What Is the Best Way to Prevent Heterotopic Ossification after Acetabular Fracture Fixation?

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Chapter 51 What Is the Best Way to Prevent Heterotopic Ossification after Acetabular Fracture Fixation?

Heterotopic ossification is common after acetabular fracture surgery. Occurring in only approximately 5% of conservatively treated patients,¹ it has been reported in as many as 90% of patients after fracture fixation, with severe involvement as high as 50% in some patient groups.²^–⁴ An association with poor results has been reported in many case series.^3,⁴ The specific cause of heterotopic ossification remains obscure, and numerous risk factors have been implicated. The most noted risk factor is stripping of the gluteal muscles from the external surface of the ilium.²^–⁷ Therefore, the use of an extended surgical approach (i.e., extended iliofemoral, triradiate, or modification thereof) in particular is thought to result in a high rate of heterotopic ossification.^2,^3,⁵^–⁷ The ilioinguinal approach has been associated with an extremely low rate of ectopic bone formation.^3,⁶

The expressions “severe heterotopic ossification” and “significant heterotopic ossification” are commonly used to describe the amount of heterotopic ossification necessary to impair hip function. However, these terms have actually been defined in differing ways,^2,^{5, 8} possibly causing confusion in the literature. Most reports have used the Brooker classification⁹ (Table 51-1), which relies solely on the anteroposterior radiographic view of the hip, to grade the severity of heterotopic ossification and have defined Classes III and IV as severe.^2,^{5, 7, 8, 10} Although this system is easy to use, its actual correlation to hip motion and function is questionable.^3,^{5, 11, 12} In fact, a study with Level II evidence has shown that the Brooker classification overestimates the functional importance of “severe heterotopic ossification.”¹¹ Greater than 20% loss of total hip motion has been proposed as the deficit necessary to impair hip function (or the “gold standard”) and heterotopic ossification causing this amount of loss has been defined as “significant.”^5,^{6, 13} In the clinical situation, however, there are many factors other than the presence of heterotopic ossification that can adversely affect hip motion. Therefore, a simple radiographic classification that accurately correlates the presence of heterotopic ossification with this amount of impaired hip motion (absent of any other motion-limiting factors) should be useful in evaluating the independent effect of heterotopic ossification on functional hip motion in patients after acetabular fracture fixation. Level II evidence research has shown that using three radiographs to grade the severity of heterotopic ossification, with the addition of the two standard oblique (Judet) pelvic radiographs, rather than relying only on the anteroposterior view, accomplishes this goal.¹¹ Using this modified Brooker method would be helpful both for individual patient prognosis and general scientific study. Unfortunately, it is the standard Brooker technique that continues in general use. Therefore, the findings from any clinical research investigating heterotopic ossification after acetabular fracture fixation, no matter what its apparent “level of evidence” based on study design, may often be diminished by the limitations inherent in the Brooker diagnostic criteria.

TABLE 51-1 Radiographic Grading of Heterotopic Ossification

GRADE	DESCRIPTION
Class I	Islands of bone within the soft tissues about the hip
Class II	Bone spurs from the pelvis or proximal end of the femur, leaving at least 1 cm between opposing bone surfaces
Class III	Bone spurs from the pelvis or proximal end of the femur, leaving less than 1 cm between opposing bone surfaces
Class IV	Apparent bony ankylosis of the hip

From Brooker AF, Bowerman JW, Robinson RA, Riley LH Jr: Ectopic Ossification following total hip replacement: Incidence and a method of classification. J Bone Joint Surg Am 55-A:1629–1632, 1973, by permission.

NATURAL HISTORY

As noted earlier, a relation exists between the severity of heterotopic ossification and limitation of hip motion. In an analysis of any intervention to prevent heterotopic ossification, it is important to know the outcome expected without any prophylactic treatments. Substantial case series (Level IV evidence) data are available for both the standard Brooker radiographic outcome measure and the hip motion (more than 20% loss) diagnostic criterion.

In their series of 499 acetabulum fractures operated on without any prophylactic treatment and followed for at least 1 year, Letournel and Judet ³ found a 25% (123/499) overall prevalence of heterotopic ossification, using the standard Brooker classification. There were 4% (18/499) with Class I, 10% (50/499) with Class II, 8% (39/499) with Class III, and 3% (16/499) with Class IV ossification. Important distinctions were made among the different surgical approaches, which are thought to be related to differences in the relative extent of the stripping of the gluteal muscles from the external surface of the ilium: the more extensive the stripping, the greater the risk for heterotopic ossification. For the extended iliofemoral approach, there were 4% (1/26) with Class I, 23% (6/26) with Class II, 19% (5/26) with Class III, and 23% (6/26) with Class IV ossification. For the Kocher–Langenbeck approach, there were 4% (11/281) with Class I, 13% (37/281) with class II, 9% (25/281) with Class III, and 2% (6/281) with Class IV ossification. For the ilioinguinal approach, there were 1% (1/138) with Class I, 2% (3/138) with Class II, 1% (2/138) with Class III, and 1% (1/138) with Class IV ossification. Adding stripping of the gluteal muscles from the external surface of the ilium to the standard ilioinguinal approach drastically changed the outcome, resulting in 9% (1/11) with Class I, 9% (1/11) with Class II, 36% (4/11) with Class III, and 0% (0/11) with Class IV ossification. Therefore, the expectation is that without prophylaxis of any kind, “severe heterotopic ossification,” defined as Class III or IV using the standard Brooker technique, will occur in 42% of patients treated through the extended iliofemoral approach, 11% of patients treated through the Kocher–Langenbeck approach, and 2% of patients treated through the ilioinguinal approach.

