Indomethacin for Prevention of Heterotopic Ossification After Total Hip

Arthroplasty

R e m z i T6zf in , M D , Hal i t P inar , M D , E c m e l Ye~iller, M D , a n d

A z m i H a m z a o ~ l u , M D

Abstract: Twenty-four patients (29 hips) undergoing total hip arthroplasty were rou- tinely given 75 mg of indomethacin daily for 4 weeks after operation and reviewed radiographically for heterotopic ossification (HO) for a minimum of 6 months. A com- parison group of 25 patients (27 hips) without indomethacin treatment was formed and studied in the same manner. This group of patients received the usual postop- erative analgesic treatment, which is diclofenac sodium twice daily parenterally for 5-10 days. The indomethacin group also received the same treatment. In the indo- methacin group no patient had grade II, III, and grade IV HO and the incidence of grade I HO was 31% (nine patients). In the comparison group one patient (3%) had grade l, three (I ] %) grade II, and eight (30%) grade III HO. These findings suggested that indomethacin effectively prevented higher grades of HO following total hip ar- throplasty. Two patients not included in the study had gastrointestinal bleeding and recovered after withdrawa! of the drug. Key words: total hip arthroplasty, heterotopic ossification.

Heterotopic ossification (HO) is a common com- plication of total hip arthroplasty with a reported incidence of 2 - 9 0 % (4, 6, 12, 20, 22). In most cases, HO is not severe and does not adversely affect the clinical result (1, 4). It has been associated with pain and decreased range of mot ion in 3 - 1 0 % of cases (11, 22).

Although the cause of HO following total hip ar- throplasty is not known, several risk factors have been identified. These include male gender, anky- losing spondylitis, hypertrophic osteoarthritis, pre- vious trauma to the same hip, diffuse idiopathic hy- perostosis, and development of HO following previous ipsilateral or contralateral hip surgery (1, 14, 18, 19, 22). Others have emphasized the role of

From the Department of Orthopaedics and Traumatology, Istanbul Medical Faculty, Btanbul University, IstanbuL Turkey.

Reprint requests: Remzi T6zi.in, MD, Department of Orthopae- dics and Traumatology, Istanbul Medical Faculty, istanbul Uni- versity, 34390 ~apa, Istanbul, Turkey.

surgical technique such as the type of approach, tro- chanteric osteotomy, and the degree of soft tissue trauma during surgery (1, 5, 14, 16, 20, 23).

Results of excision of the ectopic bone may not be consistently good (7, 14). Therefore, some form of prophylaxis against heterotopic bone formation in high-risk patients should be considered. Different therapies such as local irradiation, diphosphonates, and nonsteroidal anti- inflammatory drugs (NSAIDs), in particular indomethacin, have been shown to affect both the incidence and grade of HO (3, 5, 9, I0, I4, 15, 18-21, 23). The disadvantages of the first two of these therapies include high cost, exposure to radiation, and the adverse effect and poor efficacy of diphosphonates (14, 23). Despite its well-known adverse effects, prophylaxis with in- domethacin is a simple and effective method of re- ducing the incidence and grade of HO in high-risk patients undergoing total arthroplasty (5, 10, 14, 15, 23).

In this study, we attempted to evaluate the effec-

57

58 The Journal of Arthroplasty Vol. 7 No. 1 March 1992

tiveness of indomethacin for the prevention of HO following total hip arthroplasty.

Materials and Methods

The prospective study group included 56 hips in 49 patients who underwent primary or revision total hip arthroplasty between Juiy 1988 and December 1989. Twenty-nine hips (24 patients) treated with indomethacin comprised group 1 and 27 hips (25 patients) without indomethacin treatment served as the comparison group (group 2). All patients were off anti-inflammatory medication for 1 week prior to operation. Indomethacin administration was started on the first postoperative day at a dose of 25 mg orally three times daily and continued for 4 weeks. Recently, we have been prescribing 75 mg of a sustained-release form (Indocid-R). Gastrointes- tinal bleeding developed in two patients. The drug was discontinued and they were dropped from the study. The patients in both groups received our usual postoperative analgesic treatment, which is diclo- fenac sodium twice daily parenterally for 5 to 10 days. Our patient populat ion is not selected, so it differs from some other studies in which only pa- tients at high risk for developing HO were included,

