Metal-on-Metal Total Hip Replacement

The Journal of Arthroplasty Vol. 20 No. 2 2005

Metal-on-Metal Total Hip Replacement What Does the Literature Say? John H. Dumbleton, PhD, DSc,* and Michael T. Manley, PhDy

Abstract: Second-generation metal-on-metal (M/M) total hip replacements were introduced into clinical use in the late 1980s and demonstrate equivalent survivorship to conventional metal-on-polyethylene prostheses. Wear rates are comparable to those of first-generation designs that survived for a long time in the body. Biological effects from metal ions remain a concern. Patients with both firstand second-generation M/M hips have higher levels of cobalt and chromium in their blood and urine than either patients with metal-on-polyethylene devices or unoperated patients. Concerns include the potential for acquired hypersensitivity, mutagenicity, and carcinogenicity. However, reports of proven adverse effects are scant. Prospective, randomized trials with follow-up in excess of 15 years will be needed to differentiate between the performance and effects of M/M and other bearing combinations. Key words: total hip arthroplasty, metal-on-metal, wear, biological effects, clinical results. n 2005 Elsevier Inc. All rights reserved.

wear debris led to the reintroduction of M/M bearings, the development of highly cross-linked polyethylenes and the more widespread use of ceramic-on-ceramic (C/C) bearings. The properties of these different bearing combinations are summarized in Table 1. Our aim was to review the literature with regard to this bearing combination, as second-generation M/M designs now have been in clinical use for over 10 years. This review addresses the clinical performance and retrieval analyses of first-generation M/M devices followed by similar analyses of second-generation designs. Biological issues with first- and second-generation M/M THRs are described. Finally, arguments for and against the use of M/M total hip bearings are presented.

Metal-on-metal (M/M) total hip replacements (THRs) were used widely in the 1960s. Designs included the McKee-Farrar and the Ring in the United Kingdom, the Mueller-Huggler in Switzerland, and the Sivash in the Soviet Union. However, by 1975 the M/M combination was phased out and replaced by metal-on-polyethylene (M/P) bearings because of the higher loosening rates with M/M hips and concerns over biological reaction to the alloy constituents. Studies showed higher rates of metal sensitivity in patients with M/M than with M/P designs [1]. However, by the late 1980s, concerns over osteolysis attributed to polyethylene

From the *Consultancy in Medical Devices, Biomaterials, and Technology Assessment, Ridgewood, New Jersey, and y Consultant Biomedical Engineer, Ridgewood, New Jersey. Submitted July 31, 2004; accepted August 8, 2004. Benefits or funds were received in partial or total support of the research material described in this article from Stryker, Mahwah, NJ. Reprint requests: Michael T Manley, PhD, 12A Chestnut Street, Ridgewood, NJ 07450. n 2005 Elsevier Inc. All rights reserved. 0883-5403/04/2002-0007$30.00/0 doi:10.1016/j.arth.2004.08.011

First-Generation M/M Hip Bearings The McKee-Farrar prosthesis was developed from the work of Wiles [2] and McKee [3] with refinement of the neck design by Farrar [4]. The device was cemented in place. The Ring prosthesis employed a hemispherical cup with a long,

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Metal-on-Metal Literature Review ! Dumbleton and Manley

175

Table 1. Comparison of Ceramic-on-Ceramic, Metal-on-Metal and Ceramic-on-Cross-linked UHMWPE Bearings Ceramic-on-Ceramic

Metal-on-Metal

Metal-on-Cross-Linked UHMWPE

2300 High 550 Reported

350 Low 950 NA

Low Low (cup)/low (head) NA (cup)/950 (head) NA

ca 1 lm 0-3 lm Not reported 0.2 lm Low Not reported Not reported Not increased

25 lm 5 lm Reported 0.05 lm High Reported Reported Increased in blood and urine

ca 100 lm creep 10-20 lm Not reported 0.5 lm Low Reported NA Not increased

Corrosion Passive layer Surface corrosion Interface fretting

NA NA Not reported

Worn every cycle Reported Reported

NA NA Head/trunnion

Biological effects Cell toxicity Local tissue reaction Systemic effects Unexplained pain Hypersensitivity Carcinogenicity

No Low Not reported Not reported Not reported Not reported

Yes Low Reported Reported Reported Consideration

No Low Not reported Not reported Not reported Not reported

Other considerations Squeaking Clicking Seizing Clinical introduction

Not reported Not reported Not reported 1970

Reported Reported Reported Restarted 1988

Not reported Not reported Not reported 1998*

Material properties Hardness, MPa Scratch resistance Bending strength, MPa Fracture of components Tribology Running-in wear Steady-state wear (linear/y) Runaway wear Particle size (mean) Friction 3-body wear Self-polishing Metal ion level in body fluids in well-fixed prosthesis

