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Radiotherapy for the prophylaxis of heterotopic ossification: A systematic review and meta-analysis of randomized controlled trials

  • Milica Milakovic
    Affiliations
    Rapid Response Radiotherapy Program, Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Canada
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  • Marko Popovic
    Affiliations
    Rapid Response Radiotherapy Program, Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Canada
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  • Srinivas Raman
    Affiliations
    Rapid Response Radiotherapy Program, Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Canada
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  • May Tsao
    Affiliations
    Rapid Response Radiotherapy Program, Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Canada
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  • Henry Lam
    Affiliations
    Rapid Response Radiotherapy Program, Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Canada
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  • Edward Chow
    Correspondence
    Corresponding author at: Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
    Affiliations
    Rapid Response Radiotherapy Program, Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Canada
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      Abstract

      Introduction

      Heterotopic ossification (HO) involves the formation of lamellar bone in nonosseous tissue. For HO, radiotherapy has been shown to be an effective prophylactic modality.

      Objective

      To compare HO outcomes following radiotherapy and to investigate the comparative efficacy of preoperative versus postoperative radiotherapy.

      Methods

      A systematic search was conducted on Ovid MEDLINE, EMBASE and Cochrane CENTRAL. Studies were included if they were randomized controlled trials (RCTs) that included patients who were prescribed prophylactic radiation for whom relevant HO progression outcomes were reported.

      Results

      From a literature search of 528 articles, 12 RCTs were included. There was a statistically significant reduction in HO prevalence with multiple as opposed to single fraction radiotherapy (p = 0.04), however there was no statistically significant difference when examining HO progression (p = 0.34). There was no statistically significant difference in HO progression when comparing a biologically effective radiation dose (BED) of >2500 cGy versus ⩽2500 cGy (p = 0.28). As well, no statistically significant difference existed in HO progression between postoperative versus preoperative radiation (p = 0.43).

      Conclusion

      There was no difference between postoperative or preoperative radiotherapy in preventing HO progression. There seems to be no relationship between BED greater or less than 2500 cGy and the efficacy of HO prophylaxis. Multiple fractions seem to be more effective than single fraction radiotherapy in preventing HO progression.