The ages of the patients in group 1 and group 2 were 20 - 75 years (mean, 47.3 years) and 2 8 - 7 0 years (mean, 52.6 years), respectively. There were 9 men and 15 w o m e n in group 1 and 9 men and 16 women in group 2. The indications for total hip ar- throplasty inbo th groups are demonstrated in Table 1.

Seven hips in group 1 and four hips in group 2 had previously been operated. The number of pa- tients under oral steroid therapy during the operation were four and one, respectively. The types of prostheses implanted were 27 cementless (17 Po- rous-Coated Anatomic [PCA], 6 PM Plasmapore, 4 Freeman) and 2 cemented (Miiller) in group 1 and 16 cementless (2 PCA, 14 PM Plasmapore) and 11 cemented (10 Miiller, 1 Charnley-Mfil ler) in group 2. The surgeons' preferences as regards the ap- proaches were 28 lateral, 1 Watson-Jones ap- proaches, and 6 lateral, 21 Watson Jones ap- proaches, respectively. Trochanteric osteotomy was not performed in any of the cases. No form of throm- bosis prophylaxis was employed in the cases.

Anteroposterior radiographs made in the imme- diate postoperative period and at last follow-up were analyzed for HO. A min imum follow-up of 6 months was necessary for inclusion in the study: 9.8 months (range, 6 - 1 8 months) for the indomethacin-treated group (group 1) and 11.6 months (range, 6 -2 2 months) for the comparison group (group 2). It is

Table 1. Indications for Total Hip Arthroplasty

Indomethacin- Comparison Treated Group Group

Primary coxarthrosis 14 20 Rheumatoid arthritis 2 2 Avascular necrosis 4 - - Juvenile rheumatoid 1 - -

arthritis Ankylosing 3 2

spondylitis Old femoral neck 2 2

fracture Sequela of 1 - -

tuberculous arthritis

Old traumatic hip 1 - - dislocation + acetabular fracture

Congenital 1 1 dislocation of hip

Total 29 27

stated that 6 months is an adequate follow-up period for accurate assessment of HO (5, 9, 15).

HO was rated on a scale with five grades according to Brooker et al. (4): grade 0, no ossification; grade I, one or two isolated areas of ossification, each less than 1 cm in diameter; grade II, more widespread isolated areas of ossification or osteophytes of the proximal femur or acetabular ring, covering less than 50% of the distance between the femur and the pel- vis; grade III, ossification covering more than 50% of the distance between the femur and the pelvis, but not bridging the entire distance between the femur and pelvis; grade IV, ossification bridging the entire distance between the femur and pelvis.

Statistical analyses were performed using the chi- square test.

Results

The incidence and grade of heterotopic ossification in both groups is given in Table 2.

Sixty-nine percent of the indomethacin-treated group and 56% of the comparison group exhibited no HO. However, in the indomethacin-treated group (group 1) there was no grade II, III, or IV HO. In group 2 the incidence of significant HO (grade III) was 30%. The difference was statistically significant (P < .001). For the same group, this is also signifi- cantly higher than the incidence of minor degrees of HO (grades I and II: 14%) (P < .001). No patient in either group had grade IV HO (apparent ankylosis).

The indications for arthroplasty in patients in group 2 with grade III HO were six primary coxar- throsis (two of them were revision arthroplasties),

Indomethacin for Prevention of Heterotopic Ossification • Tbz0n et al. 59

Table 2. Incidence and Grade of Heterotopic Ossification

0 I II III IV

N o . % N o . % N o . % N o . % N o . %

I n d o m e t h a c i n g r o u p ( n = 2 9 ) 2 0 6 9 % 9 3 1 % - - - - - -

C o m p a r i s o n g r o u p ( n = 2 7 ) 1 5 5 6 % 1 3 % 3 1 1 % 8 3 0 % - -

one congenital dislocation of the hip, and one pre- vious Moore endoprosthesis for femoral neck frac- ture. The type of prostheses in these cases were three cementless and five cemented prostheses. There were three men and five women. Comparative results are presented in Table 3.

