Metal Degradation Products: A Cause for Concern in Metal-Metal Bearings? : Clinical Orthopaedics and Related Research®

Secondary Logo

Journal Logo

SECTION I SYMPOSIUM: Papers Presented at the Hip Society Meeting 2003

Metal Degradation Products

A Cause for Concern in Metal-Metal Bearings?

Jacobs, Joshua J. MD; Hallab, Nadim J. PhD; Skipor, Anastasia K. MS; Urban, Robert M. AS

Author Information
Clinical Orthopaedics and Related Research 417():p 139-147, December 2003. | DOI: 10.1097/01.blo.0000096810.78689.62
  • Free


Joint replacement prostheses have a long history of safety and effectiveness when used for the appropriate indications and when implanted properly. It is recognized, however, that in the long-term, these implants may be associated with adverse local and remote tissue responses in some individuals. These adverse effects are mediated by the degradation products of these implant materials that may be present as (1) particulate wear and corrosion debris; (2) metal-protein complexes, (3) free metallic ions, (4) inorganic metal salts or oxides, and/or (5) sequestered in an organic storage form such as hemosiderin. 12,13

Much of the interest in the long-term effects of implant materials has centered on the metallic components because of their tendency to undergo electrochemical corrosion resulting in the formation of chemically active degradation products. Concern about the release and distribution of metallic degradation products is attributable to the known potential toxicities of the elements used in modern orthopaedic implant alloys, particularly Co and Cr. Metal toxicity may be mediated by metabolic alterations, alterations in the interaction between host and parasite, immunologic interactions of metal moieties by virtue of their ability to act as haptens (specific immunological activation), antichemotactic agents (nonspecific immunologic suppression), or lymphocyte toxins, and by chemical carcinogenesis. 13 The association of metal release from joint replacement components with any metabolic, bacteriologic, immunologic, or carcinogenic toxicity currently remains conjectural because cause and effect have not been established in human subjects or animal models. This may be attributable to the difficulty of observation; most symptoms caused by systemic and remote toxicity can be expected to occur in a finite frequency in any population of patients.

We will address the question of whether the metal degradation products originating from the current generation of metal-on-metal bearings are associated with adverse, clinically significant toxicologic sequelae.


Particulate debris comprises a substantial portion of metal degradation products generated by joint replacement prostheses. The degradation products of ceramics and polymers are exclusively in particulate form, because these classes of materials generally are considered insoluble in physiologic environments. Although PE particles generally are recognized as the most prevalent particles in the periprosthetic milieu, metallic and ceramic particulate species also are present in variable amounts and may have important sequelae. When present in sufficient amounts, particulates generated by wear, corrosion, or a combination of these processes induce the formation of an inflammatory, foreign body granulation tissue with the ability to invade the bone-implant interface. This may result in progressive, periprosthetic bone loss that threatens the fixation of cemented and cementless devices, limiting the survivorship of total joint replacement prostheses. Consequently, particulate wear debris of polymers, ceramics, and metal alloys used in prosthetic components have been the subject of intense study concerning their role in bone resorption and aseptic loosening. 14,15

Willert et al 43 reviewed their collection of retrieved metal-on-metal hip joints prostheses (nine McKee-Farrar, seven Muller, and three Huggler prostheses) and associated periprosthetic tissues. The calculated annual wear was low compared with conventional surfaces. The cellular reaction to metal wear particles was regarded as mild. Likewise, Doorn et al 6 concluded that the capsular and interface tissues retrieved from short-term and long-term metal-on-metal THRs had less intense granulomatous inflammation and foreign body giant cell reaction in comparison with tissues from patients with metal-on-polyethylene bearings. However, a more recent comparison study of periprosthetic tissues from metal-on-metal (n = 25) and metal-on-polyethylene (n = 10) THRs showed that tissues from patients with metal-on-metal bearings had more extensive and severe ulceration of the synovial surface with a predominant lymphocytic infiltrate accompanied by abundant plasma cells. Furthermore, metal-on-metal bearings were associated with a striking pattern of perivascular inflammation with prominent lymphocytic cuffs, especially deep to areas of surface ulceration. These findings raise the specter of a metal hypersensitivity-induced vasculitis, which has been reported previously in cases of metal-on-metal THRs and in a case of a severely corroded modular femoral stem. 38,42 The prevalence and clinical importance of these observations are subjects of continued scrutiny.

