Free radical scavengers are more effective than indomethacin in the prevention of experimentally induced heterotopic ossification

Bossche, L. C. Vanden; Maele, Georges Van; Wojtowicz, Iris; Cock, Kevin De; Vertriest, Sofie; Muynck, Martine De; Rimbaut, Steven; Vanderstraeten, Guy

doi:10.1002/jor.20296

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…Vanden Bossche et al 11 already demonstrated the involvement of free radicals in the pathogenesis of HO and found a relationship with the ischemia/reperfusion syndrome. This finding is becoming increasingly important in the determination of when exactly mesenchymal cells, present within soft tissue or fascia, start to differentiate into osteogenic cells.…”

Section: Discussionmentioning

confidence: 96%

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Free radical scavengers versus methylprednisolone in the prevention of experimentally induced heterotopic ossification

Bossche

Maele

Wojtowicz

et al. 2009

Journal Orthopaedic Research

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The etiology of heterotopic ossification (HO) is still obscure, it is difficult to devise an effective preventive or therapeutic approach. The options for the prevention of HO are still limited. The prophylactic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is insufficient. Moreover, NSAIDs increase the risk of nonunion and loosening in patients with multiple joint injuries. The present experimental study was designed to compare methylprednisolone with free radical scavengers for the prevention of HO. The model of Michelsson et al. was used to induce HO in the hind legs of 30 female New Zealand albino rabbits, weighing approx. 4 kg. The animals were randomized into three groups of 10 animals each, and received daily either placebo, a free radical scavenger cocktail [allopurinol and Nacetylcysteine (A/A)], or methylprednisolone in a randomized, double-blind fashion. Every four days, X-rays were obtained to measure the thickness and the length of new bone formation at the thigh. A statistically significant difference in thickness and length of newly formed bone was found between the three groups. In the placebo group HO increased from day 16 toward a medium length of 6 mm and a median thickness of 1.5 mm. In the A/A group, no signs of HO were found. In the methylprednisolone group, only one animal presented minor HO from day 32. Both free radical scavengers and methylprednisolone were found to inhibit HO, and may be considered effective measures for the prevention of heterotopic bone formation. However, it could not be demonstrated which of the two had the strongest inhibitory effect. Keywords: methylprednisolone; free radical scavengers; heterotopic ossification; prevention Strictly defined, heterotopic ossification (HO) is the formation of lamellar bone inside soft-tissue structures where bone normally does not exist. Myositis ossificans rather refers to a condition in which ectopic bone is formed within muscle or connective tissue following chemical or physical trauma.1-3 However, this term has fallen into disfavor because primary muscle inflammation is not necessarily a precursor, and ossification does not always occur in muscle tissue. For these reasons, the term heterotopic ossification has largely replaced myositis ossificans in the literature. 4 HO frequently complicates central nervous system disorders such as brain and spinal cord injuries, brain tumors, and encephalitis.5 HO is of common occurrence in orthopedic patients as a consequence of hip, knee, shoulder, and elbow arthroplasty. The reported incidence of HO after hip arthroplasty is as high as 53%. 6,7 Patients with a history of osteoarthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, and Paget's disease are at high risk for HO. The condition is also frequently present in burn patients, and has recently been reported to occur after long-term mechanical ventilation following trauma. 8Because nonsteroidal anti-inflammatory drugs (NSAIDs) have important systemic side effects and may increase the risk of ps...

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Section: Discussionmentioning

confidence: 96%

“…9,10 In 2007, the effectiveness of free radical scavengers in the prevention of HO was demonstrated in an animal model. 11 Already in 1994, Michelsson et al 12 had reported an inhibitory effect of methylprednisolone on HO formation in rabbits. This study was never substantiated by other authors.…”

mentioning

confidence: 99%

Free radical scavengers versus methylprednisolone in the prevention of experimentally induced heterotopic ossification

Bossche

Maele

Wojtowicz

et al. 2009

Journal Orthopaedic Research

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“…Based on the latter assumption, FR scavengers like the combined allopurinol and N-acetylcysteine (A/A) may prevent HO formation. Limited in vivo data indicate that A/A is superior to indomethacin [16] and equivalent to methylprednisolone in preventing experimentally induced HO in rodents [17]. Two randomized, controlled trials comparing etidronate disodium versus placebo were reviewed recently by Haran and colleagues in Cochrane Reviews, showing that etidronate disodium delays rather than prevents HO mineralization [18].…”

Section: Nuclear Retinoic Acid Receptor G Agonists (Rar-g)mentioning

confidence: 99%

Pharmacological treatment of heterotopic ossification following hip surgery: an update

Pavlou¹,

Kyrkos²,

Tsialogiannis³

et al. 2012

Expert Opinion on Pharmacotherapy

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“…A major new area of investigation of FOP research is beginning to focus on the relationship of inflammatory triggers, mutant ACVR1/ALK2 receptors, and local environmental factors, such as free radicals, pO 2, and pH in the episodic flare‐ups of the disease 34,55,75–82 . Recent protein modeling studies by Groppe et al .…”

Section: Metamorphosis and The Immune Systemmentioning

confidence: 99%

Morphogen Receptor Genes and Metamorphogenes

Kaplan

Groppe

Pignolo

et al. 2007

Annals of the New York Academy of Sciences

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Morphogen receptors are nodal points in signal transduction pathways that regulate morphogenesis during embryonic development. A recent discovery identified a recurrent missense mutation in a gene encoding a morphogen receptor responsible for the elusive process of skeletal metamorphosis in humans. Metamorphosis, the postnatal transformation of one normal tissue or organ system into another, is a biological process rarely seen in higher vertebrates or mammals, but exemplified pathologically by the disabling autosomal dominant disorder, fibrodysplasia ossificans progressiva (FOP). Individuals with FOP experience episodes of spontaneous or trauma-induced metamorphosis that convert normal functioning aponeuroses, fascia, ligaments, tendons, and skeletal muscles into a highly ramified and disabling second skeleton of heterotopic bone. The recurrent single nucleotide missense mutation in the gene encoding activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that causes FOP in all classically affected individuals worldwide, is one of the most specific disease-causing mutations in the human genome and the first identified human metamorphogene. These findings provide deep insight into a signaling pathway that regulates tissue and organ stability following morphogenesis, and that when dysregulated in a specific manner, orchestrates the metamorphosis of one normal tissue or organ system into another. The study of skeletal metamorphosis in FOP provides profound insight into the molecular mechanisms that ensure phenotypic stability following morphogenesis and that ordinarily lay deeply hidden in the highly conserved signaling pathways that regulate cell fate. Such insight is applicable to a broad range of human afflictions.

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Free radical scavengers are more effective than indomethacin in the prevention of experimentally induced heterotopic ossification

Cited by 9 publications

References 34 publications

Free radical scavengers versus methylprednisolone in the prevention of experimentally induced heterotopic ossification

Free radical scavengers versus methylprednisolone in the prevention of experimentally induced heterotopic ossification

Pharmacological treatment of heterotopic ossification following hip surgery: an update

Morphogen Receptor Genes and Metamorphogenes

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