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Short-course indomethacin prevents heterotopic ossification in a high-risk population following total hip arthroplasty
The Journal of Arthroplasty Vol. 12 No. 2 1997
Short-course Indomethacin Prevents Heterotopic Ossification in a High-risk Population Following Total Hip Arthroplasty Harlan
C. A m s t u t z ,
MD, Vincent A. Fowble, and Frederick
MD, Thomas
P. S c h m a l z r i e d ,
MD,
J. D o r e y , P h D
Abstract: The efficacy of a 10-day course of indomethacin in preventing heterotopic ossification after total hip arthroplasty was studied in a consecutive series of male patients who were at increased risk for bone formation. Between September 199I and June I994, all male patients (123 hips in 109 patients) who underwent total hip, revision, or surface arthroplasty were placed on a I0-day course of indomethacin. Of these, 106 patients (119 hips) successfully completed the i0-day course. There was no significant formation of heterotopic ossification (Brooker grade III or IV). From a group of 45 known heterotopic bone formers following previous total hip arthroplasty, only 2 developed new heterotopic ossification. Overall there were 9 (7.6%) new cases of heterotopic ossification: 7 Brooker grade I (5 primary and 2 revision cases) and 2 Brooker grade II (both primary cases). A 10-day course of indomethacin prevents the more significant grades of heterotopic ossification and is effective at reducing the incidence of heterotopic ossification following total hip arthroplasty. Further, this regimen appears safe and cost effective. Key words: total hip arthroplasty, heterotopic, ossification, indomethacin.
The incidence of heterotopic ossification after total hip arthroplasty (THA) has b e e n well documented. The combined overall incidence of heretotopic ossification based on a review of the literature is 34% (1,719/5,122 hips) []-19] in the untreated, m i x e d patient population. Although there was a wide variation in the incidence, this is in part due to the classification system used (ie, w h e t h e r the small, b o n y islands, grade I in m o s t systems, are included). The c o m b i n e d incidence of the m o r e severe forms of heterotopic ossification, w h i c h significantly reduces the range of hip motion, is 14.5% (356/2,470 hips) [2,3,5-8,10-15,17-19].
Previous heterotopic ossification and male gender are the m o s t significant risk factors for f o r m a tion of b o n e following THA [5,6,20]. The patient w h o has previously d e v e l o p e d h e t e r o t o p i c ossification after THA has a 90% probability of developing either the same or an increased a m o u n t of heterotopic b o n e following revision or p r i m a r y surgery [4]. The c o m b i n e d incidence of heterotopic ossification in males is 33.5% (3151939 hips) as c o m p a r e d w i t h 13.8% (26111,887) in w o m e n [4,6,17,18]. Ritter a n d Vaughn n o t e d a 42.5 % incidence of heterotopic ossification in their male patients versus 21.3 % in their female patients [6]. DeLee et al. n o t e d that heterotopic ossification occurs three times m o r e often in m e n [4]. A l t h o u g h the male a n d female differences w e r e less, A h r e n g a r t a n d Lindgren f o u n d an 8 4 % incidence in m e n versus 67% in w o m e n and reported that m e n tended to f o r m larger a m o u n t s of b o n e (31% Brooker grades III a n d IV c o m p a r e d with
From the Joint Replacement Institute at Orthopaedic Hospital, Los Angeles, California. Reprint requests: I-Iarlan C. Amstutz, MO, Joint Replacement Institute at Orthopaedic Hospital, 2400 South Flower Street, Los Angeles, CA 90007.
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Indomethacin for Heterotopic Ossification
12% in women) {17]. Other risk factors predisposing to heterotopic ossification after THA include revision surgery, bilateral operations, active ankylosing spondylitis, and severe coxarthrosis with extensive osteophyte formation [5,6,20,21]. An increased incidence of heterotopic ossification after surface arthroplasty [9], as well as with cementless femoral components {22], has also been reported. Ethylhydroxydiphosphonate [23], irradiation [5, I3,24], and nonsteroidal antiinflammatory medications [7,i0-12,14-16,18,19,25,261 have been advocated to prevent the formation of postoperative heterotopic ossification. Ethylhydroxydiphosphonate has not been effective because it does not prevent the osteoid matrix from forming and mineralization occurs after withdrawal of the medication [9]. Irradiation has been demonstrated to be effective prophylaxis against heterotopic ossification if administered within the first 4 to 5 postoperative days [5,13,24]. Indoln.ethacin was first noted to inhibit heterotopic ossification after THA by Dahl [271. Subsequently, numerous studies have confirmed his findings and verified the efficacy of indomethacin and other nonsteroidal antiinflammatory medications as prophylaxis after primary THA in mixed patient populations [11,12,14-16,18,19,26], as well as in those assessed to be at high risk [7,10,25] for recurrence after excision [7,12,27]. Disadvantages of the indomethacin regimens include the high incidence of side effects [10,12], potential inhibition of bony ingrowth into a porous-coated system [28,291, and possible interference with anticoagulation prophylaxis. The majority of studies have looked at indomethacin in a 6-week course of therapy [7,I0,12, 16,25]. More recently, shorter courses of treatment have been studied [11,14,18,26]. Sodemann et al. demonstrated in 69 patients that a 3-week course of indomethacin or ibuprofen was effective in preventing the more severe grades of heterotopic ossification, with no incidence of grade III or IV reported [11]. Kjaersgaard-Andersen and Ritter used a 2-week course of indomethacin in 13 patients after cementless THA and reported no incidence of heterotopic ossification [26]. In a randomized, double-blind clinical trial, Pritchett reported no clinically significant grades of heterotopic ossification in 152 patients following treatment with six doses of ketorolac {19]. McMahon et al. showed that a 10-day course of indomethacin in a mixed patient population is effective in reducing the incidence and severity of heterotopic ossification after primary cementless THA [14]. They reported a 20% overall incidence of heterotopic ossification in the test group of 85
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patients and only 1 (1.2%) Brooker grade III or IV hip versus a 70% incidence in the control group of 100 patients with 24 (24%) Brooker grade III or IV hips. In this study we evaluated the ability of a 10-day course of indomethacin in a high-risk population (previous heterotopic bone formers and men) to prevent heterotopic ossification after THA. The incidence of heterotopic ossification was compared with previous results reported in the literature.
