Heterotopic ossification(HO) is a common complication following spinal cord injury(SCI); however, its underlying pathophysiology remains relatively unknown. Although there are options for treating HO, prophylactic treatment is limited. Additionally, evidence supporting the effectiveness of these prophylactic treatments is scarce. Electronic literature search was conducted using four databases. Studies comparing prophylactic medication for HO versus placebo for patients with acute spinal cord injury were included. A meta-analysis comparing the incidence of HO between the two groups was conducted, with a subgroup analysis of non-steroidal anti-inflammatory drugs (NSAIDs) and non-NSAIDs. A total of 5 studies and 815 patients were included. Overall incidence of HO was 9.73 % (n = 25) in the medication group versus 16.5 %(n = 92) in the placebo group. However, the two groups do not statistcally differ(p = 0.21). In the subgroup analysis for NSAIDs, those who received prophylactic treatment with NSAIDs had a lower incidence of HO compared to those who received placebo (RR[95 % CI]:0.32[0.15, 0.68]; p = 0.003). As for studies that used bisphosphonates, a statistically significant difference in incidence of HO was not found (RR[95 % CI]:1.30[0.52, 3.24];p = 0.58) and the overall evidence was inconclusive. In present systematic review and meta-analysis comparing prophylactic medications to placebo for prevention of HO, we found similar incidence rates for both groups. However, subgroup analysis showed a significantly lower incidence rate for those who recevied NSAIDs for HO prophylaxis. Altough this finding is promising for secondary prevention of HO among patients suffering from SCI, further prospective studies with longer follow-ups are required to assess other appropriate medications for HO prevention.

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