Abstract
Background: Total hip arthroplasty with use of metal-on-metal
bearings has been reintroduced as an alternative to the use of
metal-on-polyethylene bearings because of theoretical advantages such as
reduced wear and a lower prevalence of osteolysis. However, we observed early
osteolysis in a cohort of patients who had been managed with second-generation
metal-on-metal hip replacements and investigated the possible etiologic role
of metal hypersensitivity.
Methods: We retrospectively analyzed 165 patients (169 hips) who had
undergone primary cementless total hip replacement with a contemporary
metal-on-metal total hip design between 2000 and 2002. After a minimum
duration of follow-up of twenty-four months, nine patients (ten hips) had an
osteolytic lesion localized to the greater trochanter. Skin-patch tests for
hypersensitivity to metals were performed on the nine patients and on nine
randomly selected patients with total hip replacements who did not have
osteolytic changes and who were matched to the study cohort for age and
gender. Microbiological cultures, histopathologic examinations, and
immunohistochemical analysis were performed on samples of periprosthetic
tissue that were collected during revision arthroplasty on two hips with early
osteolysis.
Results: The patients with early osteolysis had a significantly
higher rate of hypersensitivity reaction to cobalt compared with controls (p =
0.031). The retrieved periprosthetic tissues showed no evidence of metallic
staining, but histologic analysis revealed a perivascular accumulation of
CD3-positive T-cells and CD68-positive macrophages and an absence of both
particle-laden macrophages and polymorphonuclear cells. Immunohistochemical
analysis demonstrated that bone-resorbing cytokines such as IL-1ß and
TNF-a were produced mainly by infiltrating lymphocytes and activated
macrophages.
Conclusions: These findings raise the possibility that early
osteolysis in patients with this second-generation metal-on-metal hip
replacement is associated with abnormalities consistent with delayed-type
hypersensitivity to metal. A prospective study in which a large group of
patients is evaluated with multiple diagnostic methods is needed in order to
establish whether there is a causal relationship between metal
hypersensitivity and osteolysis.
Level of Evidence: Therapeutic Level III. See
Instructions to Authors for a complete description of levels of evidence.
Early loosening of the first-generation metal-on-metal McKee-Farrar
total hip prosthesis has been attributed to substandard implant design,
inconsistent manufacturing tolerances, and poor surgical technique rather than
suboptimal performance of the
articulation1-3.
In 1988, Muller and Weber reintroduced metal-on-metal bearings (Metasul;
Sulzer Orthopedics, Winterthur, Switzerland) with improved materials, design,
and manufacturing quality control as an alternative to the conventional
metal-on-polyethylene articulation. Modern metal-on-metal hip prostheses have
the theoretical advantage of producing less abrasive wear than
metal-on-polyethylene prostheses do. In addition, the metal particles that are
produced are smaller than polyethylene particles and, hence, they may induce
less tissue
reaction4-7.
Recent clinical studies on the outcomes associated with contemporary
metal-on-metal total hip prostheses have shown mostly good results without
osteolysis4,8,9,
and total hip replacements involving these alternative bearings are being
performed more frequently, particularly for younger patients. However, recent
studies on patients with metal-on-metal bearings have shown that the serum
levels of cobalt and chromium ions were significantly higher than those in
normal individuals without
implants10-12.
All metals that are in contact with biological systems corrode, and the
released ions can activate the immune system by forming metal-protein
complexes that are considered to be candidate antigens for eliciting
hypersensitivity
responses13-15.
Although many studies have demonstrated the loosening of first-generation
metal-on-metal hip prostheses in association with hypersensitivities to
cobalt, nickel, and
chromium16-18,
it has not been determined whether the devices failed because the patients had
a preexisting metal hypersensitivity or whether the patients became
hypersensitive to metal as a result of the failed implants. Moreover, to the
best of our knowledge, there have been only two studies that have suggested
the possibility of metal hypersensitivity in patients with contemporary
metal-on-metal hip
replacements19,20.
In the present study, rapidly progressive osteolysis was observed in a
cohort of patients with a second-generation metal-on-metal design. We
investigated the possible role of metal hypersensitivity with skin-patch
tests, histopathologic examinations, and immunohistochemical analysis of
samples of periprosthetic tissue retrieved at the time of revision
operations.