Materials and Methods Between September 1991 and July 1994 all men undergoing total hip, surface, and revision arthroplasty were entered,in an indomethacin prophylaxis protocol against heterotopic ossification at a dose of 25 mg orally three times a day for a total of 10 days. During this period there were 123 consecutive hips in I09 male patients entered into the study. The mean age of the population at the time of surgery was 56 years (range, 19-88 years). There were 57 primary and 66 revision cases. The diagnoses of the 57 primary cases included 26 with hypertrophic osteoarthritis, 14 with osteonecrosis, and 17 with secondary osteoarthritis. Forty-eight hips in 45 patients had formed heterotopic bone following previous THAs. Thirtynine of these cases of heterotopic ossification were in the ipsilateral hip and classified as grade I in 11 hips, grade II in 10 hips, grade III in 17 hips, and grade IV in 1 hip. The other 9 cases of heterotopic ossification involved the contralateral hip and were classified as grade I in 2 hips, grade II in 3 hips, and grade III in 4 hips. All surgeries were performed by the senior author (H. C. A.) using the posterolateral approach in 95 and the transtrochanteric approach in 28 (24 primary and 4 revision cases). A complete capsulectomy was performed in each case. Hypotensive epidural anesthesia and laminar flow were used for each case. Pulsed saline lavage was used to clean the wound a n d closed-suction drainage, along with a hip spica elastic dressing, was routine. Postoperative management included low-dose warfarin prophylaxis against thromboembolic disease as previously described [30] and early mobilization by postoperative day 2 with physical therapy. Indomethacin was started on the first postoperative day and continued for 10 days. All patients were followed prospectively with serial anteroposterior pelvis radiographs obtained after surgery and at 2, 4, and i2 months. Heterotopic ossification was evaluated using the Brooker classification system [2]. In the 39 ipsilateral hips,
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residual small ossicles of heterotopic ossification were noted on the immediate postoperative anteroposterior pelvic radiographs despite excision. These ossicles were followed prospectively for progression and/or formation of n e w bone. Patients were evaluated clinically using the hip rating system of the University of California at Los Angeles for pain, walking, function, and activity separately [31]. Results are reported with 95% confidence intervals, which represent the range of values that contain the actual incidence of heterotopic ossification in an infinite population of similar patients. A comparison group (historical control) was f o r m e d from 82 patients (78% men) from a previous study [9] in w h i c h similar operative techniques and procedures w e r e p e r f o r m e d by the senior author. None of these patients received any nonsteroidal a n t i i n f l a m m a t o r y medication following the operation, and all were followed for a m i n i m u m of 2 years. The i n d o m e t h a c i n and historical control groups were c o m p a r e d using Fisher's exact test.
Results One h u n d r e d and nine patients (i23 hips) were started on the indomethacin prophylactic protocol. Four hips in three patients were dropped from the study. One (an 83-year-old patient w h o had a primary THA) had a w o u n d bleed on postoperative day 1 with a drop in the hematocrit from 27 to 20, despite a normal prothrombin time, requiring transfusion. The indomethacin along with warfarin was discontinued on the second postoperative clay. The patient subsequently developed grade I heterotopic ossification. The second patient excluded was a 64-
year-old undergoing revision surgery w h o developed a w o u n d bleed on postoperative day 5 with a drop in hematocrit from 26 to 20, requiring additional transfusions; however, indomethacin was given for the first 5 postoperative days and he did not form any n e w heterotopic bone. A third patient w h o had bilateral primary surface arthroplasties did not receive indomethacin on postoperative days 3 and 4, but had initial and subsequent medication per protocol. This patient developed grade II lesions bilaterally. One h u n d r e d six patients (119 hips) successfully completed the 10-day course of indomethacin. No Brooker grade III or IV cases were f o u n d (95% confidence interval, 0 % - 2 . 5 % ) (Figs. 1 and 2, Table 1). In the comparison group, 21 hips (25%) developed Brooker grade III and IV heterotopic bone (P < .001) (Table 1). Of the 45 previously k n o w n heterotopic bone formers, 2 (4.4%) s h o w e d evidence of n e w heterotopic ossification with a 95% confidence interval of 0 . 5 4 % - 1 5 . 1 5 % . One patient had ipsilateral grade II heterotopic ossification partially excised at the time of surgery, with residual bone islands after surgery. The 1-year radiograph revealed a progression in size of those bone islands. A second patient, w h o had a grade III heterotopic ossification in the right hip after primary THA and subsequently had a recurrence after surgical excision of the heterotopic ossification and radiation therapy (probably because of inadequate placement of the Ceroband shield to protect inhibition of ingrowth and trochanteric healing), developed a grade II lesion in the left hip after a primary surface replacement arthroplasty. There were a total of 9 n e w cases (7.6%) of heterotopic ossification in the 119 hips (106 patients)
Fig. 1. Radiographs of a 51-year-old man. (A) Two months after left porous surface arthroplasty for osteoarthritis secondary to slipped capital femoral epiphysis with grade III heterotopic ossification and an ostosis on the right iliac wing. (B) Left side is 4 years after surgery following excision of the heterotopic ossification and single-dose radiation with 700 tad. Grade III heterotopic ossification has reformed. The right side is I year after hybrid surface arthroplasty for osteoarthritis treated with indomethacin. No heterotopic ossification formed.
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Fig. 2. (A) Radiograph of a 63-year-old man with failed porous surface arthroplasty for osteoarthritis demonstrating femoral neck osteolysis and grade III heterotopic ossification. (B) One year after revision with a few residual heterotopic bone spurs originating from the greater trochanter and superior acetabular rim. There was no new heterotopic ossification with indomethacin prophylaxis.
with a 95% confidence interval of 2 . 9 % - 1 2 . 7 % (Table 1). Seven of these were grade I, 5 following p r i m a r y surgery and 2 after revisions. Two primary cases developed grade II heterotopic ossification. In the comparison group, a total of 68 hips (83%) formed heterotopic ossification (P < .001) (Table 1). With respect to the surgical approach used, 4 of the 28 patients (14.3%) with a transtrochanteric approach and 5 of the 95 patients (5.3%) with a posterolateral approach developed heterotopic ossification. There was no statistical difference (P = .21) in relation to the approach used. All hips r e m a i n functioning well clinically with average UCLA hip scores (pain, walking, function, and activity respectively) of 9.0, 8.0, 6.6, and 5.1 and average ranges of motions of 112 ° flexion, 3I ° abduction, I9 ° adduction, and 58 ° rotation arc. There were three trochanteric n o n u n i o n s (10.7%),
two following primary surgery and one after revision of a previous trochanteric osteotomy. One case of femoral nerve palsy (0.8%) occurred following a surface replacement arthroplasty using a posterolateral approach. There was no associated w o u n d h e m a t o m a . No difficulty with anticoagulation was noted. There were four (3.2%) cases of postoperative bleeding complications. There was one gastrointestinal bleed with passage of a melanic stool and a drop in hematocrit f r o m 28 to 19, along with one modest thigh h e m a t o m a developing on postoperative day 4 with a decrease in the hematocrit from 29 to 23 requiring discontinuance of warfarin, but the indomethacin course was completed. As previously noted there were two significant postoperative h e m a t o m a s requiring discontinuation of the prophylaxis. None of the h e m a t o m a s needed to be evacuated and all w o u n d s healed w i t h o u t drainage.