The morphologic features of particulate debris from metal-on-metal bearings also have been a topic of considerable interest. Doorn et al 5 reported on a transmission electron microscopic analysis of metal particulate debris retrieved from 13 patients having revision of a metal-on-metal THR. The majority of the Co-alloy wear particles were less than 50 nm (range, 6–834 nm), approximately one order of magnitude smaller than what has been reported for retrieved PE particles. Based on reported volumetric wear rates from metal-on-metal bearings, this translates into 6.7 X 1012 to 2.5 X 1014 particles per year. This is 13 to 500 times the number of particles produced by a typical metal-on-polyethylene bearing. 5 Therefore, even though the volumetric wear rate is lower for metal-on-metal bearings in comparison with metal-on-polyethylene bearings, the number of particles actually is greater, because of the smaller particle size. It is unknown whether these nanometer-sized particles are more or less bioreactive than micrometer-sized particles because of the difficulty of isolation of nanometer particulate debris for study in cell culture. The very small (nanometer) size of metallic debris released by metal-on-metal bearings, 5 combined with the fact that the bioavailibility of metal is thought to be a function of the total surface area of the released debris rather than on its volume or weight, 33 casts doubt on the supposition that the net adverse biologic response will be reduced by modern metal-on-metal designs even though the volumetric wear is reduced.

Less attention has been focused on particles generated by corrosion, perhaps because evidence of macroscopic corrosion in the current generation of single-part components is rare. Willert et al 43 reported that the preponderance of particles in the periprosthetic tissues of 19 patients with failed metal-on-metal THRs were corrosion products, based on a reversal of the Cr/Co ratio in the tissues relative to the alloy. In addition, there has been a report of corrosion product deposition on a retrieved McKee-Farrar metal-on-metal bearing. 35 Although characteristics (composition, size, morphologic features) and biologic response to corrosion debris from metal-on-metal bearings has yet to be determined, there have been several reports indicating that modular femoral THR components can undergo severe corrosion at the tapered interface between their head and neck 4,8,27 and produce solid products of corrosion that are similar, if not identical, to that produced by metal-on-metal bearings. 40 In the setting of modular femoral head corrosion, the corrosion products have been well-characterized and were determined to be an amorphous chromium (III) orthophosphate. This debris has been recovered from osteolytic lesions adjacent to corroded modular femoral stems 20 and has been shown to be capable of inducing the release of proinflammatory cytokines from macrophage cell culture and bone resorption in organ culture. 24 Furthermore, similar debris generated from corrosion of modular stainless steel femoral intramedullary nails has been associated with diaphyseal osteolysis, in the absence of PE wear debris, in the adjacent femur. 22 The elucidation of the role of solid corrosion products in the clinical performance of metal-on-metal bearings will require additional study of implants and periprosthetic tissues retrieved post mortem and at revision surgery.


Metallic implants, or wear debris generated from implants, may release chemically active metal ions into the surrounding tissues. Although these ions may stay bound to local tissues, metal ions also may bind to protein moieties that then are transported in the bloodstream and/or lymphatics to remote organs. Broad reviews of the toxicology of the elements used in orthopaedic metal alloys are available elsewhere. 7,10,21,23,36,44 However, when considering the litany of documented toxicities of these elements, it is important to remember that the toxicities generally apply to soluble forms of these elements and may not apply to the chemical species that result from the degradation of prosthetic implants.

