This study was designed to prospectively evaluate the efficacy of indomethacin as prophylaxis for heterotopic ossification (HO) after operatively treated acetabular fractures.

An IRB approved, prospective double blind placebo controlled clinical trial was performed at two level I trauma centres to evaluate the efficacy of indomethacin as prophylaxis for heterotopic ossification after the operative treatment of acetabular fractures. Between January 1, 1999 and May 31, 2003, two hundred and thirty-two patients with acetabular fractures were treated operatively through a posterior approach. Patients with the following conditions were excluded from study participation: age < 18, spinal cord injury, ankylosing spondylitis, burns, gastrointestinal bleed, Glasgow coma scale < 12, cerebrovascular accident, pregnancy and use of other non-steroidal anti-inflammatory drugs. One hundred and fifty-seven eligible patients were identified and one hundred and twenty-five patients were enrolled in the clinical trial. One hundred and seven patients have sufficient follow up to be included in data analysis. All patients underwent operative stabilization of their ace-tabular fractures by either a combined anterior and posterior approach or an isolated posterior Kocher-Lan-genbock approach. After fixation and prior to wound closure, any necrotic gluteus minimus muscle was debrided to viable muscle. Sixty-one patients were randomized to the placebo group and forty-six patients to the indomethacin treatment group. Indomethacin 75 mg SR and the placebo were administered to the patients by the investigational drug pharmacy in a blinded fashion. The medication was taken once daily for six weeks. Patient compliance was measured by obtaining indomethacin serum levels at the first postoperative visit (2 weeks). The extent of HO was evaluated on plain radiographs (AP and Judet) at three months postoperatively. The radiographs were scored for the presence of HO using the Brooker classification as modified by Moed. The data were analyzed two ways: 1) by excluding patients with protocol deviations and 2) by using an intent-to-treat model, where all enrolled subjects with 3 month Brooker scores were included in the analysis, regardless of whether they withdrew or were dropped from the study for clinical reasons. The sample size was estimated to produce a statistical power of 80% to detect a difference of 15% between the two treatment groups with alpha = .05.

There were no significant differences with regards to age, sex, body mass index (BMI), ISS (injury severity score) and complications between the two treatment groups. The overall incidence of HO (Brooker I-IV) was 52.8% and the overall incidence of significant HO (Brooker III/IV) was 19.6%. There were four patients with Brooker IV HO. There was no significant difference between the treatment groups in the incidence of HO according to Brooker class (p=0.23). Significant HO (Brooker grades III-IV) occurred in 8 cases (17%) in the indomethacin group and 13 cases (21%) in the placebo group. There was no significant difference in the presence of moderate to severe HO (Brooker III/IV) between the two treatment groups (Fisher’s exact test p=0.81). Eighty-two of one hundred and seven patients enrolled completed the protocol. Twenty-five patients did not complete the treatment protocol for the following reasons: stopped medication due to side effects, did not receive medication at discharge, lost medication, or medication stopped by another physician who did not understand the purpose of the study. Nine patients (8.4%) did not receive the full medication course, sixteen patients (15%) were dropped or withdrew from the study for adverse events or gastrointestinal symptoms. Twelve patients dropped or withdrew from the indomethacin group and three from the placebo group. Forty percent of patients in the indomethacin group had non-detectable serum levels at two weeks. Complications identified in the indomethacin treatment group included deep venous thrombosis (5), wound infection (2), nonunion (1), gastrointestinal bleed (1) and perforated ulcer (1). Complications identified in the placebo group included deep venous thrombosis (6) and wound infection (2).

In this prospective randomized study, a placebo provided as effective prophylaxis against the development of heterotopic ossification as indomethacin. More patients withdrew from the indomethacin group for gastrointestinal side effects or adverse events than in the placebo group. Patient compliance with indomethacin was poor with 40% of patients having no detectable indomethacin serum level. Serious gastrointestinal complications (gastrointestinal bleed and perforated ulcer) occurred in two patients treated with indomethacin.