Table 1. Incidence of Heterotopic Ossification With Indomethacin Prophylaxis Versus Historical Controls
Discussion
Historical Controls ( C o m p a r i s o n Group) No. cases Grade0 Grade I GradelI Grade III Grade IV Total heterotopic ossification
82 14 30 17 15 6 68
(17%) (37%) (21%) (18%) (7%) (83%)
Indomethacin T h e r a p y (%) 1 I9 110 7 2 0 0 9*
*Rank s u m test c o m p a r i n g distributions, P < .001.
(92) (5.9) (1.7)
(7.6)
Our study confirms that a short, 10-day course of i n d o m e t h a c i n is effective in p r e v e n t i n g the m o r e significant grades of heterotopic ossification (95% confidence interval, 0 % - 2 . 5 %) in a n all-male p o p ulation and results in a lower incidence of overall heterotopic ossification following THA (95% confidence interval, 2 . 9 % - 1 2 . 7 % ) . In addition, we h a d no grade III or IV lesions in a p o p u l a t i o n of 45 m e n w h o w e r e k n o w n heterotopic b o n e formers following previous THA.
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A weakness of the study is that there is no randomized control group; however, we felt a randomized trial was not ethically justified as the natural history and incidence of clinically significant Brooker grades of heterotopic ossification are well d o c u m e n t e d in the literature and some patients w h o form bone (Brooker grade III or IV) wilt subsequently undergo a n o t h e r operation to r e m o v e the heterotopic bone. As stated earlier, the combined incidence of clinically significant heterotopic ossification in the mixed patient population is 14.5%; it was 26% in our comparison group. At the initiation of the study, we believed that the incidence of clinically significant grades of heterotopic ossification was likely to be higher in male patients, especially those w h o had previously formed heterotopic ossification. Hence, it was not, in our view, ethically justified to not use some prophylactic agent in those patients. At our hospital, the 10-day course of indomethacin at the dose described has a patient-billed cost of $48.75 for 5 days of hospitalization and $3.70 for a 5-day outpatient course. For singledose radiotherapy, the patient-billed cost varies from $560 to $800 and includes the cost for the dose calculation, simulation, lead block shielding, and actual treatment. This real cost savings should be weighed against the potential costs associated with w o u n d h e m a t o m a s requiring transfusion or operative m a n a g e m e n t . Objections to the use ot indomethacin include concern with its potential adverse effects, inhibition of bone ingrowth into porous-coated systems, interference with low-dose warfarin therapy, and gastrointestinal disturbances. With a decrease in the duration of therapy from the usual 6-week course it appears that the incidence of side effects (such as dyspepsia, gastritis, and peptic ulcers) diminishes. Schmidt et al., in their double-blind, placebo-controlled study, noted that 19.8% (50/253) of patients were w i t h d r a w n secondary to side effects of nonsteroidal antiinflammatory medications [12]; however, they did note that the placebo group reported dyspepsia just as frequently as the test group. Cella et al. looked at 74 high-risk patients, noting that 19% had contraindications to the use of nonsteroidal antiinflammatory medications such as previously d o c u m e n t e d gastritis and peptic ulcer disease, history ot adverse effects to nonsteroidal antiinflammatory medications, r e q u i r e m e n t of postoperative warfarin and, in one case, impaired renal function [10]. They reported 18% having notable side effects with the 6-week course of therapy. In our study, we were careful to have all doses given with meals and a liquid
antacid available for any complaints of dyspepsia. All 106 patients were able to tolerate the 10-day course of indomethacin w i t h o u t significant gastrointestinal symptoms. A decrease in the duration of t h e r a p y m a y also reduce the potential effect of inhibition of bone ingrowth into porous-coated systems and the adverse effect on trochanteric union. Although nonsteroidal antiinflammatory medications have been shown to inhibit bone ingrowth into a porous system in animal models [28,29], Trancik et al., reporting a histomorphometric analysis that calculated the a m o u n t of bone occupying the pores, s h o w e d that at 2 weeks postimplantation there were no differences b e t w e e n the control and test animals [29]. To date there has b e e n n o apparent adverse effect of osseointegration of our cementless devices, but we are currently undertaking a more critical analysis. Ritter and Sieber s h o w e d no differences in trochanteric n o n u n i o n rates b e t w e e n indomethacin-treated (10.3%) and untreated (12.5%) groups [25]. This is comparable to the 10.7% trochanteric n o n u n i o n rate in this study, but there was a relatively small n u m b e r of patients w h o had had an osteotomy, and we do not believe this to be a significant variation from the 5 % rate after primary THA and 7% after revision surgery as previously reported by the senior a u t h o r using the same three-wire interlocking technique [32]. M c M a h o n et al., w h o used a 10-day course of indomethacin after cementless THA, suggest that it does not interfere with the bone-prosthesis interface, but their follow-up period is short [14]. In this study, there have b e e n no acetabular c o m p o n e n t migrations to date and there are no extensive radiolucencies involving more t h a n one zone. As 1 year is too short a time to assess the long-term durability of bone ingrowth within a porous-coated system, no detailed radiographic analysis is presented. Further long-term studies are n e e d e d to answer this question. The interaction of nonsteroidal antiinflammatory medications and the anticoagulation profile of the patient is of concern. Nonsteroidal antiinfiammatory medications are k n o w n to have an inhibitory effect on platelet aggregation, which can place a patient at an increased risk of postoperative bleeding complications, especially w h e n used in conjunction with other prophylactic agents such as warfarin. In this study there were four postoperative bleeds. This prevalence of 3.2% is higher than the 1.5% overall bleeding complication rate previously reported with the use of low-dose warfarin [30]. This difference is not statistically significant; however, we r e c o m m e n d caution as there m a y be an
Indomethacin for Heterotopic Ossification
increased risk of bleeding complications w h e n i n d o m e t h a c i n is used in conjunction w i t h other anticoagulants. Further studies to evaluate p o t e n tial interaction are currently ongoing. We continu e d to study this issue by carefully following o u r patients after surgery a n d strongly believe that the p r e v e n t i o n of heterotopic ossification a n d t h r o m b o e m b o l i c disease is w o r t h the slight risk. The question t h e n arises as to w h e t h e r an e v e n shorter course w o u l d also be effective. Pritchett recently reported the absence of a n y Brooker grade III or IV heterotopic ossification occurring in a double-blind placebo-controlled trial using six doses of ketorolac following p r i m a r y THA [19]; however, he did h a v e a higher incidence of Brooker grade I a n d II l e s ~ n s (33%) t h a n in o u r study, e v e n t h o u g h h ~ h - r i s k patients such as those with spondyloarthropathy, idiopathic skeletal hyperostosis, previous surgery, a n d history of pelvic or h e a d t r a u m a w e r e excluded f r o m his study. Extrapolation f r o m the radiation t h e r a p y experience m a y indicate a 5-day course to be sufficient at p r e v e n t i n g the m o r e significant grades of heterotopic ossification. We currently h a v e modified our protocol to include 100 m g per r e c t u m i m m e d i a t e l y after surgery followed by 5 days of oral therapy, but there are insufficient data as yet to substantiate reco m m e n d i n g a change to a shorter course.
