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PubMed2004

Pharmacological interventions for treating acute heterotopic ossification.

BACKGROUND: Heterotopic ossification (HO) is the formation of mature lamellar bone in soft tissue sites outside the skeleton. HO frequently complicates burns, arthroplasty, fractures, and spinal cord and brain injuries. It can impair joint function. OBJECTIVES: To determine the efficacy of medications to treat acute HO on radiological, symptomatic, functional impairment, and disability outcomes. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Injuries Group specialised register, the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to August 2004), CINAHL (1982 to August 2004), other databases, reference lists of articles, and contacted trialists and drug companies. No language restrictions were applied. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials that assessed the efficacy of any medication for treating acute HO (confirmed by bone scintigraphy, radiography, ultrasonography, or biopsy) and which used radiography to grade post-treatment HO severity. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the study quality and extracted data. We analysed two dichotomous outcomes: no progression in HO grade (versus progression) and improvement in HO grade (versus no improvement). MAIN RESULTS: Two randomised trials comparing disodium etidronate versus placebo were included (Ono 1988; Stover 1976), from which ninety-two participants with spinal cord injury had radiographically-proven HO at baseline. At the completion of the 12 week intervention, the Ono study but not the Stover study, suggested that disodium etidronate was associated with a significantly greater likelihood of successfully preventing the progression of radiographic HO grade, (relative risk (RR) 1.50; 95% confidence interval (CI) I 1.16 to 1.93; and RR 1.48; 95% CI 0.78 to 2.84 respectively) and a significantly greater likelihood of improvement in HO grade (RR 2.78; 95% CI 1.66 to 4.66; and RR 0.71; 95% CI 0.20 to 2.53 respectively). There was evidence of statistical heterogeneity for the latter outcome. Longer term radiographic, clinical or side effect outcomes were unavailable. Data was not pooled due to this heterogeneity and the inadequate duration of follow up. REVIEWERS' CONCLUSIONS: Given the absence of long term radiographic outcomes in the included studies, there is insufficient evidence to recommend the use of disodium etidronate or other pharmacological agents for the treatment of acute HO. It has been previously suggested that disodium etidronate acts by delaying, rather than preventing, the mineralization of HO, and that mineralization may occur after treatment cessation in many cases, thereby negating the benefit of disodium etidronate on eventual HO grade. Further studies are required to assess all pharmacological treatments for acute HO with sufficient follow-up duration.

Etidronic Acid↗
PubMed2003

The value of serum creatine kinase in early diagnosis of heterotopic ossification.

BACKGROUND: Heterotopic ossification (HO) is a complication of spinal cord injury (SCI) characterized by formation of ectopic bone. Early diagnosis is critical, but available diagnostic methods have drawbacks. Serum creatine kinase may be a marker for the development and severity of HO. PARTICIPANTS: 18 SCI patients with diagnosed HO based on clinical findings and bone scintigraphy. METHODS: Serum creatine kinase levels were taken at the time of diagnosis of HO and during subsequent etidronate therapy. RESULTS: Of the 14 patients with normal creatine kinase values, 13 had no evidence of HO on follow-up radiographic examination. Of the 4 patients with elevated creatine kinase, all developed radiographic signs of HO. CONCLUSION: Elevated serum creatine kinase may be associated with a more aggressive course of HO as well as resistance to etidronate therapy. Further studies are needed to determine whether creatine kinase may serve as a marker for early, active HO.

Adult↗
PubMed2003

Radiation-induced suppression of the Bmp2 signal transduction pathway in the pluripotent mesenchymal cell line C2C12: an in vitro model for prevention of heterotopic ossification by radiotherapy.

