Drs Vasileiadis, Mavrogenis, Babis, and Papagelopoulos are from the First Department of Orthopedics, Dr Vlasis is from the Department of Anatomy, Athens University Medical School, and Dr Sioutis is from the Department of Physical Medicine and Rehabilitation, Asklipieion General Hospital, Voula, Athens, Greece.
The material presented in any Vindico Medical Education continuing education activity does not necessarily reflect the views and opinions of ORTHOPEDICS or Vindico Medical Education. Neither ORTHOPEDICS nor Vindico Medical Education nor the authors endorse or recommend any techniques, commercial products, or manufacturers. The authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or using any product.
Correspondence should be addressed to: George I. Vasileiadis, MD, First Department of Orthopedics, Athens University Medical School, ATTIKON University Hospital, 1 Rimini Str, 12462, Haidari, Athens, Greece (email@example.com).
Heterotopic ossification, sometimes referred to as ectopic ossification or heterotopic bone formation, is the formation of mature lamellar bone in nonosseous tissues and is a frequent complication following total hip arthroplasty (THA). The precise pathogenesis is unknown, but surgical trauma to soft tissue or bone appears to induce the process. It has been estimated that between a quarter and two-fifths of all patients undergoing elective THA will develop heterotopic ossification. For most of these patients, heterotopic ossification is mild to moderate in extent, but in a few cases it is severe.1 Risk factors for heterotopic ossification after THA include hypertrophic osteoarthritis,2 male sex,3 age older than 60 years,4 diffuse idiopathic skeletal hyperostosis,5 heterotopic ossification in the ipsilateral or contro-lateral hip,6 and ankylosing spondylitis.7 The most common and by far the most important symptom of severe heterotopic ossification (Brooker stages III and IV8) is the limitation of range of motion (ROM) of the involved joint.5
Two prophylactic therapy options exist for heterotopic ossification: irradiation of the surgical field and the use of nonsteroidal anti-inflammatory drugs (NSAIDs).7 A 1996 study suggested preoperative irradiation for the prevention of heterotopic ossification following THA to eliminate the discomfort and morbidity associated with conventional postoperative treatment.9 Of particular importance is the oncogenic risk imposed by radiation therapy. However, to our knowledge, no reports exist of neoplasms or cancers after hip radiation, even in larger doses, in series using it for heterotopic ossification prevention.
Several studies have provided evidence for the high efficacy of NSAIDs in preventing heterotopic ossification after THA.10 The beneficial action of NSAIDs for prophylaxis against heterotopic ossification is attributed to the inhibition of cyclooxygenase 2 (COX-2) enzyme, an inducible enzyme in the osteoblasts. COX-2 is the enzyme that catalyzes the first reaction of arachidonic acid toward prostaglandin formation. The increased concentration of prostaglandins, especially PGE2, results in new bone matrix production and thus in heterotopic ossification formation.11 These prostaglandins are also responsible for inflammation and pain.12 Concurrently, prostaglandins’ synthesis by cyclooxygenase 1 (COX-1), a constitutive enzyme, is inhibited when conventional NSAIDs are being ingested. These prostaglandins are among other functions responsible for maintenance and protection of the gastrointestinal tract. As a result of this inhibition, increased risk of serious side effects, most notably gastrointestinal,13 may occur with ingestion of conventional NSAIDs, even for only 1 week.14
According to the medical literature, the percentage of side effects for indomethacin, the gold standard regarding prophylaxis against heterotopic ossification after THA with NSAIDs, is 37%.15 Also, a matter of great concern is excessive wound bleeding after perioperative administration of conventional NSAIDs.16 These detrimental side effects warrant a search for the use of alternative drugs that block only the activity of COX-2. This would prevent heterotopic ossification formation after THA without having the well-recognized toxic effects related to COX-1 inhibition.
The goal of this review was to compare the effectiveness and side effects of the perioperative use of selective COX-2 inhibitors with those of conventional NSAIDs in patients undergoing THA. The preference of selective COX-2 inhibitors may be crucial for these patients with a history of gastrointestinal problems.
Materials and Methods
We identified all studies published until April 2009 using the review’s inclusion criteria and the updated method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group.17 The selected studies passed methodological quality assessment based on the Cochrane Bone, Joint and Muscle Trauma Group score for reporting of methodological quality.
