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Endoscopic Excision of Hip Heterotopic Ossification, Plus Indomethacin and Radiation, Is Effective in Treating and Preventing Recurrence

Open AccessPublished:January 05, 2023DOI:https://doi.org/10.1016/j.asmr.2022.11.008

      Purpose

      To describe the clinical and patient-reported outcomes of heterotopic ossification (HO) excision as well as the results of a standardized HO prophylaxis protocol among a group of patients who previously underwent open or arthroscopic hip surgery.

      Methods

      Patients who developed HO after index hip surgery and were subsequently treated with arthroscopic excision of HO and postoperative HO prophylaxis using 2 weeks of indomethacin and radiation were retrospectively identified. All patients were seen by a single surgeon and were treated with the same arthroscopic technique. Patients were also placed on a regimen of 2 weeks of indomethacin 50 mg and radiation therapy with 700 cGy in one fraction on the first postoperative day. Outcomes assessed included recurrence of HO and conversion to total hip arthroplasty by latest follow-up. Other outcomes included Modified Harris Hip Scores and Non-Arthritic Hip Scores, which were collected preoperatively and at 1-year and 2-year follow-up.

      Results

      There were 5 female and 9 male subjects, with an average age of 39 years (range 22-66) and average body mass index of 27.1 (19.1-37.5). Average follow-up time was 46 months (range 4-136). No patients had experienced HO recurrence by latest follow-up. Only 2 patients converted to total hip arthroplasty, one at 6 months and the other at 11 months postexcision. Average outcome scores improved by 2-year follow-up (average Modified Harris Hip Scores 52.8 improved to 86.5, average Non-Arthritic Hip Scores 49.4 improved to 83.8).

      Conclusions

      Minimally invasive arthroscopic excision of HO and postoperative prophylaxis with combined indomethacin and radiation therapy effectively treats and prevents the recurrence of HO.

      Level of Evidence

      Level IV, case series, therapeutic.
      Historically, treatment of most orthopaedic hip pathologies has involved open surgical technique. However, advancements in the field of hip arthroscopy have enabled minimally invasive interventions for a variety of hip disorders including femoroacetabular impingement syndrome (FAI) and labral injuries.
      • Kyin C.
      • Maldonado D.R.
      • Go C.C.
      • Shapira J.
      • Lall A.C.
      • Domb B.G.
      Mid- to long-term outcomes of hip arthroscopy: A systematic review.
      ,
      • Bozic K.J.
      • Chan V.
      • Valone 3rd, F.H.
      • Feeley B.T.
      • Vail T.P.
      Trends in hip arthroscopy utilization in the United States.
      Complication rates following hip arthroscopic procedures are low, but approximately 1% to 12% of cases are associated with the postoperative development of heterotopic ossification (HO).
      • Ong C.
      • Hall M.
      • Youm T.
      Surgical technique: Arthroscopic treatment of heterotopic ossification of the hip after prior hip arthroscopy.
      ,
      • Kurz A.Z.
      • LeRoux E.
      • Riediger M.
      • et al.
      Heterotopic ossification in hip arthroscopy: An updated review.
      HO can lead to compromised functional outcomes following hip arthroscopy, including recurrent pain, limited range of motion (ROM), and the need for further surgeries.
      • Amar E.
      • Sharfman Z.T.
      • Rath E.
      Heterotopic ossification after hip arthroscopy.
      Therefore, early identification and treatment of HO is essential for preserving hip function among patients undergoing arthroscopic procedures.
      Early-stage hip HO may be treated conservatively with physical therapy and ROM exercises, but late-stage HO usually necessitates surgical intervention via open or arthroscopic excision. Little is known about standardized treatment of symptomatic HO following hip arthroscopy. A previous case series described a surgical technique for the arthroscopic excision of HO after previous hip arthroscopy and discussed postoperative outcomes of HO excision among 3 patients treated at single urban academic medical center.
      • Ong C.
      • Hall M.
      • Youm T.
      Surgical technique: Arthroscopic treatment of heterotopic ossification of the hip after prior hip arthroscopy.
      The present case series is a follow-up on those patients plus additional patients who underwent arthroscopic HO excision at our center. The purpose of this study was to describe the clinical and patient-reported outcomes of HO excision as well as the results of a standardized HO prophylaxis protocol among a group of patients who previously underwent open or arthroscopic hip surgery. We hypothesized that patients treated with HO excision and prophylaxis would remain recurrence-free for up to 1 year postoperatively.