Heterotopic ossification is a common complication after total hip replacement. Clinical studies showed the effectiveness of radiation for prevention of heterotopic ossification. The mechanism of radiotherapy responsible for the reduction of heterotopic ossification is unclear. The purpose of this study was to study an analogue model showing a time- and dose-dependent effect of radiation. Using cells of the defined embryonic mouse cell line C2C12, the influence of ionizing radiation on the Bmp-induced signal cascade leading to osteogenic differentiation was analyzed. Binding of iodinated Bmp2 to the receptors, Smad1 activation, and alkaline phosphatase (ALP) activity were determined in cells with or without irradiation. The cytotoxic effect of radiotherapy was evaluated using viability tests. Radiotherapy reduced formation of the Bmp2/Bmp receptor complex. This effect was dependent on dose. The phosphorylation (activation) of Smad1 decreased after irradiation in a time-dependent manner, whereas the level of total Smads was not influenced by radiotherapy. The ALP activity decreased after radiotherapy. A dose of 7 Gy delivered 6 h before or after incubation with Bmp resulted in about a 30% decrease in ALP activity. No signs of cytotoxic effects were observed within the time window studied using doses of 0 to 20 Gy. The time- and dose-dependent effect of radiotherapy for prevention of heterotopic ossification known from the results of clinical studies has an analogue in the C2C12 cell model. The primary mechanism of radiotherapy seems to be an influence on cellular responsiveness to the Bmp2-induced osteoblastic differentiation. The results suggest a down-regulation of the Bmp2/receptor complex.

Alkaline Phosphatase↗
PubMed1995

Heterotopic ossification and rhabdomyolysis.

Heterotopic ossification and rhabdomyolysis are well described entities but, as far as we know, their association has never been described in the literature. We recently treated a patient who presented with this association. After a suicide attempt, this patient developed rhabdomyolysis of the left upper and lower limbs with peripheral neurological impairment. Two months later radiographs showed ectopic ossification around the left hip. Rhabdomyolysis is underdiagnosed, and is due to local disturbance of the calcium-phosphorus metabolism resulting in soft tissue calcifications. Underlying rhabdomyolysis may be a possible aetiology of heterotopic ossification. Recognition of this may help us to understand the pathophysiology and to improve the management of heterotopic ossification.

Adult↗
PubMed2005

Heterotopic ossification: a review.

Heterotopic ossification is defined as the presence of lamellar bone at locations where bone normally does not exist. The condition must be distinguished from metastatic calcifications, which mainly occur in hypercalcaemia, and dystrophic calcifications in tumours. It is a frequent complication following central nervous system disorders (brain injuries, tumours, encephalitis, spinal cord lesions), multiple injuries, hip surgery and burns. In addition to this acquired form, hereditary causes also exist, such as fibrodysplasia ossificans progressiva, progressive osseous heteroplasia and Albright's hereditary osteodystrophy. Although these conditions are extremely rare, they can provide useful information on the physiopathology of heterotopic ossification, and thus lead to novel and causal treatment modalities. Heterotopic ossification is no trivial complication. A limitation of the range of joint motion may have serious consequences for the daily functioning of people who are already severely incapacitated because of their original lesion. Increased contractures and spasticity, pressure ulcers and increasing pain further compromise the patient's capabilities. Consequently, we feel that attention should be paid to the pathogenesis and particularly the prevention and treatment of this disorder.

Burns↗
PubMed2005

Heterotopic ossification: a review.

Heterotopic ossification is the formation of bone in the soft tissues. Soft tissue bone deposition may range from the minimal and inconsequential to massive and clinically significant. In some clinical settings it is a predictable finding with an unpredictable course and in other settings it may be diagnostically confounding. Heterotopic ossification may be encountered in clinically disparate disease processes and circumstances. We review the genetic, neurogenic, post-traumatic, post-surgical and "reactive" causes of heterotopic ossification and discuss some current concepts of its pathogenesis.

Arthroplasty, Replacement, Hip↗
PubMedDate not supplied

Aspiration cytology of heterotopic ossification. A case report.

