Bisphosphonates

Three bisphosphonates, Alendronate, Etidronate (didronel) and pamidronate, have been studied in the treatment of HO progression post SCI. Alendronate is a potent N-containing second generation bisphosphonate and is thought to inhibit bone resorption, have a small effect on mineralization and has been observed to reduce the rate of HO (Ploumis et al. 2015). Etidronate was introduced in the 1970s for the treatment of HO post SCI and is still commonly used today (Banovac et al. 1997; Fleisch 1991). Etidronate works by inhibiting the transformation of amorphous calcium phosphate into crystalline hydroxyapetite (Fleisch 1991; Fleisch et al. 1969; Banovac et al. 1997). Although commonly used, its efficacy in prophylaxis has been questioned (Finerman & Stover 1981). Pamidronate is a new generation nitrogen-containing bisphosphonate (Schuetz et al. 2005).

Discussion

Alendronate

Ploumis et al. (2015) prescribed 70 mg per week of Alendronate to 125 SCI patients over a mean of 267 days. Development of HO was compared with 174 SCI patients who did not receive Alendronate. No direct correlation was found between prevention of HO and Alendronate intake; however, there appeared to be an indirect link between the two as abnormal ALP serum levels were significantly correlated with patients with HO whilst normal ALP serum levels were significantly correlated with Alendronate intake. Therefore, Alendronate may be effective in reducing one of the risk factors of developing HO rather than a direct prophylactic advantage. A potential drawback for the use of Alendronate was the finding that patients were more likely to develop contractures whilst taking the drug compared to patients who were not (Ploumis et al. 2015).

Etidronate

Several studies aimed to determine the effect of Etidronate on HO and the regimen of administration. Garland et al. (1983) assessed the effectiveness of Etidronate treatment on SCI patients with clinical signs of HO over a two-year period. Ossification appeared to plateau in only one of nine patients, while an increase in HO was reported to varying degrees in the remaining patients. Banovac (2000) studied 40 patients with SCI and HO, who were diagnosed early with positive bone scan but negative x-rays, and were treated with Etidronate (intravenous for three days, then oral for six months). Of the 40, 11 individuals (27.5%) developed radiographic evidence of HO 1.5-6.0 years post initiation of therapy.

Banovac et al. (1993) provided intravenous Etidronate for three-five days followed by oral Etidronate for six months to 27 patients with SCI following a diagnosis of HO; outcomes were compared to 11 SCI patients treated with only oral Etidronate Disodium for six months. After the initial intravenous therapy, 20 patients showed prompt reduction in swelling over the first 48 hours while seven patients had no change or an increase in swelling. Overall, treatment reduced swelling (p<0.01); there was no significant difference in effect between the intravenous and orally treated groups on HO.

Banovac et al. (1997) studied 46 patients (five excluded due to discontinuation of therapy) treated with three days of intravenous Etidronate Disodium followed by oral Etidronate for six months. Of the 33 patients with a positive bone scan but a negative x-ray for HO, five discontinued treatment and showed gradual progression of HO. In the remaining 28 patients, 22 had no x-ray evidence of HO while six developed HO on x-ray. Among 13 patients who had a positive bone scan and a positive x-ray for HO, progression of soft tissue ossification was inhibited by Etidronate in six of these patients, while the remaining seven did not respond to treatment and showed further progression of HO.

Stover et al. (1987) conducted a pre-post trial of 87 adult SCI patients and found that there was no difference between patients treated with Etidronate Disodium for three months versus those receiving therapy for six months. However, those who received earlier treatment did better on x-rays. Secondary prevention of HO post surgical excision was examined by Subbarao et al. (1987, N=5). Subbarao et al. (1987) examined Etridonate treatment pre- and post-surgical hip wedge resection and found that patients still had severe restriction in their range of motion at follow-up.

Pamidronate

Schuetz et al. (2005) reported that pamidronate was administered pre- and post-surgical removal of HO among individuals with SCI and had no recurrences. It is important to note that sample sizes in both studies were small.

The lack of RCTs and variable treatment regimens make it difficult to form definitive conclusions. It appears that Etidronate is able to delay or inhibit HO progression once it is diagnosed and it tends to work better when given earlier after diagnosis.

Conclusions

There is Level 2 evidence (from one prospective controlled trial; Ploumis et al. 2015) that Alendronate does not inhibit the development of heterotopic ossification and in fact may contribute to the development of contractures.

There is conflicting Level 2 evidence (from two prospective controlled trials; Banovac et al. 1993; Banovac et al. 1997) and Level 4 evidence (from one case series; Branovac 2000) that Etidronate can stop the progression of heterotopic ossification once the diagnosis is made and prevent further HO sites.

There is Level 2 evidence (from one prospective controlled trial; Banovac et al. 1997) that Etidronate is not effective once radiographs are positive for HO.

There is Level 4 evidence (from one case series; Schuetz et al. 2005) that Pamidronate effectively halts secondary HO progression after surgical resection of HO.

• Alendronate does not prevent the development of heterotopic ossification and may cause contractures.

  Etidronate may be effective for halting the progression of heterotopic ossification when administered early.

  Etidronate can halt the progression of heterotopic ossification.

  Pamidronate halts secondary progression of heterotopic ossification post-surgical excision.