HETEROTOPIC OSSIFICATION AFTER SPINAL CORD INJURY: PREVENTION AND TREATMENT - A SISTEMATIC REVIEW

SCHINCARIOL, CINDY YUKIE NAKANO; ECHAURI, EDUARDO MARTIN INSFRÁN; SILVESTRE, ORCIZO FRANCISCO; CLIQUET JUNIOR, ALBERTO

doi:10.1590/1413-785220233103e267451

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Acta Ortopédica Brasileira

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REVIEW ARTICLE, SPINE • Acta ortop. bras. 31 (3) • 2023 • https://doi.org/10.1590/1413-785220233103e267451 copy

HETEROTOPIC OSSIFICATION AFTER SPINAL CORD INJURY: PREVENTION AND TREATMENT - A SISTEMATIC REVIEW

OSSIFICAÇÃO HETEROTÓPICA NO LESADO MEDULAR: PREVENÇÃO E TRATAMENTO - REVISÃO SISTEMÁTICA

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Trauma configures the main cause of spinal cord injuries. Patients with traumatic spinal cord injury often develop severe and debilitating outcomes that require multidisciplinary care to adapt patients to their new reality. Heterotopic ossification (HO) is one of the frequent comorbidities in these patients but it still lacks well-established treatments or a gold standard one. Thus, this systematic review aimed to search the current literature for HO treatment and prevention. This study was conducted following PRISMA recommendations (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) and searches were conducted in three databases (PubMed, Embase, and Web of Science). A total of 193 articles were found in an initial search. After screening following the established criteria, eight articles were included in this review; of these, two reported prevention and the others, treatments. Based on data analysis, the use of non-steroidal anti-inflammatory drugs in the acute post-traumatic period proved to be the best method of prevention. In cases of mature HO or accompanied by ankylosis, surgical resection proved to be the most effective treatment despite the high rate of postoperative infections. Level of Evidence III, Systematic Review.

Keywords:
Spinal Cord Injuries; Ossification, Heterotopic; Therapeutics

ID	Author and year	Study design	Population	Control	Intervention	Intervention details
1	de l'Escalopier et al., 2019¹¹11. de l’Escalopier N, Salga M, Gatin L, Genêt F, Denormandie P. Resection of heterotopic ossification around the hip after trauma. EFORT Open Rev. 2019;4(6):263-8.	Retrospective cohort	377 (104 SCI)		Surgical resection	Surgical resection in symptomatic patients. Minimal resection to achieve functional ROM. Post-procedure physical therapy and pre-procedure ATB
2	Ploumis et al., 2015¹²12. Ploumis A, Donovan JM, Olurinde MO, Clark DM, Wu JC, Sohn DJ, O’Connor KC. Association between alendronate, serum alkaline phosphatase level, and heterotopic ossification in individuals with spinal cord injury. J Spinal Cord Med. 2015;38(2):193-8.	Retrospective control case	125	174	Alendronate	Administration of alendronate 70 mg per week, averaging 38.17 ± 57.89 weeks. The patients were followed for an average of 626.72 ± 620.49 days.
3	Ester et al., 2022¹³13. Ester EC, Gallaher IS, Jones DA, Lynch JG. The role of radiation therapy in the management of neurogenic heterotopic ossification. Oncology. 2022;28(1S):1-10.	Retrospective cohort	3 SCI and 1 CCT		Radiotherapy (8 Gy) + resection + NSAIDs Radiotherapy (8 Gy) + etidronate	Irradiated 3 hips, post resection, with 8 Gy, followed by 6 weeks of 25 mg of indomethacin, 3 times/day. Three hips and 2 elbows were irradiated + etidronate, no surgery.
4	Honore et al., 2020¹⁴14. Honore T, Salga M, Grelier A, Denormandie P, Genet G, Labib A, et al. Effectiveness of radiotherapy to prevent recurrence of heterotopic ossification in patients with spinal cord injury and traumatic head injury: a retrospective case-controlled study. J Rehabil Med. 2020;52(5):jrm00066.	Retrospective control case	11 SCI and 8 CCT	76 (SCI or CCT)	Radiotherapy (7.5 Gy)	RT was performed with 7.5 Gy perioperatively to prevent recurrence.
5	Zakrasek et al., 2019¹⁵15. Zakrasek EC, Yurkiewicz SM, Dirlikov B, Pence BT, Crew JD. Use of nonsteroidal anti-inflammatory drugs to prevent heterotopic ossification after spinal cord injury: a retrospective chart review. Spinal Cord. 2019;57(3):214-20.	Retrospective control case	27	81	NSAIDs	Use of NSAIDs (indomethacin 25 mg 3 times/day or celecoxib 200 mg/day) for 15 days or more. Followed up for an average of 63 days, being evaluated an average of 21 days after trauma.
6	Romero-Muñoz et al., 2018¹⁶16. Romero-Muñoz LM, Barriga-Martín A, DeJuan-García J. Surgical treatment of hip ankylosis due to heterotopic ossification secondary to spinal cord injury. Rev Esp Cir Ortop Traumatol. 2018;62(6):458-66.	Retrospective cohort	20		Surgical resection + NSAIDs	Surgical resection of HO in 16 cases and Girdlestone in 4 cases. Goal of surgery: gain 90° of flexion and 20° of abduction. Physical therapy + celecoxib 200 mg/day for 4 weeks after the procedure.
7	Müseler et al., 2017¹⁷17. Müseler AC, Grasmücke D, Jansen O, Aach M, Meindl R, Schildhauer TA, Citak M. In-hospital outcomes following single-dose radiation therapy in the treatment of heterotopic ossification of the hip following spinal cord injury - an analysis of 444 cases. Spinal Cord. 2017;55(3):244-6.	Retrospective cohort	244		Radiotherapy (7 Gy)	Single radiation dose of 7 Gy in patients detected with HO (via biweekly US screening). After an average of 4.9 days after diagnosis, treatment was performed, which was on average 63.2 days after SCI.
8	Citak et al., 2016¹⁸18. Citak M, Grasmücke D, Cruciger O, Königshausen M, Meindl R, Schildhauer TA, Aach M. Heterotopic ossification of the shoulder joint following spinal cord injury: an analysis of 21 cases after single-dose radiation therapy. Spinal Cord. 2016;54(4):303-5.	Retrospective cohort	13		Single radiation dose (7 Gy, 6 Gy in two cases)	Single radiation dose in patients with HO (via biweekly US screening).

