Effectiveness of indomethacin in preventing Heterotopic Ossification: a systematic review and meta-analysis of randomized controlled trials
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Heterotopic ossification is often a severe clinical complication of joint arthroplasty, neurologic trauma, and muscle injury. In rare genetic disorders, such as fibrodysplasia ossificans progressiva, heterotopic ossification can be crippling and often leads to premature death. Reliable animal models of heterotopic ossifications that mimic pathologies seen in man would be invaluable for the development of new treatments to combat heterotopic ossification. Various methods used to induce heterotopic ossification in animals including the use of bone morphogenetic proteins, urinary tract epithelia, and transformed cell lines are described. Genetic animal models of heterotopic ossification and various miscellaneous examples of heterotopic ossification in animals are described. Finally, the use of transgenic mice to manipulate bone morphogenetic protein expression is discussed as a possible future animal model of heterotopic ossification.
Fibrodysplasia Ossificans Progressiva
Heterotopic bone
Myositis ossificans
Animal model
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Heterotopic ossification is often a severe clinical complication of joint arthroplasty, neurologic trauma, and muscle injury. In rare genetic disorders, such as fibrodysplasia ossificans progressiva, heterotopic ossification can be crippling and often leads to premature death. Reliable animal models of heterotopic ossifications that mimic pathologies seen in man would be invaluable for the development of new treatments to combat heterotopic ossification. Various methods used to induce heterotopic ossification in animals including the use of bone morphogenetic proteins, urinary tract epithelia, and transformed cell lines are described. Genetic animal models of heterotopic ossification and various miscellaneous examples of heterotopic ossification in animals are described. Finally, the use of transgenic mice to manipulate bone morphogenetic protein expression is discussed as a possible future animal model of heterotopic ossification.
Fibrodysplasia Ossificans Progressiva
Heterotopic bone
Myositis ossificans
Animal model
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Heterotopic ossification, or the appearance of ectopic bone in para-articular soft tissues after surgery, immobilization, or trauma, complicates the surgical and physiatric management of injured joints. The chief symptoms of heterotopic ossification are joint and muscle pain and a compromised range of motion. Current therapies for prevention or treatment of heterotopic ossification include surgery, physical therapy, radiation therapy, and medical management. Unlike heterotopic ossification of the hip, heterotopic ossification of the elbow has not been extensively investigated, leaving its optimal management ill-defined. To remedy this deficiency, we review risk factors, clinical anatomy, physical findings, proposed mechanisms, and current practice for treatment and prevention of heterotopic ossification. We then consider and draw conclusions from four cases of elbow injury treated at our institutions (three complicated by heterotopic ossification) in which treatment included surgery, radiation therapy, physical therapy, and medical therapy. We summarize our institutional practices and conclude with a call for a randomized clinical trial to better define optimal management of heterotopic ossification of the elbow.
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Heterotopic bone
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We investigated the status of the development of heterotopic ossification and compared the frequency of heterotopic ossification in the EHDP group with that in the untreated (control) group to evaluate the efficacy and safety of EHDP. Seventy-seven patients who had undergone total hip arthroplasty or femoral head prosthesis for the treatment of osteoarthritis and femoral neck fracture were enrolled in the study. Heterotopic ossification surrounding the hip joint was evaluated according to the roentgenographic classification. In the control group, heterotopic ossification was found in 10 patients (20%) during the period, while in the EHDP group, it was found in one patient (3.7%) during the treatment period after the operation. Gastrointestinal disorder, in one case only was a side effect observed during EHDP treatment. It was revealed that EHDP inhibits heterotopic ossification following total hip replacement in patients with osteoarthritis.