      Methods

      This study was approved by the New York University Langone Health Institutional Review Board (#20-01686).

      Patient Selection

      Patients were identified via retrospective review of the senior author’s (T.Y.) surgical case log at a single urban academic medical center from August 2008 to November 2021. All patients included in the case series developed HO after index hip surgery and were subsequently treated with arthroscopic excision of HO and postoperative HO prophylaxis using 2 weeks of nonsteroidal anti-inflammatory drugs (NSAIDs) and radiation. Patients whose HO was treated via an open approach were excluded from this series. All patients were assessed by the senior author, a sports medicine fellowship-trained orthopaedic surgeon.

      Radiographic Analysis

      HO severity was assessed on plain anteroposterior view hip radiographs obtained before HO excision. HO severity was graded using a 4-stage classification system previously described by Brooker et al.
      • Brooker A.F.
      • Bowerman J.W.
      • Robinson R.A.
      • Riley Jr., L.H.
      Ectopic ossification following total hip replacement. Incidence and a method of classification.
      Grade 1 describes islands of bone within soft tissues, grade 2 describes bone spurs leaving >1 cm between opposing bone surfaces, grade 3 describes bone spurts leaving <1 cm between opposing bone surfaces, and grade 4 describes radiographic ankylosis of the hip.
      • Hug K.T.
      • Alton T.B.
      • Gee A.O.
      Classifications in brief: Brooker classification of heterotopic ossification after total hip arthroplasty.

      Surgical Technique

      A surgical technique for arthroscopic excision of HO was described previously.
      • Ong C.
      • Hall M.
      • Youm T.
      Surgical technique: Arthroscopic treatment of heterotopic ossification of the hip after prior hip arthroscopy.
      To summarize in brief, surgery was indicated for symptomatic patients with limitations in ROM, radiographic evidence of HO, and concomitant intra-articular hip disorder (FAI or labral pathology). Arthroscopic HO excision was not performed on patients with Booker grade 4 HO. Additionally, immature HO and severe hip osteoarthritis that would impede arthroscopic access to the joint were contraindications. Arthroscopic HO excisions were performed in the supine position with general anesthesia. Diagnostic and therapeutic arthroscopy of the central and peripheral compartments was performed. Intraoperative fluoroscopy with spinal needle localization was used to locate HO deposits. Once a deposit was identified, a cannula was inserted over the spinal needle, an arthroscope was inserted to visualize the deposit, and a burr and grasper were used to excise the HO and remove any loose fragments.

      Postoperative Protocol

      Patients were placed in a hinged hip brace for the first postoperative week and instructed to remain foot-flat partial-weight-bearing on crutches for 14 weeks depending on concomitant procedures such as labral repair and FAI resection. Formal physical therapy commenced once full weight-bearing was allowed. Physical therapy was scheduled for 2 to 3 times per week for a minimum of 4 weeks up to 3 months until full ROM and strength were achieved. At 3- to 6-month follow-up, patients could be cleared for return to all activities without restriction. Patients were also placed on a standardized HO prophylaxis regimen consisting of 2 weeks of indomethacin 50 mg and radiation therapy with 700 cGy in one fraction on the first postoperative day.

      Outcome Scores

      The 3 patients from the previous study completed the modified Harris Hip Score (mHHS)
      • Kemp J.L.
      • Collins N.J.
      • Roos E.M.
      • Crossley K.M.
      Psychometric properties of patient-reported outcome measures for hip arthroscopic surgery.
      before HO excision surgery. The remaining 11 patients completed the mHHS as well as the Non-Arthritic Hip Score (NAHS)
      • Christensen C.P.
      • Althausen P.L.
      • Mittleman M.A.
      • Lee J.A.
      • McCarthy J.C.
      The nonarthritic hip score: Reliable and validated.
      before surgery. mHHS and/or NAHS were collected again at 1-year and 2-year follow-up. In addition to functional scores, primary outcomes of interest included recurrence of HO. Secondary outcomes included conversion to total hip arthroplasty (THA) by the most recent follow-up. We used the minimum clinically important difference (MCID) cutoffs of 8 points on the mHHS and 8.5 points on the NAHS that was were previously published by Bloom et al.
      • Bloom D.A.
      • Kaplan D.J.
      • Kirby D.J.
      • Buchalter D.B.
      • Lin C.C.
      • Fried J.W.
      • et al.
      The minimal clinically important difference for the nonarthritic hip score at 2-years following hip arthroscopy.

