HETEROTOPIC OSSIFICATION IN ACETABULAR FRACTURES: SYSTEMATIC REVIEW AND META-ANALYSIS OF PROPHYLAXIS

BUENO, THIAGO SANCHEZ PIRES; GODOY, GABRIEL PARIS DE; FURUKAVA, REBECA BARROS; GAGGIOLI, NICOLE TAKAKURA; TAMAOKI, MARCEL JUN SUGAWARA; MATSUNAGA, FABIO TERUO; BELLOTI, JOÃO CARLOS

doi:10.1590/1413-785220212906244689

THIAGO SANCHEZ PIRES BUENO

Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brasil.

http://orcid.org/0000-0001-9186-0062

GABRIEL PARIS DE GODOY

Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brasil.

http://orcid.org/0000-0002-7874-7476

REBECA BARROS FURUKAVA

Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brasil.

http://orcid.org/0000-0002-4033-5134

NICOLE TAKAKURA GAGGIOLI

Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brasil.

http://orcid.org/0000-0002-6103-5763

MARCEL JUN SUGAWARA TAMAOKI

Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brasil.

http://orcid.org/0000-0002-9539-4545

FABIO TERUO MATSUNAGA

Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brasil.

http://orcid.org/0000-0001-7328-1446

JOÃO CARLOS BELLOTI

Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brasil.

http://orcid.org/0000-0003-3396-479X

Correspondence: Thiago Sanchez Pires Bueno. Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Ortopedia e Traumatologia. Rua Botucatu, 740, Vila Clementino, São Paulo, SP, Brasil, 04023062. thiagospbueno@hotmail.com

All authors declare no potential conflict of interest related to this article.

AUTHORS’ CONTRIBUTION:

Each author contributed individually and significantly to the development of this article. TSPB: conception or design of the paper, or acquisition, analysis or interpretation of the data for the paper, drafting of the intellectual work, final approval of the manuscript version for publication; GPG: conception or design of the paper, or acquisition, analysis or interpretation of the data for the paper, drafting of the intellectual work, final approval of the manuscript version for publication; RBF: conception or design of the paper, or acquisition, analysis or interpretation of the data for the paper, drafting of the intellectual work, final approval of the manuscript version for publication; NTG: conception or design of the paper, or acquisition, analysis or interpretation of the data for the paper, drafting of the intellectual work, final approval of the manuscript version for publication; FTM: conception or design of the paper, or acquisition, analysis or interpretation of the data for the paper, drafting of the intellectual work, final approval of the manuscript version for publication; JCB: conception or design of the paper, or acquisition, analysis or interpretation of the data for the paper, drafting of the intellectual work, final approval of the manuscript version for publication.

