Arch Orthop Trauma Surg (1990) 109 : 224-226

Arhve°fOrthopaedic dTrauma Surgery © Spfinger-Verlag 1990

Flurbiprofen inhibits heterotopic bone formation in total hip arthroplasty V. Hoikka, T. S. Lindholm, and A. Eskola Department of Clinical Orthopedics, Orthopedic Hospital of the Invalid Foundation, Tenholantie 10, SF-00280 Helsinki 28, Finland

Summary. A double-blind prospective parallel group study c o m p a r i n g slow-release flurbiprofen with placebo in the control of ectopic b o n e f o r m a t i o n was carried out in 68 patients u n d e r g o i n g total hip arthroplasty. Eight weeks after surgery there was evidence, significant at the 1% level, that the incidence and extent of periarticular calcification was lower in the flurbiprofen group. A t an early phase, s e r u m calcium level d e c r e a s e d and after 8 weeks s e r u m alkaline p h o s p h a t a s e level increased m o r e in the placebo group than in the flurbiprofen group, indicating an effect of flurbiprofen on b o n e mineral m e t a b o lism. Six patients were withdrawn in each t r e a t m e n t group, four due to side effects in the flurbiprofen group and three due to side effects in the p l a c e b o group. Overall, five patients in each group r e p o r t e d side effects, the nature and severity of the side effects being very similar in each group. W e conclude that flurbiprofen is an efficient and safe drug in limiting ectopic b o n e f o r m a t i o n following total hip arthroplasty. H e t e r o t o p i c b o n e form a t i o n is a f r e q u e n t complication after total hip replacem e n t [1, 2, 4 - 6 , 8-16]. H e t e r o t o p i c b o n e reduces the extent of hip m o t i o n , reduction being m o r e evident in cases with extensive ectopic b o n e f o r m a t i o n a r o u n d the hip joint [3, 10, 11]. Various t r e a t m e n t regimens have b e e n p r o p o s e d for discouraging h e t e r o t o p i c b o n e formation. A n t i - i n f l a m m a t o r y agents such as i n d o m e t h a c i n and i b u p r o f e n have turned out effective [11, 12, 14]. Local irradiation also prevents ectopic b o n e f o r m a t i o n [4], but d i p h o s p h o n a t e s s e e m not be effective in this respect [15]. T h e aim of the p r e s e n t study was to assess the efficacy of flurbiprofen, a new a n t i - i n f l a m m a t o r y agent, in limiting h e t e r o t o p i c b o n e f o r m a t i o n , and to note the f r e q u e n c y and severity of any side effects of the treatment.

Patients and methods A double-blind prospective parallel group study comparing slowrelease flurbiprofen with placebo in the control of ectopic bone Offprint requests to: V. Hoikka

formation was carried out in 68 patients undergoing total hip arthroplasty. Patients were excluded if pregnant or lactating. Patients with a history of peptic ulceration, gastric bleeding, hepatic or renal disease, asthma or known allergy to nonsteroid anti-inflammatory agents were also excluded. The indication for the operation was primary or secondary osteoarthrosis of the hip joint (Table 1). In the flurbiprofen group there were 34 patients, 12 men and 22 women, with a mean age of 46 years (range 31-76 years). In the placebo group there were 34 patients, 15 men and 19 women, with a mean age of 52 years (range 22-80 years). At the operation the patient was laid on his or her side and the hip approached according to Hardinge [7] or posteriorly (in the cases of congenital dislocation of the hip joint). In the flurbiprofen group a cementless prosthesis was used in 33 cases and a cemented one in 1 case. In the placebo group a cementless prosthesis was used in 32 cases and a cemented prosthesis in t case. Patients with a cemented prosthesis were allowed full weight bearing from the 1st postoperative day; those with a cementless prosthesis were allowed full weight bearing 6 weeks to 3 months postoperatively, depending on the quality of bone and consolidation of the bone grafts or osteoplasties performed during the arthroplasty. Early active and passive mobilization of the operated hip was started on the 1st postoperative day. The patients left the hospital 10-21 days postoperatively.