UHMWPE indicates ultra high-molecular-weight polyethylene. *Charnley first used gamma sterilized in air UHMWPE in 1969. Thereafter, this sterilization method was widely adopted for hip and knee prostheses. Hence, cross-linked polyethylene has a long clinical history.

threaded stem that inserted into the iliopubic bar of the pelvis for use with a standard Moore hemiprosthesis [4]. The device was cementless. Other similar M/M designs from this era were the Stanmore THR, developed by Scales and Wilson in England, and designs by Mueller and by Huggler in Switzerland. All of these hips were of cast cobalt-chromiumalloy. The Sivash THR was introduced in the Soviet Union. It incorporated a linked articulation fabricated initially from stainless steel, and later from cobalt-chromium-alloy. The device was cementless. Each of these early designs had shortcomings. First-generation M/M bearings were relatively crude in design and quality. For example, the stem of the McKee-Farrar hip had sharp edges that produced high stress concentrations in the cement. Impingement was an issue because of the large diameter femoral necks. Fluid film lubrication may or may not have occurred depending on the bearing clearance present in each joint. Frictional

torque varied from patient to patient depending on the degree of matching of the components. However, some of these implants survived for extended periods of time as noted by Amstutz and Grigoris [4], who summarized the early history of M/M hip development. The clinical results available with first-generation M/M total hip prostheses are summarized in Table 2. There are few reports of long-term follow-up. In a few studies, survivorship was reported to be high. For example, at 13 to 14 years follow-up, a survivorship of 84.75% was reported for the McKeeFarrar design taking revision as the criterion for failure [5], although radiographic data indicated that the loosening rate (different from the revision rate) was 50% for stems and 51.1% for cups. A second study with the McKee-Farrar prosthesis [6] showed survivorship of 81.8% for RA patients and 69.4% for OA patients at 28 years’ follow-up. A comparative study of McKee-Farrar and Charnley hips showed equivalent survivorship out to 20

Author(s) August et al [5] Djerf and Wahlstrom [7]

Stem Type

Original # of Hips/ Surviving # Surviving # of Hips (Points)

Jacobsson et al [8]

McKee-Farrar 808/230 McKee-Farrar 177/154 (107) Charnley (70) M: 96, C: 58 McKee-Farrar 107/31 Charnley M: 20, C: 11

175 154

Brown et al [6]

McKee-Farrar

123/20

29 M: 18, C: 11 16

Higuchi et al [73] McKee-Farrar

40/38

Age at Surgery Range (mean) 24-78 (60.3) M: 58-75 (66.4)

13.9 5

C: 60-75.2 (67.6) 58-74 (66.0)

20 (19-21)

28-85 (61.0)

28

35

36-76 (57.0)

11.3

Zahiri et al [74]

McKee-Farrar

243/93y

79

15 S40-67 (58.3) 15 L40-80 (59.3)

Andrew et al [9]

Ring

179/154

116

21-83 (63.0)

Bryant et al [10]

Ring

253/not stated

51

(62.8 F 7.5)

*As a percentage of total revisions. ySurvivorship analysis.

Average Follow-up (y)

L-8.3 S-23.7

8.5 20

% Surviving w/ Revision as Endpoint

Revision for Aseptic Loosening*

84.75% NA

50 (78%) 5 (M4 , C1) (50%)

64 10

Not noted Not noted

M: 77%, C: 73%

24 of original 177 (80%)

30

1

Absence of macroscopic metallic debris

11

None found

27

L=6 S=4

Metallosis only found in unstable prostheses Metal particles observed in surrounding tissue (probably due to loosening) No gross metal staining

NA

NA

67

Not noted

RA 81.8 14 OA 69.4 14.6 N 60 y old 5 (45.5%) 11.9 b 60 y old NA 2 stem and cup, 4 stem only, 9 cup only Total 15 (55.5%) NA 15 10 y 70.6% 20 y 60.4%

54 (80.6%)

Revision for All Causes Osteolysis

Comments

NA

Gross metal reaction in 4 patients resulting in pseudarthrosis 61.7% of survivors had unsatisfactory clinical result and 74% had radiographic loosening

