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SECTION I: SYMPOSIUM: Papers Presented at the 2006 Meeting of the Knee Society

Does Celecoxib Have an Adverse Effect on Bone Remodeling and Ingrowth in Humans?

Hofmann, Aaron, A; Bloebaum, Roy, D; Koller, Karyn, E; Lahav, Amit

Section Editor(s): Laskin, Richard S MD, Guest Editor

Author Information
Clinical Orthopaedics and Related Research: November 2006 - Volume 452 - Issue - p 200-204
doi: 10.1097/01.blo.0000238838.18799.61

Abstract

Despite the recent recall of some COX-2 inhibitors such as rofecoxib, celecoxib remains widely available to orthopaedic surgeons and anesthesiologists for the treatment of chronic and acute orthopaedic conditions, such as in total joint arthroplasty (TJA),2,16 to inhibit inflammation. Celecoxib seems an effective perioperative analgesic17 and has been associated with reduced hospital stays.15,16,19,21 Mallory et al16 stated a multimodal approach to pain relief included the use of patient-controlled analgesia and peri-operative antiinflammatory drugs in patients having total joint arthroplasties. Providing perioperative patient comfort while achieving and maintaining consistent skeletal attachment of orthopaedic devices to the human skeleton through bone ingrowth remains a primary goal in total joint arthroplasty.

Previous studies using a rabbit model and traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) showed ibuprofen adversely affects the bone remodeling and ingrowth into porous-coated devices.20 However, a recent study by Goodman et al12 suggested a COX-2 selective NSAID (rofecoxib) did not adversely affect bone remodeling when administered for a short period in a rabbit model. Nonetheless, the literature contains contradictory data from other animal studies showing COX-2 inhibitors may delay fracture healing and tendon healing.8,11 Despite these contrasting studies, the effects of COX-2 inhibitors on human cancellous bone and bone ingrowth into porous coatings remain largely unknown.18

Hofmann et al14 previously described a human bilateral total knee model to better understand the human cancellous bone response to the presence of porous-coated implant materials. These data suggest human cancellous bone requires 6 to 9 months to achieve maximum skeletal ingrowth.3,4,6,14 The bilateral total knee arthroplasty (TKA) model also showed the remodeling rate demonstrated a regional acceleratory phenomenon9 at the interface of porous-coated devices (1 μm/day) compared to the host bone 3 mm from the interface (0.8 μm/day).4 These fundamental data have helped establish the baseline for comparing the effects of pharmaceuticals and materials on human cancellous bone ingrowth, skeletal attachment on the mineral apposition rates for bone at the interface, and formation 3 mm from the implant surface.

We first hypothesized there would be a higher MAR at the interface of the plugs when compared to the MAR in the remote cancellous bone based on the interface regional acceleratory phenomenon reported in previous studies.4,14 Our second hypothesis presumed there would be a higher MAR in the control (time zero) resected cancellous bone before administration of a COX-2 drug at the first total knee surgery when compared to the MAR in same patient's resected cancellous bone resected during the second staged total knee arthroplasty surgery. The rationale behind the second hypothesis was if celecoxib had an adverse effect, the MAR would be lower following administration. Thirdly, we hypothesized there would be no difference in the amount of bone incorporated into the two plug types after 12 weeks in-situ.

MATERIALS AND METHODS

We quantified and compared the mineral apposition rates (MAR) of the bone in different regions and measure the bone ingrowth into two different plug types in bilateral total knee patients13 taking a COX-2 inhibitor (celecoxib) as part of a perioperative pain relief protocol.16 To ensure there would be no increased risk of implant loosening if the study outcome showed celecoxib has a negative effect on bone ingrowth, only candidates for cemented total knee implants were enrolled in this study. Appropriate Institutional Review Board (IRB) approval was obtained before the initiation of the study.

Ten patients scheduled for staged cemented bilateral TKAs to be performed by the senior author (AAH) at the Veterans Administration Medical Center, Salt Lake City, UT were invited to participate in this study to evaluate the effect of celecoxib on bone remodeling and ingrowth into porous-coated titanium and pure tantalum implants. One of these patients could not be enrolled due to lack of medical clearance. The other nine patients gave consent to a designated research coordinator. Nine patients were prospectively enrolled while they were scheduled for staged cemented bilateral total knee arthroplasties. This patient sample size was estimated based on a power analysis executed using previously published data on porous coated plugs.4 The level of significance was set at α = 0.05 and power at β = 0.80 for this analysis, to account for variation within 80% of the population.