      Results

      Patient Demographics

      Fourteen patients were included in this case series, and their demographic characteristics are summarized in Table 1. There were 5 female and 9 male patients, with an average age of 39 years (range 22-66) and average body mass index of 27.1 (19.1-37.5). Average follow-up time was 46 months (range 4-136). All 3 patients included from the previous study
      • Ong C.
      • Hall M.
      • Youm T.
      Surgical technique: Arthroscopic treatment of heterotopic ossification of the hip after prior hip arthroscopy.
      had at least 8 years of follow-up, whereas only 2 of the new cases had less than 6 months of follow-up. On pre-excision radiographs, 5 patients had Brooker grade 1 HO, 7 patients had grade 2 HO, and 2 patients had grade 3 HO.
      Table 1Demographic Characteristics
      Patient No.Age, ySexWeight, kgBMIHO GradeFollow-Up Time, mo
      166M9130.4344
      228M10431.2225
      341F7025.6219
      427M9128.7242
      529F4519.1137
      653F7028.2133
      725M7724.3227
      857M8327.0117
      963M10737.5211
      1025M7423.925
      1131M8828.024
      1248F6825.81107
      1329M7423.21136
      1422F7526.73134
      Mean ± SD39 ± 1580 ± 1627.1 ± 4.346 ± 45
      BMI, body mass index; F, female; HO, heterotopic ossification; M, male; SD, standard deviation.
      Previous hip surgeries, preoperative courses, and HO excision procedure times are displayed in Table 2. Ten patients developed HO following a previous arthroscopic cam and/or pincer resection. Three patients developed HO following open procedures including THA (patient #1), derotational femoral osteotomy (patient #5), and femoral lengthening over an intramedullary rod (patient #11). Average time from index hip surgery to HO diagnosis was 39 ± 50 months (range 3-156), average time from HO diagnosis to excision was 9 ± 20 months (range 0-76), and average excision procedure time was 97 ± 29 minutes (range 45-144). No patients underwent concomitant procedures in addition to arthroscopic HO excision. No patients reported complications besides HO following their index hip surgery, and no patients reported complications following HO excision.
      Table 2Previous Hip Surgeries, Preoperative Courses, and HO Excision Procedure Times
      Patient No.Previous Hip SurgeryTime from Previous Surgery to HO Diagnosis, moTime From HO Diagnosis to Excision, moHO Excision Operative Time, min
      1Total hip arthroplasty11596
      2Cam and pincer resection1076144
      3Cam and pincer resection14<1135
      4Excision of os acromiale156396
      5Derotational osteotomy102101
      6Cam and pincer resection36<1116
      7Cam and pincer resection188118
      8Pincer resection1002080
      9Cam and pincer resection14190
      10Cam and pincer resection42<169
      11Femur lengthening with intramedullary rod120<171
      12Pincer resection5345
      13Cam and pincer resection34
      14Cam and pincer resection34
      Mean ± SD39 ± 509 ± 2097 ± 29
      HO, heterotopic ossification; SD, standard deviation.

