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Heterotopic Ossification

Non-steroidal Anti-inflammatory Drugs as Prophylaxis

Indomethacin and Rofecoxib have both been evaluated in the treatment of HO post SCI.

Author Year; Country
Research Design
Score
Total Sample Size		 Methods Outcome
Banovac et al. 2004; USA
RCT
PEDro=10
N=76

Population: Gender: males=65, females=11; Severity of injury: complete, incomplete, AIS: A-C; Mean time since injury: 24 days.
Interventions: The treatment group received oral rofecoxib 25mg daily x4/wk.
Outcome Measures: Incidence of HO and swelling of joints.
  1. A significantly lower incidence of HO was found in the rofecoxib group (13.4%) than in the placebo group (33.3%, p<0.05).
  2. In patients receiving rofecoxib, there was 2.5x lower relative risk of developing HO than in the placebo group.
Banovac et al. 2001; USA
RCT
PEDro=9
N=33

Population: Mean age: 33 yr; Gender: males=33, females=0; Severity of injury: AIS: A-D; Groups: treatment=16, placebo=17.
Treatment: Treatment was slow-release indomethacin 75 mg daily versus placebo x3/wk. Patients were followed up clinically until they showed signs and symptoms of HO; all were followed up with x-rays at 2 mo and 6 mo. Where patients had a positive bone scan for HO, the study was D/C and patient was initiated on Etidronate Disodium.
Outcomes Measures: The effect of indomethacin administration on the incidence of HO.
  1. There was a significantly higher incidence of early HO, diagnosed on bone scan, in the placebo group (11/17) than in the group taking indomethacin (4/16) (p<0.001).
  2. In the placebo group, 7/17 patients developed x-ray evidence of HO as did 2/16 in the indomethacin treated group (p<0.001).

Zakrasek et al. 2019; USA
Case Control N=108

Population: NSAID prophylaxis Group (n=27): Mean age: 31 yr; Gender: males=23, females=4; Level of injury: paraplegia=12, tetraplegia=15; Severity of injury: ASIA A=24, B=3; Time since injury: ≤60 d. No prophylaxis Group (n=81): Mean age: 37 yr; Gender: males=64, females=17; Level of injury: paraplegia=29, tetraplegia=52; Severity of injury: ASIA A=55, B=26; Time since injury: ≤60d. Intervention: A retrospective chart review of all patients consecutively admitted to the SCI acute rehabilitation program at Santa Clara Valley Medical Center between October 2013 and March 2017. The NSAID prophylaxis group received ≥ 15 days of non-steroidal anti-inflammatory drug (NSAID) therapy (overall range 6–44 days; indomethacin 75 mg sustained release once daily or 25 mg immediate release 3x / day, or celecoxib 200 mg once daily). The no prophylaxis group did not receive NSAID prophylaxis.
Outcome Measures: Occurrence of HO, UTI during hospitalization, tracheostomy, inpatient rehabilitation length of stay and adverse event data including rates of bony non-union and gastrointestinal (GI) bleeding.
  1. Two individuals receiving ≥ 15 days of NSAID prophylaxis (24 days each) were diagnosed with HO (7.4%), compared with the 29 cases of HO diagnosed in the 81 people who did not receive prophylaxis (35.8%; p=0.006).
  2. Significant predictors of HO diagnosis were tracheostomy (odds ratio (OR) 2.8, 95% confidence interval (CI) 1.1 to 7.5, p=0.039), pressure injury during hospitalization (OR 3.3, 95% CI 1.1 to 9.5, p=0.030), UTI during hospitalization (OR 4.3, 95% CI 1.5 to 12, p=0.006).
  3. Length of stay was significantly longer in those who were diagnosed with HO compared with individuals not diagnosed with HO (p=0.008).
  4. Adverse effects of NSAID use were minimal.

Discussion

Two highly rated RCTs examined the use of non-steroidal anti-inflammatory drugs in the early phase after SCI in an attempt to reduce the incidence of HO. Banovac et al. (2001) randomized 33 SCI patients approximately three weeks post SCI and treated them prophylactically with either slow-release indomethacin 75 mg daily or placebo for a total of three weeks. Patients were carefully followed with regular clinical follow-up and bone scans. There was a significantly higher incidence of HO, diagnosed on bone scan and plain radiographs, in the placebo group when compared with the group receiving indomethacin (p<0.001). Banovac et al. (2004) randomized 76 patients in the early phase post SCI into either the intervention group (25 mg rofecoxib daily for two weeks) or a placebo group. A significantly lower incidence of HO was observed in the rofecoxib group (13.4%) than in the placebo group (33.3%; p<0.05). These findings are in line with that from a recent case control study, which demonstrated a significantly lower likelihood of developing HO during the acute phase post-SCI among patients who received ≥ 15 days of non-steroidal anti-inflammatory drugs therapy compared to those who did not receive non- steroidal anti-inflammatory drugs (Zakrasek et al., 2019). Although these three studies provided compelling evidence that anti-inflammatory drugs given prophylactically reduce the likelihood of developing HO post-SCI, Rofecoxib is no longer available due to cardiovascular side effects.

Conclusion

There is strong Level 1a evidence (from two RCTs; Banovac et al. 2001; Banovac et al. 2004) and level 3 evidence (from one case control study; Zakrasek et al., 2019) that non-steroidal anti-inflammatory medications can reduce the incidence of heterotopic ossification when administered early after a spinal cord injury.

Anti-inflammatory medications given early post spinal cord injury reduces development of heterotopic ossification.

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