      Keywords

      Heterotopic ossification (HO) is the formation of lamellar bone in non-osseous tissues such as muscles, nerves and connective tissue [
      • Naraghi F.F.
      • DeCoster T.A.
      • Moneim M.S.
      • et al.
      Heterotopic ossification.
      ,
      • Shimono K.
      • Tung W.E.
      • Macolino C.
      • et al.
      Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-y agonists.
      ]. HO can develop in various sites, including the hip, knee, shoulder and elbow and is usually the result of traumatic acetabular fracture, total hip arthroplasty or central nervous injury [
      • Shehab D.
      • Elgazzar A.H.
      • Collier D.
      Heterotopic ossification.
      ,
      • Seegenschmiedt M.H.
      • Keilholz L.
      • Martus P.
      • et al.
      Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.
      ]. The incidence of HO after open reduction of acetabular fractures ranges from 5% to 90% [
      • Bedi A.
      • Zbeda R.M.
      • Bueno V.F.
      • et al.
      The incidence of heterotopic ossification after hip arthroscopy.
      ].
      HO formation is presumed to result from differentiation of pluripotent mesenchymal cells into osteoblasts [
      • Chao S.T.
      • Joyce M.J.
      • Suh J.H.
      Treatment of heterotopic ossification.
      ]. Bone morphogenic protein (BMP2) has been shown to induce this process [
      • Zhang R.
      • Oyajobi B.
      • Harris S.E.
      • et al.
      Wnt/β-catenin signalling activates bone morphogenetic protein 2 expression in osteoblasts.
      ]. Specifically, BMP2 interacts with the Wnt/β-catenin in osteoblasts, which leads to differentiation. Differentiation usually occurs 16 h after surgery and peaks at around 32 h postoperatively. It normally takes at least 4–6 weeks for mineralization to be detected by radiographs [
      • Chao S.T.
      • Joyce M.J.
      • Suh J.H.
      Treatment of heterotopic ossification.
      ].
      The risk factors for developing HO include male gender, osteoarthritis, and previous development of HO at a particular anatomic site [
      • Taussky T.
      • Cserhati M.
      • Pescia R.
      Preoperative radiotherapy without femoral shielding for prevention of heterotopic ossification in hydroxyapatite-coated hip prostheses.
      ]. In many cases, HO is asymptomatic and is only detected on imaging. In other cases, it is asymptomatic until it has reached higher degrees of ossification that may affect patients’ function [
      • Roth K.E.
      • Salzmann G.
      • Maier G.S.
      • et al.
      Risk factors for heterotopic ossification and spur formation after total knee arthroplasty.
      ]. Pain and decreased range of motion are the most common symptoms of advanced HO [
      • Garland D.E.
      A clinical perspective on common forms of acquired heterotopic ossification.
      ]. To classify the degree of ossification, the Brooker classification system is most commonly employed [
      • Brooker A.F.
      • Bowerman J.W.
      • Robinson R.A.
      • Riley L.H.
      Ectopic ossification following total hip replacement. Incidence and method of classification.
      ]. The classification is based on AP radiographic views only and is divided into five grades: grade 0, which represents no soft tissue calcification; grade 1, which represents islands of bone within the soft tissue about the hip; grade 2, which represents bone spurs in the pelvis or proximal end of the femur with at least 1 cm between the opposing bone surfaces; grade 3, which represents bone spurs from the pelvis or proximal end of femur with less than 1 cm between opposing bone surfaces; and grade 4, which represents radiographic ankylosis [
      • Brooker A.F.
      • Bowerman J.W.
      • Robinson R.A.
      • Riley L.H.
      Ectopic ossification following total hip replacement. Incidence and method of classification.
      ].
      Two common methods of prophylaxis of HO development are radiotherapy and non-steroidal anti-inflammatory drugs (NSAIDs). In a meta-analysis of randomized controlled trials (RCTs) by Vavken et al., HO outcomes were compared in NSAID vs. radiotherapy treatment arms. In total, 634 patients who received radiation and 661 patients who received NSAIDs were included in the study. There was no significant difference in the two prophylactic modalities seen (risk ratio (RR) = 1.2; 95% confidence interval (CI) = 0.8–1.8; p = 0.48) [
      • Vavken P.
      • Castellani L.
      • Sculco T.P.
      Prophylaxis of heterotopic ossification of the hip.
      ]. However, there is a significant difference between the cost effectiveness of radiotherapy versus NSAIDs [
      • Vavken P.
      • Dorotka R.
      Economic evaluation of NSAID and radiation to prevent heterotopic ossification after hip surgery.
      ]. In another meta-analysis by Vavken et al., results strongly supported the conclusion that NSAIDs are considerably more cost effective than radiotherapy [
      • Vavken P.
      • Dorotka R.
      Economic evaluation of NSAID and radiation to prevent heterotopic ossification after hip surgery.
      ]. However, compared to NSAIDs, radiation therapy may be associated with lower incidence of grade 3 and 4 HO. Therefore, radiotherapy may be a preferred option in very high risk patients or in patients with contraindications to NSAIDs.
      Currently, it is hypothesized that radiation works as a method of prophylaxis by inactivating pluripotent mesenchymal cells before they start differentiating into osteoblasts [
      • Ellerin B.E.
      • Helfet D.
      • Parikh S.
      • et al.
      Current therapy in the management of heterotopic ossification of the elbow: a review with case studies.
      ]. Radiation can be either given preoperatively or postoperatively, although the latter remains a more common treatment choice [
      • Popovic M.
      • Agarwal A.
      • Zhang L.
      • et al.
      Radiotherapy for the prophylaxis of heterotopic ossification: a systematic review and meta-analysis of published data.
      ,
      • Gregoritch S.J.
      • Chadha M.
      • Pelligrini V.D.
      Randomized trial comparing preoperative vs. postoperative irradiation for prevention of heterotopic ossification following prosthetic total hip replacement: preliminary results.
      ]. A meta-analysis by Popovic et al. examined the published literature to examine optimal prescription parameters in 5464 patients receiving prophylactic radiotherapy. They found that there was no statistically significant relationship between the percentage of patients receiving HO and radiation dose, and no significant difference in the effectiveness between preoperative versus postoperative radiotherapy [
      • Popovic M.
      • Agarwal A.
      • Zhang L.
      • et al.
      Radiotherapy for the prophylaxis of heterotopic ossification: a systematic review and meta-analysis of published data.
      ]. The purpose of our meta-analysis is to determine if these previous findings could be corroborated in a more controlled environment by only considering the results of randomized controlled trials (RCTs). Specifically, our meta-analysis asks whether there is a difference in the development of HO based on fractionation schedule (single vs. multiple), preoperative versus postoperative radiotherapy administration, and high versus low biologically effective radiation dose (BED).

      Methods

      A systematic literature search on Ovid MEDLINE and Ovid OLDMEDLINE (1946 to February week 4 2015), EMBASE and EMBASE Classic (1947–2015 week 8) and the Cochrane Central Register of Controlled Trials (January 2015) was conducted utilizing the keyword “heterotopic ossification” combined with either “radiotherapy”, “radiation prophylaxis”, “radiation therapy” or “cancer radiotherapy”.
      Studies that were included had to be RCTs that contained patients who had all been prescribed a known dose of radiotherapy. The prevalence of HO had to be reported and stratified by radiation site. Studies were only included if the average or median length of radiographic follow-up exceeded eight weeks. Only English trials were included.

      Data collection

      Collected data included the year of treatment, treatment center, site of radiation, number of treatment sites with radiographic follow-up, radiation dose, timing of radiation (postoperative or preoperative), past history of HO, percentage of sites with any HO prior to study inclusion, percentage of sites developing any HO over the study duration, as well as Brooker grade-specific data for HO prevalence prior to and during the study.

      Statistical analysis

      Review Manager (RevMan 5.2) by Cochrane IMS was used to conduct the meta-analysis. The Mantel–Haenszel method was applied and a random effects model was used to generate odds ratios (OR) and accompanying 95% confidence intervals (CI). A p-value of p < 0.05 was considered statistically significant. The intention-to-treat principle was utilized in all statistical analyses. For the pooled analysis, prevalence rates were used because not all studies included information about baseline HO rates. However, incidence of progression is a more accurate measure of the efficacy of prophylaxis; since some studies being considered have this information, different endpoints were used.