Author, year	Type of study	Sample size / gender / average age	Country	Participants and intervention time	Intervention	Comparison or control	Outcome	Results	GRADE Quality of evidence
Burd et al., 2001³¹	Randomized clinical trial.	N = 150	USA	Patients with operative stabilization of acetabular fractures by open reduction and internal fixation.	Radiation (n = 78)	Indomethacin (n = 72)	HO classified according to Brooker*	Brooker Grade III or IV heterotopic ossification developed in eight (11%) patients randomized for treatment with indomethacin and three (4%) patients randomized for treatment with radiation therapy. There were no differences between the treatment groups regarding heterotopic ossification (p = 0.22).	⊕⊕⊕⊕ DISCHARGE
		105 M					HO classified according to Brooker*
		45 F					None (grade 0)
		(Group Radiation - average age 44)					Mild (grade I and grade II)
		(Group Indomethacin - average 41 years old)		Dose: 800 cGy of local radiation therapy in the hip within seventy-two hours after the operation. Indomethacin (25 mg three times daily) starting within twenty-four hours after surgery for 6 weeks. Duration of follow-up: average thirteen and sixteen months.			Severe (grade III and grade IV)	Local radiation therapy and indomethacin were considered effective prophylaxis against heterotopic ossification after surgical treatment of acetabular fractures.
Karunakar et al., 2006 ³²	Clinical trial. prospective, randomized double-blind controlled	N = 127	USA	Patients with operative stabilization of acetabular fractures through a subsequent Kocher-Langenbeck approach.	Indomethacin (Merck Inc., Whitehouse Station, New Jersey)	Placebo	HO classified according to Brooker*	Grade III to IV occurred in nine of 59 patients (15.2%) in the indomethacin group and 12 of 62 (19.4%) who received placebo.	⊕⊕⊕⊕ DISCHARGE
		100 M					HO classified according to Brooker*
		27 F					None (grade 0)
		Indomethacin group: average age 37 years old			Before (n = 63)	Before (n = 64)	Mild (grade I and grade II)
		Placebo group: average age 39 years old		Dose: 75 mg Indomethacin a single daily dose. Intervention time: 6 weeks	After (n = 59)	After (n = 62)	Severe (grade III and grade IV)	There is no statistically significant difference between the two groups (chi-square test, p = 0.722). Fisher's exact test showed no significant association between Brooker categories (none, mild, severe) and treatment groups (p = 0.334).
Matta e Siebenrock 1997³³	Randomized clinical trial.	N = 107	USA	Patients with acetabular fractures underwent surgery by Kocher-Langenbeck (KL), ilioinguinal (II) or extended iliofemoral approach.	Indomethacin	No indomethacin	HO evaluated by AP radiograph of the pelvis and classified as grade 0 (none), grade 1 (minimum) or grade 2 (moderate to severe) ROM	Of the patients receiving indomethacin, 30 (52.6%) did not develop ossification assessed by simple radiograph compared to 19 (43.2%) in the untreated group.	⊕⊕⊕ MODERATE
		Gender NR			Indomethacin	No indomethacin
		Indomethacin group: average age 40,3 years old			Before (n = 61)	Before (n = 46)
		Non-indomethacin group: average age 45.7 years old		Dose: 100 mg per suppository at the end of the operation, then 25 mg orally or rectally. Intervention time: three times a day for six weeks.	After (n = 57)	After (n = 44)		Two patients (1.9%) developed clinically significant ossification (grade 2) with loss of hip motion greater than 20% compared to the non-involved side. Both received indomethacin and the operation was by a KL approach.
Moore et al., 1998³⁴	Clinical trial, prospective, randomized, blind	N = 75	USA	Adult patients who underwent open reduction and internal fixation of acetabular fractures by means of a Kocher-Langenbeck, a combined ilioinguinal and Kocher-Langenbeck, or an extended iliofemoral approach.	Indomethacin	Radiation therapy	HO evaluated by simple X-rays and classified according to Brooker*	Cochran-Armitage analysis showed no significant difference between the two treatment groups regarding the formation of HO (p = 0.089). Indomethacin and single-dose radiation therapy are safe and effective in preventing HO after the operation of acetabular fractures.	⊕⊕⊕ MODERATE
		52 men
		23 women
		Indomethacin group: average age 43 years old		Dose: 25 mg of Indomethacin Intervention time: three times a day for six weeks. Duration of follow-up: 12 months.	Before (n = 20)	Before (n = 46)
		Radiation group: average age 47 years old		Radiation with 800 cGy three days after the operation	After (n = 39)	After (n = 33)	None (grade 0)
							Mild (grade I and grade II)
							Severe (grade III and grade IV)
Sagi et al., 2014³⁵	Clinical trial, prospective double-blind randomized	N = 98	USA	Patients who suffered an acetabular fracture underwent open reduction and internal fixation of their acetabular fracture by a Kocher-Langenbeck approach.	Indomethacin	Placebo	HO evaluated by simple X-rays and classified according to Brooker*	A six-week long treatment with indomethacin does not appear to have a therapeutic effect to decrease the formation of HO after acetabular fracture surgery, and appears to increase the incidence of nonunion. A one-week long treatment with indomethacin may be beneficial to decrease the volume of HO formation without increasing the incidence of pseudoarthrosis. Visual analog scales for pain (VASs) were significantly higher for patients with radiographic nonunion (VAS 4 vs. VAS 1, P = 0,002).	⊕⊕⊕ MODERATE
		70 men					None (grade 0)
		28 women					None (grade 0)
		Indomethacin group: average age 43 years old			Before	Before (n = 26)	Mild (grade I and grade II)
					Group 1-3 days (n = 24)		Mild (grade I and grade II)
					Group 2 - one week) (n = 25)		Severe (grade III and grade IV)
					Group 3 - six weeks (n = 23)		Severe (grade III and grade IV)
		Radiation group: average age 47 years old		Dose: 75 mg PO daily. Intervention time: 6 weeks	After	After (n = 21)	EVA: pain assessment.
					Group 1 - (n = 17)
					Group 2- (n = 17)
					Group 3- (n = 13)

