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Investigation into Possible Association of Oxandrolone and Heterotopic Ossification Following Burn Injury.

ABSTRACT: Oxandrolone, a testosterone analog, is used to counteract the catabolic effects of burn injury. Recent animal studies suggest a possible hormonal association with heterotopic ossification (HO) development postburn. This work examines oxandrolone administration and HO development by exploring historical clinical data bridging the introduction of oxandrolone into clinical practice. Additionally, we examine associations between oxandrolone administration and HO in a standardized mouse model of burn/trauma-related HO. Acutely burned adults admitted between 2000 and 2014, survived through discharge, and had a HO risk factor of 7 or higher were selected for analysis from a single burn center. Oxandrolone administration, clinical and demographic data, and elbow HO were recorded and were analyzed with logistic regression. Associations of oxandrolone with HO were examined in a mouse model. Mice were administered oxandrolone or vehicle control following burn/tenotomy to examine any potential effect of oxandrolone on HO and were analyzed by Student's t test. Subjects who received oxandrolone had a higher incidence of elbow HO than those that did not receive oxandrolone. However, when controlling for oxandrolone administration, oxandrolone duration, postburn day oxandrolone initiation, HO risk score category, age, sex, race, burn size, and year of injury, there was no significant difference between rates of elbow HO between the two populations. In agreement with the review, in the mouse model, while there was a trend toward the oxandrolone group developing a greater volume of HO, this did not reach statistical significance.

SUBMITTER: Thorpe CR

PROVIDER: S-EPMC6587410 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Investigation into Possible Association of Oxandrolone and Heterotopic Ossification Following Burn Injury.

Thorpe Catherine R CR Ucer Ozgurel Serra S Simko Laura C LC Goldstein Richard R Grant Gabrielle G GG Pagani Chase C Hwang Charles C Vasquez Kaetlin K Sorkin Michael M Vaishampayan Anita A Goverman Jeremy J Sheridan Robert L RL Friedstat Jonathan J Schulz John T JT Schneider Jeffrey C JC Levi Benjamin B Ryan Colleen M CM

Journal of burn care & research : official publication of the American Burn Association 20190601 4

Oxandrolone, a testosterone analog, is used to counteract the catabolic effects of burn injury. Recent animal studies suggest a possible hormonal association with heterotopic ossification (HO) development postburn. This work examines oxandrolone administration and HO development by exploring historical clinical data bridging the introduction of oxandrolone into clinical practice. Additionally, we examine associations between oxandrolone administration and HO in a standardized mouse model of burn ...[more]

PMID: 31053861

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Project description:ObjectiveTo demonstrate the pro-osteogenic effect of burn injury on heterotopic bone formation using a novel burn ossicle in vivo model.BackgroundHeterotopic ossification (HO), or the abnormal formation of bone in soft tissue, is a troubling sequela of burn and trauma injuries. The exact mechanism by which burn injury influences bone formation is unknown. The aim of this study was to develop a mouse model to study the effect of burn injury on heterotopic bone formation. We hypothesized that burn injury would enhance early vascularization and subsequent bone formation of subcutaneously implanted mesenchymal stem cells.MethodsMouse adipose-derived stem cells were harvested from C57/BL6 mice, transfected with a BMP-2 adenovirus, seeded on collagen scaffolds (ossicles), and implanted subcutaneously in the flank region of 8 adult mice. Burn and sham groups were created with exposure of 30% surface area on the dorsum to 60°C water or 30°C water for 18 seconds, respectively (n = 4/group). Heterotopic bone volume was analyzed in vivo by micro-computed tomography for 3 months. Histological analysis of vasculogenesis was performed with platelet endothelial cell adhesion molecule staining. Osteogenic histological analysis was performed by Safranin O, Picrosirius red, and aniline blue staining. Qualitative analysis of heterotopic bone composition was completed with ex vivo Raman spectroscopy.ResultsSubcutaneously implanted ossicles formed heterotopic bone. Ossicles from mice with burn injuries developed significantly more bone than sham control mice, analyzed by micro-computed tomography at 1, 2, and 3 months (P < 0.05), and had enhanced early and late endochondral ossification as demonstrated by Safranin O, Picrosirius red, and aniline blue staining. In addition, burn injury enhanced vascularization of the ossicles (P < 0.05). All ossicles demonstrated chemical composition characteristic of bone as demonstrated by Raman spectroscopy.ConclusionsBurn injury increases the predilection to osteogenic differentiation of ectopically implanted ossicles. Early differences in vascularity correlated with later bone development. Understanding the role of burn injury on heterotopic bone formation is an important first step toward the development of treatment strategies aimed to prevent unwanted and detrimental heterotopic bone formation.