      Results

      From a literature search of 577 articles, title and abstract screening revealed 456 exclusions. Of the 121 remaining articles, a total of 12 RCTs that spanned 20 study arms were selected for inclusion to the present study.
      Of the included studies, six, five and one came from the United States [
      • Burd T.A.
      • Lowry K.J.
      • Anglen J.O.
      Indomethacin compared with localized irradiation for the prevention of heterotopic ossification following surgical treatment of acetabular fractures.
      ,
      • Hamid N.
      • Ashraf N.
      • Bosse M.J.
      • et al.
      Radiation therapy for heterotopic ossification prophylaxis acutely after elbow trauma.
      ,
      • Moore K.D.
      • Goss K.
      • Anglen J.O.
      Indomethacin versus radiation therapy for prophylaxis against heterotopic ossification in acetabular fractures: a randomised, prospective study.
      ,
      • Padgett D.E.
      • Holley K.G.
      • Cummings M.
      • et al.
      The efficacy of 500 CentiGray radiation in the prevention of heterotopic ossification after total hip arthroplasty: a prospective randomized, pilot study.
      ,
      • Pellegrini V.D.
      • Konski A.A.
      • Gastel J.A.
      • et al.
      Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.
      ,
      • Pellegrini V.D.
      • Gregoritch S.J.
      Preoperative irradiation for prevention of heterotopic ossification following total hip arthroplasty.
      ], Germany [
      • Seegenschmiedt M.H.
      • Keilholz L.
      • Martus P.
      • et al.
      Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.
      ,
      • Kienapfel H.
      • Koller M.
      • Wust A.
      • et al.
      Prevention of heterotopic bone formation after total hip arthroplasty: a prospective randomised study comparing postoperative radiation therapy with indomethacin medication.
      ,
      • Knelles D.
      • Barthel T.
      • Karrer A.
      • et al.
      Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation.
      ,
      • Kolbl O.
      • Knelles D.
      • Barthel T.
      • Raunecker F.
      • Flentje M.
      • Eulert J.
      Preoperative irradiation versus the use of nonsteroidal anti-inflammatory drugs for prevention of heterotopic ossification following total hip replacement: the results of a randomized trial.
      ,
      • Sell S.
      • Willms R.
      • Jany R.
      • et al.
      The suppression of heterotopic ossifications: radiation versus NSAID therapy – a prospective study.
      ] and the Netherlands [
      • van Leeuwen W.M.
      • Deckers P.
      • de, Lange W.lJ.
      Preoperative irradiation for prophylaxis of ectopic ossification after hip arthroplasty. A randomized study in 62 hips.
      ], respectively (Table 1; Supplementary Material 1). The studies were published between 1992 and 2010 with the majority published before 2000 [
      • Seegenschmiedt M.H.
      • Keilholz L.
      • Martus P.
      • et al.
      Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.
      ,
      • Moore K.D.
      • Goss K.
      • Anglen J.O.
      Indomethacin versus radiation therapy for prophylaxis against heterotopic ossification in acetabular fractures: a randomised, prospective study.
      ,
      • Pellegrini V.D.
      • Konski A.A.
      • Gastel J.A.
      • et al.
      Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.
      ,
      • Pellegrini V.D.
      • Gregoritch S.J.
      Preoperative irradiation for prevention of heterotopic ossification following total hip arthroplasty.
      ,
      • Kienapfel H.
      • Koller M.
      • Wust A.
      • et al.
      Prevention of heterotopic bone formation after total hip arthroplasty: a prospective randomised study comparing postoperative radiation therapy with indomethacin medication.
      ,
      • Knelles D.
      • Barthel T.
      • Karrer A.
      • et al.
      Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation.
      ,
      • Kolbl O.
      • Knelles D.
      • Barthel T.
      • Raunecker F.
      • Flentje M.
      • Eulert J.
      Preoperative irradiation versus the use of nonsteroidal anti-inflammatory drugs for prevention of heterotopic ossification following total hip replacement: the results of a randomized trial.
      ]. All treatment arms reported outcomes for hip radiotherapy [
      • Seegenschmiedt M.H.
      • Keilholz L.
      • Martus P.
      • et al.
      Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.
      ,
      • Burd T.A.
      • Lowry K.J.
      • Anglen J.O.
      Indomethacin compared with localized irradiation for the prevention of heterotopic ossification following surgical treatment of acetabular fractures.