Criteria for Studies in This Review
All randomized controlled trials comparing selective COX-2 inhibitors with NSAIDs for patients undergoing primary or revision THA were eligible for this review. All trials were considered regardless the language of publication. The intervention under investigation was “any NSAID at any dose” vs “a selective COX-2 inhibitor.” The primary outcome measure was the development of heterotopic ossification as verified radiologically using the Brooker grade for heterotopic ossification of the hip.8 A binary system (heterotopic ossification present or absent) was used where the Brooker scale was not used to assess the outcome. The last recorded radiological measurement was used in the analysis. Data were also sought in the secondary outcome measures of late postoperative pain, decreased ROM and physical disability, death from any cause, cerebral infarction or stroke of unknown cause, cerebral hemorrhage, deep vein thrombosis, pulmonary embolism, hematemesis or melena, excessive bleeding from the wound or drainage site, evacuation of hematoma, postoperative bleeding requiring transfusion, and gastrointestinal complications.
Search Methods for Study Identification
We performed a computer-aided search of the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases. The identification of studies to be included in this review was done using the following search strategy: (prophylaxis OR prevention OR inhibition OR prevents OR inhibits OR prevent OR inhibit) AND heterotopic ossification AND NSAIDs AND (cyclooxygenase 2 inhibitors OR COX-2 inhibitors OR COX-2 inhibitor OR celecoxib OR rofecoxib OR valdecoxib) AND (total hip arthroplasty OR total hip replacement).
Three reviewers (G.V., I.S., A.F.M.) assessed the methodological quality of the studies included in this review. The generic scheme together with the basic scoring criteria that was followed is given in The Cochrane Library 2007, Issue 4. All criteria were scored as yes, no, or unclear. The studies were considered to be of high quality if at least 6 criteria for internal validity, 3 descriptive criteria, and 1 statistical criterion were scored positively. The studies were considered to be of sufficient quality if at least 4 criteria for internal validity, 2 descriptive criteria, and 1 statistical criterion were met.
All citations identified by the search strategy were screened. Studies that conformed to the selection criteria were reviewed in detail, and if agreement occurred between the authors, all randomized controlled trials of a selective COX-2 inhibitor vs a conventional NSAID that reported the grade of postoperative heterotopic ossification at the hip were included. In case of disagreement not resolved by discussion, a fourth reviewer (P.J.P.) adjudicated. All data, including data on methodological quality, were collected independently by the 3 reviewers. Wherever possible, the published findings were confirmed and supplemented by communication with the principal study investigator. Information about randomized patients excluded from the published analyses was sought for inclusion in the analyses.
All analyses were conducted on dichotomous outcomes derived from tabular data. For each study, relative risks and 95% confidence intervals (CIs) were calculated and the results combined using a fixed effects model. These were displayed on forest plots. Heterogeneity between the results of both individual studies and, in the case of sensitivity analyses, between the results of combined trials were tested using a Cochran’s chi-square test.
Five publications were identified that met our inclusion criteria and had the methodological quality necessary for this review (Table 1).3,18–21 Eight studies were primarily identified but excluded from the review (Table 2).22–29 Studies by Macfarlane et al22 and Vuolteenaho et al23 were primarily identified; however, since only randomized controlled trials were included in the design of this review, both of these studies were excluded. Studies by Buvanendran et al24 and Franchin et al25 compared the effectiveness of rofecoxib with a placebo group. Since in the review we included only trials containing any NSAID at any dose vs a selective COX-2 inhibitor, these studies were also excluded.
Table 1: Included Studies
Table 2: Excluded Studies
Fijn et al26 addressed the prevention of heterotopic ossification after THA with NSAIDs. Barthel et al27 compared indomethacin and meloxicam, but meloxicam is not a COX-2 inhibitor, having partial COX-2 specificity.30 Vastel et al28 compared a selective COX-2 inhibitor and a conventional NSAID; however, total validity scoring was low (58.3%), and the study was completely inadequate in 5 out of 12 validity criteria, so it was excluded from the review, although the primary outcome is in accordance with that of the included trials. Finally, the computer-aided search of the Cochrane Central Register of Controlled Trials identified Persson et al’s29 comparative study of patients receiving ibuprofen. Since ibuprofen is not a COX-2 inhibitor, this study was also excluded.
Methodological Quality of Included Studies
The articles by Grohs et al,18 van der Heide et al,19 and Romanò et al21 are the highest evaluated articles (91.6%) regarding their methodological criteria. Saudan et al’s3 article was found to be of sufficient methodological quality (79.1%). In van der Heide et al’s20 second article, no major methodological statement was found, except the dosage and duration of the indomethacin group. This trial was found to be of sufficient methodological quality (62.5%) (Table 3).