All patients in this study had a primary diagnosis of osteoarthritis (OA). Because of the predominant male population in this VA study cohort, female patients were excluded from the study. This allowed for age-matched (66 ± 10 years, range 52 to 80 years) male patients for comparison to historical data.4,14 The average patient weight was 101.7 ± 16.5 kgs, range 78.0 to 122 kilograms. Medical history criteria for exclusion included osteoporosis, known hypersensitivity to celecoxib, demonstrated allergic-type reactions to oxytetracycline and sulfonamides, and asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Patients with a history of peptic ulcer disease or duodenal ulcers also were excluded from the study. Additionally, patients diagnosed with unstable hypertension or hypotension, serum creatine levels above 1.8 (may be indicative of compromised kidney function), or severe renal disease were excluded. Patients with coronary artery bypass grafting or major cardiac morbidities also were excluded.2 To eliminate potential confounding concomitant medications that may mask the effects of celecoxib and/or influence bone remolding, patients taking steroids, aspirin, warfarin, or other anti-inflammatory medications were not included in the study. Patient medical records were reviewed for history relevant to the knee, diagnosis, age, smoking habit, and antiinflammatory and/or pain medication use. Additionally, during their preoperative evaluation, patients were informed of the study protocol, objectives, and risks.

The knee receiving the first TKA and the subsequent staged second TKA (contralateral knee) were determined in a random manner by coin toss. A 12-week recovery period was used because it allows for adequate rehabilitation time after total joint arthroplasty and enough ambulation for optimal recovery before the second surgery. All joint arthroplasties were performed under the supervision of the senior author (AAH) using standard procedures with the Natural-Knee (Zimmer, Warsaw, IN) prostheses.

Patients were required to take tetracycline before the first total knee arthroplasty to establish each patient's preoperative bone mineral apposition rate (MAR). The purpose of the tetracycline was to label the bone so the mineral uptake of the bone could be measured and provide information about the growth of the bone. After the first surgery, fluorochrome double-labeling techniques were used to measure the thickness of new bone growth in the interface regions of the plugs and in the remote bone 3 mm from the plug interface. This entailed three oral doses (250 mg each) of tetracycline three times a day for 3 days, 23 days before surgery (Days 23, 22, 21) and was repeated seven days before surgery (Days 7, 6, 5) with the same regimen.4 To establish the bone remodeling rate after COX-2 inhibitor treatment, 23 days before the second total knee arthroplasty (Days 23, 22, 21), the patient repeated the tetracycline regimen of three oral doses, three times a day for 3 days, and repeated the regimen again seven days before the second surgery (Days 7, 6, 5).4 Twelve hours before the first total knee surgery, patients took an oral dose of celecoxib (400 mg). After the first total knee surgery, the patients continued taking oral doses of celecoxib (200 mg) every 12 hours for 2 weeks.16

During the first total knee arthroplasty, two small plugs were implanted. One plug was constructed of commercially available pure titanium 8 mm long by 5 mm diameter with 55% porosity, and the other was constructed of commercially available pure tantalum 8 mm long by 5 mm diameter with 80% porosity. These plugs were placed in the resected medial aspect of the femoral condyle of the distal femur as controls, then submitted for processing (Fig 1). This resected section provided the “time zero” data for comparison to test the first and second hypotheses. A second set of plugs was placed in the weightbearing region of the contralateral medial femoral condyle through a small incision. Explantation was planned for 12 weeks after the procedure, during the second total knee surgery. The bone in which the plugs were placed is usually resected and discarded according to the standard operating procedures for a total knee arthroplasty for femoral component placement, however these bone specimens containing plugs were submitted for processing and provided the time 12 week data.

Fig 1
Fig 1:
The distal resected femoral condyle showing two implanted porous coated plugs (titanium and tantalum) for control data at pre-COX-2 inhibitor administration (time zero).

