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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).

 

Table 3: Prevention of AD during Bladder Procedures

Author Year

Country

Research Design

Score

Total Sample Size

MethodsResults
Alendronate
Ploumis et al. 2015

USA

Prospective Controlled Trial

N=299

Population: Alendronate (ALN, N=125): Mean age: 40.6 yr; Gender: males=86, females=39. Non-ALN (N=174): Mean age: 44.2 yr; Gender: males=140, females=34.

Treatment: 70 mg ALN was prescribed weekly to patients who could tolerate sitting in an upright position and able to receive oral medications. Patients used ALN for a mean period of 267 days.

Outcome Measures: Documentation and presence of HO.

1.     No significant correlation between diagnosis of HO and ALN intake was found.

2.     A significant correlation was found between HO appearance and alkaline phosphate (ALP) serum abnormality (p<0.001). Further, normal ALP serum levels were significantly correlated with ALN intake (p<0.05) whilst abnormal ALP serum levels was significantly correlated with no ALN intake.

3.     Significantly more patients receiving ALN developed contractures (p<0.001).

Etidronate
Banovac et al. 1997

USA

Prospective Controlled Trial

N=46

Population: Age range: 16-55 yr; Gender: males=44, females=2; Injury etiology: SCI=46; Severity of injury: AIS: A-C; Time since injury range: 2-5 wk.

Treatment: 3 hr IV Etidronate Disodium on day of HO diagnosis and continued for 3 successive days followed by PO Etidronate for 6 mo.

Outcome Measures: Degree of HO.

1.     Group 1 (positive bone scan and negative x-ray for HO, n=33): five patients discontinued therapy and showed gradual development of HO; of the remaining 28 patients, 22 had no x-ray evidence of HO while 6 developed x-ray diagnosis of HO by follow-up.

2.     Group 2 (positive bone scan and x-ray, n=13): 6 patients’ progression of soft tissue ossification was inhibited by Etidronate Disodium while the remaining seven did not respond to treatment, and demonstrated further progression of HO.

Banovac et al. 1993

USA

Prospective Controlled Trial

N=27

Population: Age range: 15-64 yr; Gender: males=25, females=2; Injury etiology: SCI=27; Severity of injury: Frankel Class: A=15, B=12; Time since injury range: 2-6 wk.

Treatment: 300mg IV Etidronate Disodium was administered over 3 hr for 3-5 days. After parenteral therapy, 20 mg PO Etidronate was administered for 6 mo. The second group received Etidronate PO only.

Outcome Measures: Swelling.

1.     After initial IV therapy, 20 patients showed prompt reduction in swelling over the first 48 hr, while seven patients had no change or an increase in swelling.

2.     Overall, treatment reduced swelling (p<0.01).

3.     No significant differences noted between the IV and orally treated groups in effect on HO.

 

Stover 1987

USA

Pre-Post

NInitial=169, NFinal=87

 

Population: Age: >16 yr; Injury etiology: Acute SCI.

Intervention: Didronel therapy. Four subgroups: 1) 3 mo therapy, early; 2) 6 mo therapy, early; 3) 3 mo therapy, late; 4) 6 mo therapy, late.

Outcome Measures: X-ray of hips at baseline, post treatment and 1yr follow-up.

1.     There was no difference in development of HO between those receiving therapy for 3 mo versus 6 mo.

2.     Regardless of duration of Didronel, early treatment worked better than later treatment.

Banovac 2000

Denmark

Case Series

N=40

Population: Mean age: 23 yr; Gender: males=39, females=1; Injury etiology: SCI=40; Severity of injury: AIS A-B; Time since injury range: 2-5wk.

Treatment: All patients with positive clinical findings and positive bone scan were treated with IV Etidronate Disodium, then PO Etidronate 20 mg/kg/day for 6 mo.

Outcome Measures: Prevalence of HO.

1.     No statistical results reported.

2.     11/40 patients developed radiographic evidence of HO from 1.5 to 6 yr post treatment.

3.     In 95% of cases, recurrent HO in developed in different areas involving different joints.

 

 

 

 

Subbarao et al. 1987 USA

Case Series

N=5

Population: Age range: 29-41yr; Injury etiology: SCI; Time since injury range: 18-197 mo.

Treatment: Didronel given 10 days-2 wk preoperatively, medication withheld for immediate postop period (72 hr) and continued for a minimum of 3 mo. All patients underwent wedge resection at hip to permit free movement of hip in flexion.

Outcome Measures: Effects of treatment.

1.     All patients at last follow-up were able to function independently in their wheelchairs except one, who was able to function independently in a semi reclining wheelchair.

2.     Patients had severe restriction of range of motion in involved joints.

Garland et al. 1983

USA

Case Series

N=14

Population: Mean age=25 yr; Gender: males=9, females=5; Injury etiology: SCI; Level of injury: cervical=6, thoracic=5; Severity of injury: complete=7, incomplete=2.

Treatment: Bisphosphonate treatment was administered for 2wk at 20 mg/kg/day and then for 2yr at 10 mg/kg/day.

Outcome Measures: Effectiveness of treatment and adverse effects.

1.     8/9 pretreatment patients had HO in 10 hips.

2.     Post-treatment all patients showed evidence of HO.

3.     Of the 9 minimal graded hips, only 1 stayed at the minimal grade, whereas others increased (5 mild, 3 moderate, 5 severe).

4.     No adverse effects were observed.

Pamidronate
Schuetz et al. 2005

Switzerland

Case Series

N=7

Population: Age range: 47-68 yr; Gender: males=7, females=0; Injury etiology: SCI=7; Level of injury: thoracic=1, tetraplegia=2.

Treatment: All patients underwent excision surgery for removal of HO. Pamidronate was administered IV peri-op and post-op, starting at a dose level of 120 mg for the first 12 hr, gradually increasing for a total of 6-14 days.

Outcome Measures: Prevalence of HO.

No statistical results reported

1.     None of the patients treated with pamidronate showed clinical, x-ray or lab signs of HO recurrence or new forming HO at 5-54 mo follow-up.

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.