Failure of Indomethacin and Radiation to Prevent Blast-induced Heterotopic Ossification in a Sprague-Dawley Rat Model

Abstract

Background Although use of nonsteroidal antiinflammatory drugs and low-dose irradiation has demonstrated efficacy in preventing heterotopic ossification (HO) after THA and surgical treatment of acetabular fractures, these modalities have not been assessed after traumatic blast amputations where HO is a common complication that can arise in the residual limb. Questions/purposes The purpose of this study was to investigate the effectiveness of indomethacin and irradiation in preventing HO induced by high-energy blast trauma in a rat model. Methods Thirty-six Sprague-Dawley rats underwent hind limb blast amputation with a submerged explosive under water followed by irrigation and primary wound closure. One group (n = 12) received oral indomethacin for 10 days starting on postoperative Day 1. Another group (n = 12) received a single dose of 8 Gy irradiation to the residual limb on postoperative Day 3. A control group (n = 12) did not receive either. Wound healing and clinical course were monitored in all animals until euthanasia at 24 weeks. Serial radiographs were taken immediately postoperatively, at 10 days, and every 4 weeks thereafter to monitor the time course of ectopic bone formation until euthanasia. Five independent graders evaluated the 24week radiographs to quantitatively assess severity and qualitatively assess the pattern of HO using a modified This work was funded by the Department of Defense Peer Reviewed Orthopaedic Research Program (VDP, Principal Investigator; Award Number: W81XWH-10-1-0975). Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA-approval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

Progressive brachial plexopathy secondary to heterotopic ossification formation after shoulder trauma: a case report

“…However, an animal model study demonstrated both modalities to be ineffective in preventing HO in blast injuries. 19 Additionally, radiation has some significant disadvantages, including cost and risk associated with radiation exposure. 20 Thus, NSAIDs are generally the preferred initial treatment for HO prophylaxis barring any medical contraindications.…”

“…Current data suggest that radiation and NSAIDs are equally effective in preventing HO. However, an animal model study demonstrated both modalities to be ineffective in preventing HO in blast injuries 19. Additionally, radiation has some significant disadvantages, including cost and risk associated with radiation exposure 20.…”

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva

“…Clinical studies have shown some positive results for patients with non-genetic HO [ 128 ]. Surprisingly, other types of NSAIDs do not appear to have similar reductions in HO formation; for example, indomethacin was seen to fail to prevent HO in a blast-related HO rat model [ 129 ]. More research is needed to better understand how and which NSAIDs may benefit patients with FOP and how these responses differ from non-genetic HO.…”

In vivo model of human post-traumatic heterotopic ossification demonstrates early fibroproliferative signature

“…Further, it is not possible to correctly predict which patients surviving blast-injuries will develop HO; thus, there is an unmet need to better understand the molecular mechanisms leading to the onset of HO, to develop predictive biomarkers, novel treatment options and preventive strategies. To more thoroughly understand the process by which HO forms, we have utilized a previously described and validated rat blast injury model that appears to reproduce the pathologic factors necessary for the development of post-traumatic HO in the blast-injured limb [16–18]. In this model, Sprague–Dawley rats develop HO in the residual limb following extremity blast amputation without addition of any exogenous osteogenic agents.…”