The resected bone was fixed in 70% ethanol, and later dehydrated in ascending grades of ethanol, infiltrated and embedded in methylmethacrylate using standard techniques. The embedded bone specimens were sectioned vertically and approximately through the middle of both plugs with a custom, water-cooled, high-speed, cut-off saw5 with a diamond-edge blade (Rockazona, Peoria, AZ). The two sections then were ground and polished to an optical finish with a variable-speed grinding wheel (Buehler Inc, Lake Bluff, IL) using standard techniques. High-resolution contact radiographs were made of each section using a high-resolution film (Kodak S0253; Eastman Kodak, Rochester, NY) at 55 kV, 3 mA for 5 minutes in a radiography cabinet (Faxitron 43855A, Wheeling, IL). The sections were sputter-coated with a conductive layer of gold for approximately 90 seconds (Hummer VI-A; Anatech, Alexandria, VA). The sections were examined using a scanning electron microscope (JSM 6100; JEOL Inc, Peabody, MA) equipped with a backscattered electron (BSE) detector (Tetra, Oxford Instruments Ltd, Buckinghamshire, UK) and associated image capture software (ISIS 300 series, Oxford Instruments Ltd). The operating conditions of the scanning electron microscope were set at 15 mm working distance, 20 kV accelerating voltage, and -0.7 nA probe current. Digital BSE images were captured at a magnification of 100× with a resolution of 512 × 416 pixels and 8 bits/pixel (256 distinct gray levels). The entire length of the plugs was imaged. The sections then were ground to expose a new level of bone and plugs, repolished, and imaged as previously described to make a total of four levels analyzed. The images were analyzed using a semiautomated image analysis system (ISIS 300 series, Oxford Instruments, Ltd). The area (μm2) occupied by bone impaction or ingrowth into the two plug types was measured. This protocol tested the third hypothesis.

After the bone area images were obtained, the specimens were subsequently attached to plastic slides (Wasatch HistoConsultants, Winnemucca, NV), ground and polished to a thickness of approximately 0.50 μm, and viewed at 250× under a mercury lamp (Nikon, Denver, CO) microscope for evidence of fluoro-chrome double-labeled trabeculae of bone that had grown into the plug constructs and at the remote bone region 3 mm away. This comparison tested the first and second hypotheses. The width of the bone layer at the surface of the trabeculae was found by measuring the distance between parallel fluorescent tetracycline labels.10

The MAR and area measurements were averaged to obtain a single regional value per patient (n = 9) for both periods (time zero and 12 weeks), both plug types (titanium and tantalum), and for the impacted bone (time zero) or bone ingrowth (12 weeks) and the region 3 mm from the interface. Because the MAR and area values were normally distributed, differences between the means were compared using independent sample t tests. The p values were adjusted for multiple comparisons using Hochberg's multiple procedure, which controls the type I error without the need to first test the global hypothesis with ANOVA.1,23 All reported p values for these comparisons represent multiple comparison adjusted p values. Differences were considered significant at a p value < 0.05. All calculations were performed using Stata v. 8.0 (Stata Corporation, College Station, TX).

RESULTS

The MAR measured at 12 weeks was higher (p = 0.029) in the bone ingrown into the titanium plug (0.97 ± 0.108 μm/day) than the MAR in the remote bone 3 mm from the interface (0.793 ± 0.163 μm/day). The MAR measured at 12 weeks was higher (p = 0.013) in the bone ingrown into the tantalum plug (1.15 ± 0.41 μm/day) than the MAR in the bone 3 mm from the interface (0.793 ± 0.163 μm/day). The titanium bone ingrowth and the tantalum bone ingrowth showed similar results. There was an increase in the MAR of the bone ingrown after 12 weeks when compared to the remote bone 3 mm from the interface. This increase in the MAR from the remote bone 3 mm away when compared to the bone ingrown into both plug types demonstrated a regional acceleratory phenomenon and supported the first hypothesis that there would be a difference in the MAR between these two regions (Table 1, Fig 2).

Fig 2
Fig 2:
The graph illustrates a higher MAR at the interface of both plugs (titanium and tantalum) at the 12 week time period as tested by hypothesis 1 which was based on the regional acceleratory phenomenon.
TABLE 1
TABLE 1:
MAR Data Showing Difference Between Compared Regions

The baseline MAR at time zero was 0.641 ± 0.098 μm/day in the remote bone 3 mm from the interface and increased (p = 0.049) to 0.793 ± 0.163 μm/day at 12 weeks in the bone 3 mm from the interface. The MAR at 12 weeks was higher (p = 0.0002) in the bone ingrown into the titanium plug (0.97 ± 0.108 μm/day) than the MAR of the bone impacted into the time zero titanium plug (0.626 ± 0.138 μm/day). The MAR at 12 weeks was higher (p = 0.033) in the bone ingrown into the tantalum plug (1.15 ± 0.41 μm/day) than the MAR of the bone impacted into the time zero tantalum plug (0.678 ± 0.167 μm/day). This increased the amount and the rate of bone formation at 12 weeks into both plugs, showing no apparent effect of celecoxib on the bone response. This disproved the second hypothesis that there would be an effect on bone formation after perioperative celecoxib administration (Table 2, Fig 3).

