|A systematic review of the therapeutic interventions for heterotopic ossification after spinal cord injury
|Teasell RW, Mehta S, Aubut JL, Ashe MC, Sequeira K, Macaluso S, Tu L, SCIRE Research Team
This review concluded that the strongest evidence was for rofecoxib, indomethacin and pulse low-intensity electromagnetic field therapy to prevent heterotopic ossification, after spinal cord injury, but the generally poor study quality prevented definitive recommendations. These conclusions reflect the evidence, but it should be noted that rofecoxib was withdrawn from the market due to side-effects.
To evaluate the effectiveness of interventions to prevent or treat heterotopic ossification, following spinal cord injury.
MEDLINE, CINAHL, EMBASE and PsycINFO were searched for English language publications, from 1980 to April, 2009. Search terms were reported. Reference lists of included articles were handsearched to locate further studies.
Eligible for inclusion were randomised controlled trials (RCTs), non-randomised controlled trials, cohort, case-control, before-and-after, and after intervention studies, and case series. To be included, interventions had to prevent or treat heterotopic ossification, and at least half the patients had to have a spinal cord injury. Studies of children were excluded, as were studies with fewer than three patients with a spinal cord injury, non-interventional studies, and review articles.
Most of the included studies were conducted in the USA; the remainder were conducted in Europe. Most studies evaluated interventions to treat heterotopic ossification, including bisphosphonates (diphosphonates), radiotherapy, and excision. The remaining studies evaluated prophylaxis, focusing on primary and secondary prevention, including drugs and electromagnetic field therapy. The eligibility criteria, treatment regimens, and outcome measures varied across the studies.
Two reviewers selected the studies for inclusion.
Assessment of study quality
The quality of the RCTs was assessed using the PEDro scale; scores of 6 to the maximum of 10 indicated good to excellent quality. The Downs and Black checklist was used to assess the quality of all other studies, with a maximum score of 28 indicating the highest quality. A modified Sackett scale (defined in the review) was used to assess the strength of the evidence.
Two reviewers independently assessed the quality of the studies; any discrepancies were resolved by a third reviewer.
The outcome data were extracted by an unreported number of reviewers.
Methods of synthesis
Data were synthesised in a narrative, presented in sections, according to the intervention type.
Results of the review
Fourteen studies were included (as reported in the review tables). Four were prophylaxis studies; three RCTs and one observational study (365 patients). Ten were treatment studies; two prospective controlled trials, seven case series, and one case study (over 257 patients). The total PEDro score ranged from 6 to 10, for the three RCTs; the total Downs and Black score ranged from 7 to 14, for the remaining studies.
Two RCTs (109 patients), with PEDro scores of 9 and 10, demonstrated that, compared with placebo, non-steroidal anti-inflammatory drugs, rofecoxib (a withdrawn treatment) and indomethacin, statistically significantly reduced the incidence of heterotopic ossification, when administered three or four weeks after spinal cord injury (rofecoxib p<0.05; indomethacin p<0.001). The third RCT (29 patients), with a PEDro score of 6, showed that the incidence of heterotopic ossification was statistically significantly lower with pulse low-intensity electromagnetic field therapy, combined with motion and exercise therapy, compared with motion and exercise therapy alone (p=0.04).
One prospective controlled trial (27 patients) found that patients who received intravenous bisphosphonate (etidronate) for three to five days, followed by oral etidronate for six months, had a significant reduction in swelling in the first 48 hours (p<0.01), compared with patients who only received the oral etidronate. There were mixed results for the efficacy of bisphosphonates in the other five studies that evaluated them; these studies were all of low quality.
Further, low-quality evidence was reported for prevention (for example, warfarin) and for treatment (for example, radiotherapy and excision). Some data on adverse effects were reported.
The strongest evidence was found for rofecoxib, indomethacin and pulse low-intensity electromagnetic field therapy, for the prevention of heterotopic ossification, after spinal cord injury. The generally poor quality of the studies meant that definitive recommendations could not be made.
The review question was clear and was supported by broadly defined inclusion criteria. Relevant electronic databases were searched, but the restriction to studies in English and the lack of a search for grey and unpublished literature, suggest that relevant studies may have been missed. Study selection and quality assessment were performed by two people, but this was not reported for data extraction, so reviewer error and bias cannot be ruled out. Suitable quality assessment tools were used and the results showed that most studies were of low quality.
The study details were presented, and the narrative synthesis seems to have been appropriate given the clinical and methodological differences between the studies. The evidence was limited by the small samples (ranging from five to 227 patients), and the authors acknowledged that etidronate, in particular, was poorly tolerated due to adverse effects.
Overall, the authors' tentative conclusions reflect the evidence presented and their recommendations for further research seem justified; although rofecoxib was withdrawn as a treatment due to its increased risk of cardiovascular side-effects.
Implications of the review for practice and research
Practice: The authors stated that radiotherapy could have secondary complications, such as cancer, and should be used with caution. Etidronate might not be the best treatment for patients with spinal cord injury, because of the apparent need to continue it indefinitely.
Research: The authors stated that research was needed into the effectiveness of celecoxib, radiotherapy, and pamidronate, to treat or prevent heterotopic ossification. Large, high-quality studies, with long-term follow-up, were required to examine the effectiveness and clinical relevance of pulse low-intensity electromagnetic field therapy and warfarin, using a clinically relevant, standardised tool to diagnose heterotopic ossification.
Funded by the Ontario Neurotrauma Fund; SCI Solutions Network; and the Rick Hansen Man in Motion Foundation.
Teasell RW, Mehta S, Aubut JL, Ashe MC, Sequeira K, Macaluso S, Tu L, SCIRE Research Team. A systematic review of the therapeutic interventions for heterotopic ossification after spinal cord injury. Spinal Cord 2010; 48(7): 512-521
Subject indexing assigned by NLM
Databases, Bibliographic /statistics & Humans; Ossification, Heterotopic /etiology /prevention & Randomized Controlled Trials as Topic; Spinal Cord Injuries /complications /therapy; control; numerical data
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.