Matta ⁶ reported on his series of 259 patients with 262 acetabular fractures followed for at least 2 years and operated on without any prophylactic treatment. Moderate (standard Brooker Class II) or severe heterotopic ossification (standard Brooker Class III or IV) that was associated with greater than 20% loss of motion occurred in 9% (23/262) of fractures. This amount of heterotopic ossification was noted in 20% (12/59) of the extended iliofemoral approaches, 8% (9/112) of the Kocher–Langenbeck approaches, and 2% (2/87) of the ilioinguinal approaches.

PREVENTION OPTIONS

In a 1998 survey of 226 members of the Orthopaedic Trauma Association, Morgan and colleagues ¹⁴ report that prophylaxis for heterotopic ossification was used by 88.3% of the respondents. The stated rationale(s) for this preventative treatment included its effectiveness (39%), perception to be the standard of care (16%), and support in the literature (45%). More than one type of prophylaxis was used by 36.5% of the respondents. Indomethacin was used by 78.6%, low-dose irradiation by 46.5%, low-dose irradiation combined with nonsteroidal anti-inflammatory drugs (NSAIDs) by 15.1%, and NSAIDs other than indomethacin by 3.1%. Therefore, there are three basic preventative treatment options: NSAIDs, low-dose irradiation, and a combination of these two.

EVIDENCE

Indomethacin

The NSAID indomethacin has been shown to decrease the prevalence of heterotopic ossification in experimental animals ¹⁵^–¹⁷ and in a number of Level III evidence clinical studies of patients with acetabular fracture.^7,^{8, 10, 18} Most of these clinical studies were retrospective in nature, having the attendant design limitations. More recently, there have been a number of clinical reports with Level I and II evidence, prospectively evaluating the efficacy of indomethacin prophylaxis as compared with a nontreatment control group.¹⁹^–²¹ Unfortunately, the data from these studies offer conflicting results. Therefore, critical review of these studies is required, taking into consideration the main important variable of the differing expected baseline prevalence of heterotopic ossification depending on surgical approach, as well as an analysis of the statistical method.

In a Level II study, Iotov ²¹ evaluated the results of prophylaxis with indomethacin in 52 patients operated for fractures of the acetabulum. Twenty-eight received indomethacin prophylaxis, consisting of 25 mg three times per day given orally or per rectum for 30 days after surgery, and 24 composed a control group. The grade of heterotopic ossification was assessed using the Brooker classification. The development of heterotopic ossification was analyzed depending on the type of surgical approach. The rate of severe ossification was 0% in the indomethacin-treated group and 21% in the control group (P < 0.01), mainly after extensile posterior and posterior approaches. One error in this study was including in the control group the one patient who could not tolerate indomethacin because of gastrointestinal symptoms. Ragnarsson and coworkers²² in another level II study had similar findings in a group of 23 patients operated on through the triradiate surgical approach. Of the 14 patients receiving indomethacin prophylaxis (25 mg three times each day for 6 weeks), 10 had no heterotopic ossification, 2 had Brooker Class I, and 2 had Brooker Class II. In the control group, six had Brooker Class II, two had Brooker Class III, and one had Brooker Class IV (P < 0.0001). These Level II findings are consistent with those of the Level III studies.

In contradistinction, Matta and Siebenrock ¹⁹ report a Level I evidence, randomized, prospective trial indicating that indomethacin was not effective. However, this study was vastly underpowered to detect differences. This study included 107 consecutive patients. Patients with an even hospital number received 100 mg indomethacin by suppository at the end of the operation and then 25 mg by mouth or rectally three times a day for 6 weeks. Those with an odd hospital number received no prophylactic treatment. Patients with all three surgical approaches (extended iliofemoral, Kocher–Langenbeck, and ilioinguinal) were included. The ilioinguinal group (with an expected prevalence of only 2% for heterotopic ossification sufficient to cause impairment, whether by radiographs alone or in combination with measurement of joint motion) represented almost 50% (50/107) of the patients. Thirty-seven patients were in the Kocher–Langenbeck groups, and 20 were in the extended iliofemoral groups. The authors themselves did a power analysis and found low power in their numbers for the motion impairment criteria (24%), and discussed the large patient numbers they would have needed to find significant effects. A simple analysis will show the large sample sizes required in the design of a randomized, prospective study to provide the desired 80% power to minimize the risk for type II error at an alpha < 0.05. Assuming that the comparative change of clinical interest in this study would be a decrease from the expected 2% to 1% for the ilioinguinal approach, 8% to 3% for the Kocher–Langenbeck approach, and 20% to 10% for the extended iliofemoral approach, the sample sizes needed per group for the desired 80% power are approximately 2300, 325, and 200, respectively. The small clinical effect size (2%) and limited drug treatment benefit for the ilioinguinal approach indicates that there is limited value in proceeding with a prospective trial requiring such large patient numbers. In addition, although this was a Level I study, clearly there were not enough patients to answer the study question.

Karunakar and coauthors ²⁰ completed a Level I evidence study designed to compare the effect of indomethacin with that of a placebo in reducing the incidence of heterotopic ossification in a prospective, randomized trial. A total of 121 patients with fractures of the acetabulum treated using a Kocher–Langenbeck approach were randomized to receive either indomethacin (once-a-day 75-mg sustainedrelease capsule) or a placebo once daily for 6 weeks. The extent of heterotopic ossification was evaluated on plain radiographs 3 months after operation using the standard Brooker classification. Fifty-nine patients were in the indomethacin group, and 62 were in the placebo group. Significant heterotopic ossification, defined as Brooker Class III to IV, occurred in 9 of 59 patients (15.2%) in the indomethacin group and 12 of 62 (19.4%) receiving the placebo (P

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