Heterotopic ossification (myositis ossificans) is usually a posttraumatic reactive process involving new bone formation. This nonneoplastic process can be clinically and radiologically confused with osteosarcoma. A case of heterotopic ossification is reported in which cytologic material was obtained from a partially calcified thigh mass from a 17-year-old, athletic male. Aspiration cytology revealed numerous osteoclastic giant cells containing multiple plump nuclei. These cells were admixed in a benign-appearing stromal background composed of mature fibroblasts and were typified by elongated spindle cells. A small incisional biopsy showed new bone formation, osteoclasts, osteoblasts and fibroblasts consistent with maturing heterotopic ossification. Heterotopic ossification may be distinguished cytologically from osteosarcoma by the presence of numerous uniform benign stromal cells composed of mature fibroblasts and osteoclastic giant cells. The differential diagnosis may be more difficult in the early stages of this reactive and proliferative process. Adequate sampling of suspected heterotopic ossification by aspiration cytology may avoid surgery in a selected group of patients.

Adolescent↗
PubMed2004

[Radiotherapy as prevention of heterotopic ossification--preliminary results].

Heterotopic ossification is a common complication of hip arthroplasty (35-57%) and multifragmental acetabular fractures (50-70%). Due to complication level and cost of surgery in this region, more popular become methods of heterotopic ossification prevention as well as non-steroid anti inflammatory drug intake and radiotherapy (approximately 90% effectiveness in high risk groups). Presented material comprises 22 cases irradiated using a dose of 6-7 Gy delivered in one fraction to prevent ossification or to stop active process. No progress was found and only in one case secondary ossification appeared during follow up. Obtained results allow to form the conclusion that radiotherapy is easy, fast and cheap treatment modality giving good results without adverse effects.

Adult↗
PubMed2007

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

The pathogenesis of heterotopic ossification is still unclear and the preventive therapies are usually insufficient. The present study was designed to investigate the possible preventive effect of free radical scavengers on the development of experimentally induced heterotopic ossification in a rabbit model and to compare free radical scavengers with indomethacin to determine whether they act synergistically. A standard immobilization-manipulation model was used to induce heterotopic ossification in the hind legs of 40 1-year-old female New Zealand albino rabbits. The animals were divided into four groups and received daily either placebo, a free radical scavenger cocktail [allopurinol and N-acetylcysteine (A/A)], indomethacin or the combination of A/A and indomethacin in a randomized double-blind fashion. Every 4 days an X-ray was taken and the thickness and length of new bone formation was measured at the thigh. A marked statistically significant difference was found between the four groups. In the groups that received A/A, either alone or combined with indomethacin, an inhibition of bone growth, both in thickness and in length was demonstrated. In this experimental model free radical scavengers had a superior inhibitory effect on heterotopic ossification than indomethacin. Free radicals could play an important role in the pathogenesis of heterotopic ossification.

Acetylcysteine↗
PubMed2000

Heterotopic ossification in childhood and adolescence.

Heterotopic ossification, or myositis ossificans, denotes true bone in an abnormal place. The pathogenic mechanism is still unclear. A total of 643 patients (mean age, 9.1 years) admitted for neuropediatric rehabilitation were analyzed retrospectively with respect to the existence of neurogenic heterotopic ossification. The purpose of this study was to obtain information about incidence, etiology, clinical aspect, and consequences for diagnosis and therapy of this condition in childhood and adolescence. Heterotopic ossification was diagnosed in 32 patients (mean age, 14.8 years) with average time of onset of 4 months after traumatic brain injury, near drowning, strangulation, cerebral hemorrhage, hydrocephalus, or spinal cord injury. The sex ratio was not significant. In contrast to what has been found in adult studies, serum alkaline phosphatase was not elevated during heterotopic ossification formation. A persistent vegetative state for longer than 30 days proved to be a significant risk factor for heterotopic ossification. The incidence of neurogenic heterotopic ossification in children seems to be lower than in adults. A genetic predisposition to heterotopic ossification is suspected but not proven. As a prophylactic regimen against heterotopic ossification we use salicylates for those patients in a coma or persistent vegetative state with warm and painful swelling of a joint and consider continuous intrathecal baclofen infusion and botulinum toxin injection for those patients with severe spasticity. We prefer to wait at least 1 year after trauma before excision of heterotopic ossification.