Conclusion A 10-day course of indomethacin is an effective prophylactic agent,, against heterotopic ossification following THA in a high-risk patient population. C o m p a r e d with an untreated historical control group, it prevents the m o r e significant grades of heterotopic ossification and reduces the incidence of heterotopic ossification following THA. The short course, carefully delivered with meals, appears to be m u c h m o r e tolerable in terms of the reported side effects. It does not appear to interfere with low-dose warfarin prophylaxis. This regimen appears safe, is efficacious, and is less expensive t h a n radiotherapy; therefore, the routine use of indomethacin in the high-risk male patient population is advocated, and we no longer use radiotherapy.
References 1. Charnley J: The long-term results of low-friction arthroplasty of the hip performed as a primary intervention. J Bone and Joint Surg 54B:61, 1972 2. Brooker AE Bowerman JW, Robinson RA, Riley LH Jr: Ectopic ossification following total hip replace-
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ment: incidence and a method of classification. J Bone Joint Surg 55A:1629, 1973 Matos M, Amstutz HC, Finerman G: Myositis ossificans following total hip replacement. J Bone Joint Surg 57A:137, 1975 DeLee J, Ferrari A, Charnley J: Ectopic bone formation following low friction arthroplasty of the hip. Clin Orthop 121:53, 1976 Jowsey J, Coventry MB, Robins PR: Heterotopic ossification: theoretical consideration, possible etiologic factors, and a clinical review of total hip arthroplasty patients exhibiting this phenomenon, p. 210. In: The hip: proceedings of the fifth open scientific meeting of The Hip Society. CV Mosby, St. Louis, i977 Ritter MA, Vaughan RB: Ectopic ossification after total hip arthroplasty: predisposing factors, frequency, and effect on results. J Bone and Joint Surg 59A:345, 1977 Ritter MA, Gioe TJ: The effect of indomethacin on para-articular ectopic ossification following total hip arthroplasty. Clin Orthop 167:113, 1982 Morrey BE Adams RA, Cabanela ME: Comparison of heterotopic bone after anterolateral, transtrochanteric, and posterior approaches for total hip arthroplasty. Clin Orthop 188:160, 1984 Thomas BJ, Amstutz HC: Results of the administration of diphosphonate for the prevention of heterotopic ossification after total hip arthroplasty. J Bone Joint Surg 67A:400, 1985 Celia JP, Salvati EA, Sculco TP: Indomethacin for the prevention of heterotopic ossification following total hip arthroplasty: effectiveness, contraindications, and adverse effects. J Arthroplasty 3:229, 1988 Sodemann B, Persson P, Nilsson OS: Prevention of heterotopic ossification bEnonsteroid antiinflammatory drugs after total hip arthroplasty. Clin Orthop 237:I58, 1988 Schmidt SA, Kjaersgaard-Andersen P, Pedersen NW et al. The use of indomethacin to prevent the formation of heterotopic bone after total hip replacement: a randomized, double-blind clinical trial. J Bone Joint Surg 70A:834, 1988 Sylvester JE, Greenberg P, Selch MT et al: The use of postoperative irradiation for the prevention of heterotopic bone formation after total hip replacement. Int J Radiat Oncol Biol Phys 14:471, 1988 McMahon JS, Waddell JP, Morton J: Effect of short course indomethacin on heterotopic bone formation after uncemented total hip arthroplasty. J Arthroplasty 6:259, I99i Reis HJ, Kiisswetter W, Schellinger T: The suppression of heterotopicossification after total hip arthroplasty. Int Orthop 16:140, 1992 Wurnig C, Eyb R, Auersperg V: Indomethacin for prevention of ectopic ossification in cementless hip arthroplasties: a prospective 1-year study of 100 cases. Acta Orthop Scand 63:628, 1992 Ahrengart L, Lindgren U: Heterotopic bone after hip arthroplasty: defining the patient at risk. Clin Orthop 293:153, 1993
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18. Kjaersgaard-Andersen P, Nafei A, Teichert G e t al: Indomethacin for prevention of heterotopic ossification: a randomized controlled study in 41 hip arthroplasties. Acta Orthop Scand 64:639, 1993 19. Pritchett JW: Ketorolac prophylaxis against heterotopic ossification after hip replacement. Clin Orthop 314:162, 1995 20. Kjaersgaard-Andersen P, Schmidt SA: Total hip arthroplasty: the role of antiinflammatory medications in the prevention of heterotopic ossification. Clin Orthop 263:78, 1991 21. Hamblen DL: Ectopic ossification, p. 100. In: Ling, RSM (ed): Complications of total hip replacement. Churchill Livingstone, London, 1984 22. Maloney W J, Krushell R J, Jasty M, Harris WH: Incidence of heterotopic ossification after total hip replacement: effect of the type of fixation of the femoral component. J Bone Joint Surg 73A:191, 1991 23. Finerman GAM, Drengel WF, Lowell JD Jr et al: Role of diphosphonate in the prevention of heterotopic ossification alter total hip arthroplasty: a preliminary report, p. 222. In: The hip: proceedings of the fifth open scientific meeting of The Hip Society. CV Mosby, St. Louis, 1977 24. Coventry MB, Scanlon PW: The use of radiation to discourage ectopic bone: a nine-year study in surgery about the hip. J Bone Joint Surg 63A:201, 1981
25. Ritter MA, Sieber JM: Prophylactic indomeLhacin for the prevention of heterotopic bone formation following total hip arthroplasty. Clin Orthop I96:217, 1985 26. Kjaersgaard-Andersen P, Ritter MA: Short-term treatment with nonsteroidal antiinflammatory medications to prevent heterotopic bone formation after total hip arthroplasty: a preliminary report. Clin Orthop 279:157, 1992 27. Dahl HK: Kliniske Observasjoner. In: Symposium on hip arthrosis. Blindern, Norway, 1974 28. Keller JC, Trancik TM, Young FA, St. Mary E: Effect of indomethacin on bone ingrowth. J Orthop Res 7:28, 1989 29. Trancik T, Mills W, Vinson N: The effect of indomethacin, aspirin, and ibuprofen on bone ingrowth into a porous-coated implant. Clin Orthop 249:113, 1989 30. Amstutz HC, Friscia DA, Dorey F, Carney BT: Warfarin prophylaxis to prevent mortality from pulmonary embolism after total hip replacement. J Bone Joint Surg 71A:32I, 1989 31. Amstutz HC, Thomas B J, Jinnah R et al: Treatment of primary osteoarthritis of the hip: a comparison of total joint and surface replacement arthroplasty. J Bone Joint Surg 66A:228, 1984 32. Amstutz HC, Mai LL, Schmidt I: Results of interlocking wire trochanter reattachment and technique refinements to prevent complications following total hip arthroplasty. Clin Orthop 183:82, 1984
Short-course Indomethacin Prevents Heterotopic Ossification in a High-risk Population Following Total Hip Arthroplasty Harlan