Patients
The present retrospective study was carried out under a protocol
approved by the institutional review board at our medical center. Between
April 2000 and March 2002, 258 patients (264 hips) underwent a primary
cementless total hip replacement; all procedures were performed by a single
surgeon (Y.-S.P.) through an anterolateral approach. Of these, 167 patients
(171 hips) received a modern metal-on-metal bearing (DePuy/Johnson and
Johnson, Leeds, United Kingdom) and ninety-one patients (ninety-three hips)
received a ceramic-on-ceramic articulation (Lima-Lto, Udine, Italy). The
decision to use the metal-on-metal bearing depended on the preference of the
patient, who had been informed preoperatively of the specific benefits and
risks associated with these two bearings. Of the 167 patients (171 hips)
managed with a metal-on-metal prosthesis, two patients (two hips) were lost to
follow-up before a minimum of two years, leaving 165 patients (169 hips). The
study group included eighty-six men (eighty-eight hips) and seventy-nine women
(eighty-one hips) with a mean age of 54.8 years (range, twenty-one to eighty
years) at the time of the operation. The average duration of follow-up was
27.2 months (range, twenty-four to forty-one months).
The diagnosis was osteonecrosis of the femoral head for ninety hips,
osteoarthritis secondary to developmental dysplasia of the hip for twenty-one,
osteoarthritis secondary to childhood septic arthritis for nineteen,
posttraumatic osteoarthritis for twelve, primary osteoarthritis for eight, and
miscellaneous diagnoses for nineteen.
All patients underwent metal-on-metal primary total hip arthroplasty with
the S-ROM modular hip system (DePuy/Johnson and Johnson). This system consists
of an Ultima cup made of Ti-6Al-4V alloy, an Ultima insert made of a cast
cobalt-based Co-28Cr-6Mo alloy with a carbon content of >0.2% (high
carbon), an S-ROM head made of a wrought cobalt-based Co-28Cr-6Mo alloy with a
carbon content of <0.07% (low carbon), and an S-ROM stem made of Ti-6Al-4V
alloy.
Radiographic Review
Two independent observers (Y.-W.M. and S.-J.L.), who were not involved in
the clinical care of the patients, examined the radiographs of each patient.
Osteolysis was defined as a focal area of bone resorption, at least 2 mm wide,
that was not evident on the immediate postoperative
radiograph21. The
immediate postoperative anteroposterior pelvic radiograph, the most current
anteroposterior pelvic radiograph, and every other anteroposterior pelvic
radiograph made between these two time-points were assessed for
osteolysis.
Clinical and Laboratory Investigations for Infection
The nine patients (ten hips) who had an osteolytic lesion were evaluated
with regard to risk factors for infection, such as a history of persistent
drainage or delayed wound-healing. In addition, a physical examination of the
hip was performed to detect any signs of inflammation, swelling, erythema, or
localized tenderness. Laboratory investigations included a complete blood-cell
count and measurement of the erythrocyte sedimentation rate and the C-reactive
protein level.
Skin-Patch Tests
Skin-patch tests were performed according to the standard protocol of the
International Contact Dermatitis Research Group for the nine patients with
early osteolysis as well as for nine randomly selected patients from the
series, matched for age and gender, who did not have an osteolytic lesion
(Table I). Patients were tested
for allergic reactions to nickel sulfate, cobalt chloride, and potassium
dichromate (Chemotechnique Diagnostics, Tygelsjö, Sweden) with use of
Finn Chambers (Epitest, Oy, Tuusula, Finland) on Scanpor Tape (Norgeplaster
Aksjeselskap, Vennesia, Norway) that were applied to areas of the left side of
the patient's upper back that were free of erythema and dermatitis. Patients
returned forty-eight and ninety-six hours after application of the allergens
for a reading of the patch test. The skin reactions were evaluated by a
dermatologist (J.-M.Y.) who was blinded with respect to the clinical data, and
the results were graded as 0 (negative reaction), + (erythema and edema), ++
(erythema and edema with papules and vesicles confined within the chamber),
+++ (erythema and edema with papules and vesicles extending beyond the
chamber), or IR (irritant reaction).
Tissue Specimens
Two of the nine patients who had osteolysis underwent a revision operation.
One patient underwent revision surgery eighteen months postoperatively because
of recurrent dislocation, and the other patient, who had well-fixed implants,
required curettage and bone-grafting because of a large osteolytic lesion that
was associated with a risk of fracture through the greater trochanter.
Periprosthetic tissues were processed for analysis of formalin-fixed,
paraffin-embedded sections as well as for multiple microbiological cultures.
Histopathological analysis of hematoxylin and eosin-stained tissue samples was
performed in order to determine general cellular features. The tissue sections
also were viewed with polarized light, and the presence of metallic particles
was determined according to the criteria of Willert et
al.22.