Adult↗
PubMed1994

Failure of arthroscopic decompression by subacromial heterotopic ossification causing recurrent impingement.

Heterotopic ossification is a well-recognized complication of musculoskeletal trauma and elective orthopaedic surgery. A series of 10 cases of arthroscopic subacromial decompressions developed postoperative heterotopic bone. In eight, the ectopic bone caused recurrent shoulder impingement. These are the first reported cases in which heterotopic ossification compromised the results of an arthroscopic procedure. It is recommended that the patient at risk (e.g., with active spondolytic arthropathy or a profile of hypertrophic pulmonary osteoarthropathy--obesity, diabetes with a history of chronic pulmonary disease) be considered for heterotopic ossification prophylaxis.

Adult↗
PubMed2005

Colchicine inhibits heterotopic ossification: experimental study in rabbits.

BACKGROUND: Heterotopic ossification is a common complication of hip surgery and musculoskeletal or brain trauma. OBJECTIVES: To confirm by in vivo study that colchicine inhibits osteoblast cell proliferation with marked decrease in tissue mineralization. METHODS: Heterotopic ossification was induced in three groups of New Zealand white rabbits (females, 6 months old, weight 3-3.5 kg) by injecting 2 ml bone marrow drawn from the iliac crest into their right thigh muscle. To prevent heterotopic ossification, colchicine (0.25 mg/ day) was administered orally for 4 weeks to two groups of adult rabbits: group A (preload group)--1 week preceding bone marrow injection; group B--on day of injection; and group C--control group. RESULTS: After 4 weeks the rabbits were evaluated by radiographs and ultrasound for evidence of heterotopic ossification. At the end of the study histologic samples were taken from all the thighs. Imaging and histologic studies showed, with statistical significance, almost complete prevention of heterotopic ossification formation in group A (preload) and a marked decrease in group B, when compared with the controls where large new bone had formed at the injection site. These results indicated the inhibitory effects of colchicine on a bone-forming process in soft tissue such as heterotopic ossification. CONCLUSIONS: The role of colchicine in preventing heterotopic ossification in other bone-forming conditions, such as hip arthroplasty or pelvic trauma, and after brain trauma, remains to be evaluated in a clinical setting.

Animals↗
PubMed1994

[Heterotopic ossification and vascular compression].

Heterotopic ossification is common in patients with spinal cord or brain injury. Whereas the articular complications of heterotopic ossification have been well documented, the vascular complications are less well known. We report three cases with vascular compression and discuss the diagnosis and treatment in the light of a review of the literature.

Adult↗
PubMed2004

Multifactorial refractory heterotopic ossification.

Ectopic bone formation or "heterotopic ossification" can follow surgery, trauma, or neurologic injury, but the process is usually self-limited, localized to the site of injury, and responds to surgical treatment when necessary. Aggressive, systemic forms of heterotopic ossification exist that generate lesions that often resist surgical treatment and produce a high rate of recurrence. These entities typically manifest during infancy as genetic syndromes such as fibrodysplasia ossificans progressiva or progressive osseous heteroplasia. The authors describe a case of aggressive, systemic heterotopic ossification in an adult that followed a motor vehicle accident and multiple surgeries. The patient developed a large nonhealing wound around a focus of ectopic bone. Skin grafts failed as a result of the recurrence of ectopic bone, and the patient eventually required aggressive debridement and delayed rotational flap closure. A brief review of the clinical features and surgical treatment of heterotopic ossification is outlined.

Accidents, Traffic↗
PubMed2001

Heterotopic ossification in unidentified skeletal remains.

