Suppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the mechanism of each disease

doi:10.1016/j.ijom.2011.12.016

International Journal of Oral and Maxillofacial Surgery

Volume 41, Issue 3, March 2012, Pages 283-289

https://doi.org/10.1016/j.ijom.2011.12.016 Get rights and content

Abstract

Statistically, significant numbers of central bone specimens of suppurative osteomyelitis of the jaws (SOJ), bisphosphonate induced osteonecrosis of the jaws (BIONJ), and osteoradionecrosis of the jaws (ORNJ) were compared. All three evidenced the common finding of necrotic bone with empty osteocytic lacunae, Haversian and Volkmann canals, but each showed a distinctive histopathologic pattern indicating a different disease mechanism and treatment options. Suppurative osteomyelitis was characterized by intense marrow inflammation and marrow vessel thrombosis with retention of viable osteoclasts and periosteum. Bisphosphonate induced osteonecrosis was characterized by an empty marrow space with empty Howship's lacunae and an absence of osteoclasts but viable periosteum. Osteoradionecrosis was characterized by a collagenous hypocellular, hypovascular marrow space and nonviable periosteum. Histologic evidence in SOJ indicates a microorganism provoked intense inflammation and marrow vascular thrombosis creating an environment conducive to continual bacterial proliferation. BIONJ is seen as a non-inflammatory drug toxicity to bone by osteoclastic death leading to over suppression of bone renewal, and ORN as another non-inflammatory condition caused by a high linear energy transfer that impairs or kills numerous cell types in the field of radiation including periosteum, bone, and all soft tissue.

Section snippets

Materials and methods

Debrided or resected block bone specimens were obtained from 23 cases of SOJ, 37 cases of BIONJ, and 45 cases of ORNJ from 1 January 2005 to 30 December 2010. Materials were exempt from institutional review board approval as names and medical record were redacted from the study materials. Criteria for the diagnosis of SOJ were an absence of radiotherapy and bisphosphonate use; an identified source of infection; and the presence of pus, or radiographic evidence of osteolysis. Criteria for the

Suppurative osteomyelitis

All 23 cases (100%) of SOJ identified necrotic bone as evidenced by empty osteocytic lacunae, absence of osteoblastic rimming, and empty Haversian canals. All 23 cases (100%) identified inflammatory cells in the marrow space judged to be heavy 13/23 (57%), moderate 7/23 (30%), and slight 3/23 (13%). The inflammatory cells were a mixture of neutrophils, plasma cells, some histiocytes, and lymphocytes with no pattern or predominance consistently noted (Fig. 1). Osteoclasts were noted to be

Discussion

The common finding amongst the SOJ, BIONJ, and ORNJ specimens was necrotic bone with empty Haversian systems and Volkmann canals. All three evidenced an absence of normal cells in the marrow space. SOJ consistently showed viable inflammatory cells in the marrow spaces consistent with the term osteomyelitis which literally translates into inflammation of the marrow in bone. By contrast, BIONJ showed empty marrow spaces devoid of all cellular elements and normal cellular products. ORNJ showed

Funding

This study was supported by internal University of Miami Division of Oral and Maxillofacial Surgery funds.

Competing interests

The authors have no conflict of interest related to pharmaceutical companies or radiation therapy units involved in this study.

Ethical approval

Not required.

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Cited by (96)