      ,
      • Moore K.D.
      • Goss K.
      • Anglen J.O.
      Indomethacin versus radiation therapy for prophylaxis against heterotopic ossification in acetabular fractures: a randomised, prospective study.
      ,
      • Padgett D.E.
      • Holley K.G.
      • Cummings M.
      • et al.
      The efficacy of 500 CentiGray radiation in the prevention of heterotopic ossification after total hip arthroplasty: a prospective randomized, pilot study.
      ,
      • Pellegrini V.D.
      • Konski A.A.
      • Gastel J.A.
      • et al.
      Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.
      ,
      • Pellegrini V.D.
      • Gregoritch S.J.
      Preoperative irradiation for prevention of heterotopic ossification following total hip arthroplasty.
      ,
      • Kienapfel H.
      • Koller M.
      • Wust A.
      • et al.
      Prevention of heterotopic bone formation after total hip arthroplasty: a prospective randomised study comparing postoperative radiation therapy with indomethacin medication.
      ,
      • Knelles D.
      • Barthel T.
      • Karrer A.
      • et al.
      Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation.
      ,
      • Kolbl O.
      • Knelles D.
      • Barthel T.
      • Raunecker F.
      • Flentje M.
      • Eulert J.
      Preoperative irradiation versus the use of nonsteroidal anti-inflammatory drugs for prevention of heterotopic ossification following total hip replacement: the results of a randomized trial.
      ,
      • Sell S.
      • Willms R.
      • Jany R.
      • et al.
      The suppression of heterotopic ossifications: radiation versus NSAID therapy – a prospective study.
      ,
      • van Leeuwen W.M.
      • Deckers P.
      • de, Lange W.lJ.
      Preoperative irradiation for prophylaxis of ectopic ossification after hip arthroplasty. A randomized study in 62 hips.
      ] except for one trial that included patients receiving radiotherapy to the elbow [
      • Hamid N.
      • Ashraf N.
      • Bosse M.J.
      • et al.
      Radiation therapy for heterotopic ossification prophylaxis acutely after elbow trauma.
      ]. According to self-reported criteria, 469 sites (37.4%) had a high risk of developing HO. In terms of radiotherapy administration, 1035 sites (82.6%) received postoperative treatment while 218 sites (17.4%) received treatment preoperatively. The treatment year ranged from 1987–2008 (mean: 1992.5), while mean latest radiographic follow-up ranged from 6 to 31 months with a mean of 21.9 months between the studies. Only Pellegrini et al. included median follow-up which was 31 months for the first study arm and 46 weeks for the second arm [
      • Pellegrini V.D.
      • Gregoritch S.J.
      Preoperative irradiation for prevention of heterotopic ossification following total hip arthroplasty.
      ]. Combining the data, 658 sites received single fraction radiation doses while 595 received multiple fractions (Table 1).
      Table 1Baseline demographic data for included randomized controlled trials.
      Study (Author, year)Year of treatmentTreatment centerSite of radiationNumber of Treatment sites with radiographic follow-upRadiation dose (cGy)/fractionationPostoperative versus preoperative radiationPast patient history of HOPercentage of sites with any HO previous to study inclusionPercentage of sites with Brooker grade 1/2 HO previous to study inclusionPercentage of sites with Brooker grade 3/4 HO previous to study inclusion
      Burd (2001)1992–1999USAHip78800/1PostoperativeUnknownn/an/an/a
      Hamid (2010)2005–2008USAElbow21700/1PostoperativeUnknownn/an/an/a
      Kienapfel (1999)1992–1993GermanyHip49600/1PostoperativeUnknownn/an/an/a
      Knelles (1997)1988–1994GermanyHip1011200/4PostoperativeUnknownn/an/an/a
      Knelles 2nd study arm (1997)1988–1994GermanyHip95700/1PostoperativeUnknownn/an/an/a
      Knelles 3rd study arm (1997)1988–1994GermanyHip93500/1PostoperativeUnknownn/an/an/a
      Kölbl (1998)1995–1996GermanyHip46700/1PreoperativeMixedn/an/an/a
      Moore (1998)1993–1996USAHip33800/1PostoperativeUnknownn/an/an/a
      Padgett (2003)n/aUSAHip29500/2PostoperativeMixed6/29 = 20.7%n/an/a
      Padgett 2nd study arm (2003)n/aUSAHip301000/5PostoperativeMixed7/30 = 23.3%n/an/a
      Pellegrini (1992)1987–1989USAHip34800/1PostoperativeMixed12/34 = 35.3%5/34 = 14.7%7/34 = 20.6%
      Pellegrini 2nd study arm (1992)1987–1989USAHip281000/2PostoperativeMixed15/28 = 53.6%5/28 = 17.9%10/28 = 35.7%
      Pellegrini (1996)1990–1992USAHip49800/1PreoperativeMixed15/49 = 30.6%4/49 = 8.2%11/49 = 22.4%
      Pellegrini 2nd study arm (1996)1990–1992USAHip37800/1PostoperativeMixed8/37 = 21.6%5/37 = 13.5%3/37 = 8.1%