176 The Journal of Arthroplasty Vol. 20 No. 2 February 2005

Table 2. Clinical Studies with First-Generation M/M Total Hip Replacements

Metal-on-Metal Literature Review ! Dumbleton and Manley

years [7,8]. Again, it was noted that many of the patients older than 65 years had implants that were radiographically loose, but most hips continued to function. Comparison of survivorship for the Ring total hip prosthesis and the McKee-Farrar indicated that the Ring performance was inferior to the McKee-Farrar [9,10]. Analysis of retrieved first-generation M/M hips demonstrated low wear rates. Willert and Buchhorn [11] reported on 19 hips (9 McKee-Farrar hips, 7 Mueller hips, and 3 Huggler hips). The volumetric wear rates ranged from 0.22 to 22.36 mm3/year, with particles in the size range from 0.25 to 2.0 lm. A similar range of volumetric wear rates was given by Scott and Lemons [12] for retrieved Sivash M/M total hip prostheses. Schmalzried et al [13] found that the highest wear rate was 4.2 lm/ year with 1 retrieved Sivash and 5 McKee-Farrar prostheses. Low wear was reported in a group of McKee-Farrar hips retrieved after 21 to 26 years’ implantation [13]. In a group of 21 M/M retrievals, the average volumetric wear rate was less than 6 mm3/year [14]. Tissue reaction to metal particles around M/M total hip prostheses has been described [11,13]. Howie [15] noted that tissues around M/M prostheses contained large numbers of macrophages with the metal particles. Osteolysis was reported for 3 of 6 retrievals despite low wear [13]. In a group of 15 McKee-Farrar hips, there was osteolysis in 4 cases [16]. Klapperich [17] found progressive osteolysis around a Sivash hip in place for 14 years. At revision, the tissue was stained with black debris, and both components were loose. Progressive osteolysis was noted around bilateral McKeeFarrar hips [18]. Dark tissue staining and osteolysis appeared to be associated with impingement or with loose components rather than with wellfunctioning implants. In summary, clinical studies of first-generation THRs indicated that some devices survived for considerable periods of time. Radiographic evidence and retrieval measurements showed that wear rates were low generally. Findings such as those supported the conclusion that M/M hip performance might be improved by greater attention to prosthesis and bearing design and led to development of the second-generation M/M devices.

Second-Generation M/M Hip Bearings Development of second-generation, modular M/M hips began in the early 1980s and led to the Metasul M/M articulation (Sulzer, Switzerland),

177

introduced in 1988 [19]. Second-generation M/M hip prostheses incorporated improved bearing geometry (sphericity and clearance) and surface finish to promote lubrication [20,21]. Different cobalt-chromium–bearing alloys (wrought or cast, high carbon or lower carbon) were used [22,23]. In general, hip simulator studies have validated these different choices [22,24-29]. For example, with high-carbon wrought alloy 28-mm components, the steady-state wear rate was 3 to 7 lm per million cycles per component [22], which is equivalent to about 2% of that measured for a conventional (not cross-linked) M/P bearing under similar conditions [25]. There is an indication also that a further decrease in M/M wear can be achieved with increase in femoral head diameter [28]. The actual choice of bearing material remains controversial. The clinical experience with second-generation THRs is summarized in Table 3. Despite clinical usage of more than 10 years, there are only 9 reports available in the literature, 7 of which concern the Metasul design. These publications are anecdotal in character, the average follow-up is 6 years or less, and the clinical results are unremarkable. However, Holzmann et al [30] reported that in 117 hips in 104 patients, there were 13 patients (18 hips) who complained of groin pain or a click in the hip area. The conclusion was that impingement was responsible, suggesting that the design or implantation technique was not optimal. In an autopsy retrieval, it was noted that the surrounding tissue was stained with metal debris indicating impingement [31]. The wear of 83 retrieved second-generation (Metasul) hips has been compared with that of 30 retrieved first-generation (Mueller) devices [32]. The linear wear of the Mueller components averaged 2.2 lm/year per component for implantation times from 36 to 377 months. The linear wear of the Metasul hips (head plus cup) averaged 5 lm/year with implantation times in the range 2 to 72 months. Whereas the Mueller hips were mainly revised for loosening, 70% of the Metasul hips were revised for dislocation or loosening. In a second study [33], larger numbers of Metasul components were analyzed with implantation times out to 117 months. Again, about 70% of the revisions were due to dislocation or loosening. The wear rates averaged about 5 lm/year per component. In summary, although laboratory studies indicated that the wear of second-generation M/M THRs should be lower than that of first-generation devices, retrieval analyses do not indicate superiority in this regard. This may be because of the

Author(s)

