METAL DEGRADATION PRODUCTS:  A CAUSE FOR CONCERN
IN METAL-ON-METAL BEARINGS?

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

In the majority of patients, orthopaedic implants are biocompatible. However, there is an increasing recognition that, in the long-term, permanent orthopaedic implants may be associated with adverse local and remote tissue responses in some individuals. These adverse effects are mediated by the degradation products of implant materials. The recent reintroduction of metal-on-metal bearings for total hip arthroplasty has heightened concerns about the biologic response to metal degradation products in light of the fact that the serum and urine metal concentrations in patients with these implants typically are higher than those seen in patients with conventional metal-on-polyethylene bearings. From previous studies of long-term metal-on-metal McKee-Farrar implants, it seems that these elevated levels may persist for the duration of the implant's lifetime. This is of particular concern in the younger and more active patient in whom life expectancy after implantation may exceed 30 years. The association of metal release from orthopaedic implants with any metabolic, bacteriologic, immunologic, or carcinogenic toxicity currently remains conjectural because cause and effect have not been established in human subjects. However, continued surveillance of patient populations with metal implants, particularly those with metal-metal bearings, is warranted.

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,
(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 orthopedic 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 immuno-logical 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 al⁴³ reviewed their collection of retrieved metal-on-metal hip joints (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, Doom et al⁶ 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. Doom et al⁵ 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 in size (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 bio-availability 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 modem 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 al⁴³ 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 stems²⁰ 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.^17,29,37 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.¹⁶ 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 is 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 three decades ago when Coleman et al³ 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 follow up 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 follow up 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 follow up 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 al³² 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 periods postoperative compared with the concentrations observed in
controls. Gleizes et al¹¹ also reported on serum Co levels in patients with metal-on-metal articulating surfaces. Their follow up ranged from 2.6 to 35 months with a mean follow up 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 follow up of greater than 18 months were likely to have higher serum Co values than those whose follow up was less than 18 months. They attributed this increase to increased activity after 18 months after surgery.

MacDonald et al²⁵ 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 follow up. 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 follow up.

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 follow up, 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 both 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).

It should be pointed out, however, that 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.

In a unique long-term (> 20-year follow up) 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 9-fold elevations in serum Cr, 35-fold elevations in urine Cr and at least 3-fold 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, 4-fold 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 follow up 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 up 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 up until that time, this would seem to be a relatively small number of cases. This suggests that the occurrence of periimplant 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 sarcoma³¹ 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 al³⁹ have highlighted the serious limitations in the available data stemming from insufficient periods of follow up, 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 Zee-man 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.

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CLINICAL ORTHOPAEDICS AND RELATED RESEARCH
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© 2003 Lippincott Williams & Wilkins, Inc.

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