Fig 3
Fig 3:
The graph of the MAR data shows increases in each region (bone 3 mm from the interface, titanium and tantalum plugs) 12 weeks after implantation. This increase disproves hypothesis 3 and shows there was no apparent effect on bone formation after celecoxib administration.
TABLE 2
TABLE 2:
MAR Data Comparing MAR Rates Prior to Celecoxib Administration and MAR Rates Following Primary TKA and Celecoxib Administration

The amount of bone impacted at time zero was lower (p = 0.0007) in the titanium plug (360.1 ± 121.9 μm2) than the amount of bone ingrown into the titanium plug (885.7 ± 238.4 μm2) at 12 weeks. The amount of bone impacted at time zero was lower (p = 0.49) in the tantalum plug (495.4 ± 152.8 μm2) than the amount of bone ingrown into the tantalum plug (631.9 ± 532.6 μm2) at 12 weeks. This showed the amount of true ingrown bone versus bone that is mechanically driven into the coating. We found no difference at 12 weeks between the amount of bone that had ingrown into the titanium plug (885.7 ± 238.4 μm2) when compared to the amount of bone that had ingrown into the tantalum plug (631.9 ± 532.6 μm2). This finding supported the third hypothesis that there would be no difference in the amount of bone ingrown into the two plug types after 12 weeks in situ (Fig 4).

Fig 4
Fig 4:
The graph shows no difference (p > 0.05) in bone ingrowth between the two plug types (titanium and tantalum) at 12 weeks as predicted by hypothesis 3.

DISCUSSION

The short-term perioperative use of celecoxib for pain did not seem to affect the bone remodeling and ingrowth processes into the load-bearing porous-coated plugs.22 The results supported the findings of Goodman et al,12 using the rabbit model and previous clinical studies,17 that shortterm use of COX-2 inhibitors does not affect bone healing.

The limitations of our study include the sex specific (male) population and limited age range of the patients. The data suggest perioperative celecoxib in the doses used did not affect bone remodeling in either the remote or interface bone in this study and did not affect bone ingrowth into the porous coated plugs

Assessing the patient's MAR at the time of the first TKA (time zero) allowed for a direct comparison to the rate of bone remodeling within each patient at the time of the second TKA and following the administration of celecoxib. This unique clinical experimental design was helpful in confirming the bone formation (MAR) and bone ingrowth results were not adversely affected by the shortterm administration of celecoxib in this unique patient population.

The bone ingrowth measurements confirmed there were no differences in the amount of bone in each type of porous coating. The tantalum porous coating seemed to interconnect better with the cancellous bone at the initial implantation (time zero) when compared to the titanium porous coating. This phenomenon has been described by other investigators7 as a “Velcro effect” at the time of insertion owing to the tantalum coating having a porous structure that protrudes and penetrates deeper into the bone.

The bilateral TKA model4,14 continues to provide information on the differences in remodeling at the implant-bone interface in human cancellous bone compared to the remote bone region 3 mm from the interface. The results of this investigation continue to support the previous findings that the time zero impacted bone was lower than the progression of bone growth into porous coatings after 12 weeks in situ.14 The MAR data of the bone in the implant interface region support the concept of a regional acceleratory phenomenon9 attributable to the operative trauma and the presence of load-bearing implants. The MAR data suggested strategies targeting the healing bone response at the interface region of the bone at the implant interface may help promote skeletal attachment of cementless implants.

Careful patient selection criteria were important in this study design. The decision to use patients who were eligible for cemented TKA was essential. Compromised skeletal fixation caused by arresting or altering the bone response through administration of celecoxib in cementless TKA was avoided. The investigators advise celecoxib be used in accordance with the guidelines reported by Bhattacharyya and Smith.2

Acknowledgments

The authors thank Bettina Willie, PhD, Ryan M. Moore, Richard Tyler Epperson, Tanya Hanberg, Amie Tanner, Thomas M. Cook, DO, and Michael P. Bolognesi, MD of the Bone and Joint Research Laboratory, Salt Lake City, UT, for their valuable contributions to this research.

