Dataset Information

Use of imatinib in the prevention of heterotopic ossification.

ABSTRACT:

Background

Heterotopic ossification (HO) is a common complication following orthopedic and trauma surgery, which may have substantial negative effects on the postoperative outcome. Angiogenesis appears to play a critical role in heterotopic ossification. One of the involved signaling molecules is platelet-derived growth factor (PDGF) which may be inhibited by imatinib.

Questions/purposes

Our goal was to prevent HO by pharmacologically interfering with the molecular signaling pathways involved in the developmental process. We hypothesized that by administering a proven inhibitor of PDGF expression, heterotopic bone formation may be prevented.

Methods

The effect of imatinib on HO formation was studied in a murine model which reliably produces islets of HO within the soft tissue following Achilles tenotomy. The control group underwent Achilles tenotomy only. The imatinib group received imatinib mesylate. After trial completion, the limbs were harvested and scanned by micro-CT. Heterotopic bone volume was then identified and quantified.

Results

The mean volume of heterotopic bone formed in the control group was 0.976mm(3) compared to 0.221 mm(3) in the imatinib group. The volume of HO in the treatment group was reduced by 85% compared to the control group.

Conclusions

The administration of imatinib was associated with a significantly reduced volume of HO. This may be due to the inhibitory effect of imatinib on the PDGF signaling pathway during development of HO.

Clinical relevance

The successful reduction of HO formation following imatinib administration has led to further insight concerning the pathogenesis of HO which in the future may lead to new clinical approaches towards the prevention of HO.

SUBMITTER: Werner CM

PROVIDER: S-EPMC3757489 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Publications

Use of imatinib in the prevention of heterotopic ossification.

Werner Clément M L CM Zimmermann Stefan M SM Würgler-Hauri Carola C CC Lane Joseph M JM Wanner Guido A GA Simmen Hans-Peter HP

HSS journal : the musculoskeletal journal of Hospital for Special Surgery 20130621 2

<h4>Background</h4>Heterotopic ossification (HO) is a common complication following orthopedic and trauma surgery, which may have substantial negative effects on the postoperative outcome. Angiogenesis appears to play a critical role in heterotopic ossification. One of the involved signaling molecules is platelet-derived growth factor (PDGF) which may be inhibited by imatinib.<h4>Questions/purposes</h4>Our goal was to prevent HO by pharmacologically interfering with the molecular signaling pathw ...[more]

PMID: 24426864

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Project description:Heterotopic Ossification (HO) is a potential long-term complication in orthopaedic surgery. It is commonly classified according to the Brooker classification, which is based on radiological findings. To our knowledge the correlation of histological features to the Brooker grade is unknown as is the association between HO and the indication for revision. The aim of this paper is to analyze the ossification grade of HO tissue in patients undergoing revision hip and knee arthroplasty and to propose a histologically based classification system for HO. We also assess the relationship between the grade of HO and the indication for revision (septic and aseptic revision). From January to May 2019 we collected 50 human HO samples from hip and knee revision arthroplasty cases. These tissue samples were double-blinded and sent for histopathological diagnostic. Based on these results, we developed a classification system for the progression of HO. The grade of ossification was based on three characteristics: Grade of heterotopic ossification (Grade 1-3), presence of necrosis (N0 or N1) and the presence of osteomyelitis (HOES-Score Type 1 to 5). Demographic data as well as surgical details and indication for surgery was prospectively collected from clinical records. Fifty tissue samples were harvested from 44 hips and 6 knee joints. Of these 33 exhibited Grade I ossifications (66%), followed by 11 Grade II (22%) and one Grade III (2%). Necrosis was noted in two tissue samples (4%) and 2 more had osteomyelitis findings according to HOES-Score. Six samples (12%) with radiologically suggestive of HO turned out to be wear-induced synovitis, SLIM Type 1. Of these cases 16 were septic (32%) and 34 aseptic (68%) revisions. Most of the HO tissue samples were classified as a low-grade. High-grade ossification-Score is rare. Higher grades of ossification seem to be associated with septic revision cases. Wear-induced synovitis potentially influences HO development. A histological scoring system for ossification grading can be derived from the data presented in this study.