Stem Type (Cemented/ Uncemented)

Original # of % Surviving Revision Revision Hips/Surviving Surviving # Age Range at Average With Revision for Aseptic for All # of Hips (Points) Surgery (mean) Follow-up (y) as Endpoint Loosening* Causes

Doerig et al [75] Alloclassic (Metasul)

218/not stated

Not stated

25-81 (60.9)

Range: 2-6

96

2 (67%)

3

Doerig et al [76] Alloclassic (Metasul)

138/not stated

Not stated

25-81 (59.4)

Min: 5 y

99.3

1 (50%)

2

80 patients

Not stated

18-75 (49)

6

Not stated

0 (0%)

3

Min: 1 y

Not stated

0 (0%)

2

Wagner and Wagner [77]

Various (Metasul)

Delaunay [78]

Alloclassic (Metasul)

64/not stated

Not stated

36-73 (60)

Delaunay [79]

Alloclassic (Metasul)

100/94

Not stated

29-73 (59.5)

3

Not stated

0 (0%)

2

Dorr et al [80]

APR (Metasul)

55/51

45

27.4-83.5 (52.7)

3.1

Not stated

0 (0%)

1

Dorr et al [81]

APR (Metasul)

70/56

56

35-85 (70)

5.2

53/56

0 (0%)

3

97/78

78

26-73 (49.3)

3.23

Not stated

0 (0%)

0

350/ = 336

259

25-70 (55)

4.33

Stem: 96.8%, cup: 99.4% (7.6 y)

0 (0%)

6

Lombardi et al [82] Korovessis et al [83]

2

Mallory-Head (M a) Zweymueller (Sikomet)

APR indicates anatomic porous replacement. *As a percentage of total revisions.

Osteolysis

Comments

1

Osteolysis due to cerclage wires; components left in place following intervention Reported Loosening due but number to periprosthetic not clear fracture 3 wk postoperative None reported No signs of metallosis in the reoperatives None reported Revisions were exchanges due to dislocations. Discussion of metal toxicity 1 Two exchanges due to dislocations None Reoperation due to liner disassociation None reported Two revisions due to dislocations None reported None reported Low-grade metallosis (Mirra 1 or 2) seen for all revisions

178 The Journal of Arthroplasty Vol. 20 No. 2 February 2005

Table 3. Clinical Studies With Second-Generation Total Hip Replacements

Table 4. Metal Ion Levels With Second-Generation Total Hip Replacements and Controls

Author(s)

Stem Type (M/M)

No of Hips/ Patients

Control

No of Hips/ Fluid Measurement Metal Ion(s) Patients Analyzed Technique Measured

Time(s) of Measurement

Brodner et al [36]

Alloclassic (Metasul)

27 patients

Alloclassic (C/P)

28 patients

Serum

AA

Co

6 mo, 12 mo

Shaffer et al [35]

Not stated (SM21)

76 Patients

Awaiting hip surgery

26 patients

Blood, urine

GF, AA

Co, Cr

1, 2, 3 y

Metal Levels Control

Comments

1.0 lg/L, 1.1 lg/L

None detected

Median 50% levels. Detection limit 0.3 lg/L Not longitudinal study 22 patients year 1 25 patients year 2 29 patients year 3 Urinary concentrations of Co, Cr correlated significantly with blood values Manufacturers not identified

M/M Co in blood significantly greater than controls (1, 2, 3 y)

M/M Cr in urine significantly greater than controls (2, 3 y)

Lhotka et al [37]

Manufacturer 1

106 patients

Healthy subjects

31 subjects

Blood

GF, AA

Co, Cr

Postoperative: 3-6, 12-15, 35-38 mo

Manufacturer 2 97 patients Lhotka et al [38]

Metasul SM21

Favard and Damie [39]

MacDonald et al [40]

Not stated (Metasul)

Mallory-Head (M2a )

131 patients 128 patients

Healthy subjects

31 subjects

Blood

GF, AA

Co, Cr

Postoperative: 3-6, 12-15, 35-38, 42-48 mo

56 patients

PVL (M/P)

54 patients

Serum

ICP-MS-HR

Co, Cr, Ni, Mo

3, 6, 12 mo for M/M 4-5 y for MOP

Mallory-Head 18 patients (M/P)

Blood, urine

ICP-MS-HR

Co, Cr, Ti

1, 2 y

22 patients

Co: 36.5 ng/g at 35-38 mo Cr: 48.0 ng/g

Co: 0.7 ng/g Cr: 0.21 ng/g

Co: 16.95 Co: 0.7 ng/g ng/g Cr: 25.62 Cr: 0.21 ng/g ng/g (42-48 mo) Co and Cr levels significantly higher for M/M than controls at all times Blood (lg/L)