      Seegenschmiedt (1997)1992–1995GermanyHip80700/1PreoperativeMixed54/80 = 67.5%25/80 = 31.3%29/80 = 36.3%
      Seegenschmiedt 2nd study arm (1997)1992–1995GermanyHip811750/5PostoperativeMixed55/81 = 67.9%33/81 = 40.7%22/81 = 27.2%
      Seegenschmiedt 3rd study arm (1997)1987–1992GermanyHip1181750/5PostoperativeMixed59/118 = 50%29/118 = 24.6%30/118 = 25.4%
      Seegenschmiedt 4th (1997)1987–1992GermanyHip1311000/2PostoperativeMixed66/131 = 50.4%35/131 = 26.7%31/131 = 23.7%
      Sell (1998)1992–1993GermanyHip77990/3PostoperativeMixed6/77 = 7.8%5/77 = 6.5%1/77 = 1.3%
      Van Leeuwen (1998)1989–1992The NetherlandsHip43500/1PreoperativeMixed4/43 = 9.3%n/an/a
      A full summary of HO outcomes in individual study arms is presented in Table 2. Briefly, the overall percentage of sites developing any HO was 34.1% (Brooker grades 1 or 2 HO: 30.2%; Brooker grades 3 or 4 HO: 3.9%). BED calculations were performed for all applicable study arms; BED refers to the true biological dose that a tissue receives and it depends on the total dose, fraction per dose and specific tissue characteristics (Supplementary Material 2). Arms were grouped into >2500 cGy (‘high BED’) and ⩽2500 cGy (‘low BED’) to allow for head-to-head comparisons of HO outcomes between arms, and all BED values were calculated using a generic late effects alpha/beta ratio of 3. 2500 cGy was chosen as the cutoff to separate the commonly used fractionation schemes of 700/1 (=2333 cGy BED) and 800/1 cGy (=2933 cGy BED) and to have similar sample sizes between the two groups. For BED values less than or equal to 2500 cGy, the mean percentage of sites developing HO was 26.4% (range: 2.6–69%). Further, most cases involved Brooker grades 1 or 2 HO (mean 23.5%, range: 2.6–62.1%), while fewer cases of Brooker grades 3 or 4 HO were found (mean: 2.86%, range: 0–6.9%). Data with BED values greater than 2500 cGy revealed higher rates of HO formation (mean: 42.8%, range: 28.6–55.3%). For Brooker grades 1 or 2 HO formation, 37.7% (range: 24.2–49.7%) of sites developed HO while only 5.1% of sites developed Brooker grades 3 or 4 HO (range: 4.3–5.7%).
      Table 2Development rates of heterotopic ossification in individual study arms.
      Study (Author and year)Dose (cGy)/fractionationAverage time of radiographic follow-up (months)Development rates of heterotopic ossification
      Overall (any Brooker grade HO)Brooker grades 1/2 HOBrooker grades 3/4 HO
      Burd (2001)800/11619/78 = 24.4%16/78 = 20.5%3/78 = 3.85%
      Hamid (2010)700/17.57/21 = 33.3%5/21 = 23.8%2/21 = 9.5%
      Kienapfel (1999)600/11812/49 = 24.5%12/49 = 24.5%0/49 = 0%
      Knelles (1997)1200/4125/101 = 5%5/101 = 5%0/101 = 0%
      Knelles 2nd study arm (1997)700/11211/95 = 11.6%11/95 = 11.6%0/95 = 0%
      Knelles 3rd study arm (1997)500/11228/93 = 30.1%27/93 = 29%1/93 = 1.1%
      Kölbl (1998)700/1622/46 = 47.8%21/46 = 45.6%1/46 = 2.2%
      Moore (1998)800/1129/33 = 27.3%6/33 = 18.2%3/33 = 9.1%
      Padgett (2003)500/21320/29 = 69%18/29 = 62.1%2/29 = 6.9%
      Padgett 2nd study arm (2003)1000/51213/30 = 43.3%12/30 = 40%1/30 = 3.3%
      Pellegrini (1992)800/11112/34 = 35.3%10/34 = 29.4%2/34 = 5.9%
      Pellegrini 2nd study arm (1992)1000/213.59/28 = 32.1%7/28 = 25%2/28 = 7.1%
      Pellegrini (1996)800/1Minimum of 6 months15/49 = 30.6%14/49 = 28.6%1/49 = 2%
      Pellegrini 2nd study arm (1996)800/1Minimum of 6 months11/37 = 29.7%10/37 = 27%1/37 = 2.7%
      Seegenschmiedt (1997)700/1Minimum of 6 months49/80 = 61.3%38/80 = 47.5%11/80 = 13.8%
      Seegenschmiedt 2nd study arm (1997)1750/5Minimum of 6 months45/81 = 55.6%39/81 = 48.1%6/81 = 7.4%
      Seegenschmiedt 3rd study arm (1997)1750/5Minimum of 6 months65/118 = 55.1%60/118 = 50.8%5/118 = 4.2%
      Seegenschmiedt 4th (1997)1000/2Minimum of 6 months67/131 = 51.1%60/131 = 45.8%7/131 = 5.3%
      Sell (1998)990/3Minimum of 6 months2/77 = 2.6%2/77 = 2.6%0/77 = 0%
      Van Leeuwen (1998)500/1316/43 = 14%5/43 = 11.6%1/43 = 2.3%
      Next, the effect of preoperative versus postoperative radiotherapy on prevalence of HO was examined (Table 3). The overall prevalence of HO with preoperative radiotherapy was 42.2% while postoperative radiotherapy yielded 32.4% of sites that had HO development. For Brooker grades 1 or 2 HO development in the preoperative group, the prevalence was 35.8% while 6.4% of sites developed Brooker grades 3 or 4. In contrast, 29% of sites developed Brooker grade 1 or 2 HO when treated postoperatively and only 3.4% of sites were Brooker grades 3 or 4. Doses for which there was a direct comparison between preoperative and postoperative radiotherapy RCT arms were 500/1, 700/1 and 800/1 cGy and all were single fractions. The percentage of sites developing HO with preoperative 500/1 cGy radiotherapy was 14% while it was 39.3% for postoperative radiotherapy of the same dose. However, 56.3% of sites developed HO after 700/1 cGy was prescribed preoperatively compared to 15.5% of sites that developed HO after receiving postoperative radiotherapy of the same dose. Finally, prescribing 800/1 cGy preoperatively resulted in 30.6% of sites developing HO whereas postoperative radiotherapy led to HO development in 28% of sites.