ID	Outcome	Complications	Limitations
1	Recurrence: 3.5%.	Intraoperative hemorrhage; femoral neck fracture, local infection (10.3% overall, 22% in those with spinal cord injuries)
2	No statistical difference was observed for the prevention of HO. However, patients who developed HO had altered serum ALP levels, and the group taking alendronate was positively correlated with normal ALP levels.	No reported complications	Inhomogeneous group; no exact protocol for the treatment beginning and duration
3	Efficacy rate of 87.5% in total; 1 patient progressed to HO in the etidronate group.	Grade 2 dermatitis in a patient	The effect of radiation alone has not been proven. Small sample, short follow-up (11 weeks), unknown effect and long-term toxicity.
4	Case group: 10.5% of recurrence, 47% with postoperative complications. Control group: 5.3% of recurrence, 23.3% with postoperative complications. There was no statistical difference in the recurrence of HO between groups but a higher rate of postoperative complications in the study group.	Main complication: postoperative sepsis, especially in the case group.	Patients undergoing RT tended to recurrence (inhomogeneous groups). A total of 78.9% of case patients had HO recurrence, while only 5.3% in the control group.
5	A total of 28.4% reduction in the rate of occurrence of HO in patients who used NSAIDs for 15 days or more in the acute phase of rehabilitation after SCI. (indomethacin 75 mg/day or celecoxib 200 mg/day) p < 0.006.	No observed adverse effects or complications	Non-randomized choice and non-blinded patients. Average follow-up of only 60 days. Non-standardization of days of use of NSAIDs and date of introduction.
6	Recurrence: 0% Important ROM gain. Flexion 90°, abduction 20°, IR 20°, and ER of 40° on average. All patients were satisfied with the postoperative outcome, even those with complications. Minimum follow-up of 1 year.	Complication in 30%: Deep infections (3 cases); retained bruises (2 cases); intraoperative deep femoral lesion (1 case)	Small sample
7	Recurrence: 13 patients (5.3%), of which, 26 hips (5.9%). A further dose was repeated in these patients, in which only 1 patient developed ankylosis. On average, patients were followed for 89.4 days.	No observed complications	The lower recurrence rate may stem from two reasons: short follow-up and early treatment due to screening. Recurrence cases were based on clinical pictures, which allows for underdiagnosis.
8	Average follow-up: 88.8 days. ROM gain: 92.1° flexion, 94.5° abduction, 26.4° external rotation. Recurrence: 0%	No observed complications	Only screened people with symptoms, there may be underdiagnosis of HO recurrence. Short follow-up time.

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[1] Correspondence: Cindy Yukie Nakano Schincariol. Rua Tessália Vieira de Camargo, 126, Campinas, SP, Brazil, 13083887. cindy1306@hotmail.com