Blood (lg/L)

Co: 1.10 Cr: 2.50 Ti: 1.80 Urine (lg/L) Co: 14.73 Cr: 4.73 Ti: 0.39

Co: 0.17 Cr: 1.30 Ti: 1.50 Urine (lg/L) Co: 0.29 Cr: 0.30 Ti: 0.38

M/M values for manufacturer 1 Extension of study (110) M/M values for Metasul (manufacturer 1) Co levels increase for MOP hips if cement fracture occurs 23 M/M patients, but 1 died before 2-y follow-up Values are at 2 y (median)

179

(continued on next page)

Metal-on-Metal Literature Review ! Dumbleton and Manley

M/M

Author(s)

Stem Type (M/M)

No of Hips/ Patients

Maezawa et al [84]

Not stated (Metasul)

32 patients

Savarino et al [42]

Not stated (Metasul)

26 patients

Clarke et al [41]

Resurfacing Birmingham hip Cormet 2000 Standard Ultima Alloclassic (Metasul)

22 resurfacing 22 standard

Brodner et al [72]

50/50

Control Lord and others (M/P)

No of Hips/ Fluid Measurement Metal Ion(s) Patients Analyzed Technique Measured 47 patients

Urine, serum

AA

Not stated 15 patients (M/P): Awaiting hip 22 patients replacement: Healthy 22 patients subjects: Literature NA

Serum

GF, AA

Serum

ICP-MS

Serum

AA

Alloclassic (Biolox/ UHMWPE)

50/50

Co, Cr

Time(s) of Measurement 1y

Metal Levels M/M Serum and urine Cr increased in 37.5% and 90.6% of patients, respectively

Control

Serum and urine Cr increased in 28.6% and 85.7% of patients with loose prostheses. Containing Co-Cr alloy Co, Cr, Mo 14-38 mo Highly significant Co and Cr release for M/M patients compared with M/P patients, patients awaiting hip replacement, and healthy subjects Co, Cr Median: 16 mo Resurfacing Max: 5 (range 7-56 mo) Co: 38, Cr: nmol/L for 53 nmol/L Co or Cr Standard Co: 22, Cr: 19 nmol/L Co Regular At 5 y Median: All below intervals 0.7 Ag/L detection out to 25th percentile: limit 5y 0.225 0.3 Ag/L 75th percentile: 1.75

Comments Co levels did not increase for any patients irrespective of bearing or whether well fixed or loose

No difference found for Mo between groups

Birmingham hip and Comet are resurfacing hipsUltima is standard 28-mm M/M hip

180 The Journal of Arthroplasty Vol. 20 No. 2 February 2005

Table 4. Continued

Not stated (Metasul)

15/15

22 patients awaiting hip replacement (Group B) 27 healthy subjects (Group C)

NA

Serum

GF, AA

Co, Cr, Mo, Al

Median: 48 mo (range, 48-66)

Co: 0.80 ng/mL, Cr: 0.99 ng/mL

B: Co: 0.36 ng/mL; Cr: 0.26 ng/mL C: Co: 0.31 ng/mL; Cr: 0.24 ng/mL

Masse et al [71]

Various Sulzer products (Metasul)

30/30

Preoperative values

NA

Blood, urine

AA

Co, Cr, Mo, Ni

Samples: preoperative, at 7 d, 2 mo, 6 mo

Blood (Ag/L) Co: 1.43 (7 d); 2.13 (2 mo); 2.32 (6 mo) Cr: 1.57 (7 d); 1.34 (2 mo); 1.70 (6 mo) Urine (Ag/L) Co: 2.32 (7 d); 6.41 (2 mo); 10.07 (6 mo) Cr: 2.62 (7 d); 2.10 (2 mo); 2.81 (6 mo)

Blood (Ag/L) Co: 1.23 Cr: 1.14 Urine (Ag/L) Co: 1.13 Cr: 0.86

MS indicates mass spectrometer; HR, high resolution; GF, graphite furnace.