      Clinical and Patient-Reported Outcomes

      Postexcision outcomes are summarized for each patient in Table 3. No patients experienced recurrent episodes of HO by latest follow-up. Of the 13 patients who did not previously undergo THA, 2 (15%) underwent THA by latest follow-up. Patient #3 underwent THA at 6 months postexcision and patient #6 underwent THA at 11 months postexcision. Neither of the patients who underwent THA had developed postoperative HO after arthroscopic excision.
      Table 3Clinical and Patient-Reported Outcomes
      Previous No.HO RecurrenceTHAmHHS

      Preoperative/ 1-year/2-year
      2-Year MCID for mHHSNAHS

      Preoperative/ 1-year/2-year
      2-Year MCID for NAHS
      1No40.5 / – / 90.2Yes42.5 / – / 87.5Yes
      2NoNo57.2 / 62.7 / 62.7No87.5 / 67.5 / 67.5No
      3NoYes36.3 / – / –23.8 / – / –
      4NoNo53.9 / – / 95.7Yes56.3 / – / 92.5Yes
      5NoNo44 / – / 70.4Yes38.8 / – / 78.8Yes
      6NoYes31.9 / – / –25.0 / – / –
      7NoNo62.7 / – / 95.7Yes62.5 / – / 92.5Yes
      8NoNo48.4 / 70.4 / –42.5 / 67.5 / –
      9NoNo40.5 / – / –42.5 / – / –
      10NoNo48.4 / – / –71.25 / – / –
      11NoNo57.1 / – / –51.25 / – / –
      12NoNo70.0 / – / 85.0Yes– / – / –
      13NoNo78.0 / – / 96.0Yes– / – / –
      14NoNo70.0 / – / 96.0Yes– / – / –
      Mean ± SD52.8 ± 13.8 / 66.6 ± 5.4 / 86.5 ± 13.049.4 ± 19.1 / 67.5 ± 0.0 / 83.8 ± 10.7
      HO, heterotopic ossification, MCID, minimum clinically important difference, mHHS, modified Harris Hip Score; NAHS, Non-Arthritic Hip Score; SD, standard deviation; THA, total hip arthroplasty.
      Mean baseline mHHS among all 15 patients was 52.8 (range 31.9-78.0). Mean baseline NAHS among the 13 new patients was 49.4 (range 23.8-87.5). On average, patients experienced improvement by 2-year follow-up in both mHHS (mean 52.8 improved to 86.5) and NAHS (mean 49.4 improved to 83.8), although it should be noted that only 8 patients had 2-year follow-up mHHS and only 5 patients had 2-year follow-up NAHS. In total,7 of 8 patients achieved the MCID for mHHS by 2-year follow-up, whereas 4 of 5 patients achieved the MCID for NAHS by 2-year follow-up.