Risk Factors for Infection Recurrence After Surgical Resection of Advanced Stage Osteonecrosis of the Mandible
2024, Journal of Oral and Maxillofacial Surgery
Advanced stage osteoradionecrosis (ORN) and medication-related osteonecrosis of the jaw (MRONJ) are challenging disease entities requiring multimodal therapy including surgical resection. However, risk factors associated with infection recurrence are poorly understood.
The purpose of this study was to identify risk factors associated with infection recurrence following resection of advanced stage ORN or MRONJ of the mandible.
This was a retrospective cohort study including patients who underwent segmental mandibulectomy for management of ORN or MRONJ between 2016 and 2021 at the authors' institution. Subjects who did not have margin viability data were excluded.
The primary predictor variable was viability of resection margins on histopathologic analysis (viable or nonviable). Secondarily, other risk factors categorized as demographic (age, sex, race), medical (comorbidities), and perioperative (reconstructive modality, antibiotic duration, microbiological growth) were evaluated.
The primary outcome variable was time to infection recurrence defined as time from surgical resection to clinical diagnosis of a fistula tract, abscess, or persistent inflammatory symptoms necessitating surgical intervention.
Not applicable.
Descriptive and bivariate statistics were used to identify associations between risk factors and time to infection recurrence. A significance level of P ≤ .05 was considered significant.
The cohort consisted of 57 subjects with a mean age of 63.3 ± 10.0 years (71.9% Male, 75.4% White) treated for ORN (47.4%) or MRONJ (52.6%). A total of 19/57 (33%) subjects developed a recurrence of infection with 1 and 2 year survival of 75.8 and 66.2%, respectively. Nonviable resection margins were associated with earlier time to infection recurrence (P ≤ .001, hazard ratio (HR) = 11.9, 95% confidence interval (CI) = 3.84 to 36.7) as was younger age (P = .005, HR = 0.921, 95% CI = 0.869 to 0.976) and atypical pathogen growth on culture (P = .002, HR = 8.58, 95% CI = 2.24 to 32.8).
Histopathologic margin viability was associated with earlier time to infection recurrence following resection of advanced stage ORN or MRONJ of the mandible. Additional studies are needed to identify interventions that may improve outcomes in this demographic.
Duration and timing of bisphosphonate treatment as factors determining osteoblast mineralization
2022, Journal of Oral Biology and Craniofacial Research
Alendronate is a drug for the treatment of excessive bone resorption. Alendronate reduces osteoblast viability and mineralization in a dose-dependent manner. Other views of alendronate could affect mineralization. Therefore, the effects of timing and duration of alendronate treatment on mineralization were investigated.
MC3T3 cells were treated with alendronate at different time periods ranging from 1 to 3 weeks. Mineralization was quantified using image analysis. Cell viability was measured by Thiazolyl Blue Tetrazolium Bromide assay.
At low concentration (1 μM), 2–3 weeks of alendronate addition decreased mineralized area and staining intensity. Longer exposure to alendronate had more effect than short exposure. At moderate to high concentrations (5–10 μM), every alendronate treatment timing inhibited mineralization. Week 3 treatment of alendronate showed less reduction of mineralization than other time treatments. Furthermore, 10 μM alendronate reduced osteoblast viability at week 1, week 1–2, and week 1–3.
Timing and duration of alendronate addition inhibited total mineralization. Longer period of treatment reduced mineralization more than short period of treatment. In addition, reduction of total mineralization depended upon both osteoblast viability and function.
Osteocyte Apoptosis, Bone Marrow Adiposity, and Fibrosis in the Irradiated Human Mandible
2022, Advances in Radiation Oncology
Citation Excerpt :
Few studies on irradiated human mandibles report data on marrow adiposity. Marx et al28 described histologic findings in 45 ORN specimens in a qualitative report and found an absence of fat cells in the bone marrow. Instead, the bone marrow in these specimens was replaced with acellular collagen.28
To assess the effect of radiation therapy on osteocyte apoptosis, osteocyte death, and bone marrow adipocytes in the human mandible and its contribution to the pathophysiology of radiation damage to the mandibular bone.
Mandibular cancellous bone biopsies were taken from irradiated patients and nonirradiated controls. Immunohistochemical detection of cleaved caspase-3 was performed to visualize apoptotic osteocytes. The number of apoptotic osteocytes per bone area and per total amount of osteocytes, osteocytes per bone area, and empty lacunae per bone area were counted manually. The percentage fibrotic tissue and adipose tissue per bone marrow area, the percentage bone marrow of total area, and the mean adipocyte diameter (μm) was determined digitally from adjacent Goldner stained sections.
Biopsies of 15 irradiated patients (12 men and 3 women) and 7 nonirradiated controls (5 men and 2 women) were assessed. In the study group a significant increase was seen in the number of empty lacunae, the percentage of adipose tissue of bone marrow area, and the adipocyte diameter. There was no significant difference in bone marrow fibrosis nor apoptotic osteocytes between the irradiated group and the controls.
Irradiation alone does not seem to induce excessive bone marrow fibrosis. The damage to bone mesenchymal stem cells leads to increased marrow adipogenesis and decreased osteoblastogenic potential. Early osteocyte death resulting in avital persisting bone matrix with severely impaired regenerative potential may contribute to the vulnerability of irradiated bone to infection and necrosis.
Actinomyces and MRONJ: A retrospective study and a literature review
2021, Journal of Stomatology, Oral and Maxillofacial Surgery
Citation Excerpt :