Multiple studies have shown chronic elevations in serum and urine Co and Cr after total joint replacement. 19,29,37 In addition, transient elevations of urine and serum Ni have been observed immediately after surgery. 37 This hypernickelemia and hypernickeluria may be unrelated to the implant because there is such a small percentage of Ni within these implant alloys. Rather, this may be related to the use of stainless steel surgical instruments (that contain a relatively higher percentage of Ni in the alloy) or metabolic changes associated with the surgery. Chronic elevations in serum Ti concentrations in subjects with total joint replacements with Ti-containing components also have been reported. 17 Serum and urine V concentrations have not been found to be elevated in patients with total joint replacements partially because of the technical difficulty associated with measuring the minute concentrations present in serum. 17

There are an increasing body of data available on systemic metal concentrations in patients with metal-on-metal articulating surfaces. One of the earliest reports was published approximately 3 decades ago when Coleman et al 3 reported approximately threefold elevations of Cr in whole blood, 11-fold elevations of Co in whole blood, and 15-fold elevations of Cr in urine in nine patients with CoCr metal-on-metal THRs in comparison with their preoperative values. No such elevations were observed in patients with metal-on-polyethylene THRs. For three patients for whom longitudinal data were provided, a strong pattern of time-dependent Cr and Co concentration increases in blood and urine were observed. With the reintroduction of the new generation metal-on-metal THRs there has been a resurgence of interest in systemic distribution of metal degradation products. Brodner et al, 2 in a prospective study with a followup of 2 years, reported that all of the 27 patients with metal-on-metal THRs had detectable serum Co values after surgery. These values were significantly higher than in patients with ceramic-on-polyethylene articulating surfaces. Their data show than in the majority of patients, serum Co levels increased at the 2-year interval compared with the 3- and 6-month intervals. The authors suggested that the wear-in period for these devices may exceed 2 years. In a followup study at 5 years postoperative, these authors suggested that the serum Co levels were relatively constant, and no “wear-in” period could be ascertained.

Schaffer et al 32 retrospectively studied 76 patients with stable metal-on-metal THRs. The patients were grouped according to their postoperative period of 1, 2, and 3 years. A group of patients about to have surgery served as controls. These investigators measured Cr and Co in whole blood and urine. Their data indicate that Co and Cr concentrations in blood were elevated at selected postoperative intervals and that urinary concentrations for Co and Cr were increased significantly at all postoperative periods compared with the concentrations observed in controls. Gleizes et al 11 also reported on serum Co levels in patients with metal-on-metal articulating surfaces. Their followup ranged from 2.6 to 35 months with a mean followup of 12.9 months. All of the patients with metal-on-metal implants had higher serum Co values than a group of patients with no implants. They observed that patients who had a followup of greater than 18 months were likely to have higher serum Co values than those whose followup was less than 18 months. They attributed this increase to increased activity after 18 months after surgery.

MacDonald et al 25 reported erythrocyte metal levels in a randomized, controlled study of 41 patients having metal-on-metal versus metal-on-polyethylene THRs at a minimum of 2-years of followup. In comparison with patients with PE inserts, patients with metal inserts had a 5.3-fold increase in erythrocyte Co, no increase in erythrocyte Cr, a 35.1-fold increase in urine Co, and a 17.4-fold increase in urine Cr. Forty-one percent of patients with metal-on-metal implants had increasing metal levels at the most recent followup.

Metal-on-metal resurfacing arthroplasty has become increasingly popular as a more conservative option for hip reconstruction. It is of interest to determine the impact of the altered geometry of surface replacements (absence of modularity, larger head size and smaller femoral stem size in comparison to total hip replacements) on the serum and urine metal concentrations. In a preliminary study with 1 year postoperative followup, the serum and urine Co and Cr concentrations in patients with metal-on-metal surface replacements were within the same range as those from patients with metal-on-metal THRs. 34 For surface replacement and THR, however, the concentrations were considerably higher than those present in patients with conventional metal-on-polyethylene THRs using identical analytic techniques (Fig 1). However, in contrast to surface replacements, several THR designs, including the one in the aforementioned study, have two metal-on-metal modular taper connections (in the acetabular and femoral component), which are potential sources of metal release. 13,19 Therefore, it is not possible to isolate the amount of metal generated from the bearing versus the amount generated from other sources.

Fig 1:
This figure summarizes several longitudinal and cross sectional cohort studies on serum Cr levels in patients having total hip reconstruction with either metal-on-metal resurfacing arthroplasty (Conserve plus, 34 McMinn/Wagner 18), metal-on-metal THA (Perfecta, McKee-Farrar 18), or metal-on-polyethylene THA 19 (hybrid, extensively porous-coated cementless CoCr, proximally porous-coated cementless Ti/CoCr head). All of these studies used identical analytic techniques. Metal-on-metal bearings were associated with approximately sixfold to 10-fold elevations in serum Cr with respect to metal-on-polyethylene bearings, even in patients with clinically successful long-term (> 20 years) McKee-Farrar implants. Serum Cr levels in patients with contemporary metal-on-metal surface replacements were similar to those in patients with contemporary metal-on-metal THRs.