      Discussion

      In this study, we found that endoscopic excision of HO followed by appropriate prophylaxis is effective in treating and preventing HO recurrence. Furthermore, patients exhibited pre- to postoperative improvement in outcome scores, suggesting that treatment of symptomatic HO has a tangible impact on hip function and quality of life. Our study supports the clinical efficacy of our arthroscopic technique as well as the efficacy of our prophylaxis regimen, which combines indomethacin with radiation therapy.
      Prophylaxis for HO may consist of a course of NSAIDs in the form of nonselective cyclooxygenase inhibitors, selective cyclooxygenase-2 inhibitors, or aspirin in addition to or in lieu of radiation therapy.
      • Amar E.
      • Sharfman Z.T.
      • Rath E.
      Heterotopic ossification after hip arthroscopy.
      Although others have proposed the use of bone morphogenetic protein type 1 receptor inhibitors, bone morphogenetic protein antagonists, nuclear retinoic acid receptor γ agonists, free radical scavengers, or bisphosphonates, such pharmacologic agents are rarely used in common clinical practice. Regarding radiation, most protocols include external beam radiation of 600 to 800 Gy preoperatively or postoperatively, typically within 3 days after surgery.
      • Ayers D.C.
      • Evarts C.M.
      • Parkinson J.R.
      The prevention of heterotopic ossification in high-risk patients by low-dose radiation therapy after total hip arthroplasty.
      • 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.
      • 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.
      • 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.
      To date, no studies have shown that one radiation protocol is superior to another.
      Amar et al.
      • Amar E.
      • Sharfman Z.T.
      • Rath E.
      Heterotopic ossification after hip arthroscopy.
      published a literature review examining the pharmacologic agents for HO prophylaxis posthip arthroscopy and found that only a few small studies have compared the efficacy of certain drugs, without a clear consensus on the best agent. After reviewing the available literature comparing NSAID prophylaxis to no prophylaxis, the authors concluded that NSAIDs are generally effective at preventing HO after hip arthroscopy. Randelli et al.
      • Randelli F.
      • Pierannunzii L.
      • Banci L.
      • Ragone V.
      • Aliprandi A.
      • Buly R.
      Heterotopic ossifications after arthroscopic management of femoroacetabular impingement: The role of NSAID prophylaxis.
      retrospectively assessed a cohort of patients (hips) that received arthroscopic treatment for FAI, of which 285 hips received NSAID prophylaxis and 15 did not. The authors’ analysis identified 5 patients who experienced postoperative HO, all of whom had not received NSAID prophylaxis. As such, they concluded that NSAIDs appeared to be an effective option for HO prophylaxis. Bedi et al.
      • Bedi A.
      • Zbeda R.M.
      • Bueno V.F.
      • Downie B.
      • Dolan M.
      • Kelly B.T.
      The incidence of heterotopic ossification after hip arthroscopy.
      reviewed a cohort of 616 hip arthroscopies, compared HO rates between patients with versus without indomethacin prophylaxis, and found a statistically significant difference in that patients who received indomethacin had a lower prevalence of HO after surgery (1.8% vs 6.3%; P < .05). Beckmann et al.
      • Beckmann J.T.
      • Wylie J.D.
      • Kapron A.L.
      • Hanson J.A.
      • Maak T.G.
      • Aoki S.K.
      The effect of nsaid prophylaxis and operative variables on heterotopic ossification after hip arthroscopy.
      demonstrated in a prospective study of 357 consecutive hip arthroscopy cases that patients not on NSAID prophylaxis were 13.6 times more likely to develop postoperative HO (P = .003). The authors concluded that routine NSAID prophylaxis reduces but does not eliminate the incidence of HO in patients undergoing hip arthroscopy.
      Although radiation is often used as an adjunct treatment for HO along with NSAIDs, it is associated with some potential side effects. Radiation therapy may increase the risk of malignant transformation, though small single doses of <3,000 cGy likely carry little risk.
      • Kim J.H.
      • Chu F.C.
      • Woodard H.Q.
      • Melamed M.R.
      • Huvos A.
      • Cantin J.
      Radiation-induced soft-tissue and bone sarcoma.
      Furthermore, NSAID therapy also carries some risk; drugs of this class have been shown to negatively affect the gastrointestinal, cardiovascular, hepatic, renal, cerebral, and pulmonary systems.
      • Bindu S.
      • Mazumder S.
      • Bandyopadhyay U.
      Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective.
      Indomethacin can cause platelet aggregation, interaction with other medications, and gastrointestinal upset, although a short, 2-week course administered with meals may mitigate these effects.
      • Cella J.P.
      • Salvati E.A.
      • Sculco T.P.
      Indomethacin for the prevention of heterotopic ossification following total hip arthroplasty.
      We recommend minimizing the duration and dosage of both radiation therapy and NSAID use for HO prophylaxis to reduce potential side effects and improve patient compliance.

      Limitations

      We note several important limitations of this study. First, our study constitutes a small case series without a comparison group of patients treated with either no HO prophylaxis or an alternative form of prophylaxis. Second, we did not have follow-up outcome scores for all patients due to a combination of factors including patients having recent surgery (<6 months) or failing to complete 1-year or 2-year follow-up surveys. Third, although patients’ symptoms correlated with the development of HO and were improved with its excision, there may be confounding variables that influenced the presentation and resolution of their symptoms before and after HO excision that we did not identify.

      Conclusions

      The development of HO after hip procedures can be debilitating for some patients. Minimally invasive arthroscopic excision of HO and postoperative prophylaxis with combined indomethacin and radiation therapy effectively treats and prevents the recurrence of HO.