Table 3: Methodological Quality of Included Studies
Evaluation of the Prophylactic Effect of Selective COX-2 Inhibitors on Heterotopic Ossification vs Conventional NSAIDs
In the 5 included studies, there was a nonsignificant 23% reduction (P=.150; 95% CI, 46%–10%) in the risk of heterotopic ossification among patients who were administered COX-2 inhibitors. Among these studies, there were marked differences in the size of the observed effects of COX-2 inhibitors on heterotopic ossification, which ranged between an increase of 54% and a reduction of 66% without statistically significant heterogeneity (P=.252).
Overall, in the studies included in this review, heterotopic ossification formed in 55 of 446 patients who received a selective COX-2 inhibitor treatment and in 102 of 615 who received treatment with conventional NSAIDs. The difference between the 2 treatments was not statistically significant (Figure 1).
Figure 1: Forest Plot of Ratios for Test Results from the Studies of COX-2 and NSAIDs Administration for Heterotopic Ossification Prevention. In the Studies Included in This Review, the Overall Difference Regarding Heterotopic Ossification Formation Was not Statistically Significant.
Evaluation of Discontinuation Due to Side Effects of Selective COX-2 Inhibitors vs Conventional NSAIDs
In all studies combined, there was a nonsignificant 30% decrease (P=.177, 95% CI, 58%–17%) in the risk of discontinuation due to side effects among patients who were administered COX-2 inhibitors. There was no statistically significant heterogeneity among the studies (P=.120).
Overall, in the studies included in this review, 23 of 450 patients who received prophylaxis against heterotopic ossification with a selective COX-2 inhibitor had to discontinue the prophylactic treatment due to side effects, compared to 41 of 615 patients who had prophylaxis with conventional NSAIDs. The difference between the 2 treatments was not statistically significant (Figure 2).
Figure 2: Forest Plot of Likelihood Ratios for Test Results from the Studies of COX-2 and NSAIDs Administration for Heterotopic Ossification Prevention Regarding Discontinuation of Treatment Due to Side Effects. In the Studies Included in This Review, the Overall Difference Regarding the Discontinuation of Prophylactic Treatment Due to Side Effects Was not Statistically Significant.
In this review, we examined the current literature about the preventive use of selective COX-2 inhibitors against heterotopic ossification formation after THA in comparison with that of conventional NSAIDs. From the literature search up to April 2009, five articles were considered to be of sufficient methodological quality and were included. In these articles, it appears that this new subcategory of NSAIDs is equally efficient with conventional NSAIDs. In addition, although this was found to be not statistically significant, the patients that were administered selective COX-2 inhibitors had fewer side effects. Selectivity for COX-2 inhibition can halve the risk of peptic ulceration without affecting the other side effects, most notably the increased danger of renal failure in older hypertensive patients, a population in which arthritis and hypertension are common comorbidities.31 However, one can argue that this may be attributed to the small number of trials performed. We acknowledge this and conclude that more studies are needed to come to a definite conclusion.
The danger of renal hypertension in combination with the imbalance that favors platelet aggregation, which results into thrombus formation from COX-2 inhibitors,32 calls their safety into question. However, the increased incidence of cardiovascular and cardiorenal events associated with the use of rofecoxib or celecoxib becomes apparent only after 12 to 18 months of continuous treatment.33,34 Moreover, COX-2 inhibitors appear to result in less perioperative blood loss in comparison with blood loss associated with the use of indomethacin.16 This is particularly important in patients undergoing major surgical operations such as THA where prophylaxis for deep vein thrombosis is implemented as a rule for 5 to 6 weeks postoperatively. In the studies included in this review, none of the patients treated with a COX-2 inhibitor presented bleeding as a complication. On the contrary, in the study by Romanò et al,21 four patients who were administered indomethacin had to discontinue the prophylactic treatment due to excessive bleeding. In the included studies, none of the patients had to stop the treatment due to hypertension or other vascular side effect, complications that are feared when selective COX-2 inhibitors are prescribed. However, this may be attributed to the short-term use of the drug (eg, 7 days in van der Heide et al19,20 and Grohs et al,18 10 days in Saudan et al,3 and 20 days in Romanò et al21).
Based on our findings, selective COX-2 inhibitors play a role in the prevention of heterotopic ossification. However, they do not prevent heterotopic ossification statistically significantly better than conventional NSAIDs. In addition, when selective COX-2 inhibitors are used, there is a tendency toward a lower rate of side effects that would lead to the discontinuation of the prophylactic measurements against the appearance of heterotopic ossification after THA; however, this has also been found not statistically significant compared to conventional NSAIDs, and moreover, it can be attributed to the short duration of the time needed to treat patients undergoing THA. Due to the small number of clinical studies, the effects and side effects of selective COX-2 inhibitors need to be proved in a large-scale review to determine the balance of benefits and risks for all outcomes and to draw a firm conclusion.