In a unique long-term (> 20-year followup) study examining serum and urine metal levels in eight patients with well-functioning McKee-Farrar metal-on-metal THRs, it was shown that these patients had ninefold elevations in serum Cr, 35-fold elevations in urine Cr, and at least threefold elevations in serum Co with respect to control subjects without implants. 18 With respect to a longitudinal cohort of patients with well-functioning metal-on-polyethylene implants studied up to 3 years postoperative using identical analytic techniques, 19 the patients with long-term metal-on-metal bearings have approximately 6.4-fold elevations in serum Cr, fourfold elevations in urine Cr, and 3.5-fold elevations in serum Co (Fig 1). This study suggests that the elevated serum and urine Co and Cr concentrations observed in the recent studies on the newer generation of metal-on-metal bearings may persist throughout the lifetime of the implant. This only can be established with continued followup of patients with such devices.


Dermal hypersensitivity to metals is fairly common, affecting approximately 10% to 15% of the population. 14 The term hypersensitivity refers to the induction of the immune system by a sensitizer. This response can be humoral (initiated by antibody or formation of antibody-antigen complexes) that takes place within minutes (Type I, Type II and Type III reactions), or cell-mediated (a delayed-type hypersensitivity (DTH) response) that occurs over days (Type IV). Dermal contact and ingestion of metals have been documented to cause immune reactions. 14

Data from numerous investigations regarding the prevalence of metal sensitivity, albeit with heterogeneous patient populations and testing methodologies, have been compiled. The combined results of approximately 50 studies shows that the prevalence of metal sensitivity among the general population is approximately 10% to 15%, with Ni sensitivity the highest (approximately 14%). 14 Because the cross-reactivity of these antigens is high, the prevalence of metal sensitivity generally is considered to be 10%, the approximate average of the three metals. Cross reactivity between Ni and Co is the most common. 14

The incidence of metal sensitivity among patients with well-functioning and poorly-functioning implants is approximately twice as high (approximately 25%) as that of the general population. Furthermore, the prevalence of metal sensitivity among patients with a failed implant, compiled from five investigations, is 50% to 60%, approximately five times the incidence of metal sensitivity observed in the general population and two to three times that of all patients with metal implants. 14 The increased prevalence of metal sensitivity among patients with loose prostheses has prompted the speculation that immunologic processes may be a factor in implant loosening. Currently, however, it is unclear whether metal sensitivity caused the increased prevalence of implant loosening or whether implant loosening results in the development of metal sensitivity. It currently is unknown whether metal sensitivity exists only as an unusual complication in a few susceptible patients, or is more common and plays a contributory role in implant failure. These considerations are of particular concern in patients with metal-on-metal bearings, which consistently have serum metal concentrations that are higher than in patients with metal- or ceramic-on-polyethylene bearings. Patients with metal-on-metal bearings also have had a higher prevalence of metal sensitivity as determined by patch testing. 14


The carcinogenic potential of the metallic elements used in orthopaedic implants has historically been of interest. This particularly is true for joint replacement components because the large surface areas of cementless porous-coated devices are intended for implantation in younger, more active patient populations that may have life expectancies exceeding 30 years. Animal studies have documented the carcinogenic potential of orthopaedic implant materials; small increases in rat sarcomas were observed to correlate with metal implants that had high Co, Cr, or Ni content. 28 Furthermore, lymphomas with bone involvement were more common in rats with metallic implants. 28 Implant site tumors in dogs and cats, primarily osteosarcoma and fibrosarcoma, have been associated with stainless steel internal fixation devices. 1

The occurrence of tumors at the site of metallic implants in humans also has been reported. In a review of the literature that included publications until 1992, 24 cases of malignancies adjacent to a total joint replacement device were cited. The most common lesion was malignant fibrous histiocytoma. 16 Because of the large number of joint replacement devices inserted until that time, this would seem to be a relatively small number of cases. This suggests that the occurrence of peri-implant malignancies may be coincidental. However, because many such cases may go unreported and because these tumors may have relatively long latency periods, additional surveillance and broad-based epidemiologic studies are warranted.