Project description:PurposeHeterotopic ossification (HO) is a potentially disabling disorder of ectopic bone formation secondary to orthopedic surgery or trauma. In this retrospective analysis we evaluated the outcomes of patients who received radiation therapy (RT) for HO prophylaxis.Methods and materialsA total of 287 patients who received RT for HO prophylaxis at a major trauma center from 2007 to 2018 were analyzed. Data collected included types of injury, surgery, time intervals between key events, development of postprophylaxis HO, and secondary malignancies. Associations between various factors and the risk of developing HO were analyzed. Kaplan-Meier analysis was used to estimate failure rates.ResultsThe most common indication for RT was traumatic acetabular fracture (83.3%). Twelve patients (4.2%) developed postprophylaxis HO with a median time to failure of 8.6 months (2.8-24.5). Kaplan-Meier 1-, 2-, and 5-year failure rates were 3.7%, 4.4%, and 7.4%, respectively. Injury type and timing of RT were not associated with the risk of failure, but we observed a trend of increased risk of failure in patients with longer time between surgery and RT (odd ration [OR] 1.68, P = .056). Current or former smokers (51.7%) were less likely to fail (OR 0.10, P = .03). There was no incidence of in-field secondary malignancy.ConclusionsThere was no significant association between injury and fracture type, surgical approach, or timing of RT and development of HO, contrary to published reports of increased HO risk with certain surgical approaches and longer time intervals between injury and surgery, suggesting that prophylactic RT might play a role in mitigating these effects. Decreased risk of postprophylaxis HO among former or current smokers was unexpected. No secondary malignancy in the RT field was identified, although the median follow-up was only 17 months. Compared with published HO incidences (17%-39%) in patients who receive no prophylaxis after traumatic acetabular fractures, our results are highly suggestive of the efficacy of prophylactic RT.

Project description:BackgroundTo prevent symptomatic heterotopic ossification (HO) and guide primary prophylaxis in patients with combat wounds, physicians require risk stratification methods that can be used early in the postinjury period. There are no validated models to help guide clinicians in the treatment for this common and potentially disabling condition.Questions/purposesWe developed three prognostic models designed to estimate the likelihood of wound-specific HO formation and compared them using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) to determine (1) which model is most accurate; and (2) which technique is best suited for clinical use.MethodsWe obtained muscle biopsies from 87 combat wounds during the first débridement in the United States, all of which were evaluated radiographically for development of HO at a minimum of 2 months postinjury. The criterion for determining the presence of HO was the ability to see radiographic evidence of ectopic bone formation within the zone of injury. We then quantified relative gene expression from 190 wound healing, osteogenic, and vascular genes. Using these data, we developed an Artificial Neural Network, Random Forest, and a Least Absolute Shrinkage and Selection Operator (LASSO) Logistic Regression model designed to estimate the likelihood of eventual wound-specific HO formation. HO was defined as any HO visible on the plain film within the zone of injury. We compared the models accuracy using area under the ROC curve (area under the curve [AUC]) as well as DCA to determine which model, if any, was better suited for clinical use. In general, the AUC compares models based solely on accuracy, whereas DCA compares their clinical utility after weighing the consequences of under- or overtreatment of a particular disorder.ResultsBoth the Artificial Neural Network and the LASSO logistic regression models were relatively accurate with AUCs of 0.78 (95% confidence interval [CI], 0.72-0.83) and 0.75 (95% CI, 0.71-0.78), respectively. The Random Forest model returned an AUC of only 0.53 (95% CI, 0.48-0.59), marginally better than chance alone. Using DCA, the Artificial Neural Network model demonstrated the highest net benefit over the broadest range of threshold probabilities, indicating that it is perhaps better suited for clinical use than the LASSO logistic regression model. Specifically, if only patients with greater than 25% risk of developing HO received prophylaxis, for every 100 patients, use of the Artificial Network Model would result in six fewer patients who unnecessarily receive prophylaxis compared with using the LASSO regression model while not missing any patients who might benefit from it.ConclusionsOur findings suggest that it is possible to risk-stratify combat wounds with regard to eventual HO formation early in the débridement process. Using these data, the Artificial Neural Network model may lead to better patient selection when compared with the LASSO logistic regression approach. Future prospective studies are necessary to validate these findings while focusing on symptomatic HO as the endpoint of interest.Level of evidenceLevel III, prognostic study.

Dataset Information

Use of imatinib in the prevention of heterotopic ossification.

Background

Questions/purposes

Methods

Results

Conclusions

Clinical relevance

Publications

Use of imatinib in the prevention of heterotopic ossification.

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