- Neal B, Gray H, McMahon S, Dunn L. Incidence of heterotopic ossification after major hip surgery. ANZ J Surg. 2002; 72(11):808–821. doi:10.1046/j.1445-2197.2002.02549.x [CrossRef]
- Goel A, Sharp DJ. Heterotopic bone formation after hip replacement. The influence of the type of osteoarthritis. J Bone Joint Surg Br. 1991; 73(2):255–257.
- Saudan M, Saudan P, Perneger T, Riand N, Keller A, Hoffmeyer P. Celecoxib versus ibuprofen in the prevention of heterotopic ossification following total hip replacement: a prospective randomised trial. J Bone Joint Surg Br. 2007; 89(2):155–159. doi:10.1302/0301-620X.89B2.17747 [CrossRef]
- Ahrengart L, Lindgren U. Heterotopic bone after hip arthroplasty. Defining the patient at risk. Clin Orthop Relat Res. 1993; (293):153–159.
- Naraghi FF, DeCoster TA, Moneim MS, Miller RA, Rivero D. Heterotopic ossification. Orthopedics. 1996; 19(2):145–151.
- Sodemann B, Persson PE, Nilsson OS. Periarticular heterotopic ossification after total hip arthroplasty for primary coxarthrosis. Clin Orthop Relat Res. 1988; (237):150–157.
- Kjaersgaard-Andersen P, Ritter MA. Prevention of formation of heterotopic bone after total hip arthroplasty. J Bone Joint Surg Am. 1991; 73(6): 942–947.
- Brooker AF, Bowerman JW, Robinson RA, Riley LH Jr, . Ectopic ossification following total hip replacement. Incidence and a method of classification. J Bone Joint Surg Am. 1973; (558):1629–1632.
- Pellegrini VD Jr, Gregoritch SJ. Preoperative irradiation for prevention of heterotopic ossification following total hip arthroplasty. J Bone Joint Surg Am. 1996; 78(6):870–871.
- Fransen M, Neal B. Non-steroidal anti-inflammatory drugs for preventing heterotopic bone formation after hip arthroplasty. Cochrane Database Syst Rev. 2004; (3):CD001160.
- Raisz LG. Potential impact of selective cyclooxygenase-2 inhibitors on bone metabolism in health and disease. Am J Med. 2001; 110(Suppl 3A):43S–45S. doi:10.1016/S0002-9343(00)00684-7 [CrossRef]
- Kaplan-Machlis B, Klostermeyer BS. The cyclooxygenase-2 inhibitors: safety and effectiveness. Ann Pharmacother. 1999; 33(9):979–988. doi:10.1345/aph.18415 [CrossRef]
- Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999; 340(24):1888–1899. doi:10.1056/NEJM199906173402407 [CrossRef]
- van der Heide HJ, Koorevaar RT, Schreurs BW, van Kampen A, Lemmens A. Indomethacin for 3 days is not effective as prophylaxis for heterotopic ossification after primary total hip arthroplasty. J Arthroplasty. 1999; 14(7):796–799. doi:10.1016/S0883-5403(99)90027-X [CrossRef]
- Cella JP, Salvati EA, Sculco TP. Indomethacin for the prevention of heterotopic ossification following total hip arthroplasty. Effectiveness, contraindications, and adverse effects. J Arthroplasty. 1988; 3(3):229–234. doi:10.1016/S0883-5403(88)80020-2 [CrossRef]
- Weber EW, Slappendel R, Durieux ME, Dirksen R, van der Heide H, Spruit M. COX 2 selectivity of non-steroidal anti-inflammatory drugs and perioperative blood loss in hip surgery. A randomized comparison of indomethacin and meloxicam. Eur J Anaesthesiol. 2003; 20(12):963–966. doi:10.1097/00003643-200312000-00005 [CrossRef]
- van Tulder M, Furlan A, Bombardier C, Bouter LEditorial Board of the Cochrane Collaboration Back Review Group. Updated method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group. Spine (Phila Pa 1976). 2003; 28(12):1290–1299. doi:10.1097/01.BRS.0000065484.95996.AF [CrossRef]
- Grohs JG, Schmidt M, Wanivenhaus A. Selective COX-2 inhibitor versus indomethacin for the prevention of heterotopic ossification after hip replacement: a double-blind randomized trial of 100 patients with 1-year follow-up. Acta Orthop. 2007; 78(1):95–98. doi:10.1080/17453670610013484 [CrossRef]
- van der Heide HJ, Rijnberg WJ, Van Sorge A, Van Kampen A, Schreurs BW. Similar effects of rofecoxib and indomethacin on the incidence of heterotopic ossification after hip arthroplasty. Acta Orthop. 2007; 78(1):90–94. doi:10.1080/17453670610013475 [CrossRef]
- van der Heide HJ, Koorevaar RC, Lemmens JA, van Kampen A, Schreurs BW. Rofecoxib inhibits heterotopic ossification after total hip arthroplasty [published online ahead of print November 16, 2006]. Arch Orthop Trauma Surg. 2007; 127(7):557–561.