      Table 3Pooled development rates of heterotopic ossification based on radiotherapy dose and preoperative versus postoperative prescription.
      Pooled study referencesRadiotherapy dose (cGy)BEDOverall (any Brooker grade)Brooker grades 1/2Brooker grades 3/4Overall outcome after preoperative radiotherapyBrooker grades 1/2 HO after preoperative radiotherapyBrooker grades 3/4 HO after preoperative radiotherapyOverall outcome after postoperative radiotherapyBrooker grades 1/2 HO after postoperative radiotherapyBrooker grades 3/4 HO after postoperative radiotherapy
      24,27500/112.33 Gy34/136 = 25%32/136 = 24%2/136 = 1.47%6/43 = 14%5/43 = 11.6%1/43 = 2.3%28/93 = 30.1%27/93 = 29%1/93 = 1.1%
      20500/29.17 Gy20/29 = 69%18/29 = 62.1%2/29 = 6.9%n/an/an/a20/29 = 69%18/29 = 62.1%2/29 = 6.9%
      23600/118 Gy12/49 = 24.5%12/49 = 24.5%0/49 = 0%n/an/an/a12/49 = 24.5%12/49 = 24.5%0/49 = 0%
      4,18,24–25700/123.33 Gy89/242 = 36.8%75/242 = 31%14/242 = 5.8%71/126 = 56.3%59/126 = 46.8%12/126 = 9.5%18/116 = 15.5%16/116 = 13.6%2/116 = 17%
      17,19,21–22800/129.33 Gy66/231 = 28.6%56/231 = 24.2%10/231 = 4.3%15/49 = 30.6%14/49 = 28.8%1/49 = 2%51/182 = 28%42/182 = 23.1%9/182 = 4.9%
      26990/320.79 Gy2/77 = 2.6%2/77 = 2.6%0/77 = 0%n/an/an/a2/77 = 2.6%2/77 = 2.6%0/77 = 0%
      4,211000/226.67 Gy76/159 = 47.8%67/159 = 42.1%9/159 = 5.7%n/an/an/a76/159 = 47.8%67/159 = 42.1%9/159 = 5.66%
      201000/516.67 Gy13/30 = 43.3%12/30 = 40%1/30 = 3.3%n/an/an/a13/30 = 43.3%12/30 = 40%1/30 = 3.3%
      241200/424 Gy5/101 = 5%5/101 = 5%0/101 = 0%n/an/an/a5/101 = 5%5/101 = 5%0/101 = 0%
      41750/537.92 Gy110/199 = 55.3%99/199 = 49.7%11/199 = 5.5%n/an/an/a110/199 = 55.3%99/199 = 49.7%11/199 = 5.5%
      4,17–27Overall427/1253 = 34.1%378/1253 = 30.2%49/1253 = 3.9%92/218 = 42.2%78/218 = 35.8%14/218 = 6.4%335/1035 = 32.4%300/1035 = 29.0%35/1035=3.4%
      Five included RCTs contained multiple fraction study arms which allowed for head-to-head comparison of different radiotherapy schedules [
      • Seegenschmiedt M.H.
      • Keilholz L.
      • Martus P.
      • et al.
      Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.
      ,
      • Padgett D.E.
      • Holley K.G.
      • Cummings M.
      • et al.
      The efficacy of 500 CentiGray radiation in the prevention of heterotopic ossification after total hip arthroplasty: a prospective randomized, pilot study.
      ,
      • Pellegrini V.D.
      • Konski A.A.
      • Gastel J.A.
      • et al.
      Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.
      ,
      • Pellegrini V.D.
      • Gregoritch S.J.
      Preoperative irradiation for prevention of heterotopic ossification following total hip arthroplasty.
      ,
      • Knelles D.
      • Barthel T.
      • Karrer A.
      • et al.
      Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation.
      ]. The study by Knelles et al. compared 1200/4 cGy with 700/1 cGy and 500/1 cGy all prescribed postoperatively [
      • Knelles D.
      • Barthel T.
      • Karrer A.
      • et al.
      Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation.
      ]. The total number of sites receiving radiation was 289; of this total, 101 sites were randomized to 1200/4 cGy, 95 were randomized to 700/1 cGy and 93 were randomized to 500/1 cGy. There was a statistically significant difference in HO prevalence following 1200/4 and 500/1 cGy regimens (p = 0.001) as well as between 700/1 and 500/1 cGy arms (p < 0.015) with the 500/1 cGy arm being statistically inferior to other treatment arms. When comparing 1200/4 with 700/1 cGy, there was no statistically significant difference between arms (p = 0.087) [
      • Knelles D.
      • Barthel T.
      • Karrer A.
      • et al.
      Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation.
      ]. Padgett et al. compared postoperative 500/2 cGy (n = 29) with 1000/5 cGy (n = 30). For the sites given 500/2 cGy, 20 out of 29 developed HO (69%), while 13 out of 30 sites (43.3%) developed HO after receiving 1000/5 cGy (p = 0.086) [
      • Padgett D.E.
      • Holley K.G.
      • Cummings M.
      • et al.
      The efficacy of 500 CentiGray radiation in the prevention of heterotopic ossification after total hip arthroplasty: a prospective randomized, pilot study.