Table 1. Indications for operation Flurbiprofen group Primary osteoarthrosis Secondary osteoarthrosis Congenital dislocation of the hip joint Perthes disease Posttraumatic Old tuberculous coxitis Old diphterium coxitis Old purulent coxitis Paraparesis spastica Multiple epiphyseal dysplasia Epiphyseolysis capitis femoris Coxa vara Revision arthroplasty

Placebo group

9

13

24 15 3 2 1 1

19 11 2 2

1 1 1

1

1 1 1 1

V. Hoikka et al.: Flurbiprofen inhibits heterotopic bone formation

225

Treatment was allocated using a single randomization list balanced in blocks of ten. In the event, 68 patients were documented during the study, 34 patients being assigned to each treatment group. Patients assigned flurbiprofen were given a single 200-rag sustained-release dose on the evening before surgery, on the evening after surgery, and then each morning for a period of 3 weeks. Patients assigned the placebo treatment followed an identical regimen with a matching placebo tablet. Before surgery, demographic data, disease history, and concurrent diseases were recorded. Radiological examination of the hip joint was carried out along with laboratory measurements of serum calcium, alkaline phosphatase and phosphate. Radiographs of the hip joint were taken prior to surgery and repeated at 8 weeks and 6 months. Laboratory measurements were performed before surgery, at day 3, and after 8 weeks. All side effects and reasons for withdrawal were recorded.

phytes, cysts, b o n e destruction), or duration of surgery. T h e flurbiprofen g r o u p had a lower incidence of periarticular calcification, with the pattern of frequencies towards the less severe end of the ordinal o u t c o m e scale (Table 2). A one degree of f r e e d o m test specific to the "displacement" hypothesis yielded a Z 2 statistic of 11.83, significant at the 0.1% level (obtained from a comparison of the fit of two generalized logistic regression models). D u r i n g the study, 12 patients were withdrawn f r o m treatment, 6 f r o m each group. In the flurbiprofen g r o u p four of the withdrawals were due to side effects (nausea, vomiting, s t o m a c h pain), and two patients did not receive any drug on the day of o p e r a t i o n or subsequently because of vomiting. In the p l a c e b o group, three of the withdrawals were due to side effects (nausea, vomiting, s t o m a c h pain, dizziness, headache), and a fourth patient was withdrawn after vomiting p r e v e n t e d administration of the trial drug. O n e patient was withdrawn on day 5 for t r e a t m e n t of p u l m o n a r y embolism, and one further patient died of cerebral infarction 12 days after surgery.

Statistical analys& The study was a simple parallel group study involving two treatments and was conducted in a single center. There were no clear covariates or blocking factors which needed incorporating into the analysis. Student's t test and the Z2 test were used in the statistical analyses.

Discussion Results

T h e r e were no statistically significant differences between the groups in age, sex, weight, height, o t h e r diseases or medication of the patients, duration or severity of the disease (joint space narrowing, sclerosis, osteo-

Table 2. Incidence of periarticular calcification

Periarticular calcification

None Faint Scattered Widespread

Number of hips (%) Flurbiprofen group

Placebo group

29 3 0 0

17 8 5 1

(90.6) (9.4) (0.0) (0.0)

Test of treatment homogeneity: Z 2

=

(54.8) (25.8) (16.1) (3.2)

11.39; df = 3; P < 0.01

T h e results of this study show that flurbiprofen is effective in preventing heterotopic b o n e f o r m a t i o n after total hip arthroplasty. In the placebo group, the incidence and extent of ectopic b o n e f o r m a t i o n was high, which is in accord with previous results [11, 12, 14]. In their study of 200 total hip replacements, Sodem a n n et al. [14] d e m o n s t r a t e d that i n d o m e t h a c i n and ibuprofen are effective in preventing h e t e r o t o p i c b o n e formation. T h e y also s h o w e d that the t r e a t m e n t is not effective if initiated later than the 5th postoperative day. In the present study the t r e a t m e n t was started on the evening before surgery. It was c o n t i n u e d for 3 weeks postoperatively, as was the t r e a t m e n t in the study of S o d e m a n n et al. [14]. Ritter and G i o e [11] and Ritter and Sieber [12] used i n d o m e t h a c i n t r e a t m e n t for 6 weeks postoperatively. Different approaches to the hip joint do not seem to have different effects on h e t e r o t o p i c b o n e f o r m a t i o n [9,