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The aim of the current study was to reveal whether 7 days of indomethacin treatment sufficiently prevents heterotopic ossification after cementless total hip arthroplasty. One group received indomethacin for 14 days (n = 102), and the second for 7 days (n = 99) after cementless total hip arthroplasty. At followup 1 year postoperatively, the average Harris Hip Score was 91 points in the 14-day treatment group and 89 points in the 7-day treatment group. The incidence of heterotopic ossification as outlined by Brooker was similar in both groups. Ninety-six patients in the 14-day treatment group had heterotopic ossification Grades 0 or 1, and 6 patients had Grade II heterotopic ossification; whereas in the 7-day treatment group, 95 patients had Grades 0 or 1 heterotopic ossification and 4 patients had Grade II ossification. None of the patients had Grades III or IV heterotopic ossification. In the 14-day treatment group, headache, dizziness, or gastritic disorders develop in 10 patients, and in the 7-day treatment group, 7 patients had these effects. This study shows that treatment with 100 mg indomethacin daily for 7 days is not significantly different than 14 days of treatment for the prevention of formation of severe heterotopic ossification after cementless hip arthroplasty.
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The incidence of primary and revision total knee arthroplasty (TKA) is increasing worldwide. Heterotopic ossification is a common and concerning complication of TKA. There are few described cases of severe heterotopic ossification after revision TKA and no known cases of heterotopic ossification causing functional ankylosis after revision TKA. We describe a case of extensive heterotopic ossification in a patient who underwent right TKA for extensive adhesions and stiffness. After early range of motion improvement postoperatively, the patient discontinued a physical therapy regimen. The patient presented 13 years after revision TKA with radiographically evidenced severe heterotopic ossification resulting in a functional ankylosis. The patient elected for nonsurgical management. This case demonstrates a delayed finding of severe heterotopic ossification. The case prompted an applied literature review of several topics: heterotopic ossification as a complication of revision arthroplasty, the contribution of autoimmune and inflammatory conditions to heterotopic ossification; the use of medication, radiation, and physical therapy as prophylaxis against heterotopic ossification; and the range of treatment strategies for severe heterotopic ossification at the knee joint. Consent by the patient involved in this case report was obtained.
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Summary: Thirty-seven male patients with acetabular fractures requiring an extensile surgical approach were treated using a uniform protocol that was begun in July 1984. In 1987, prophylactic indomethacin was added to the protocol to study its effects on the prevention of heterotopic ossification. Nineteen patients with at least 12 months' follow-up were operated on prior to, and 16 after the initiation of the indomethacin treatment program. Two patients were lost to follow-up. The severity of heterotopic ossification was evaluated for each of these two patient groups using the Brooker classification and was correlated with hip joint mobility. Statistical analysis revealed that indomethacin was effective in decreasing the overall incidence of heterotopic ossification (p<0.01). The occurrence of severe heterotopic ossification (Brooker class III and class IV) was also significantly reduced (p<0.01) and functional results thereby improved. The maximal extent of heterotopic ossification was evident by 6 weeks postoperatively in all patients. In the patients receiving indomethacin, heterotopic ossification did not progress after the drug was discontinued.
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The role of kinesiotherapy in heterotopic ossification remains unclear. The goal of this study was to revisit the literature on the preventive role of kinesiotherapy against heterotopic ossification formation and maturation.A systematic review was performed in MEDLINE, OVID, Scopus, and Cochrane databases.A high-quality clinical trial is missing from the literature. Of 9617 studies primarily identified, nine studies offered the proper data and were included. They infer that satisfactory results on neurogenic heterotopic ossification prevention were achieved with passive exercises, including continuous passive motion, that were initiated early and at a painless range of motion. On the contrary, for elbow posttraumatic heterotopic ossification and major joints burn-associated heterotopic ossification, active range of motion is indicated as early as possible.Because of the very low quality of the studies included in this review, firm conclusions cannot be drawn about the effectiveness of kinesiotherapy. Nevertheless, it is recommended that controlled passive range of motion exercises (especially continuous passive motion) be applied early and pain-free especially in the neurogenic heterotopic ossification patients while active range of motion in painless limits is beneficial in the heterotopic ossification prevention of traumatic elbows or burn joints.
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