Two patients not included in the study had gas- trointestinal bleeding on the third day of indometh- acin treatment and recovered with stoppage of the drug. No other adverse effects were encountered with indomethacin.

Discussion

Significant variations in the reported incidences of HO after total hip arthroplasty exist. This is partly due to the differences in diagnostic criteria and in classification systems of HO (7). Besides, minor os- sifications may be missed on radiographs. Another reason may be that the patient populations are not similar as regards the risk factors for the development of HO. Most of risk factors are controversial at the present time. Puzas et al. (13) stated that cementless arthroplasties reveal a higher number of HO. On the other hand, Rockwood et al. (17) claimed that there were no differences between cementless and ce- mented arthroplasties. In the present study cement- less cases are mostly in group 1. We cannot say whether the type of surgical approach has any in-

fluence on the development of HO because we con- sidered the two groups similar regarding surgical ap- proach. During lateral and Watson-Jones approaches, we detach the anterior fibers of gluteus medius from the greater trochanter and retract it. It has been stated that ischemia of that muscle is the factor that increases the risk of HO (1, 11). Trauma to the muscle is similar in both approaches in our practice. Although we accept the possibility of se- lection bias, the aim of the study was not focused on the type of surgical approach and use of cement.

Generally, it is accepted that grade I and grade II HO is benign and that grade III and grade IV HO adversely affect the functional result (19, 21, 23). The incidence of HO associated with functional im- pairment is reported to be 3 - 1 0 % (4, l 1, 14, 18, 22).

In the present study, indomethacin treatment for the first 4 postoperative weeks definitely prevented grade III HO. Although we did not evaluate the pa- tients clinically, it can be said that the drug prevented some amount of functional impairment in almost 30% of the cases. The incidence of grade I HO in the indomethacin-treated and comparison groups (31% vs. 3%) is worth mentioning. From these data, it seems reasonable to speculate that indomethacin prevented grade I heterotopic bone formation from progressing to grade III, rather than preventing HO completely. Almasbakk and Roysland (2) also re- ported the drug to be effective in decreasing the in- cidence of "high-grade" HO.

Table 3. Comparison of Groups Treated With and Without Indomethacin, According to Surgical Approach, Indication, and Use of Cement

S u r g i c a l

A p p r o a c h I n d i c a t i o n C e m e n t

C e - C e m e n t - G r a d e o f H O L a t e r a l W J P C R A J R A A S A v N F N F T A T H D + A F C D H m e n t e d l e s s

G r o u p l n = 2 8 n = 1 n = 1 4 n = 2 n = 1 n = 3 n = 4 n = 2 n = 1 n = 1 n = 1 n ~ 2 n = 2 7 ( i n d o m e t h a c i n )

0 19 1 12 1 1 1 2 1 1 1 - - 1 19 I 9 - - 2 1 - - 2 2 1 - - - - 1 I 8

G r o u p 2 n = 6 n = 2 1 n ~ 2 0 n = 2 n = 2 n = 2 n = 1 n = 11 n ~ 16 ( c o m p a r i s o n )

0 4 l l l l 1 2 1 - - 4 11 I - - i 1 - - - - - - II 1 2 2 1 - - - -

- - 3 - - III 1 7 6 - - - - 1 1 3 5

H O ; H e t e r o t o p i c o s s i f i c a t i o n ; W J ; W a t s o n - J o n e s ; PC; p r i m a r y c o x a r t h r o s i s ; RA; r h e u m a t o i d a r t h r i t i s ; J R A ; j u v e n i l e r h e u m a t o i d a r t h r i t i s ; A S ; a n k y l o s i n g s p o n d y l i f i s ; A v N ; a v a s c u l a r n e c r o s i s ; F N F ; f e m o r a l n e c k f r a c t u r e ; TA; s e q u e l a o f t u b e r c u l o u s a r t h r i t i s ; T H D + A F ; o l d t r a u m a t i c h i p d i s l o c . + a c e t a b u l a r fracture; e H D ; c o n g e n i t a l d i s l o c a t i o n o f h i p .