Project description:We previously reported the development of a new acquired neurogenic HO (NHO) mouse model, combining spinal cord transection (SCI) and chemical muscle injury. Pathological mechanisms responsible for ectopic osteogenesis after central neurological damage are still to be elucidated. In this study, we first hypothesized that peripheral nervous system (PNS) might convey pathological signals from injured spinal cord to muscles in NHO mouse model. Secondly, we sought to determine whether SCI could lead to intramuscular modifications of BMP2 signaling pathways. Twenty one C57Bl6 mice were included in this protocol. Bilateral cardiotoxin (CTX) injection in hamstring muscles was associated with a two-stage surgical procedure, combining thoracic SCI with unilateral peripheral denervation. Volumes of HO (Bone Volume, BV) were measured 28 days after surgery using micro-computed tomography imaging techniques and histological analyses were made to confirm intramuscular osteogenesis. Volume comparisons were conducted between right and left hind limb of each animal, using a Wilcoxon signed rank test. Quantitative polymerase chain reaction (qPCR) was performed to explore intra muscular expression of BMP2, Alk3 and Id1. Nineteen mice survive the complete SCI and peripheral denervation procedure. When CTX injections were done right after surgery (n = 7), bilateral HO were detected in all animals after 28 days. Micro-CT measurements showed significantly increased BV in denervated paws (1.47 mm3 +/- 0.5) compared to contralateral sides (0.56 mm3 +/-0.4), p = 0.03. When peripheral denervation and CTX injections were performed after sham SCI surgery (n = 6), bilateral HO were present in three mice at day 28. Quantitative PCR analyses showed no changes in intra muscular BMP2 expression after SCI as compared to control mice (shamSCI). Peripheral denervation can be reliably added to spinal cord transection in NHO mouse model. This new experimental design confirms that neuro inflammatory mechanisms induced by central or peripheral nervous system injury plays a key role in triggering ectopic osteogenesis.

Project description:Objective: In spinal cord injury (SCI), heterotopic ossification is a frequent secondary complication, commonly associated with limited range of motion of affected joints, which could lead to secondary disability in activities of daily living. Additionally, heterotopic ossifications might challenge the effect of regeneration-promoting therapies on neurological and functional recovery. This study evaluated the impact of heterotopic ossification on clinical recovery within the first year after SCI. Methods: The study was conducted as a monocentric longitudinal paired cohort study. Recruitment was based on consecutive sampling in the framework of the European Multicenter about Spinal Cord Injury (EMSCI). Recovery profiles were determined using standardized neurological and functional clinical assessments within the 1st year following SCI. All study participants underwent at least two comprehensive standardized neurological and functional clinical examinations according to the International Standards for Neurological Classification of SCI and the Spinal Cord Independence Measure, respectively. Data regarding the diagnosis and treatment of heterotopic ossification were obtained by reviewing the patient medical records. The most similar "digital twin" from the entire EMSCI database were matched in terms of age, acute neurological and functional status to each individual with SCI, and heterotopic ossification. Results: Out of 25 participants diagnosed with heterotopic ossification, 13 individuals were enrolled and matched to control individuals. Most individuals presented with motor complete injury (75%). Ossifications were most frequently located at the hip joints (92%) and mainly occurred within the first 3 months after SCI. Individuals with heterotopic ossification achieved around 40% less functional improvement over time compared to their matched counterparts, whereas neurological recovery was not altered in individuals with SCI and heterotopic ossification. Conclusion: Heterotopic ossification-a common complication of SCI-unfavorably affects functional recovery, which in the end is most relevant for the best possible degree of independence in activities of daily living. Upon presentation with heterotopic ossification, neurological improvement achieved through potential restorative therapies might not translate into clinically meaningful functional improvement. Diagnostic algorithms and effective early prevention/treatment options for heterotopic ossification need to be established to ensure the best possible functional outcome. Clinical Trial Registration: NCT01571531 (https://clinicaltrials.gov).

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Investigation into Possible Association of Oxandrolone and Heterotopic Ossification Following Burn Injury.

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Investigation into Possible Association of Oxandrolone and Heterotopic Ossification Following Burn Injury.

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