C. A m s t u t z ,
MD, Vincent A. Fowble, and Frederick
MD, Thomas
P. S c h m a l z r i e d ,
MD,
J. D o r e y , P h D
Abstract: The efficacy of a 10-day course of indomethacin in preventing heterotopic ossification after total hip arthroplasty was studied in a consecutive series of male patients who were at increased risk for bone formation. Between September 199I and June I994, all male patients (123 hips in 109 patients) who underwent total hip, revision, or surface arthroplasty were placed on a I0-day course of indomethacin. Of these, 106 patients (119 hips) successfully completed the i0-day course. There was no significant formation of heterotopic ossification (Brooker grade III or IV). From a group of 45 known heterotopic bone formers following previous total hip arthroplasty, only 2 developed new heterotopic ossification. Overall there were 9 (7.6%) new cases of heterotopic ossification: 7 Brooker grade I (5 primary and 2 revision cases) and 2 Brooker grade II (both primary cases). A 10-day course of indomethacin prevents the more significant grades of heterotopic ossification and is effective at reducing the incidence of heterotopic ossification following total hip arthroplasty. Further, this regimen appears safe and cost effective. Key words: total hip arthroplasty, heterotopic, ossification, indomethacin.
The incidence of heterotopic ossification after total hip arthroplasty (THA) has b e e n well documented. The combined overall incidence of heretotopic ossification based on a review of the literature is 34% (1,719/5,122 hips) []-19] in the untreated, m i x e d patient population. Although there was a wide variation in the incidence, this is in part due to the classification system used (ie, w h e t h e r the small, b o n y islands, grade I in m o s t systems, are included). The c o m b i n e d incidence of the m o r e severe forms of heterotopic ossification, w h i c h significantly reduces the range of hip motion, is 14.5% (356/2,470 hips) [2,3,5-8,10-15,17-19].
Previous heterotopic ossification and male gender are the m o s t significant risk factors for f o r m a tion of b o n e following THA [5,6,20]. The patient w h o has previously d e v e l o p e d h e t e r o t o p i c ossification after THA has a 90% probability of developing either the same or an increased a m o u n t of heterotopic b o n e following revision or p r i m a r y surgery [4]. The c o m b i n e d incidence of heterotopic ossification in males is 33.5% (3151939 hips) as c o m p a r e d w i t h 13.8% (26111,887) in w o m e n [4,6,17,18]. Ritter a n d Vaughn n o t e d a 42.5 % incidence of heterotopic ossification in their male patients versus 21.3 % in their female patients [6]. DeLee et al. n o t e d that heterotopic ossification occurs three times m o r e often in m e n [4]. A l t h o u g h the male a n d female differences w e r e less, A h r e n g a r t a n d Lindgren f o u n d an 8 4 % incidence in m e n versus 67% in w o m e n and reported that m e n tended to f o r m larger a m o u n t s of b o n e (31% Brooker grades III a n d IV c o m p a r e d with
From the Joint Replacement Institute at Orthopaedic Hospital, Los Angeles, California. Reprint requests: I-Iarlan C. Amstutz, MO, Joint Replacement Institute at Orthopaedic Hospital, 2400 South Flower Street, Los Angeles, CA 90007.
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12% in women) {17]. Other risk factors predisposing to heterotopic ossification after THA include revision surgery, bilateral operations, active ankylosing spondylitis, and severe coxarthrosis with extensive osteophyte formation [5,6,20,21]. An increased incidence of heterotopic ossification after surface arthroplasty [9], as well as with cementless femoral components {22], has also been reported. Ethylhydroxydiphosphonate [23], irradiation [5, I3,24], and nonsteroidal antiinflammatory medications [7,i0-12,14-16,18,19,25,261 have been advocated to prevent the formation of postoperative heterotopic ossification. Ethylhydroxydiphosphonate has not been effective because it does not prevent the osteoid matrix from forming and mineralization occurs after withdrawal of the medication [9]. Irradiation has been demonstrated to be effective prophylaxis against heterotopic ossification if administered within the first 4 to 5 postoperative days [5,13,24]. Indoln.ethacin was first noted to inhibit heterotopic ossification after THA by Dahl [271. Subsequently, numerous studies have confirmed his findings and verified the efficacy of indomethacin and other nonsteroidal antiinflammatory medications as prophylaxis after primary THA in mixed patient populations [11,12,14-16,18,19,26], as well as in those assessed to be at high risk [7,10,25] for recurrence after excision [7,12,27]. Disadvantages of the indomethacin regimens include the high incidence of side effects [10,12], potential inhibition of bony ingrowth into a porous-coated system [28,291, and possible interference with anticoagulation prophylaxis. The majority of studies have looked at indomethacin in a 6-week course of therapy [7,I0,12, 16,25]. More recently, shorter courses of treatment have been studied [11,14,18,26]. Sodemann et al. demonstrated in 69 patients that a 3-week course of indomethacin or ibuprofen was effective in preventing the more severe grades of heterotopic ossification, with no incidence of grade III or IV reported [11]. Kjaersgaard-Andersen and Ritter used a 2-week course of indomethacin in 13 patients after cementless THA and reported no incidence of heterotopic ossification [26]. In a randomized, double-blind clinical trial, Pritchett reported no clinically significant grades of heterotopic ossification in 152 patients following treatment with six doses of ketorolac {19]. McMahon et al. showed that a 10-day course of indomethacin in a mixed patient population is effective in reducing the incidence and severity of heterotopic ossification after primary cementless THA [14]. They reported a 20% overall incidence of heterotopic ossification in the test group of 85
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patients and only 1 (1.2%) Brooker grade III or IV hip versus a 70% incidence in the control group of 100 patients with 24 (24%) Brooker grade III or IV hips. In this study we evaluated the ability of a 10-day course of indomethacin in a high-risk population (previous heterotopic bone formers and men) to prevent heterotopic ossification after THA. The incidence of heterotopic ossification was compared with previous results reported in the literature.