A total of 83 specimens revealed the presence of Actinomyces infection (82.18%). In the histological specimen some osteoclasts are detached from the bone, whereas some others are nonviable: this confirms the apoptotic process induced by bisphosphonates, proposed in many articles [3,56,57]. Criteria used for the diagnosis of Actinomyces colonies include the presence of filamentous bacteria, aggregated to constitute a mass, with colour shades between the centre and periphery on the colony, visible with H&E stains (the so called “sun-ray” effect) and with the Gram stain [21].
The AAOMS in 2014 changed from BRONJ to the term Medication-Related Osteonecrosis of the Jaw (MRONJ), because of the growing number of osteonecrosis cases associated with other antiresorptive and antiangiogenic therapies. Even if the drugs involved are different, the histopathological findings are the same. Colonies of Actinomyces are encountered in most cases. The aim of the present study is to report on Actinomyces prevalence among the cases of MRONJ, taking into consideration also antiresorptive and antiangiogenic therapies in the literature and in our sample between 2005 and 2020.
The review was performed using the database Medline the linkage between Actinomyces infection and MRONJ. The retrospective study was conducted on patients between with clinical and radiological manifestations of MRONJ May 2005 and February 2020.
A total of 42 articles were found, 30 publications have been taken into consideration for the review. A total of 114 patients have been examined at the Padua Hospital. A total of 101 oncological patients presented the histological confirmation of MRONJ. 83 specimens revealed the presence of Actinomyces infection (82.18%).
Actinomyces-associated lesions are frequent and present a wide spectrum of clinical manifestation.
Impaired Callus Formation in Pathological Mandibular Fractures in Medication-Related Osteonecrosis of the Jaw and Osteoradionecrosis
2021, Journal of Oral and Maxillofacial Surgery
Nonsurgical treatment of mandibular fractures secondary to medication-related osteonecrosis of the jaw (MRONJ) or osteoradionecrosis (ORN) mostly results in nonunion, whereas nonsurgical fracture treatment of atrophic fractures can achieve favorable results in selected cases. The aim of this study was to compare callus formation in pathological mandibular fractures due to MRONJ, ORN, or extreme mandibular atrophy.
A retrospective cohort study reviewing the medical records of all MRONJ-, ORN-, or atrophy-related fractures treated at the departments of maxillofacial surgery in the Leuven or Lille university hospitals between 2010 and 2019 was undertaken. The primary predictor variable in this study was disease state (MRONJ, ORN, or extreme mandibular atrophy). The primary outcome variable was callus formation after 1 month of follow-up (present, absent). Additional study variables measured included patient age and gender. T-tests, Fisher exact tests, and multiple logistic regression were used for statistical analysis. The significance level was set at P < .05.
Seventy patients were analyzed (12 MRONJ cases, 54 ORN fractures, 4 atrophic fractures). The callus formation prevalence in nonsurgically approached fractures secondary to ORN and MRONJ after 1 month of follow-up was 3.03% (2/66 cases). In contrast, callus was detected in all patients in the mandibular atrophy-related fracture group. Osteonecrosis was statistically correlated with impaired callus formation (P = .0121).
Whereas one would expect indirect fracture healing and thus callus formation to occur in all non-surgically treated fractures, our data demonstrate its absence in the majority of MRONJ- and ORN-related fractures. Multiple plausible explanations for this phenomenon were identified: periosteal damage with loss of callus-forming cells, compromised vasculature, and bacterial colonization.
Are Oral Antibiotics an Effective Alternative to Intravenous Antibiotics in Treatment of Osteomyelitis of the Jaw?
2021, Journal of Oral and Maxillofacial Surgery
To review treatment of osteomyelitis of the jaw (OMJ) and determine whether antibiotic route and/or length of administration impacts resolution of infection postsurgically.
The investigators designed a retrospective cohort study enrolling a sample of patients treated at Harborview Medical Center from January 1, 2009 to December 31, 2019. The primary predictor variable was antibiotic administration route: oral (PO) only, intravenous (IV) only, IV transitioned to PO (IV + PO), or none. The secondary predictor was duration of antibiotic therapy (≤6 weeks or >6 weeks). The primary outcome variable was resolution of infection at 2 months follow-up posttreatment completion. The secondary outcome variable was number of surgeries to resolution of infection. Descriptive, bivariate, and multiple linear regression statistics were computed, with statistical significance set at P < .05.
Sixty-seven individuals met inclusion criteria (38 male), mean age 51 years (18 to 88). Forty-nine (73%) received PO antibiotics, 12 (18%) IV + PO, 3 (4%) IV, and 3 (4%) none. Both PO and IV antibiotics were associated with clinical resolution (P = .022, .005, respectively) compared with debridement alone. Antibiotic duration of ≤6 weeks compared with >6 weeks was not significant. Seventy-six percent (51 of 67) required only 1 surgery. In the multivariate logistic regression, PO was associated with clinical resolution (P = .025, OR = 5.05). Penicillin allergy (P = 0.049, OR = 0.223) and diabetes (P = .008, OR = 0.104) were adversely associated with outcome.
OMJ was successfully treated with oral antibiotics and surgery. Prescribing 6 weeks of IV antibiotics may be antiquated. Clinicians should consider oral penicillins as first line whenever possible. Further studies are recommended.

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Research PaperClinical PathologySuppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the mechanism of each disease

Abstract

Section snippets

Materials and methods

Suppurative osteomyelitis

Discussion

Funding

Competing interests

Ethical approval

Bone

J Oral Maxillofac Surg

Bone

American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws

J Oral Maxillofacial Surg

Anti-remodeling agents influence osteoblast activity differently in modeling and remodeling – associated bone formation

Calcif Tissue Int

Research Paper
Clinical Pathology
Suppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the mechanism of each disease