15 M/M patients were from group of 26 followed for longer time [42] M/M ion levels lower at longer follow-up but still higher than controls Mo and Al levels unmeasurable for all groups Metal levels of Co and Cr increase in blood and urine compared to preoperative values Mo values increase in urine only Ni spikes in urine at 7 d only

Metal-on-Metal Literature Review ! Dumbleton and Manley

Savarino et al [43]

181

182 The Journal of Arthroplasty Vol. 20 No. 2 February 2005 small head size used for most of the Metasul hips, which makes full-film lubrication less likely and impingement and dislocation more likely than for the larger diameter bearings of first-generation M/M designs. The clinical studies to date do not indicate superiority of second-generation M/M to M/P total hip prostheses with regard to implant survivorship.

Metal Ion Release and Biological Effects with M/M Bearings Metal Ion Release Although the wear rate of M/M bearings is low, there can be considerable amounts of metal generated during articulation. This was a concern with first-generation total hip prostheses. A recent study on the systemic metal levels associated with firstgeneration M/M hips confirmed that metal levels can be elevated with an early design [34]. Eight patients with McKee-Farrar prostheses were evaluated for metal levels in serum and urine. There was a control group of 3 patients with no implants. The serum chromium was 9 times greater for the McKee-Farrar group than for the control group. The serum level of cobalt was 3 times higher for the McKee-Farrar group than for the control group. Urine chromium levels were elevated to 1 part per billion for the McKee-Farrar patients compared with barely measurable levels in the control group. Similar concerns about second-generation M/M hips have resulted in many studies of metal levels in patients with these devices [35-43,71,72,84]. Data are summarized in Table 4. Studies are listed in the table. Most studies measured metal ion levels in serum (6/12) or blood (5/12) and 4 of 12 provided measurements for urine. The techniques used were atomic absorption (AA) spectrometry or inductively coupled plasma (ICP) mass spectrometry. Not all studies were longitudinal. All studies except 1 [41] had controls for comparison. Control groups were healthy subjects in 4 of 12 studies, patients awaiting surgery in 4 of 12 studies, and patients with M/P hips in 6 of 12 studies. The longest follow-up for M/M patients was 60 months. The studies showed a wide range of Co and Cr metal levels from patient to patient. Generally, metal levels were increased with M/M bearings over those for both the unoperated hips and the M/P controls in serum, blood, and urine. In one study, a large number of M/M patients (29/76) exceeded the metal levels of cobalt and chromium in blood and urine defined by the German Health Authorities for Occupational Exposure (Deutsche Forschungsge-

meinschaft) [35]. In a second study, the majority of 26 M/M patients studied exceeded the upper limit for cobalt (17/26) and chromium (20/26) levels established by the Istituto Superiore di Sanita in Italy [42]. However, the values were somewhat lower at longer follow-up [43]. One study indicated higher cobalt and chromium levels in surface replacements (diameter median 48 mm) compared with 28-mm M/M implants [41]. Biological Responses to M/M Wear Debris The higher level of metallic ions from M/M bearings is due to the large surface area of metallic debris generated during wear. Metallic wear debris is typically smaller than 0.05 lm in size [44,45]. This is below the size range of the polyethylene particles needed for highest macrophage activation (0.2-0.8 lm) [46], although metallic debris can elicit an osteolytic response [47]. Even at the low levels of M/M wear observed, the small particle size results in large numbers of particles for a given wear volume compared with M/P joints [46]. Chromium-enriched particles indicative of particle corrosion have been observed in tissues around M/M implants [48]. Metallic particles have been shown to travel beyond the periprosthetic tissue to the para-aortic lymph nodes, the liver, and spleen [49]. High concentrations of particles result in granulomas in the liver or spleen [49] or in the regional lymph nodes [50,34]. Cobalt-chromiumalloy wear debris particles are toxic to macrophages [51], and cobalt-chromium-alloy particles can modulate the growth of osteoblast cells in vitro [52], which can interfere with bone formation [53]. Corrosion products (chromium orthophosphate) released from the wear particles themselves can induce bone resorption in vitro and, consequently, osteolysis [54,55]. Hypersensitivity Dermal hypersensitivity to metals occurs in about 10% to 15% of the general population with double the incidence in patients with hip prostheses [56]. For first-generation M/M hip prostheses, 9 of 14 patients with loose devices were shown to have sensitivity to alloy constituents [57]. In patients with either Charnley or McKee-Farrar prostheses, only 3% of Charnley patients exhibited metal sensitivity, whereas 28% of M/M patients had sensitivity [1]. A recent review has highlighted the difficulties in testing for sensitivity to metals in patients with implants [58]. It remains unclear whether hypersensitivity to metallic biomaterials