Materials and Methods Between September 1991 and July 1994 all men undergoing total hip, surface, and revision arthroplasty were entered,in an indomethacin prophylaxis protocol against heterotopic ossification at a dose of 25 mg orally three times a day for a total of 10 days. During this period there were 123 consecutive hips in I09 male patients entered into the study. The mean age of the population at the time of surgery was 56 years (range, 19-88 years). There were 57 primary and 66 revision cases. The diagnoses of the 57 primary cases included 26 with hypertrophic osteoarthritis, 14 with osteonecrosis, and 17 with secondary osteoarthritis. Forty-eight hips in 45 patients had formed heterotopic bone following previous THAs. Thirtynine of these cases of heterotopic ossification were in the ipsilateral hip and classified as grade I in 11 hips, grade II in 10 hips, grade III in 17 hips, and grade IV in 1 hip. The other 9 cases of heterotopic ossification involved the contralateral hip and were classified as grade I in 2 hips, grade II in 3 hips, and grade III in 4 hips. All surgeries were performed by the senior author (H. C. A.) using the posterolateral approach in 95 and the transtrochanteric approach in 28 (24 primary and 4 revision cases). A complete capsulectomy was performed in each case. Hypotensive epidural anesthesia and laminar flow were used for each case. Pulsed saline lavage was used to clean the wound a n d closed-suction drainage, along with a hip spica elastic dressing, was routine. Postoperative management included low-dose warfarin prophylaxis against thromboembolic disease as previously described [30] and early mobilization by postoperative day 2 with physical therapy. Indomethacin was started on the first postoperative day and continued for 10 days. All patients were followed prospectively with serial anteroposterior pelvis radiographs obtained after surgery and at 2, 4, and i2 months. Heterotopic ossification was evaluated using the Brooker classification system [2]. In the 39 ipsilateral hips,
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residual small ossicles of heterotopic ossification were noted on the immediate postoperative anteroposterior pelvic radiographs despite excision. These ossicles were followed prospectively for progression and/or formation of n e w bone. Patients were evaluated clinically using the hip rating system of the University of California at Los Angeles for pain, walking, function, and activity separately [31]. Results are reported with 95% confidence intervals, which represent the range of values that contain the actual incidence of heterotopic ossification in an infinite population of similar patients. A comparison group (historical control) was f o r m e d from 82 patients (78% men) from a previous study [9] in w h i c h similar operative techniques and procedures w e r e p e r f o r m e d by the senior author. None of these patients received any nonsteroidal a n t i i n f l a m m a t o r y medication following the operation, and all were followed for a m i n i m u m of 2 years. The i n d o m e t h a c i n and historical control groups were c o m p a r e d using Fisher's exact test.
Results One h u n d r e d and nine patients (i23 hips) were started on the indomethacin prophylactic protocol. Four hips in three patients were dropped from the study. One (an 83-year-old patient w h o had a primary THA) had a w o u n d bleed on postoperative day 1 with a drop in the hematocrit from 27 to 20, despite a normal prothrombin time, requiring transfusion. The indomethacin along with warfarin was discontinued on the second postoperative clay. The patient subsequently developed grade I heterotopic ossification. The second patient excluded was a 64-
year-old undergoing revision surgery w h o developed a w o u n d bleed on postoperative day 5 with a drop in hematocrit from 26 to 20, requiring additional transfusions; however, indomethacin was given for the first 5 postoperative days and he did not form any n e w heterotopic bone. A third patient w h o had bilateral primary surface arthroplasties did not receive indomethacin on postoperative days 3 and 4, but had initial and subsequent medication per protocol. This patient developed grade II lesions bilaterally. One h u n d r e d six patients (119 hips) successfully completed the 10-day course of indomethacin. No Brooker grade III or IV cases were f o u n d (95% confidence interval, 0 % - 2 . 5 % ) (Figs. 1 and 2, Table 1). In the comparison group, 21 hips (25%) developed Brooker grade III and IV heterotopic bone (P < .001) (Table 1). Of the 45 previously k n o w n heterotopic bone formers, 2 (4.4%) s h o w e d evidence of n e w heterotopic ossification with a 95% confidence interval of 0 . 5 4 % - 1 5 . 1 5 % . One patient had ipsilateral grade II heterotopic ossification partially excised at the time of surgery, with residual bone islands after surgery. The 1-year radiograph revealed a progression in size of those bone islands. A second patient, w h o had a grade III heterotopic ossification in the right hip after primary THA and subsequently had a recurrence after surgical excision of the heterotopic ossification and radiation therapy (probably because of inadequate placement of the Ceroband shield to protect inhibition of ingrowth and trochanteric healing), developed a grade II lesion in the left hip after a primary surface replacement arthroplasty. There were a total of 9 n e w cases (7.6%) of heterotopic ossification in the 119 hips (106 patients)
Fig. 1. Radiographs of a 51-year-old man. (A) Two months after left porous surface arthroplasty for osteoarthritis secondary to slipped capital femoral epiphysis with grade III heterotopic ossification and an ostosis on the right iliac wing. (B) Left side is 4 years after surgery following excision of the heterotopic ossification and single-dose radiation with 700 tad. Grade III heterotopic ossification has reformed. The right side is I year after hybrid surface arthroplasty for osteoarthritis treated with indomethacin. No heterotopic ossification formed.