Immunohistochemical Analysis
Four-micrometer-thick sections were placed onto coated slides,
deparaffinized, subjected to a microwave oven treatment (10 mmol/L sodium
citrate buffer [pH 6.5] for twenty minutes at 700 W), and immersed in
Tris-buffered saline solution with 0.3% (volume per volume) hydrogen peroxide.
After blocking with 1% (weight per volume) bovine serum albumin in
Tris-buffered saline solution containing 0.05% (volume per volume) Tween 20
for thirty minutes, the slides were incubated for one hour at room temperature
with monoclonal antibodies to B lymphocytes (CD20), T lymphocytes (CD3, CD4,
CD8), and macrophages (CD68) for characterization of the cellular components.
For detection of bone-resorbing cytokines, the slides were incubated overnight
at 4°C with a mouse anti-human interleukin-1ß (IL-1ß) polyclonal
antibody (Santa Cruz Biotechnology, Santa Cruz, California) at a dilution of
1:20 or a mouse anti-human tumor necrosis factor-alpha (TNF-a)
monoclonal antibody (HyCult Biotechnology, Uden, The Netherlands) at a
dilution of 1:10. The immunoperoxidase staining was performed with use of the
streptavidin-biotin peroxidase complex method (LSAB universal kit; Dako,
Carpinteria, California). Equivalent amounts of the subtype-matched normal
mouse IgG were used as negative controls, and tissue sections of tonsils were
used as positive controls. The final reaction product was visualized with a
liquid DAB substrate kit (Zymed Laboratories, San Francisco, California).
Statistical Analysis
To test for differences in the rate of metal hypersensitivity between
patients with early osteolysis and the randomly selected age and
gender-matched patients who did not have osteolytic lesions, McNemar tests
were performed with use of standard software (SPSS for Windows, Version 11.5).
The level of significance was set at p < 0.05.
Periprosthetic osteolytic lesions were detected in nine patients
(ten hips; 5.9%) with at least twenty-four months of follow-up. In nine of the
ten hips with osteolysis, the osteolytic lesions were localized within the
greater trochanter superior to the proximal-lateral aspect of the S-ROM sleeve
(zone 1 according to the system of Gruen et
al.23). The
remaining hip had a large lesion that extended from the bone-prosthesis
interface in zone 1 into the proximal aspect of the greater trochanter. The
average size of the lesions was 132.5 mm2 (range, 54.0 to 299.5
mm2). No osteolytic lesions were evident around the acetabular
component. In all ten hips with periprosthetic osteolysis, the acetabular and
femoral components were stable and well-fixed at the time of the latest
follow-up evaluation. As no clear distinction could be made between the edge
of the femoral head and the articulation surface of the acetabular component,
wear could not be measured on plain radiographs.
There was no evidence of persistent drainage and no sign of inflammation in
any of the ten hips. The complete blood-cell count, erythrocyte sedimentation
rate, and C-reactive protein values were within normal limits in all nine
patients. The gram stains, smears for acid-fast bacilli, and multiple
microbiological cultures of all of the retrieved periprosthetic tissues from
the two revised hips were negative.
Eight of the nine patients with early osteolysis, including the two
patients who underwent revision surgery, had a positive patch test for cobalt
chloride. In contrast, only two of the nine control patients had a positive
test for cobalt chloride. Two patients in the study group and none of the
patients in the control group had a positive test for nickel sulfate. One
patient in the study group and two patients in the control group had a
positive test for potassium dichromate (see Appendix). The patients with
osteolysis had a significantly higher rate of hypersensitivity reaction to
cobalt chloride compared with controls (p = 0.031), but, with the numbers
available, there were no significant differences between the groups with
regard to the rate of hypersensitivity reaction to nickel sulfate (p >
0.05) or potassium dichromate (p > 0.05).
Two patients who had a positive patch test for both cobalt chloride and
nickel sulfate had had cutaneous symptoms. These patients had complained of a
generalized eczematous or urticarial reaction after the metal-on-metal
prosthesis had been implanted.
The two hips that underwent revision surgery had no evidence of metallic
staining in the periprosthetic tissue at the time of the revision, and no
notch or groove was apparent in the neck of the femoral component that would
have been suggestive of impingement between the socket and the femoral neck.
The bearing surfaces of the prosthesis that was retrieved because of recurrent
dislocation were inspected with a non-contact, optical, three-dimensional
scanner (REXCAN 400; Solutionix, Seoul, Korea). Although there were some fine
scratches in the femoral head, there were no visible areas of wear when
compared with unused prostheses.