Table 3. Serum calcium, alkaline phosphatase, and phorphorus 3 days and 8 weeks after total hip arthroplasty Mean F Serum calcium (mmol/1)

BL d3 w8

2.31 - 0.17 0.07

Serum alkaline phosphatase (IU/1)

BL d3 w8

156 - 5 32

Serum phosphate (mmol/1)

BL d3 w8

1.10 0.16 - 0.01

N P 2.37 - 0.26 0.01 173 - 30 82 1.10 - 0.06 0.09

SD

F

P

22 20 17

24 21 20

22 20 17

24 21 20

22 20 17

24 21 20

F 0.11 0.14 0.11 36 47 46 0.15 0.94 0.13

P

Difference Pooled F-P SD

0.09 0.12 0.09

- 0.06 0.08 0.06

35 50 76 0.17 0.24 0.20

- 16 26 - 51 0.00 0.23 - 0.10

0.10 0.13 0.10 36 49 64 0.16 0.68 0.17

P < 0.05 < 0.05 NS NS NS < 0.05 NS NS NS

F, Flurbiprofen group; P, placebo group; BL, baseline; d3, difference between values at baseline and day 3; w8, difference between values at baseline and week 8; NS, not significant

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V. Hoikka et al.: Flurbiprofen inhibits heterotopic bone formation

14]. Technically demanding operation predisposes to ectopic bone formation, probably due to more extensive tissue trauma [8]. In the present study most of the cases were of secondary osteoarthrosis of the hip joint, and hence m a y be considered technically demanding and more prone to ectopic ossification. This was in fact the case in the placebo group, but in the flurbiprofen group only faint heterotopic bone formation was seen, showing the efficacy of flurbiprofen in preventing heterotopic bone formation even in these risk patients. In Ritter and Vaughan's study [10], ectopic ossification was first noted 6 weeks after total hip arthroplasty and in 96% of cases did not change in amount thereafter. In the present series heterotopic bone was seen on the radiographs 8 weeks after surgery and was similar in extent 6 months after operation. Hence, it is probable that although we followed the patients for only 6 months, the results we obtained can be considered reliable in respect of later outcome. The mechanism by which nonsteroid anti-inflammatory drugs prevent heterotopic bone formation is unknown. In the present study, laboratory data demonstrated significant differences between the treatment groups (Table 3). Serum calcium levels had dropped more in the placebo group than in the flurbiprofen group at day 3, but not after 8 weeks. Serum alkaline phosphatase did not show any difference between the groups at day 3, but its serum level was significantly m o r e increased in the placebo group than in the flurbiprofen group after 8 weeks. Changes in serum phosphate did not show any difference between the groups. These changes may explain the mechanism of heterotopic bone formation: at an early phase, calcium is mobilized from serum to bone (and perhaps to soft tissues of the operated hip as well), and thereafter new bone formation starts, shown by an increase in serum alkaline phosphatase. Flurbiprofen seems to inhibit these changes, thereby preventing ectopic bone formation in soft tissues. Side effects were similar in both groups, suggesting that fiurbiprofen is well tolerated. Mostly side effects were of gastrointestinal origin, including nausea and vomiting, and stomach pain. It is possible that most of these side effects were caused by the operation and drugs given to relieve postoperative pain, such as oxycodone hydrochloride. We conclude that 3 weeks' administration of flurbiprofen is an effective and safe treatment against hetero-

topic bone formation around the hip joint after total hip arthroplasty.

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