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Fig. 2. (A) Radiograph of a 63-year-old man with failed porous surface arthroplasty for osteoarthritis demonstrating femoral neck osteolysis and grade III heterotopic ossification. (B) One year after revision with a few residual heterotopic bone spurs originating from the greater trochanter and superior acetabular rim. There was no new heterotopic ossification with indomethacin prophylaxis.
with a 95% confidence interval of 2 . 9 % - 1 2 . 7 % (Table 1). Seven of these were grade I, 5 following p r i m a r y surgery and 2 after revisions. Two primary cases developed grade II heterotopic ossification. In the comparison group, a total of 68 hips (83%) formed heterotopic ossification (P < .001) (Table 1). With respect to the surgical approach used, 4 of the 28 patients (14.3%) with a transtrochanteric approach and 5 of the 95 patients (5.3%) with a posterolateral approach developed heterotopic ossification. There was no statistical difference (P = .21) in relation to the approach used. All hips r e m a i n functioning well clinically with average UCLA hip scores (pain, walking, function, and activity respectively) of 9.0, 8.0, 6.6, and 5.1 and average ranges of motions of 112 ° flexion, 3I ° abduction, I9 ° adduction, and 58 ° rotation arc. There were three trochanteric n o n u n i o n s (10.7%),
two following primary surgery and one after revision of a previous trochanteric osteotomy. One case of femoral nerve palsy (0.8%) occurred following a surface replacement arthroplasty using a posterolateral approach. There was no associated w o u n d h e m a t o m a . No difficulty with anticoagulation was noted. There were four (3.2%) cases of postoperative bleeding complications. There was one gastrointestinal bleed with passage of a melanic stool and a drop in hematocrit f r o m 28 to 19, along with one modest thigh h e m a t o m a developing on postoperative day 4 with a decrease in the hematocrit from 29 to 23 requiring discontinuance of warfarin, but the indomethacin course was completed. As previously noted there were two significant postoperative h e m a t o m a s requiring discontinuation of the prophylaxis. None of the h e m a t o m a s needed to be evacuated and all w o u n d s healed w i t h o u t drainage.
Table 1. Incidence of Heterotopic Ossification With Indomethacin Prophylaxis Versus Historical Controls
Discussion
Historical Controls ( C o m p a r i s o n Group) No. cases Grade0 Grade I GradelI Grade III Grade IV Total heterotopic ossification
82 14 30 17 15 6 68
(17%) (37%) (21%) (18%) (7%) (83%)
Indomethacin T h e r a p y (%) 1 I9 110 7 2 0 0 9*
*Rank s u m test c o m p a r i n g distributions, P < .001.
(92) (5.9) (1.7)
(7.6)
Our study confirms that a short, 10-day course of i n d o m e t h a c i n is effective in p r e v e n t i n g the m o r e significant grades of heterotopic ossification (95% confidence interval, 0 % - 2 . 5 %) in a n all-male p o p ulation and results in a lower incidence of overall heterotopic ossification following THA (95% confidence interval, 2 . 9 % - 1 2 . 7 % ) . In addition, we h a d no grade III or IV lesions in a p o p u l a t i o n of 45 m e n w h o w e r e k n o w n heterotopic b o n e formers following previous THA.
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A weakness of the study is that there is no randomized control group; however, we felt a randomized trial was not ethically justified as the natural history and incidence of clinically significant Brooker grades of heterotopic ossification are well d o c u m e n t e d in the literature and some patients w h o form bone (Brooker grade III or IV) wilt subsequently undergo a n o t h e r operation to r e m o v e the heterotopic bone. As stated earlier, the combined incidence of clinically significant heterotopic ossification in the mixed patient population is 14.5%; it was 26% in our comparison group. At the initiation of the study, we believed that the incidence of clinically significant grades of heterotopic ossification was likely to be higher in male patients, especially those w h o had previously formed heterotopic ossification. Hence, it was not, in our view, ethically justified to not use some prophylactic agent in those patients. At our hospital, the 10-day course of indomethacin at the dose described has a patient-billed cost of $48.75 for 5 days of hospitalization and $3.70 for a 5-day outpatient course. For singledose radiotherapy, the patient-billed cost varies from $560 to $800 and includes the cost for the dose calculation, simulation, lead block shielding, and actual treatment. This real cost savings should be weighed against the potential costs associated with w o u n d h e m a t o m a s requiring transfusion or operative m a n a g e m e n t . Objections to the use ot indomethacin include concern with its potential adverse effects, inhibition of bone ingrowth into porous-coated systems, interference with low-dose warfarin therapy, and gastrointestinal disturbances. With a decrease in the duration of therapy from the usual 6-week course it appears that the incidence of side effects (such as dyspepsia, gastritis, and peptic ulcers) diminishes. Schmidt et al., in their double-blind, placebo-controlled study, noted that 19.8% (50/253) of patients were w i t h d r a w n secondary to side effects of nonsteroidal antiinflammatory medications [12]; however, they did note that the placebo group reported dyspepsia just as frequently as the test group. Cella et al. looked at 74 high-risk patients, noting that 19% had contraindications to the use of nonsteroidal antiinflammatory medications such as previously d o c u m e n t e d gastritis and peptic ulcer disease, history ot adverse effects to nonsteroidal antiinflammatory medications, r e q u i r e m e n t of postoperative warfarin and, in one case, impaired renal function [10]. They reported 18% having notable side effects with the 6-week course of therapy. In our study, we were careful to have all doses given with meals and a liquid