Metal-on-Metal Literature Review ! Dumbleton and Manley

affects implant performance or survivorship. The issue remains open with second-generation M/M hip prostheses, although Willert et al [59] have shown that the tissue around second-generation hips exhibits a diffuse and perivascularly oriented lymphocytic infiltration that appears to be specific to these M/M bearings. Mutagenicity Patients with cobalt chromium alloy implants were found to demonstrate a 2.5-fold increase in aneuploidy and a 3.5-fold increase in chromosomal translocations in peripheral blood lymphocytes that is not explained by confounding variables such as smoking, sex, age, and diagnostic radiographs [60]. The highest level of chromosomal translocations was found in 3 patients: 1 with a Ring M/M hip in place for 19 years, 1 with a McKee-Farrar M/M hip in place for 28 years, and 1 with a fractured M/P hip stem. There were clastogenic changes in peripheral blood cells and bone marrow cells consisting of both potentially lethal and nonlethal chromosomal changes. The effects seen were due to the metal constituents of the alloys [61]. One of the hallmarks of malignancy is an increase in aneuploidy and chromosome translocations. It is not known whether chromosomal changes presage the development of cancer. Carcinogenicity The International Agency for Research into Cancer classifies cobalt and nickel as possibly carcinogenic in humans, but orthopaedic implants were not classifiable [62]. Tharani et al [63] recently reviewed 6 studies on the risk of cancer after total hip or knee arthroplasty. The 95% confidence intervals (CIs) for relative risk (RR) for all cancers bridged unity except for 2 studies in which the confidence intervals were less than unity. Only 2 studies separated M/P from M/M prostheses. In a group of 579 McKee-Farrar patients, there were 113 observed cases of cancer compared with 118.36 cases expected (RR 0.95: 95% CI 0.79-1.13) [64]. In a separate study with only M/P hip replacements, there were 2367 observed and 2626 expected cases of cancer (RR 0.90: 95% CI 0.87-0.94) (91). Visuri et al [64] compared the relative risk for leukemia between M/M and M/P patients and found it to be 3.77 (95% CI 0.96-17.6) for a higher risk with M/M patients. However, the follow-up was only 7.5 years on average. In a review of the causes of death of Finnish THR patients, 24 638 patients with

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a primary total hip arthroplasty were followed for a mean of 6.2 years. The standardized mortality ratio (SMR) was 0.69. The SMR for cancers was 0.54. The findings could be explained by preoperative patient selection, higher activity after M/M THR, and the use of anti-inflammatory drugs. In 698 Finnish McKee-Farrar patients, the total number of expected cancers was 130.4 and the number observed 134. The SMR values were 1.0 (95% CI 0.7-1.5), 1.0 (95% CI 0.8-1.3), and 1.0 (95% CI 0.8-1.4) at 5 years, 10 years, and 15 years, respectively [65]. Individual types of cancers were not remarkable in incidence. At 10 years, the implant survivorship was 76% and included a high number of loosened prostheses that would have been expected to contribute to the metal load in the body [66]. The epidemiological and other studies do not allow a conclusion regarding the incidence of cancer with THRs in general, and M/M THRs in particular.

Discussion Second-generation THRs were introduced in the late 1980s, and their use became widespread in the mid-1990s. The rationale for the reintroduction of M/M bearings was that shortcomings with firstgeneration devices were well understood and could be addressed with design and material changes. This is an assumption that can be proven with second-generation hip prostheses only by success in large numbers of patients at long times of implantation. Those laboratory studies that have been reported do indicate that the issues of bearing design are better understood with second-generation M/M designs than before [20-29]. Based on the literature, it may be concluded that a head-to-cup clearance between 50 and 100 lm, bearing sphericity of less than 5 lm, and bearing surface finish in the range 10 to 50 nm should provide satisfactory bearing performance. Wear is reduced at the lower end of each range provided tolerances can be maintained. There is disagreement on the preferred alloy for M/M bearings [67,68], although the choice appears to be less important than bearing fit and finish [69]. Metasul bearings were introduced in 28- and 32mm femoral head diameters with 28-mm heads being used most widely. Perhaps this choice was due to the prevalence of the 28-mm head size with M/P devices. With an M/M bearing, a larger head size can be recommended to increase range of motion and minimize neck-cup impingement. In