Histologic examination of the retrieved periprosthetic tissues from the two
revised hips showed perivascular infiltration of lymphocytes and mononuclear
phagocytes in both cases. In one case, several lymphoid follicles also were
noted. Neither particle-laden macrophages nor polymorphonuclear cells were
seen on standard and polarized microscopic examination of the tissue sections.
Immunophenotyping analysis revealed that most tissue-infiltrating lymphocytes
in the periprosthetic tissue expressed the CD3 marker and therefore could be
identified as T-cells. Additional staining showed that mixed CD4 and
CD8-positive T-cells were present throughout the periprosthetic tissue.
CD68-positive macrophages also were diffusely distributed throughout the
periprosthetic tissue, and small numbers of CD20-positive cells were
preferentially encountered within the lymphoid follicles. Immunohistochemical
localization for the bone-resorbing cytokines revealed that IL-1ß and
TNF-a were expressed by T-cells and CD68-positive macrophages
(Fig. 1).
Complications
In addition to the two patients who required revision surgery, one patient
required internal fixation of a periprosthetic fracture of the femur without
revision of the femoral component. Another patient with high-riding
developmental dysplasia of the hip had a nonunion following a subtrochanteric
shortening derotational femoral osteotomy and cementless total hip
arthroplasty. The nonunion was treated with dual onlay strut allografts and
cable fixation. One patient had an incomplete sciatic nerve palsy, noted
immediately after the index operation, that resolved almost completely by
twelve months postoperatively.
Although reports on contemporary metal-on-metal hip prostheses have
been generally
favorable4,8,9,
some retrieval studies have revealed evidence of metallic deposits in the
periprosthetic tissues due to impingement of the neck on the
socket24-26.
In the cases of the two revised hips in the present study, no evidence of
impingement of the components was seen at the time of revision surgery, no
metallic deposits were detected in the periprosthetic tissues, and no metal
particle-laden macrophages or foreign-body giant cells were found on standard
and polarized microscopic examination of the tissue sections. We did, however,
observe perivascular infiltrations of T-cells and macrophages in the tissue
sections, which were similar to the histologic findings recently reported by
Willert et al.20.
Although the lack of observable metal debris under the polarized light
microscope does not rule out the presence of undetectable metal wear particles
in the nanometer size-range, our tissue findings are inconsistent with those
typical of particle-induced osteolysis, which is associated with abundant
particle-laden macrophages within periprosthetic
tissues27,28.
Our findings also differ from those of Beaulé et
al.29, who reported
progressive diaphyseal osteolysis in patients with well-fixed,
second-generation metal-on-metal hip replacements. We believe that the
histologic features observed in the cases of our two patients are suggestive
of an immune-system response to metal ions in the periprosthetic tissue. We
speculate that antigen-specific sensitization of T-cells may play a role in
the development of early osteolysis following second-generation metal-on-metal
hip replacement.
Metal ions are allergens that are known to cause contact dermatitis, a
delayed-type hypersensitivity reaction mediated by T-lymphocytes specific for
the relevant
metal13,14,30.
Allergic reactions also can take place within the joint capsule and
pericapsular
tissue13. The most
common metal sensitizer in humans is nickel, followed by cobalt and chromium,
and cross-sensitivity reactions between metals are most common with nickel and
cobalt14,15,30.
The prevalence of metal sensitivity among patients with a well-functioning
implant is roughly twice that in the general population and, among patients
with a failed or poorly functioning implant, it is approximately six times
that in the general population and approximately two or three times that among
all patients with metal
implants14. We
found only one follow-up study that demonstrated an association between metal
hypersensitivity and prosthetic failure in patients with second-generation
metal-on-metal hip
replacements19. The
authors of that study analyzed 200 surface metal-on-metal hip replacements
(containing nickel, cobalt, and chromium), including five replacements that
failed because of aseptic or septic loosening. Three of the five hips that
loosened were in patients who had positive skin-patch testing, all for nickel.
In contrast, only three of eighteen controls had positive skin-patch tests.
While that study documented a higher rate of metal hypersensitivity among
patients with loose prostheses, it provided neither a statistical analysis of
the results of the patch tests nor any histologic findings.
In the present study, the nine patients (ten hips) who had an osteolytic
lesion had a significantly higher rate of hypersensitivity to cobalt, as
determined with patch testing, compared with controls. These data agree with
previous
observations16-18
that the loosening of first-generation metal-on-metal hip prostheses had an
association with hypersensitivities to cobalt, nickel, and chromium. In one of
the earliest studies investigating a possible association between metal
hypersensitivity and aseptic loosening, Evans et
al.18 evaluated the
histopathologic features of skin-biopsy specimens from four patients as well
as skin biopsy specimens from one patient, in which they found a prominent
granulomatous collection of cells with a surrounding zone of lymphocytes.