Summary of findings:
Interventions to prevent heterotopic ossification in patients with acetabular fractures
Patient or population: Patients with surgical stabilization of acetabular fractures
Setting: Hospital
Intervention: Indomethacin
Comparison: Placebo
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with [Placebo/ no intervention]	Risk with [Indomethacin]	Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
Heterotopic ossification assessed with: Placebo versus Indomethacin follow up: average 6 weeks	598 per 1.000	497 per 1.000	RR 0.83	256	⊕⊕⊕ MODERATE	No differences were found between the studies regarding the outcome
	598 per 1.000	(395 to 622)	(0.66 to 1.04)	(3 RCTs)	⊕⊕⊕ MODERATE
Range of motion	0 %	20 %	-	101	⊕⊕⊕ MODERATE	Two patients (1.9%) developed clinically significant ossification (grade 2) with loss of hip movement greater than 20% compared with the uninvolved side.
Range of motion	0 %	20 %	-	(1 study)	⊕⊕⊕ MODERATE	The moderate quality of the studies is a result of the small sample size and because there is no available study protocol.
Pain (VAS) in Patients with Nonunion versus Patients with Union	4	1	-	34	⊕⊕⊕ MODERATE	Pain as reported by VAS was significantly greater in the patients with radiographic nonunion at both the 6-month and 1-year follow-up intervals (P = 0.002).
	4	1	-	(1 studies)	⊕⊕⊕ MODERATE	The moderate quality of the studies is a result of the small sample size.
Summary of findings:
Interventions to prevent heterotopic ossification in patients with acetabular fractures
Patient or population: Patients with surgical stabilization of acetabular fractures
Setting: Hospital
Intervention: Indomethacin
Comparison: Placebo
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with [Placebo/ no intervention]	Risk with [Indomethacin]	Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

[1] Correspondence: Thiago Sanchez Pires Bueno. Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Ortopedia e Traumatologia. Rua Botucatu, 740, Vila Clementino, São Paulo, SP, Brasil, 04023062. thiagospbueno@hotmail.com

1	Acetabulum [MeSH Terms]
2	Fractures, Bone OR Fracture Fixation OR Fracture Healing
3	Ossification, Heterotopic
4	Myositis Ossificans
5	pathologic* OR ectopic or heterotopic
6	extraosseous OR heterotopic OR metaplastic OR para-articular OR paraarticular OR pathologic* OR periarticular
7	myositis OR dystrophic OR ectopic OR heterotopic OR metaplastic OR para-articular OR paraarticular OR pathological OR periarticular
8	myo-osteosis OR neurogenic osteoma OR osseous heteroplasia OR ossifying fibromyopathy OR synostosis
9	3 or 4 or 5 or 6 or 7 or 8
10	1 AND 2 AND 9

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HETEROTOPIC OSSIFICATION IN ACETABULAR FRACTURES: SYSTEMATIC REVIEW AND META-ANALYSIS OF PROPHYLAXIS

OSSIFICAÇÃO HETEROTÓPICA NAS FRATURAS DO ACETÁBULO: REVISÃO SISTEMÁTICA E METANÁLISE DA PROFILAXIA

ABSTRACT

Objective:

Methods:

Results: