Serum Metal Ion Concentrations After Unilateral vs Bilateral Large-Head Metal-on-Metal Primary Total Hip Arthroplasty

The Journal of Arthroplasty Vol. 26 No. 8 2011

Serum Metal Ion Concentrations After Unilateral vs Bilateral Large-Head Metal-on-Metal Primary Total Hip Arthroplasty Christopher E. Pelt, MD, Adam G. Bergeson, MD, Lucas A. Anderson, MD, Gregory J. Stoddard, MPH, and Christopher L. Peters, MD

Abstract: It is unknown if the presence of bilateral well-functioning large-head metal-on-metal (MOM) total hip arthroplasties (THAs) leads to higher serum metal ion concentrations than unilateral MOM THA. Elevated levels (chromium, 17 μg/L; cobalt, 19 μg/L) have been associated with poorly functioning MOM THA with metallosis. Fourteen patients having undergone bilateral and 25 patients having undergone unilateral large-head primary MOM THA were compared. Harris Hip Scores, University of California Los Angeles activity scores, radiographs, serum creatinine, and serum cobalt and chromium levels were obtained. Only cobalt ion levels were significantly higher in the bilateral group than in the unilateral group (1.8 μg/L vs 1.0 μg/L, P = .029). Comparatively, this magnitude is clinically rather low because ion levels did not approach those associated with metallosis in either group. We conclude that although patients with well-functioning bilateral MOM THA may have slightly higher cobalt levels, neither cobalt nor chromium levels approach those seen in poorly functioning MOM THA with metallosis. Keywords: metal-on-metal, serum metal ions, total hip arthroplasty, cobalt, chromium. © 2011 Elsevier Inc. All rights reserved.

Metal-on-metal (MOM) total hip arthroplasty (THA) has been a popular alternative to metal on polyethylene in the search for an ideal bearing surface [1]. This alternative bearing, however, has been associated with increased serum and urine metal ion levels when compared with metal on polyethylene in patients [2-6]. Other specific concerns include delayed type hypersensitivity reactions, local tissue toxicity, immune system modulation, chromosomal abnormalities, and carcinogenicity [7-11]. Even in well-functioning MOM THA, increased steady-state levels of metal ions are detectable, although the level above which serum metal ion concentrations become clinically significant remains undefined [1218]. Increased serum ion levels are associated with painful or poorly functioning MOM THA and have been shown to be valuable as a diagnostic tool in the workup of painful MOM THA [19-21]. De Smet et al [19]

From the University of Utah Department of Orthopaedics, Utah. Submitted January 17, 2011; accepted March 24, 2011. The Conflict of Interest statement associated with this article can be found at doi: 10.1016/j.arth.2011.03.037. Reprint requests: Christopher L. Peters, MD, 590 Wakara Way, Salt Lake City, UT 84108. © 2011 Elsevier Inc. All rights reserved. 0883-5403/2608-0059$36.00/0 doi:10.1016/j.arth.2011.03.037

demonstrated that chromium ion levels above 17 μg/L and cobalt ion levels above 19 μg/L were associated with high joint fluid ion levels and metallosis. These values may represent levels at which clinical significance might be considered for serum metal ion concentrations. Multiple variables affect serum metal ion levels after MOM THA. Tribologic factors, such as increased sphericity, increased carbon content, decreased clearance, and surface roughness, have been shown to decrease wear and, therefore, presumably, serum metal ion levels [22,23]. Larger head size has also been shown to decrease wear and serum metal ion concentrations [18,24]. Recent studies have also highlighted the importance of optimizing component position to decrease failures in MOM articulations [18,24-28]. The effect of the presence of bilateral large-head MOM THA on circulating metal ions levels has not been thoroughly studied. Metal ion levels in patients with unilateral MOM vs bilateral MOM resurfacing and small-head THA have been reported [19]; however, to our knowledge, no study has investigated the differences in serum metal ion levels in unilateral vs bilateral largehead (≥38 mm) MOM THA. The objective of this study was to compare serum cobalt and chromium levels in patients who have undergone unilateral vs bilateral large-head MOM THA to better understand the effect of the presence of bilateral implants on circulating metal

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ion levels. We believe that further understanding baseline levels in well-functioning MOM THA will increase the clinical utility of checking serum metal ion levels in the workup of the painful MOM THA. Our hypothesis was that serum metal ion levels in patients with well-functioning bilateral large-head MOM THA would be higher than levels in patients with wellfunctioning unilateral large-head MOM THA, but these levels would not approach those seen with metallosis.

Materials and Methods Patients After institutional review board approval, a single surgeon's (CLP) prospective database was examined, and all patients who met criteria for inclusion in the study were contacted. Two groups were identified: the first group having undergone unilateral large-head (≥38 mm) primary MOM THA and the second having undergone bilateral large-head primary MOM THA. Patients were at least 18 years old, were at least 1 year out from their index procedure, and had well-positioned components. Patients with other metal implants, renal insufficiency (estimated creatinine clearance b30 mL/ min), component malpositioning (cup inclination angle N55°), evidence of osteolysis on radiographs, or a poorly functioning hip (Harris Hip Score [HHS] b70) were excluded. Patients were invited to attend dedicated clinics for a blood draw, radiographs, and clinical evaluation. Patients in both cohorts had cementless modular titanium alloy proximally porous-coated, tapered femoral stems (Biomet Taperloc or Bi-Metric; Biomet, Warsaw, Ind). Both MOM cohorts had cobalt-chromium (CoCr) nonmodular acetabular components with titanium plasma spray porous coating, and coverage angles that range from 157° to 167.2° (Biomet M2a and M2aMagnum; Biomet). Head sizes of 38 and 40 mm were solid cast CoCr with sphericity of less than 5 μm, radial clearance of 25 to 76 μm, and carbon content of 0.35%. Head sizes greater than 40 mm were modular cast CoCr with sphericity of less than 5 μm, radial clearance of 76152 μm, and carbon content of 0.35%. All surgeries were done between the years of 2003 and 2009. Serum Cobalt and Chromium Ion Levels All blood samples were obtained under the supervision of a trained research assistant. Blood was taken from antecubital veins using a disposable intravenous cannula (BD Vacutainer Push Button Blood Collection Set; BD Biosciences, Franklin Lakes, NJ) and collected in certified metal-free Vacutainers (BD Vacutainer Trace Element; BD Biosciences). To avoid contamination and to assist in determining baseline renal function, the first 5 to 10 mL of blood drawn was sent for basic metabolic profile (BD Vacutainer SST; BD Biosciences). Two tubes of blood (5-10 mL) were then collected for analysis. Blood was allowed to sit for 10 minutes and then

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centrifuged for 10 minutes at 3600 rpm (Hamilton Bell Vanguard V6500; Hamilton Bell Co. Inc., Montvale, NJ). Serum was then separated in an ARUP Trace ElementFree Transport Tube (ARUP Laboratories, Salt Lake City, Utah). All samples were then transported to the laboratory (ARUP Laboratories) for serum metal analysis. The final analysis of serum cobalt and chromium levels was performed by inductively coupled plasma/ mass spectrometry with a detection level of 0.1 μg /L. Blood Ion Level and Follow-Up Per a previously published protocol from our institution, 1 year was selected as the minimum time for follow-up because we sought to determine differences in steady-state serum ion levels, which result after an average running-in phase of 500 000 to 1 million cycles [24,29-31]. With an average of 2 million cycles per year in the typical THA, follow-up and ion level analysis performed around 1 year postoperatively should represent the steady state [32]. Clinical and Radiographic Analysis Standard radiographs including anteroposterior pelvis and groin lateral of both hips were evaluated for evidence of osteolysis, component migration, and acetabular component position. Acetabular component inclination was measured on the anteroposterior pelvis radiograph, and acetabular component anteversion, on the groin lateral radiograph. The presence of osteolysis was evaluated according to the Engh classification [33]. An HHS [14] for each hip that had undergone THA and the University of California Los Angeles (UCLA) activity score [12] were obtained at the time of followup by a member of the research team who was not the operating surgeon (LAA). The UCLA activity score was based on participation in the highest rated activity, regardless of the frequency or intensity of participation. Statistical Methods For patient characteristic variables, continuous variables were compared between the unilateral and bilateral groups using an independent samples t test. For skewed distributions, the comparison of continuous variables was made using a Wilcoxon-Mann-Whitney test (many statisticians now refer to the test by this name because the Wilcoxon rank sum test and the MannWhitney U test are essentially the same and give identical P values) [34]. For categorical variables, a χ2 or Fisher exact test, as appropriate, was used. Inclination angle and anteversion were measured by 2 independent readers (CEP, LAA) on standing anteroposterior and supine groin lateral radiographs, respectively. Interrater reliability was assessed using an intraclass correlation coefficient and found to be high (see “Results”), after which the 2 readers' measurements were combined into an average for data analysis.

1496 The Journal of Arthroplasty Vol. 26 No. 8 December 2011 The laboratory that tested the metal ion levels determined that the lower limit of accuracy of the assay was 1.0 μg/L or higher for both cobalt and chromium, despite a detection limit of 0.1 μg/L. A value of less than 1.0 μg/L was set to 1 μg/L for data analysis. This is consistent with the truncation approach to outliers [35]. This created a distribution for both the cobalt and chromium outcomes with approximately 50% having a score of 1, and then skewed to the right with values greater than 1 μg/L. Therefore, the metal ion data were analyzed with generalized γ regression, also called a generalized linear model with log link and γ family, which does not assume a normal distribution but is pliable to the shape of the observed distribution [36]. In the generalized γ regression multivariable models, potential confounders considered were age, sex, creatinine clearance, time to final follow-up, HHS, UCLA activity score, head size, inclination angle, and anteversion angle. Those potential confounders that had P b .25 when comparing the unilateral to the bilateral groups were put into the multivariable model. Variables were then removed in an interactive backward variable selection fashion if the variable did not change the regression coefficient on the primary variable of interest, the bilateral variable, by at least 10%. This approach is known as the change-in-estimate method of variable selection, and has been shown to produce more reliable models than variable selection methods based on statistical significance [37]. The generalized γ regression uses a natural logarithm transformation of the outcome variable. The interpretation is therefore reported as a percentage change or percentage increase in the average value of outcome per 1 unit increase in predictor, instead of absolute change [38].

increase attributable to bilateral implants was slightly higher, but again, this did not reach statistical significance (increase, 28%; 95% CI, −100% to 100%; P = .32). Neither cobalt nor chromium levels approached levels associated with metallosis (Fig. 1). With the exception of HHS, time to follow-up, and head size, patient characteristics were similar between groups (Table 1). No significant differences were detected when comparing age, sex, kidney function, UCLA activity score, inclination angle, and anteversion angle between bilateral and unilateral groups (Table 1). Harris Hip Scores were significantly higher (P = .013) in the bilateral group (median, 100; range, 86-100) when the minimum of left and right HHS was compared with unilateral HHS (median, 99; range, 76-100). Time to follow-up was significantly longer in the unilateral (40 ± 11 months; range, 20-63 months) vs bilateral (23 ± 12 months; range, 11-42 months) group. Head size was significantly greater in the bilateral (48 ± 6 mm; range, 40-56 mm) vs unilateral (40 ± 4 mm; range, 38-52 mm) group (P b .001). The interrater reliability was high for inclination angle measurements (intraclass correlation coefficient, 0.82; 95% CI, 0.72-0.90). Similarly, interrater reliability was high for anteversion measurements (intraclass correlation coefficient, 0.90; 95% CI, 0.83-0.94). A total of 4 patients were excluded from the analysis. Two patients were excluded from the study based on component malpositioning, 1 from the unilateral and 1 from the bilateral group. The patient in the unilateral

Results Median serum cobalt levels were higher in the bilateral group (1.8 μg/L; range, 1.0-4.2 μg/L) vs the unilateral group (1.0 μg/L; range, 1.0-5.6 μg/L) in both univariable and multivariable analysis. In a univariable model, bilateral implants increased the serum cobalt ion levels by 63% over unilateral implants (increase, 63%; 95% CI, 5%-153%; P = .029). In a multivariable model, controlling for potential confounding variables, the increase attributable to bilateral implants was similar (increase, 68%; 95% CI, 0%-181%; P = .050). Median serum chromium levels were similar in the bilateral (1.4 μg/L; range, 1.0-5.4 μg/L) vs the unilateral group (1.0 μg/L; range, 1.0-5.5 μg/L) in both the univariable and multivariable models. In a univariable model, bilateral implants increased the serum chromium ion levels by 18% over unilateral implants, although this did not reach statistical significance (increase, 18%; 95% CI, −27% to 88%; P = .50). In a multivariable model, controlling for potential confounding variables, the

Fig. 1. Unilateral vs bilateral cobalt and chromium serum metal ion comparisons. The interquartile range is shown as a box containing a horizontal line representing the median. The horizontal lines above represent levels associated with poorly functioning THA and metallosis.

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Table 1. Patient Characteristics Compared Between Unilateral and Bilateral Groups Age (y), mean ± SD (range) Male, n (%) Creatinine clearance, mean ± SD (range) Time to final follow-up (mo), mean ± SD (range) HHS, * median (IQR †) min-max UCLA activity score, mean ± SD (range) Head size (mm), mean ± SD (range) Inclination angle, ‡ mean ± SD Anteversion angle, ‡ mean ± SD

Unilateral (n = 25)

Bilateral (n = 14)

P

56 ± 13 (30-77) 14 (56) 76 ± 22 (36-143) 40 ± 11 (20-63) 99 (95-99) 76-100 7 ± 2 (4-10) 40 ± 4 (38-52) 43 ± 6 (30-56) 39 ± 7 (23-51)

57 ± 17 (30-90) 8 (57) 92 ± 40 (32-190) 23 ± 12 (11-42) 100 (96-100) 86-100 7 ± 2 (5-10) 48 ± 6 (40-56) 45 ± 4 (36-51) 38 ± 6 (26-46)

.80 .95 .18 b.001 .013 .41 b.001 .17 .42

* Used minimum of left and right hip for bilateral patients. † Interquartile range (25th-75th percentiles). ‡ Used maximum of left and right hip for bilateral patients.

group had no pain and a HHS of 99 but was found to have a cup inclination of 62° and had significantly elevated serum cobalt and chromium levels of 79.3 and 25.4 μg/L, respectively. In the bilateral group, 1 patient had an inclination level of 62° and cobalt and chromium levels that were only mildly elevated at 5.6 and 1.9 μg/L, respectively. Both patients have been asymptomatic and are being closely followed up. Two other patients, both in the bilateral MOM THA group, met exclusion criteria and thus were not included in the analysis. One patient, a 36-year-old woman, was excluded because of the presence of spinal fusion instrumentation that was not disclosed to the research team at the time of initial screening. She had been complaining of increased pain at the left hip and had an HHS of 91 with a UCLA activity score of 9 and was believed to have increased acetabular anteversion. She was found to have significantly elevated cobalt and chromium ion levels of 143 and 98 μg/L, respectively, and underwent revision at an outside institution. The other patient, a 54-year-old active man with an HHS of 100 and a UCLA activity score of 9, had complained of significant hip pain present for several months that had since improved significantly. He was excluded for signs of osteolysis and was found to have significantly elevated cobalt and chromium ion levels of 143 and 98 μg/L, respectively. He recently underwent revision THA where his cup was found to be loose.

Discussion It is unknown whether the presence of bilateral wellfunctioning MOM THAs raises baseline serum metal ion levels over those seen in unilateral MOM THA. We tested the hypothesis that serum metal ion levels in patients with well-functioning bilateral large-head MOM THA would be higher than levels in patients with well-functioning unilateral large-head MOM THA, but that these levels would not approach those seen with metallosis. We found that only cobalt ion levels were significantly higher in the bilateral group than in the unilateral group (1.8 μg/L vs 1.0 μg/L, P = .029),

whereas chromium levels were similar between the two groups (1.4 μg/L vs 1.0 μg/L, P = .5). Although the increase in cobalt ion levels represent a statistically significant difference, ion levels did not approach those seen with metallosis, and therefore, the levels are likely not significant clinically. Nonetheless, we feel that it is important to report both the chromium and cobalt levels as potential baseline reference values that may be applied in the workup of poorly functioning MOM THA. Trends in serum metal ion levels may be used diagnostically, but definitive levels for clinical diagnosis have not been established. De Smet et al [19] demonstrated that chromium ion levels above 17 μg/L and cobalt ion levels above 19 μg/L were significantly associated with high joint fluid ion levels and metallosis and may represent the point at which serum cobalt and chromium levels reach clinical significance. The mean absolute values reported in this study are within previously published reference ranges for cobalt and chromium, 0.1 to 5 μg/L and 0 to 10 μg/L, respectively [39]. In the present study, however, values less than 1.0 μg/L were not reported as absolute values because of our laboratory's conclusion that the test accuracy is poor at very low serum ion levels. Cobalt and chromium levels less than 1.0 μg/L were therefore reported as 1.0 μg/L. Reporting in this way clusters the results and increases the mean, and thus, the absolute values reported in this study likely represent an overestimation of cobalt and chromium levels in the setting of bilateral well-functioning large-head MOM THA. The difference in cobalt but not chromium levels between groups may have been because of several factors. Cobalt is the more abundant metal composing the alloy and more soluble than chromium, thereby facilitating entrance into the blood stream [40]. Recently, Hur et al [41] also showed that increased cobalt levels do not accrue in the blood if the kidneys are functioning properly, hence the importance of renal disease as a criterion for exclusion. Previous studies have looked at the presence of bilateral MOM hip arthroplasties and its effect on metal ion exposure [42-44]. One study showed that

1498 The Journal of Arthroplasty Vol. 26 No. 8 December 2011 neither chromium nor cobalt levels were statistically different in unilateral vs bilateral comparisons but is limited because of the small number of bilateral patients (n = 7) and heterogeneity of implant types. In addition, to this point, most studies have primarily investigated MOM hip resurfacings. It is our opinion that this presents a significant limitation to the generalizability of these results to the large-head MOM THAs often used today because of the inherent differences between hip resurfacing and THA components, such as femoral component modularity, fixation type, and differences in component metallurgy. Lee et al [45] demonstrated findings that contradict our own, with significantly higher ion levels in the setting of bilateral implants, but looked at small diameter (28 mm) bearings, again, limiting the ability to interpret the results in the setting of today's commonly used large-diameter heads. There were a few noteworthy differences between the 2 groups in this study, including the HHSs, time to follow-up, and head sizes (Table 1). After the M2aMagnum (Biomet) became commercially available in October 2004, most of the implanted head sizes were greater than 40 mm, which accounts for a systematic difference in head size seen between bilateral and unilateral groups. We looked only at large-head (≥38 mm) MOM THA to eliminate potential differences in ion levels between the 2 groups as a function of the size of the head. Previous studies have shown conflicting data regarding the effect of head size on ion exposure in the setting of MOM hip arthroplasties. Moroni et al [44] showed no difference in metal ion levels between largediameter hip resurfacing implants compared with smalldiameter (28 mm) THA implants. In contrast, Clarke et al [4] showed higher serum ion levels with larger diameter hip resurfacing bearings compared with smalldiameter (28 mm) THAs. None of these studies accounted for the aforementioned modularity and manufacturing differences between the comparison groups. We recently compared 2 groups of MOM THA and found lower ion levels in the large head group compared with the small head group [24]. When comparing 38 mm heads to larger heads, it is possible that there could be a graduated differential in ion release as a function of the size of the head. However, in light of the relatively low ion levels seen in both groups, we dismiss this as a significant limitation in this study. A few other differences between the groups were noted. Harris Hip Scores were significantly higher (P = .013) in the bilateral group (median, 100; range, 86-100) when the minimum of left and right HHS was compared with unilateral HHS (median, 99; range, 76-100); although meeting statistical significance, it is unlikely of clinical significance. The unilateral group contained 2 patients with scores of 78 and 76. These scores met inclusion criteria but represent outlying values compared with the bilateral group in which the lowest HHS

was 86. The means for the unilateral and bilateral group HHS were 95 and 98, respectively. The effect size for the HHS has been shown to be 2.5, and thus, the difference in the means between groups, which is statistically significant, is of marginal clinical significance [46]. Time to follow-up was significantly longer in the unilateral (median, 40 months) vs bilateral (median, 23 months) groups. Follow-up time was measured from time of second THA in the bilateral group. This created a systematic difference between groups because all THAs in both groups were done during this relatively recent and finite period of large-head MOM THA implant availability as we gradually incorporated this new technology in clinical practice. There are some limitations of the present study. This study has some limitations of a retrospective study, including changes in clinical practice and implants over time. The present study attempted to control for several of the aforementioned confounding implant-related variables such as femoral fixation type, component modularity, and component metallurgy, allowing better isolation of the independent effect of the presence of bilateral compared with unilateral replacements on metal ion production. Despite this attempt, component design, modularity, and manufacturing differences still existed between groups secondary to technological advances and evolution of clinical practice over the study period. The unilateral group contained more M2a38 components than the bilateral group, and, as the head and cup size changes, so do the coverage angles of the acetabular components. As has been discussed in the literature, both surgical factors, such as component malposition, and component factors including lower coverage angles may lead to increased edge loading and consequent metal ion production [25,27]. Any patients with components that were not appropriately positioned were excluded from the study so as to minimize this as a potential source of error. These remaining component differences could, however, represent confounding variables that may also contribute to any differences in ions between the groups, and as such remains a limitation of this study. Ideally, identically manufactured components would have been used. However, in the clinical setting, this remains difficult because of the decline in the use of smaller heads and changes in manufacturing with tribiologic and technological advancements. As such, we believe that this study offers the best available information on the differences in serum ion levels in unilateral vs bilateral large-head MOM THA in vivo. In summary, patients in this study with well-functioning bilateral MOM THA had slightly higher cobalt levels, although neither cobalt nor chromium levels approached those seen in poorly functioning MOM THA with metallosis. We conclude that the presence of bilateral large-head MOM THAs alone cannot account

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for significant elevations in serum chromium or cobalt levels, and if such are found, further clinical investigation and workup may be indicated.

Acknowledgment This investigation was supported by the University of Utah Study Design and Biostatistics Center, with funding in part from the Public Health Services research grant numbers UL1-RR025764 and C06-RR11234 from the National Center for Research Resources. The authors would like to thank Jill Erickson, PA-C, and Nousheen Alasti for their ongoing research assistance.

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