients with DRONJ, sequestra (P = .015) and lysis of the cortical border of the jaw (P = .033) were significantly less common than in patients with BRONJ. Subperiosteal bone formation did not differ between the groups (P = .545). There was no association between stage of disease and duration of drug therapy or duration of symptoms for either medication group.
The radiologic features of DRONJ may be different from those of BRONJ with regard to the presence of sequestra and cortical lysis and might, therefore, be improperly diagnosed. Underestimation and undertreatment of DRONJ may potentially lead to progression of disease and, thus, make treatment more difficult.
Comparison of findings of radiographic and fractal dimension analyses on panoramic radiographs of patients with early-stage and advanced-stage medication-related osteonecrosis of the jaw
2019, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
The aim of this study was to compare the panoramic radiographs of patients with early-stage and advanced-stage medication-related osteonecrosis of the jaw (MRONJ) for differences in radiographic findings and fractal dimension (FD).
Data were collected from the medical records of 66 patients confirmed as having MRONJ. Panoramic radiographs of 66 patients (group I; without bone exposure; and group II; with bone exposure) were evaluated for the following signs; osteolysis, cortical erosion, focal and diffuse sclerosis, sequestrum, lamina dura thickening, enhancement of the inferior alveolar canal (IAC), persistent alveolar socket, pathologic fractures, and enhancement of the external oblique ridge. FD values were also compared between groups.
The signs of focal and diffuse sclerosis, sequestrum, and enhancement of the IAC were observed significantly more often in group II than group I (P < .05). The mean FD values were 1.42 ± 0.11 in group I and 1.44 ± 0.18 in group II and were significantly different only in 1 region but not significantly different overall.
Radiographic alterations of bone structures appeared more frequently in patients with advanced stages of MRONJ. No significant difference was detected in the FD values among the tested regions except the cancellous bone above the mandibular canal on the distal side of the mental foramen.
Medication-related osteonecrosis of the jaw in a minipig model: Parameters for developing a macroscopic, radiological, and microscopic grading scheme
2019, Journal of Cranio-Maxillofacial Surgery
To devise a macroscopic, radiological, and histological scale for assessing pathological changes associated with medication-related osteonecrosis of the jaw in a minipig model.
Medication-related osteonecrosis of the jaw was induced in Göttingen minipigs by weekly intravenous administration of bisphosphonate (zoledronic acid) combined with a tooth extraction procedure. Controls either did not receive zoledronic acid or did not undergo tooth extraction. After 20 weeks, minipigs were euthanized and underwent computed tomography and micro-computed tomography scanning. The mandible underwent additional histological examination.
The most consistent macroscopic findings in animals that had developed bisphosphonate-related osteonecrosis of the jaw (BRONJ) were necrotic, denuded bone, and formation of fistula and pus. Under radiological examination, impaired extraction socket healing, decrease in attenuation of bone beneath the extraction site, and periosteal reaction were observed. Under histological examination, demineralization of the extracellular bone matrix, denuding of bone, and osteonecrosis were recorded.
These parameters were used to develop a scoring system for grading BRONJ.
Across-sectional survey on medication-related osteonecrosis of the jaws' knowledge and awareness in a sample of dental society
2019, Journal of Cranio-Maxillofacial Surgery
Medication-related osteonecrosis of the jaws (MRONJ) is a prominent complication and growing problem related to the oral and maxillofacial region due to antiresorptive and antiangiogenic agents. Awareness about MRONJ is crucial for all dental practitioners identify ‘at risk’ patients for appropriate advice and management. This cross-sectional survey aimed to appraise MRONJ awareness and knowledge among dentists.
A questionnaire-based survey was carried out through one hundred and seventy eight dentist who recruited in three groups; the first group comprised 113 general dental practitioners (GDP), 33 dental radiologist (DR) included in the second, and 32 oral and maxillofacial surgeon (OMS) in the third group. MRONJ awareness was evaluated by asking all respondents a question of “Did you heard about MRONJ? In addition, the detailed knowledge on the subject in question were addressed through fourteen, nine, and three questions for OMSs, DRs, and GDPs respectively.
A significant difference were existed among groups with a rate of MRONJ's awareness of 33.6%, 48.5%, and 84.4% for GDPs, DRs, and OMSs respectively. Concerning MRONJ knowledge, significantly highest rates seen in OMSs set with 48.55%. In contrast, the average scores of DRs were 30.64%, and the GDPs group recorded the least value with 16.67%.
Strengthen the MRONJ awareness and knowledge among general dentists and dental specialists are essential to identify ‘at risk’ patients for appropriate advice and management.

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Basic and patient-oriented researchRadiographic Findings in Bisphosphonate-Treated Patients With Stage 0 Disease in the Absence of Bone Exposure

Purpose

Materials and Methods

Results

Conclusion

Section snippets

Materials and Methods

Results

Discussion

Acknowledgments

Am J Med

J Oral Maxillofac Surg

J Oral Maxillofac Surg

J Oral Maxillofac Surg

J Oral Maxillofac Surg

J Oral Maxillofac Surg

J Oral Maxillofac Surg

J Oral Maxillofac Surg

Joint Bone Spine

J Oral Maxillofac Surg

J Oral Maxillofac Surg

Oral Surg Oral Med Oral Pathol Oral Radiol Endod

Oral Surg Oral Med Oral Pathol Oral Radiol Endod

Clin Radiol

J Oral Maxillofac Surg

Biochim Biophys Acta

Oral Surg Oral Med Oral Pathol Oral Radiol Endod

J Oral Maxillofac Surg

Bone

Basic and patient-oriented research
Radiographic Findings in Bisphosphonate-Treated Patients With Stage 0 Disease in the Absence of Bone Exposure