Importantly, the author could not determine whether the patients became
hypersensitive to metal because of the failed device or whether the device
failed because the patients had a preexisting metal hypersensitivity.
Patch testing is the most common method used to diagnose contact allergy to
metals31,32.
However, it has certain limitations when used as a method to determine
deep-tissue hypersensitivity. Patch testing involves exposure to the relevant
allergen for a short period of time (forty-eight to ninety-six hours), whereas
a closed periprosthetic environment involves constant exposure to the
orthopaedic
implant14. While
the antigen-presenting cells on dermal contact are dendritic cells, the
possible antigen-presenting cells in a joint are synoviocytes, which are
capable of presenting metal ions to the pericapsular tissue-infiltrating
T-lymphocytes13. In
addition, immunologic tolerance can be induced by implantation of a metal
prosthesis33,34,
thus possibly diminishing the sensitivity of patch tests. Rooker and
Wilkinson33, in a
study in which fifty-four patients were given patch tests before and after
metal-on-plastic hip replacement, reported that five of six patients had lost
their metal sensitivity at the time of postoperative retesting.
Since Brown et
al.35 first used
migration inhibition assays to investigate delayed-type hypersensitivity to
metallic orthopaedic implants, only a few
investigators36,37
have applied in vitro delayed-type hypersensitivity testing methods to assess
the biocompatibility of implanted devices. These methods remain a
labor-intensive and clinically unpopular means of assessment. To date, a
standardized, effective testing methodology for the clinical determination of
hypersensitivity reaction to metal implants has not been well established.
Delayed-type hypersensitivity is characterized by antigen activation of
sensitized T-cells releasing various cytokines that result in the recruitment
and activation of
macrophages38.
Among the cytokines released by activated T-cells and macrophages, IL-1ß
and TNF-a potently stimulate
osteoclastogenesis39.
In addition, TNF-a is also capable of downregulation of collagen-type-I
synthesis in osteoblasts, another potentially important contributor to
periprosthetic bone
loss40.
Our immunohistochemical analysis of periprosthetic tissue from two hips
with early osteolysis revealed that most tissue-infiltrating cells were
CD3-positive T-cells and CD68-positive macrophages. It is notable that
CD8-positive T-cells were also abundant in the periprosthetic tissue,
suggesting that T-cell-mediated cytotoxicity might be associated with the
development of osteolysis. We also identified the potent bone-resorbing
cytokines such as IL-1ß and TNF-a in the periprosthetic tissue in
association with T-cells and activated macrophages.
Taken together, these findings raise the possibility that early osteolysis
in patients with this second-generation metal-on-metal hip replacement is
associated with a delayed-type hypersensitivity to metal, mainly cobalt.
However, our data must be interpreted with caution because only two patients
with early osteolysis had tissues available for histologic analysis.
Additional weaknesses of our study include the lack of preoperative
immunologic evaluation of the patients and the limitation of skin-patch
testing as a method of determining deep-tissue hypersensitivity. Additionally,
we studied only one design of prosthesis and therefore cannot generalize our
findings to all second-generation metal-on-metal hip prostheses.
It is unclear whether delayed-type hypersensitivity to metal contributed to
the development of osteolysis or whether the patients became hypersensitive to
metal secondary to an immune response to an osteolytic process. As a result of
our findings, we are reluctant to implant modern metal-on-metal bearings in
patients who have a history of allergic reaction to a metal implant or
metallic wear. A prospective study in which a large group of patients with
contemporary metal-on-metal bearings are evaluated with multiple testing
methods, including in vitro delayed-type hypersensitivity assays as well as
skin-patch testing, is needed to better explain any causal relationship
between metal hypersensitivity and osteolysis.
A table presenting the results of the patch tests is available with the
electronic versions of this article, on our web site at
(go to
the article citation and click on "Supplementary Material") and on
our quarterly CD-ROM (call our subscription department, at 781-449-9780, to
order the CD-ROM). ?
The authors did not receive grants or outside funding in support of their
research or preparation of this manuscript. They did not receive payments or
other benefits or a commitment or agreement to provide such benefits from a
commercial entity. No commercial entity paid or directed, or agreed to pay or
direct, any benefits to any research fund, foundation, educational
institution, or other charitable or nonprofit organization with which the
authors are affiliated or associated.
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