References

1. Aickin M, Gensler H. Adjusting for multiple testing when reporting research results: the Bonferroni vs Holm methods. Am J Public Health. 1996;86:726-729.
2. Bhattacharyya T, Smith RM. Cardiovascular risks of coxibs: the orthopaedic perspective. J Bone Joint Surg Am. 2005;87:245-246.
3. Bloebaum RD, Bachus KN, Jensen JW, Scott DF, Hofmann AA. Porous-coated metal-backed patellar components in total knee replacement. J Bone Joint Surg Am. 1998;80:518-528.
4. Bloebaum RD, Bachus KN, Momberger NG, Hofmann AA. Mineral apposition rates of human cancellous bone at the interface of porous coated implants. J Biomed Mater Res. 1994;28:537-544.
5. Bloebaum RD, Merrell M, Gustke K, Simmons M. Retrieval analysis of a hydroxyapatite-coated hip prosthesis. Clin Orthop Relat Res. 1991;267:97-102.
6. Bloebaum RD, Mihalopoulus NL, Jensen JW, Dorr LD. Postmortem analysis of bone growth into porous-coated acetabular components. J Bone Joint Surg Am. 1997;79:1013-1022.
7. Bobyn JD, Poggie RA, Krygier JJ, Lewallen DG, Hanssen AD, Lewis RJ, Unger AS, O'Keefe TJ, Christie MJ, Nasser S, Wood JE, Stulberg SD, Tanzer M. Clinical validation of a structural porous tantalum biomaterial for adult reconstruction. J Bone Joint Surg Am. 2004;86(Suppl 2):123-129.
8. Dahners LE, Mullis BH. Effects of nonsteroidal anti-inflammatory drugs on bone formation and soft-tissue healing. J Am Acad Orthop Surg. 2004;12:139-143.
9. Frost HM. The regional acceleratory phenomenon: a review. Henry Ford Hosp Med J. 1983;31:3-9.
10. Frost HM, Villanueva AR, Roth H, Stanisavljevic S. Tetracycline bone labeling. J New Drugs. 1961;206-216.
11. Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D, Einhorn TA. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res. 2003;21:670-675.
12. Goodman SB, Ma T, Mitsunaga L, Miyanishi K, Genovese MC, Smith RL. Temporal effects of a COX-2-selective NSAID on bone ingrowth. J Biomed Mater Res A. 2005;72:279-287.
13. Hofmann AA, Bachus KN, Bloebaum RD. Comparative study of human cancellous bone remodeling to titanium and hydroxyapatite coated implants. J Arthroplasty. 1993;8:157-166.
14. Hofmann AA, Bloebaum RD, Bachus KN. Progression of human bone ingrowth into porous-coated implants. Acta Orthop Scand. 1997;68:161-166.
15. Mallory TH, Lombardi AV Jr, Fada RA, Dodds KL. Anesthesia options: choices and caveats. Orthopedics. 2000;23:919-920.
16. Mallory TH, Lombardi AV Jr, Fada RA, Dodds KL, Adams JB. Pain management for joint arthroplasty: preemptive analgesia. J Arthroplasty. 2002;17:129-133.
17. Reuben SS, Ekman EF. The effect of cyclooxygenase-2 inhibition on analgesia and spinal fusion. J Bone Joint Surg Am. 2005;87: 536-542.
18. Seidenberg AB, An YH. Is there an inhibitory effect of COX-2 inhibitors on bone healing? Pharmacol Res. 2004;50:151-156.
19. Straube S, Derry S, McQuay HJ, Moore RA. Effect of preoperative Cox-II-selective NSAIDs (coxibs) on postoperative outcomes: a systematic review of randomized studies. Acta Anaesthesiol Scand. 2005;49:601-613.
20. Trancik T, Mills W, Vinson N. The effect of indomethacin, aspirin, and ibuprofen on bone ingrowth into a porous-coated implant. Clin Orthop Relat Res. 1989;249:113-121.
21. Williams-Russo P, Sharrock NE, Haas SB, Insall J, Windsor RE, Laskin RS, Ranawat CS, Go G, Ganz SB. Randomized trial of epidural versus general anesthesia: outcomes after primary total knee replacement. Clin Orthop Relat Res. 1996;331:199-208.
22. Willie B, Bloebaum R, Bireley W, Bachus K, Hofmann A. Determining relevance of a weight-bearing ovine model for bone ingrowth assessment. J Biomed Mater Res Part A. 2004;69:567-576.
23. Wright S. Adjusted p-values for simultaneous inference. Biometrics. 1992;48:1005-1013.
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