      Supplementary Data

      References

        • Kyin C.
        • Maldonado D.R.
        • Go C.C.
        • Shapira J.
        • Lall A.C.
        • Domb B.G.
        Mid- to long-term outcomes of hip arthroscopy: A systematic review.
        Arthroscopy. 2021; 37: 1011-1025
        • Bozic K.J.
        • Chan V.
        • Valone 3rd, F.H.
        • Feeley B.T.
        • Vail T.P.
        Trends in hip arthroscopy utilization in the United States.
        J Arthroplasty. 2013; 28: 140-143
        • Ong C.
        • Hall M.
        • Youm T.
        Surgical technique: Arthroscopic treatment of heterotopic ossification of the hip after prior hip arthroscopy.
        Clin Orthop Relat Res. 2013; 471: 1277-1282
        • Kurz A.Z.
        • LeRoux E.
        • Riediger M.
        • et al.
        Heterotopic ossification in hip arthroscopy: An updated review.
        Curr Rev Musculoskelet Med. 2019; 12: 147-155
        • Amar E.
        • Sharfman Z.T.
        • Rath E.
        Heterotopic ossification after hip arthroscopy.
        J Hip Preserv Surg. 2015; 2: 355-363
        • Brooker A.F.
        • Bowerman J.W.
        • Robinson R.A.
        • Riley Jr., L.H.
        Ectopic ossification following total hip replacement. Incidence and a method of classification.
        J Bone Joint Surg Am. 1973; 55: 1629-1632
        • Hug K.T.
        • Alton T.B.
        • Gee A.O.
        Classifications in brief: Brooker classification of heterotopic ossification after total hip arthroplasty.
        Clin Orthop Relat Res. 2015; 473: 2154-2157
        • Kemp J.L.
        • Collins N.J.
        • Roos E.M.
        • Crossley K.M.
        Psychometric properties of patient-reported outcome measures for hip arthroscopic surgery.
        Am J Sports Med. 2013; 41: 2065-2073
        • Christensen C.P.
        • Althausen P.L.
        • Mittleman M.A.
        • Lee J.A.
        • McCarthy J.C.
        The nonarthritic hip score: Reliable and validated.
        Clin Orthop Relat Res. 2003; 406: 75-83
        • Bloom D.A.
        • Kaplan D.J.
        • Kirby D.J.
        • Buchalter D.B.
        • Lin C.C.
        • Fried J.W.
        • et al.
        The minimal clinically important difference for the nonarthritic hip score at 2-years following hip arthroscopy.
        Knee Surg Sports Traumatol Arthrosc. 2022; 30: 2419-2423
        • Ayers D.C.
        • Evarts C.M.
        • Parkinson J.R.
        The prevention of heterotopic ossification in high-risk patients by low-dose radiation therapy after total hip arthroplasty.
        J Bone Joint Surg Am. 1986; 68: 1423-1430
        • 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.
        J Arthroplasty. 2003; 18: 677-686
        • 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.
        Arch Orthop Trauma Surg. 1999; 119: 296-302
        • 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.
        J Bone Joint Surg Am. 2001; 83: 1783-1788
        • Randelli F.
        • Pierannunzii L.
        • Banci L.
        • Ragone V.
        • Aliprandi A.
        • Buly R.
        Heterotopic ossifications after arthroscopic management of femoroacetabular impingement: The role of NSAID prophylaxis.
        J Orthop Traumatol. 2010; 11: 245-250
        • Bedi A.
        • Zbeda R.M.
        • Bueno V.F.
        • Downie B.
        • Dolan M.
        • Kelly B.T.
        The incidence of heterotopic ossification after hip arthroscopy.
        Am J Sports Med. 2012; 40: 854-863
        • Beckmann J.T.
        • Wylie J.D.
        • Kapron A.L.
        • Hanson J.A.
        • Maak T.G.
        • Aoki S.K.
        The effect of nsaid prophylaxis and operative variables on heterotopic ossification after hip arthroscopy.
        Am J Sports Med. 2014; 42: 1359-1364
        • Kim J.H.
        • Chu F.C.
        • Woodard H.Q.
        • Melamed M.R.
        • Huvos A.
        • Cantin J.
        Radiation-induced soft-tissue and bone sarcoma.
        Radiology. 1978; 129: 501-508
        • Bindu S.
        • Mazumder S.
        • Bandyopadhyay U.
        Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective.
        Biochem Pharmacol. 2020; 180: 114147
        • Cella J.P.
        • Salvati E.A.
        • Sculco T.P.
        Indomethacin for the prevention of heterotopic ossification following total hip arthroplasty.
        J Arthroplasty. 1988; 3: 229-234