184 The Journal of Arthroplasty Vol. 20 No. 2 February 2005 addition, laboratory and theoretical studies indicate that there is a greater probability of developing fullfilm lubrication with larger head sizes because of the increased relative sliding velocity of the bearing surfaces achieved with a larger bearing diameter [28,29]. The trend since the late 1990s has been to introduce femoral head sizes larger than 32 mm for M/M hip prostheses. However, the somewhat surprising finding of higher metal ion levels for M/M surface replacement devices may place an upper limit on this diameter [41]. The average wear measured from different studies of retrieved second-generation M/M components [32,19] is similar to that seen with firstgeneration M/M hip prostheses [11,14]. Wear of clinical retrievals is measured by dividing the total depth of wear by the total implantation time in years. This method results in higher calculated wear rates for shorter implantation times because of the greater contribution of wearing-in and might bias the results in favor of first-generation M/M prostheses. Wearing-in is reported to be complete at 12 months clinically or at 1 million cycles for hip simulator studies [11,14,19,32]. Hip simulator data for the steady-state wear of second-generation M/M hips are in agreement with clinical retrieval wear measurements [19]. Comparison of first- and second-generation hip wear has been done on a year-by-year basis [32] allowing direct comparison and demonstrating similarity of wear rates. Consequently, if there is a bias it is small. The similarity of wear rates may be because the first-generation bearings from which measurements were made were the long-term survivors and perhaps represented the best conditions of bearing tolerances or fit. It may also be because the second-generation retrievals were mainly 28-mm components that did not develop full fluid film lubrication because of their lower relative sliding velocity [29]. The wear in individual patients can be markedly higher than the average for a given group suggesting that the degree of lubrication varies within the patient population or within the manufacturing tolerances allowed. Reports of squeaking or clicking suggest that bearing lubrication is not always optimal [30,32]. The clinical results with second-generation M/M bearings at present are at the short- to mediumterm follow-up (Table 3). The studies are largely anecdotal, represent confounding factors of stem and cup design and fixation, and tend to focus on the Metasul design. No study demonstrates superiority of M/M to M/P bearings regarding survivorship or reduced incidence of complications. At best, equivalence has been shown. With the low wear

rates apparently achieved with all modern bearing pairs, large patient numbers and long clinical follow-up will be needed to differentiate one bearing type from another. Impingement and dislocation have been mentioned in several reports with M/M bearings [32,33]. It is difficult to determine whether the incidence of impingement is higher with modern M/M devices than with M/P hip prostheses. However, impingement is more serious for a hard-on-hard bearing than a hard-on-soft bearing. Severe damage and notching of the femoral neck has been reported. Impingement can lead to loosening and the liberation of large amounts of metallic debris and, consequently, increased metal ion release from surfaces not designed to make articular contact. Biological issues continue to be a concern [70]. Generally, the local tissue reaction is mild, because the wear debris load is small [44,45] and is transported away via the lymphatics [34,49,50]. The number and character of the metal particles for the second-generation M/M bearings are similar to that of their first-generation predecessors. The metallic constituents of orthopedic alloys are biologically active. Hypersensitivity has been raised as a concern with the observation that this may be a phenomenon more prevalent with second-generation M/M bearings [59]. Cobalt and chromium alloy constituents in M/M bearings have been noted as sensitizers with mutagenic and, in some ionization states, carcinogenic effects [62]. Cobaltchromium wear debris is toxic to cells [51]. The literature does not provide guidance regarding long-term effects of metallic debris and metal ion release [63-66]. However, metallic wear debris is distributed around the body. This has led to the formation of granulomas in lymph nodes and organs with higher concentrations of particles [49,50]. Dissolution of particles [48] results in elevated metal levels in body fluids. The adverse effects may be subtle and may require follow-up of 20 to 30 years in large numbers of patients to determine the level of risk. There are an increasing number of studies on the level of metal ions in body fluids for patients with M/M total hip prostheses (Table 4). The general finding is that metal ion levels are increased with M/M bearings when compared with either M/P designs or unoperated individuals. Red blood cells are a reservoir for cobalt and chromium. Excretion of cobalt and chromium in the urine is important to control metal ion levels [71]. However, even with excretion the levels in some patients have been shown to exceed the norms laid down by regula-

Metal-on-Metal Literature Review ! Dumbleton and Manley

tory agencies. The effect of continued elevated levels of metal ions is not known. The loss of efficacy of clearance with increasing age may result in further elevation of metal ion levels. It is also possible that continued stress on the kidneys from the metal load could result in earlier compromise of function, thus leading to a vicious cycle. A recent clinical study remarks that M/M articulations were no longer used in patients with chronic renal disease because of these concerns [72]. What is the long-term risk of an M/M bearing? The literature does not provide an answer. It appears reasonable to assume that the biological risk is higher than for M/P, C/P, or C/C bearings because of a demonstrated higher level of metal ion release. It also appears reasonable to assume that the risk increases with time of implantation.

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