- Romanò CL, Duci D, Romanò D, Mazza M, Meani E. Celecoxib versus indomethacin in the prevention of heterotopic ossification fter total hip arthroplasty. J Arthroplasty. 2004; 19(1):14–18. doi:10.1016/S0883-5403(03)00279-1 [CrossRef]
- Macfarlane RJ, Ng BH, Gamie Z, et al. Pharmacological treatment of heterotopic ossification following hip and acetabular surgery. Expert Opin Pharmacother. 2008; 9(5):767–786. doi:10.1517/146565220.127.116.117 [CrossRef]
- Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process [published online ahead of print October 31, 2007]. Basic Clin Pharmacol Toxicol. 2008; 102(1):10–14.
- Buvanendran A, Kroin JS, Berger RA. Preoperative cyclooxygenase-2 inhibitor treatment reduces the incidence of heterotopic ossification after hip arthroplasty: six-month follow-up. Anesthesiology. 2007; 107(2):358–359. doi:10.1097/01.anes.0000271873.86164.74 [CrossRef]
- Franchin F, Sanguineti F, Caione G. Preliminary study of rofecoxib (25 mg) in prevention of heterotopic ossification after total hip replacement. J Orthop Traumatol. 2004; 5(2):77–80. doi:10.1007/s10195-004-0047-4 [CrossRef]
- Fijn R, Koorevaar RT, Brouwers JR. Prevention of heterotopic ossification after total hip replacement with NSAIDs. Pharm World Sci. 2003; 25(4):138–145. doi:10.1023/A:1024830213832 [CrossRef]
- Barthel T, Baumann B, Nöth U, Eulert J. Prophylaxis of heterotopic ossification after total hip arthroplasty: a prospective randomized study comparing indomethacin and meloxicam. Acta Orthop Scand. 2002; 73(6):611–614. doi:10.1080/000164702321039543 [CrossRef]
- Vastel L, Rosencher N, Siney H, Courpied JP. Prevention of heterotopic ossifications in hip arthroplasty: effectiveness of selective COX-2 inhibitors (celecoxib) versus ketoprofen [in French]. Rev Chir Orthop Reparatrice Appar Mot. 2005; 91(1):64–69.
- Persson PE, Nilsson OS, Berggren AM. Do non-steroidal anti-inflammatory drugs cause endoprosthetic loosening? A 10-year follow-up of a randomized trial on ibuprofen for prevention of heterotopic ossification after hip arthroplasty. Acta Orthop. 2005; 76(6):735–740. doi:10.1080/17453670510045309 [CrossRef]
- Van Hecken A, Schwartz JI, Depré M, et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol. 2000; 40(10):1109–1120.
- Whelton A, Fort JG, Puma JA, et al. Cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther. 2001; 8(2):85–95. doi:10.1097/00045391-200103000-00003 [CrossRef]
- Lipsky PE, Brooks P, Crofford LJ, et al. Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease. Arch Intern Med. 2000; 160(7):913–920. doi:10.1001/archinte.160.7.913 [CrossRef]
- Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial [published online ahead of print February 15, 2005]. N Engl J Med. 2005; 352(11):1092–1102. doi:10.1056/NEJMoa050493 [CrossRef]
- Oviedo JA, Schroy PC III, . Does celecoxib use increase the risk of cardiovascular events?Gastroenterology. 2005; 129(4):1348–1350. doi:10.1053/j.gastro.2005.08.029 [CrossRef]
|Saudan et al, 20073|
|Grohs et al, 200718|
|van der Heide et al, 200719|
|van der Heide et al, 200720|
|Romanò et al, 200421|
|Macfarlane et al, 200822|
|Vuolteenaho et al, 200823|
|Buvanendran et al, 200724|
|Franchin et al, 200425|
|Fijn et al, 200326|
|Barthel et al, 200227|
|Vastel et al, 200528|
|Persson et al, 200529|
Methodological Quality of Included Studiesa
|Saudan et al, 20073||Grohs et al, 200718||van der Heide et al, 200719||van der Heide et al, 200720||Romanó et al, 200421|