There have been several human epidemiologic studies of systemic and remote cancer incidence in the first and second decades after THR. In two studies, slight increases in the risk of lymphoma and leukemia were observed in patients who had a Co-alloy THR, particularly in those patients who had a metal-on-metal device. 9,41 Larger, more recent studies have showed no significant increase in leukemia or lymphoma;26,30 however, these studies did not include as large a proportion of subjects with metal-on-metal prostheses. Interestingly, studies have shown a decreased incidence of certain tumors, including breast carcinoma, 9 sarcoma 31 and stomach 30,41 in recipients of total joint replacements. Therefore, it may be that there are constitutive differences in the populations with and without implants that are independent of the implant. This clearly confounds the interpretation of these epidemiologic investigations. In a recent review on the relationship between cancer and TJR, Tharani et al 39 highlighted the serious limitations in the available data stemming from insufficient followup, a lack of information regarding dose-response, the presence of confounding comorbidities, and the dearth of data from populations outside of Scandinavia. Currently, the association of metal release from orthopaedic implants with carcinogenesis remains conjectural because causality has not been definitely established in human subjects.


Implants fabricated from nonbiologic engineering materials continue to be crucial tools in the armamentarium of the orthopaedic surgeon. When used for the appropriate indications and when inserted with proper technique, these implants have been successful with few serious short-term and long-term clinical sequelae. However, as more experience is gained with these devices, it is evident that, in certain situations, adverse biologic effects may occur that may compromise the clinical outcome.

Characterization of the bioavailability and bioreactivity of the metal species that have been released from prosthetic materials is the next step in this line of investigation. Central to this determination is the speciation of the metal moieties present in body fluids and tissue stores that result from implant degradation, because many of the metals used in implants have valence- and ligand- dependent toxicities in mammalian systems. Such studies represent an enormous challenge because of the technical complexities of working with nanometer-sized particles and ion concentrations in the parts per billion range. Current technologic tools (graphite furnace Zeeman atomic absorption spectrophotometry and inductively coupled plasma-mass spectrometry) can measure only the concentration of the element and provide no information on the chemical form or biologic activity. Currently, there is limited information in the literature that describes the physical chemical form of the degradation products of metallic joint replacement prostheses. Ultimately, specific toxicologic investigation of relevant species can be used in animal models and cell cultures to delineate the biologic effects of these degradation products.

Finally, longer-term multicenter epidemiologic studies are required to fully address the issues of metal implant associated carcinogenesis, hypersensitivity, and remote toxicity. Additional advances in molecular biology and materials science, applied to the study of the host tissue response to implanted devices, promises to increase our understanding of the critical determinants of implant biocompatability. This will provide new opportunities for the development of improved biomaterials, novel diagnostic and screening modalities, and pharmacological strategies to modify host response. Ultimately, this promises to lead to improved clinical outcomes for patients requiring implanted devices.


We thank our collaborators at the Joint Replacement Institute/Orthopaedic Hospital in Los Angeles, CA who provided access to materials from their patients with metal-on-metal bearings: Harlan Amstutz, MD, Thomas P. Schmalzried, MD, and Patricia Campbell, PhD.