Heterotopic ossification is a benign, ectopic bone growth that develops in muscle and other soft tissue. The exact cause is poorly understood, but it is a rarely serious complication of soft tissue trauma. Its most common form, myositis ossifications traumatica, occurs as a secondary complication of direct muscle injury. However, other forms are less common and can result from specific pathologic conditions, such as spinal cord trauma and metabolic disorders. In patients who have had spinal cord injury and subsequent paraplegia, heterotopic ossification often results in ankylosis of the hip and a loss in range of motion. Ectopic ossification occurs below the injury site, and, although the specific muscle groups can vary, it usually involves those for which the origin and insertion involve the anterior pelvis and proximal femur. In dried bone, heterotopic ossification can appear as a smooth, irregularly shaped benign tumor of mature bone, extending from the surface but not invading the cortical bone. These tumors range in size from a few millimeters to several centimeters. Because heterotopic ossification is often associated with specific types of injuries, it has a unique anthropological use in forensic cases.

Femur↗
PubMed2006

Adenovirus-mediated transfer of siRNA against Runx2/Cbfa1 inhibits the formation of heterotopic ossification in animal model.

The heterotopic ossification of muscles, tendons, and ligaments is a common problem faced by orthopaedic surgeons. Runx2/Cbfa1 plays an essential role during the osteoblast differentiation and is considered as a molecular switch in osteoblast biology. RNA interference technology is a powerful tool for silencing endogenous or exogenous genes in mammalian cells. In this study, we investigated the effect of Runx2/Cbfa1-specific siRNA on osteoblast differentiation and mineralization in osteoblastic cells, and then constructed adenovirus containing siRNA against Runx2/Cbfa1 (Ad-Runx2-siRNA) to inhibit the formation of heterotopic ossification induced by BMP4, demineralized bone matrix, and trauma in animal model. Our results showed that the Runx2/Cbfa1-specific siRNA could inhibit the expression of Runx2/Cbfa1 at the level of mRNA and protein. Analysis of the expression of osteoblast maturation genes including type I collagen, osteopontin, bone sialoprotein, and osteocalcin, alkaline phosphatase activity, and matrix mineralization (von kossa) revealed that osteoblast differentiation was inhibited in cultured primary mouse osteoblasts transduced with Ad-Runx2-siRNA. Furthermore, adenovirus-mediated transfer of siRNA against Runx2/Cbfa1 could inhibit the formation of heterotopic ossification induced by BMP4, demineralized bone matrix, and trauma in animal model. It is likely that the inhibition of Runx2/Cbfa1 by RNAi could be developed as a powerful approach to prevent or treat heterotopic ossification.

Adenoviridae↗
PubMed1976

Disodium etidronate in the prevention of heterotopic ossification following spinal cord injury (preliminary report).

Heterotopic ossification is a frequent complication following spinal cord injury with 16 per cent to 53 per cent of patients developing varying degrees of pathologic ossification. The diphosphonates are known to block the transformation of amorphous calcium phosphate into crystalline hydroxyapatite. Therefore, one of the diphosphonates, disodium etidronate (generic name of disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP) was selected fro clinical trials to study the effectiveness of EHDP in preventing heterotopic ossification following spinal cord injury. In a double-blind, clinical study of 149 spinal cord injury patients, disodium etidronate has proven its effectiveness in the prevention of heterotopic ossification. The extent of heterotopic ossification development as measured by the total heterotopic ossification X-ray grade was significantly less in EHDP-treated patients compared to placebo-treated patients (P less than 0-05). For maximal effectiveness, EHDP treatment must be started before the onset of the pathological process initiating the development of heterotopicossification. Further studies are necessary to determine the optimal time to institute EHDP treatment, length of treatment, and minimal effective dose. EHDP is the first hterapeutic agent known to alter the formation of heterotopic ossification after spinal injury and may prove useful in other conditions where heterotopic ossification prevention is clinically indicated.

Adolescent↗