60 The Journal of Arthroplasty Vol. 7 No. 1 March 1992

Similarly, Ritter (15, 16) found that, after 6 weeks of indomethacin treatment, 11% had grade I HO and none had more severe grades. More recently, Schmidt et al. (21) obtained similar results. These results tally with ours. Kjaersgaard-Andersen and Schmidt (10) found that indomethacin prevented HO in 75% of patients w h o had developed "high- grade" HO after previous contralateral total hip ar- throplasty. They also concluded that indomethacin decreased the n um ber of severe cases of HO but did not prevent the milder ones. In a similar study, So- demann et al. (23) found that widespread HO oc- curred in 14 of 38 untreated total hip arthroplasties, but was not found after total hip arthroplasty on the side treated with indomethacin or ibuprofen.

A review of the literature reveals that indometh- acin appears to be the bes t -examined drug against HO after hip arthroplasty. In a small placebo-con- trolled study, ibuprofen was also shown to be effec- tive (8). Comparat ive studies with NSAIDs are very few. In the study of Sodemann et al. (23) no differ- ence in efficacy be tween indomethacin and ibupro- fen was detected. In an experimental study, indo- methacin and diclofenac inhibited HO to an equal extent (12). These studies support the assumption that the inhibitory effect by NSAIDs on HO is most probably caused by their ability to inhibit the for- mat ion of prostaglandins, as is c o m m o n for all drugs in this group. It is generally r ecommended that in-

1. domethacin t reatment be started on the first post- operative day and cont inued for 3 - 6 weeks (5, 15, 16, 23). The r ecommended doses are 25 mg orally 2. three times daily, 75 mg orally once daily, or 50 mg orally twice daily. In our study the drug was given for 4 weeks. The results of Sodemann et al. (23) in- 3. dicated that 3 weeks of postoperative t reatment was as effective as longer periods of treatment. They added that the t reatment period could be shortened even further. Freeman recently stated that 2 days of 4. t reatment was adequate (personal communicat ion) . If indomethacin and diclofenac inhibit HO to an equal extent, as concluded f rom an experimental study (12), then 2 days of t reatment is not adequate 5. because all the patients in our comparison group were given diclofenac for 5 to 10 days. Thus, there should not have been any "h igh-grade" HO in our 6. comparison group. Again, it may be that 2 days of indomethacin t reatment is adequate but a t reatment period of more than 10 days, and perhaps~ at leas, t 3 . . . . . 7. weeks, is necessary for diclofenac. However, th is ' cannot be concluded f rom our study. In our opinion NSAIDs should be further investigated for m i n i m u m daily and total doses necessary for adequate effect.

Besides the we l l -known adverse effects of NSAIDs, two possible drawbacks of such t reatment should be

borne in mind. First, the use of such drugs, especially in cementless total hip arthroplasty, theoretically may delay or abolish the ingrowth of bone into the components . However, no clinical information as re- gards their effects on loosening can be obtained f rom the literature at the present time. Second, it should be remembered that NSAIDs may interact with oth- ers such as dicumarol and heparin, which are fre- quently given for prophylaxis against deep-venous thrombosis. It is evident that t rea tment with NSAIDs should be shortened as much as possible.

In conclusion, this study has shown that 4 weeks of t reatment with indomethacin is effective for the prevent ion of severe grades of HO following total hip arthroplasty. Whether less than 3 weeks of admin- istration will suffice or not is debatable at the present time. The risk of gastrointestinal bleeding should be borne in mind even though the rate of this compli- cation seems not to be very high. Based on our re- sults, we recommend the routine use of indometh- acin for the prevent ion of HO after total hip arthroplasty, provided that the patient is not at risk for gastrointestinal bleeding.

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