1. Black J: Orthopaedic Biomaterials in Research and Practice. New York, Churchill Livingstone 292–295, 1988.
2. Brodner W, Bitzan P, Meisinger V, et al: Elevated serum cobalt with metal-on-metal articulating surfaces [published erratum appears in J Bone Joint Surg 79B:585, 1997]. J Bone Joint Surg 79B:316–321, 1997.
3. Coleman RF, Herrington J, Scales JT: Concentrating of wear products in hair, blood and urine after total hip replacement. BMJ 1:527–529, 1973.
4. Collier JP, Surprenant VA, Jensen RE, Mayor MB, Surprenant HP: Corrosion between the components of modular femoral hip prostheses. J Bone Joint Surg 74B:511–517, 1992.
5. Doorn PF, Campbell PA, Worrall J, et al: Metal wear particle characterization from metal on metal total hip replacements: Transmission electron microscopy study of periprosthetic tissues and isolated particles. J Biomed Mater Res 42:103–111, 1998.
6. Doorn PF, Mirra JM, Campbell PA, Amstutz HA: Tissue reaction to metal on metal total hip prostheses. Clin Orthop 329(Suppl):S187–S205, 1996.
7. Elinder CG, Friberg L: Cobalt. In Friberg L, Nordberg GF, Vouk VB (eds). Handbook of the Toxicology of Metals. Vol 2. Amsterdam, Elsevier 211–232, 1986.
8. Gilbert JL, Buckley CA, Jacobs JJ: In vivo corosion of modular hip prosthesis in mixed and similar metal combinations: The effect of crevice, stress, motion, and alloy coupling. J Biomed Mater Res 27:1533–1544, 1993.
9. Gillespie WJ, Frampton CMA, Henderson RJ, Ryan PM: The incidence of cancer following total hip replacement. J Bone Joint Surg 70B:539–542, 1988.
10. Gitelman HJ: Aluminum and Health: A Critical Review. New York, Dekker 1989.
11. Gleizes V, Poupon J, Lazennec JY, Chamberlin B, Saillant G: [Value and limits of determining serum cobalt levels in patients with metal on metal articulating prostheses]. Rev Chir Orthop Reparatrice Appar Mot 85:217–225, 1999.
12. Hallab NJ, Jacobs JJ, Skipor AK, et al: Systemic metal-protein binding associated with total joint replacement arthroplasty. J Biomed Mater Res 49:353–361, 2000.
13. Jacobs JJ, Gilbert JL, Urban RM: Current concepts review: Corrosion of metal orthopaedic implants. J Bone Joint Surg 80A:268–282, 1998.
14. Jacobs JJ, Goodman SB, Sumner DR., Hallab NJ: Biologic Response to Orthopaedic Implants. In Buckwalter JA, Einhorn TA, Simon SR (eds). Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System. Ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons 401–426, 2000.
15. Jacobs JJ, Roebuck KA, Archibeck M, Hallab NJ, Glant TT: Osteolysis: Basic science. Clin Orthop 393:71–77, 2001.
16. Jacobs JJ, Rosenbaum DH, Hay RM, Gitelis S. Black J: Early sarcomatous degeneration near a cementless hip replacement: A case report and review. J Bone Joint Surg 74B:740–744, 1992.
17. Jacobs JJ, Skipor AK, Black J, Urban RM, Galante JO: Release and excretion of metal in patients who have a total hip-replacement component made of titanium-base alloy. J Bone Joint Surg 73A:1475–1486, 1991.
18. Jacobs JJ, Skipor AK, Doorn PF, et al: Cobalt and chromium concentrations in patients with metal on metal total hip replacements. Clin Orthop 329(Suppl):S256–S263, 1996.
19. Jacobs JJ, Skipor AK, Patterson LM, et al: Metal release in patients who have had a primary total hip arthroplasty: A prospective, controlled, longitudinal study. J Bone Joint Surg 80A:1447–1458, 1998.
20. Jacobs JJ, Urban RM, Gilbert JL, et al: Local and distant products from modularity. Clin Orthop 319:94–105, 1995.
21. Jandhyala BS, Hom GJ: Minireview: Physiological and pharmacological properties of vanadium. Life Sci 33:1325–1340, 1983.
22. Jones DM, Marsh JL, Nepola JV, et al: Focal osteolysis at the junctions of a modular stainless-steel femoral intramedullary nail. J Bone Joint Surg 83A:537–548, 2001.