antacid available for any complaints of dyspepsia. All 106 patients were able to tolerate the 10-day course of indomethacin w i t h o u t significant gastrointestinal symptoms. A decrease in the duration of t h e r a p y m a y also reduce the potential effect of inhibition of bone ingrowth into porous-coated systems and the adverse effect on trochanteric union. Although nonsteroidal antiinflammatory medications have been shown to inhibit bone ingrowth into a porous system in animal models [28,29], Trancik et al., reporting a histomorphometric analysis that calculated the a m o u n t of bone occupying the pores, s h o w e d that at 2 weeks postimplantation there were no differences b e t w e e n the control and test animals [29]. To date there has b e e n n o apparent adverse effect of osseointegration of our cementless devices, but we are currently undertaking a more critical analysis. Ritter and Sieber s h o w e d no differences in trochanteric n o n u n i o n rates b e t w e e n indomethacin-treated (10.3%) and untreated (12.5%) groups [25]. This is comparable to the 10.7% trochanteric n o n u n i o n rate in this study, but there was a relatively small n u m b e r of patients w h o had had an osteotomy, and we do not believe this to be a significant variation from the 5 % rate after primary THA and 7% after revision surgery as previously reported by the senior a u t h o r using the same three-wire interlocking technique [32]. M c M a h o n et al., w h o used a 10-day course of indomethacin after cementless THA, suggest that it does not interfere with the bone-prosthesis interface, but their follow-up period is short [14]. In this study, there have b e e n no acetabular c o m p o n e n t migrations to date and there are no extensive radiolucencies involving more t h a n one zone. As 1 year is too short a time to assess the long-term durability of bone ingrowth within a porous-coated system, no detailed radiographic analysis is presented. Further long-term studies are n e e d e d to answer this question. The interaction of nonsteroidal antiinflammatory medications and the anticoagulation profile of the patient is of concern. Nonsteroidal antiinfiammatory medications are k n o w n to have an inhibitory effect on platelet aggregation, which can place a patient at an increased risk of postoperative bleeding complications, especially w h e n used in conjunction with other prophylactic agents such as warfarin. In this study there were four postoperative bleeds. This prevalence of 3.2% is higher than the 1.5% overall bleeding complication rate previously reported with the use of low-dose warfarin [30]. This difference is not statistically significant; however, we r e c o m m e n d caution as there m a y be an
Indomethacin for Heterotopic Ossification
increased risk of bleeding complications w h e n i n d o m e t h a c i n is used in conjunction w i t h other anticoagulants. Further studies to evaluate p o t e n tial interaction are currently ongoing. We continu e d to study this issue by carefully following o u r patients after surgery a n d strongly believe that the p r e v e n t i o n of heterotopic ossification a n d t h r o m b o e m b o l i c disease is w o r t h the slight risk. The question t h e n arises as to w h e t h e r an e v e n shorter course w o u l d also be effective. Pritchett recently reported the absence of a n y Brooker grade III or IV heterotopic ossification occurring in a double-blind placebo-controlled trial using six doses of ketorolac following p r i m a r y THA [19]; however, he did h a v e a higher incidence of Brooker grade I a n d II l e s ~ n s (33%) t h a n in o u r study, e v e n t h o u g h h ~ h - r i s k patients such as those with spondyloarthropathy, idiopathic skeletal hyperostosis, previous surgery, a n d history of pelvic or h e a d t r a u m a w e r e excluded f r o m his study. Extrapolation f r o m the radiation t h e r a p y experience m a y indicate a 5-day course to be sufficient at p r e v e n t i n g the m o r e significant grades of heterotopic ossification. We currently h a v e modified our protocol to include 100 m g per r e c t u m i m m e d i a t e l y after surgery followed by 5 days of oral therapy, but there are insufficient data as yet to substantiate reco m m e n d i n g a change to a shorter course.
Conclusion A 10-day course of indomethacin is an effective prophylactic agent,, against heterotopic ossification following THA in a high-risk patient population. C o m p a r e d with an untreated historical control group, it prevents the m o r e significant grades of heterotopic ossification and reduces the incidence of heterotopic ossification following THA. The short course, carefully delivered with meals, appears to be m u c h m o r e tolerable in terms of the reported side effects. It does not appear to interfere with low-dose warfarin prophylaxis. This regimen appears safe, is efficacious, and is less expensive t h a n radiotherapy; therefore, the routine use of indomethacin in the high-risk male patient population is advocated, and we no longer use radiotherapy.
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18. Kjaersgaard-Andersen P, Nafei A, Teichert G e t al: Indomethacin for prevention of heterotopic ossification: a randomized controlled study in 41 hip arthroplasties. Acta Orthop Scand 64:639, 1993 19. Pritchett JW: Ketorolac prophylaxis against heterotopic ossification after hip replacement. Clin Orthop 314:162, 1995 20. Kjaersgaard-Andersen P, Schmidt SA: Total hip arthroplasty: the role of antiinflammatory medications in the prevention of heterotopic ossification. Clin Orthop 263:78, 1991 21. Hamblen DL: Ectopic ossification, p. 100. In: Ling, RSM (ed): Complications of total hip replacement. Churchill Livingstone, London, 1984 22. Maloney W J, Krushell R J, Jasty M, Harris WH: Incidence of heterotopic ossification after total hip replacement: effect of the type of fixation of the femoral component. J Bone Joint Surg 73A:191, 1991 23. Finerman GAM, Drengel WF, Lowell JD Jr et al: Role of diphosphonate in the prevention of heterotopic ossification alter total hip arthroplasty: a preliminary report, p. 222. In: The hip: proceedings of the fifth open scientific meeting of The Hip Society. CV Mosby, St. Louis, 1977 24. Coventry MB, Scanlon PW: The use of radiation to discourage ectopic bone: a nine-year study in surgery about the hip. J Bone Joint Surg 63A:201, 1981
25. Ritter MA, Sieber JM: Prophylactic indomeLhacin for the prevention of heterotopic bone formation following total hip arthroplasty. Clin Orthop I96:217, 1985 26. Kjaersgaard-Andersen P, Ritter MA: Short-term treatment with nonsteroidal antiinflammatory medications to prevent heterotopic bone formation after total hip arthroplasty: a preliminary report. Clin Orthop 279:157, 1992 27. Dahl HK: Kliniske Observasjoner. In: Symposium on hip arthrosis. Blindern, Norway, 1974 28. Keller JC, Trancik TM, Young FA, St. Mary E: Effect of indomethacin on bone ingrowth. J Orthop Res 7:28, 1989 29. Trancik T, Mills W, Vinson N: The effect of indomethacin, aspirin, and ibuprofen on bone ingrowth into a porous-coated implant. Clin Orthop 249:113, 1989 30. Amstutz HC, Friscia DA, Dorey F, Carney BT: Warfarin prophylaxis to prevent mortality from pulmonary embolism after total hip replacement. J Bone Joint Surg 71A:32I, 1989 31. Amstutz HC, Thomas B J, Jinnah R et al: Treatment of primary osteoarthritis of the hip: a comparison of total joint and surface replacement arthroplasty. J Bone Joint Surg 66A:228, 1984 32. Amstutz HC, Mai LL, Schmidt I: Results of interlocking wire trochanter reattachment and technique refinements to prevent complications following total hip arthroplasty. Clin Orthop 183:82, 1984