      ]. An RCT by Pellegrini et al. examined HO outcomes for 800/1 cGy and 1000/2 cGy [
      • Pellegrini V.D.
      • Konski A.A.
      • Gastel J.A.
      • et al.
      Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.
      ]. The total number of sites in the study was 62; 34 were randomized to 800/1 cGy and 28 were randomized to 1000/2 cGy. Although no statistical comparison was performed between treatment arms, the number of sites developing HO was 12 out of 34 (35.3%) for 800/1 cGy and 9 out of 28 exposed sites (32.1%) for the 1000/2 cGy group [
      • Pellegrini V.D.
      • Konski A.A.
      • Gastel J.A.
      • et al.
      Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.
      ]. A follow-up study by Pellegrini et al. examined preoperative (n = 49) compared with postoperative (n = 355) radiotherapy both at a dose of 800/1 cGy. For those sites that received preoperative radiation, 15 out of 49 developed HO (30.6%) while 12 sites out of 34 (35.3%) developed HO after postoperative 800/1 cGy radiation (p = 0.99) [
      • Pellegrini V.D.
      • Gregoritch S.J.
      Preoperative irradiation for prevention of heterotopic ossification following total hip arthroplasty.
      ].The final article that included multiple study arms was conducted by Seegenschmiedt et al. [
      • Seegenschmiedt M.H.
      • Keilholz L.
      • Martus P.
      • et al.
      Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.
      ]. This article was a compilation of two studies, the first of which looked at HO outcomes following 1000/2 cGy versus 1750/5 cGy postoperative radiotherapy, while the second study examined 700/1 cGy prescribed preoperatively versus 1750/5 cGy prescribed postoperatively. A total of 410 sites were randomized into four groups. From study one, the number of sites developing HO after 1000/2 cGy was 67 out of 131 (51.1%) and for 1750/5 cGy, the number of sites was 65 out of 118 (55.1%). For study 2, 49 of 80 sites (61.3%) developed HO following preoperative administration of 700/1 cGy while 45 of 81 sites (55.6%) developed HO after receiving postoperative 1750/5 cGy radiotherapy [
      • Seegenschmiedt M.H.
      • Keilholz L.
      • Martus P.
      • et al.
      Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.
      ].
      Either development of new HO and progression of Brooker grade can both be used to assess the efficacy of prophylaxis. Progression of HO was reported in three trials and was used as an endpoint for this meta-analysis [
      • Seegenschmiedt M.H.
      • Keilholz L.
      • Martus P.
      • et al.
      Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.
      ,
      • Pellegrini V.D.
      • Konski A.A.
      • Gastel J.A.
      • et al.
      Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.
      ,
      • Knelles D.
      • Barthel T.
      • Karrer A.
      • et al.
      Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation.
      ]. This endpoint accounts for some of the trials which included patients with HO at baseline. Overall, there was no statistically significant difference in HO progression between high and low BED treatment arms (p = 0.28, OR: 0.46) (Supplementary Material 3a). As well, no statistically significant difference existed between high or low BED arms in terms of Brooker grades 1 or 2 (p = 0.61, OR = 0.66) and Brooker grades 3 or 4 HO development (p = 0.22, OR = 0.35) (Supplementary Material 3b and 3c).
      The second analysis for the progression of HO compared single versus multiple fractions. Overall, there was a statistically significant reduction in HO progression with multiple as opposed to single fraction radiotherapy (p = 0.04, OR = 0.34); similarly, progression of HO in Brooker grades 1 or 2 was statistically significant (p = 0.0009, OR = 0.29) (Supplementary Material 4a and 4b). However, progression of Brooker grades 3 or 4 HO was not significant between single versus multiple fraction arms (p = 0.32, OR = 0.39) (Supplementary Material 4c).
      The last comparison in treatment efficacy concerned preoperative versus postoperative radiotherapy. No statistically significant differences existed between preoperative versus postoperative radiation for overall HO (p = 0.43, OR = 1.91), Brooker grades 1 or 2 HO (p = 0.51, OR = 1.52), and Brooker grade 3 or 4 (p = 0.27, OR = 2.88) (Supplementary Material 5a–5c).
      Lastly, assessing side effects in the included studies was not possible because only one study reported side effects data [
      • Knelles D.
      • Barthel T.
      • Karrer A.
      • et al.
      Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation.
      ]. Therefore, a meta-analysis was not performed.