23. Langard S, Norseth T: Chromium. In Friberg L, Nordberg GF, Vouk VB (eds). Handbook of the Toxicology of Metals. Vol 2. Ed 2. Amsterdam, Elsevier 185–210, 1986.
24. Lee S-H, Brennan FR, Jacobs JJ, et al: Human monocyte/macrophage response to cobalt-chromium corrosion products and titanium particles in patients with total joint replacements. J Orthop Res 15:40–49, 1997.
25. MacDonald SJ, McCalden RW, Chess DG, et al: Metal-on-metal versus polyethylene in hip arthroplasty: A randomized clinical trial. Clin Orthop 406:282–296, 2003.
26. Mathiesen EB, Ahlbom A, Bermann G, Lindgren JU: Total hip replacement and cancer: A cohort study. J Bone Joint Surg 77B:345–350, 1995.
27. Mathiesen EB, Lindgren JU, Blomgren GGA, Reinholt FP: Corrosion of modular hip prostheses. J Bone Joint Surg 73B:569–575, 1991.
28. Memoli VA, Urban RM, Alroy J, Galante JO: Malignant neoplasms associated with orthopaedic implant materials in rats. J Orthop Res 4:346–355, 1986.
29. Michel R, Hofmann J, Löer F, Zilkens J: Trace element burdening of human tissues due to the corrosion of hip-joint prostheses made of cobalt-chromium alloys. Arch Orthop Trauma Surg 103:85–95, 1984.
30. Nyren O, McLaughlin JK, Gridley C, et al: Cancer risk after hip replacement with metal implants: A population-based cohort study in Sweden. J Nat Cancer Inst 87:28–33, 1995.
31. Paavolainen P, Pukkala E, Pulkkinen P, Visuri T: Cancer incidence in Finnish hip replacement patients from 1980 to 1995: A nationwide cohort study involving 31,651 patients. J Arthoplasty 14:272–280, 1999.
32. Schaffer AW, Pilger A, Engelhardt C, Zweymueller K, Ruediger HW: Increased blood cobalt and chromium after total hip replacement. J Toxicol Clin Toxicol 37:839–844, 1999.
33. Shanbhag AS, Jacobs JJ, Black J, et al: Macrophage/particle interactions: Effect of size, composition and surface area. J Biomed Mater Res 28:81–90, 1994.
34. Skipor AK, Campbell PA, Patterson LM, et al: Serum and urine metal levels in patients with metal on metal surface arthroplasty. J Mater Sci Mater Med 13:1227–1234, 2002.
35. Smethurst E, Waterhouse RB: Causes of failure in total hip prostheses. J Mater Sci 12:1781–1792, 1977.
36. Sunderman FW: A pilgrimage into the archives of nickel toxicology. Ann Clin Lab Sci 19:1–16, 1989.
37. Sunderman Jr FW, Hopfer SM, Swift T, et al: Cobalt, chromium, and nickel concentrations in body fluids of patients with porous-coated knee or hip prostheses. J Orthop Res 7:307–315, 1989.
38. Svensson O, Mathiesen EB, Reinholt FP, Blomgren G: Formation of a fulminant soft-tissue tumor after uncemented hip arthroplasty: A case report. J Bone Joint Surg 70A:1238–1242, 1988.
39. Tharani R, Dorey FJ, Schmalzried TP: The risk of cancer following total hip or knee arthroplasty. J Bone Joint Surg 83A:774–780, 2001.
40. Urban RM, Jacobs JJ, Gilbert JL, Galante JO: Migration of corrosion products from modular hip prostheses: Particle microanalysis and histopathological findings. J Bone Joint Surg 76A:1345–1359, 1994.
41. Visuri T, Pukkala F, Paavolainen P, Pulkkinen P, Riska EB: Cancer risk after metal on metal and polyethylene on metal total hip arthroplasty. Clin Orthop 329(Suppl):S280–S289, 1996.
42. Willert HG, Buchhorn GH, Fayyazi A, Lohmann CH: Histopathological changes around metal/metal joints indicate delayed type hypersensitivity: Preliminary results of 14 cases. Osteologie 9:2–16, 2000.
43. Willert HG, Buchhorn GH, Gobel D, et al: Wear behavior and histopathology of classic cemented metal on metal hip endoprostheses. Clin Orthop 329(Suppl):S160–186, 1996.
44. Williams DF: Biological Effects of Titanium. In Williams DF (ed). Systemic Aspects of Biocompatibility. Vol 1. Boca Raton, FL, CRC Press 169–177, 1981.
© 2003 Lippincott Williams & Wilkins, Inc.