      Discussion

      Radiation is a commonly used prophylactic method for the development of HO. Radiation is either prescribed postoperatively or preoperatively with the former more commonly employed in the literature [
      • Seegenschmiedt M.H.
      • Keilholz L.
      • Martus P.
      • et al.
      Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.
      ,
      • Burd T.A.
      • Lowry K.J.
      • Anglen J.O.
      Indomethacin compared with localized irradiation for the prevention of heterotopic ossification following surgical treatment of acetabular fractures.
      ,
      • Hamid N.
      • Ashraf N.
      • Bosse M.J.
      • et al.
      Radiation therapy for heterotopic ossification prophylaxis acutely after elbow trauma.
      ,
      • Moore K.D.
      • Goss K.
      • Anglen J.O.
      Indomethacin versus radiation therapy for prophylaxis against heterotopic ossification in acetabular fractures: a randomised, prospective study.
      ,
      • Padgett D.E.
      • Holley K.G.
      • Cummings M.
      • et al.
      The efficacy of 500 CentiGray radiation in the prevention of heterotopic ossification after total hip arthroplasty: a prospective randomized, pilot study.
      ,
      • Pellegrini V.D.
      • Konski A.A.
      • Gastel J.A.
      • et al.
      Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.
      ,
      • Pellegrini V.D.
      • Gregoritch S.J.
      Preoperative irradiation for prevention of heterotopic ossification following total hip arthroplasty.
      ,
      • Kienapfel H.
      • Koller M.
      • Wust A.
      • et al.
      Prevention of heterotopic bone formation after total hip arthroplasty: a prospective randomised study comparing postoperative radiation therapy with indomethacin medication.
      ,
      • Knelles D.
      • Barthel T.
      • Karrer A.
      • et al.
      Prevention of heterotopic ossification after total hip replacement. A prospective, randomised study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation.
      ,
      • Sell S.
      • Willms R.
      • Jany R.
      • et al.
      The suppression of heterotopic ossifications: radiation versus NSAID therapy – a prospective study.
      ]. The present meta-analysis examined the effects of radiation dose, fractionation scheme and timing on the prevalence of HO and the incidence of HO progression.
      In our study, the most commonly prescribed dose was 700/1 cGy (n = 242 out of 1253) with radiation mostly prescribed postoperatively (82.6%). Overall, the prevalence of any Brooker grade HO was 34.1% and there were very few cases of Brooker grades 3 or 4 HO (weighted mean: 3.9%). For BED less than or equal to 2500 cGy, the number of sites that developed HO was 26.4%, while BED greater than 2500 cGy yielded a much higher result of 42.8%. However, in terms of progression of HO, our analysis showed no significant difference between high (>2500 cGy) vs. low BED (⩽2500 cGy) treatment arms. In the meta-analysis by Popovic et al., [
      • Popovic M.
      • Agarwal A.
      • Zhang L.
      • et al.
      Radiotherapy for the prophylaxis of heterotopic ossification: a systematic review and meta-analysis of published data.
      ] the authors found a statistically non-significant relationship between radiation dose and the prevalence of HO, which is in agreement with the progression analysis.
      Although the percentage of sites developing HO was higher with a higher BED, we found no difference between high (>2500 cGy) and low (⩽2500 cGy) BED treatment arms for all conducted progression analyses. Therefore, given that higher doses of radiotherapy can lead to further possible side effects, such as secondary malignancies and infertility [
      • Vanden Bossche L.
      • Vanderstraeten G.
      Heterotopic ossification: a review.
      ], and given that the present results show an inconclusive relationship for the progression of HO, we believe that lower BED treatments should be used to prevent the progression of HO. This holds especially true for patients with poor performance status, for whom it is important to minimize any associated psychosocial burden associated with further visits to the radiotherapy center.
      Radiotherapy may be more efficacious when administered in multiple fractions as opposed to single fractions. For the overall progression endpoint and for Brooker grades 1 or 2 HO, multiple fractions were statistically superior to single fractions. Given that we found no significant effect of BED on HO progression, the effect of fraction schedule seems to be an independent contribution. Even though this difference in efficacy may exist, single fraction radiotherapy could minimize visits to the radiotherapy center and could thus lower associated patient burden. As such, administration of single fraction radiotherapy may be more appropriate if the prognosis and performance status of the patient is poor.
      In terms of preoperative versus postoperative radiotherapy, arms administering preoperative radiation had a higher resultant prevalence of HO (overall mean: 42.2% compared with 32.4% for postoperative radiation). For both Brooker grades 1 or 2 and grades 3 or 4 HO development, preoperative radiotherapy resulted in a higher proportion of HO development than postoperative radiation. However, when examining the data for progression of HO, there was no statistically significant difference between the administration of preoperative and postoperative radiotherapy for any of the included endpoints. This is in contrast to the findings published by Popovic et al., who found a statistically significantly higher proportion of Brooker grade 1 or 2 HO development in sites that were treated postoperatively (p = 0.0499) [
      • Popovic M.
      • Agarwal A.
      • Zhang L.
      • et al.
      Radiotherapy for the prophylaxis of heterotopic ossification: a systematic review and meta-analysis of published data.
      ].
      There are limitations to the current meta-analysis. Despite having a large sample size of radiation sites (n = 1253) and including only RCTs, the population of patients in published RCTs may not reflect the entire population of patients receiving radiotherapy for the prevention of HO. Also, due to the inclusion criteria of our study, only a subset of the RCT’s could be included, limiting the generalizability of our results. Finally, due to the nature of the meta-analysis, interpretations based on our data should be made at the level of the cohort instead of the patient.
      The importance of performing a meta-analysis in a controlled environment using appropriate endpoints is highlighted in this paper. Despite a pooled analysis showing a difference in HO incidence based on dose and radiotherapy timing, our meta-analysis shows that low-dose is as effective as high-dose radiotherapy for preventing HO progression. Likewise, based on our findings, there is no difference between the efficacy of pre-operative and post-operative radiotherapy. Finally, our meta-analysis does show that multiple fraction radiation is superior to single fractions. The results of this study can help optimize radiation prescription parameters and develop future guidelines for optimal use of resources. Ultimately, the present analysis has shown that low-dose radiotherapy is an effective method of prophylaxis for HO development, either when prescribed postoperatively or preoperatively.

      Conflict of interest

      None.

      Acknowledgments

      We thank the generous support of the Bratty Family Fund , Michael and Karyn Goldstein Cancer Research Fund , Pulenzas Cancer Research Fund, Joseph and Silvana Melara Cancer Research Fund , and Ofelia Cancer Research Fund .

      Appendix A. Supplementary data

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