There is a possible
relationship between joint replacements and malignancy. We
review the current state of metal-on-metal hip implants, the
process of metal ion release from the implants, the effect of
released metal ions in vivo, the association between
neoplasm and metal debris and ions, and the six documented cases
of neoplasm around a metal-on-metal total hip replacement. We
find no link between released metal ions and the occurrence of
metal-on-metal hip implants, metal ion
release, metal debris, total hip arthroplasty, total hip
replacement, neoplasm, malignancy, cancer.
Total hip arthroplasty (THA) has evolved into one of the most
common and cost-effective orthopedic reconstructive procedures
with a high long-term success rate. However, due to the dynamic
nature of the hip implants and the direct contact with
biological tissue, particulate wear and corrosion debris are
liberated into the joint space and surrounding tissues 1, 2. The
subsequent biological response poses a problem to the durability
and long-term efficacy of the hip implants. Metal ions that are
released, such as cobalt and chromium, are of importance because
of their carcinogenic potential3, 4. Of particular interest are
hip implants with metal-on-metal bearings (MOM). There have been
several cases of malignant tumors that have developed at the
site of such implants. The purpose of this review is to examine
if there is any connection between neoplasia and metal ion
debris in THA. The following review is organized into six
sections: (1) current state of MOM THAs, (2) metal bearing wear
and ion release, (3) biology of ions, (4) neoplasia associated
with metal debris and ions, (5) reported cases of neoplasia
around THA (6) conclusion.
Current State of MOM THA
Metal-on-metal (MOM) bearing coupling was popular in the 1960ís
and 1970ís, but was abandoned by US surgeons in favor of
metal-on-polyethylene bearings due to concerns over biological
reactions and reported high loosening rates. One of the
limitations of polyethylene is wear debris generation at the
bearing surface. This led to the development of alternative
bearing surfaces including the reintroduction of MOM bearings in
the late 1980ís5. These newer designs with MOM bearings have
been shown to be clinically efficacious and more durable than
earlier designs. Dorr et al.6 reported mechanical failure rates
(combined rates of revision and loosening) in 56 patients with
the Metasul (Zimmer, Warsaw, IN) design from 1991 to 1994. There
were 49 patients with primary osteoarthritis, 3 with congenital
dysplasia, and 2 each with posttraumatic arthritis and femoral
head osteonecrosis. All patients had well functioning hips at an
average of 5.2 years of follow-up.
Wear debris and metal ion release are clinical concerns. Jacobs
et al.7 reported 3-fold serum concentration increases in
titanium and 5-fold increases in chromium at thirty-six months
following surgery in 55 patients with MOM THAs compared to
control patients without implants. Sauve et al.8 reported 5-fold
and 3-fold serum concentration increases for cobalt and
chromium, respectively in 310 patients with Ring MOM THAs as
long as 30 years after the index surgery. It is of interest to
note that in 3 of the patients who underwent revision for
aseptic loosening, serum metal concentrations were within normal
Meat bearing wear is influenced by several factors: carbon
content, manufacturing process, and diametral clearance. Rieker
et al.9 reported on analysis of a large collection of retrieved
MOM components. These included 608 components from 337
revisions. 172 of these were analyzed for clearance (surface
geometry match between the head and the liner). These components
were in-vivo from one month to 12 years. They reported several
important findings: 1) the mean wear rate in the first year was
high (27.8 um/year), 2) the mean wear rate following the second
year was low (6.2 um/year), 3) regression analysis showed
clearance to be the most important variable correlated with the
linear wear rate (p=0.0005). Current laboratory and clinical
retrieval data on MOM couplings support the idea that superior
wear characteristics are associated with high carbon content,
wrought manufacturing, large diameter, and low clearance.
Metal Bearing Wear and Ion Release
Metal ions release can occur by two proposed mechanisms: 1) wear
as a function of adhesion, abrasion, or fatigue of the materials
resulting in particulate debris, and 2) corrosion of the metal
bearing wear resulting in the release of metal ions. Metallic
implants have the ability to achieve passivity in-vivo, in which
active and passive surfaces between metallic biomaterials and
electrolytes exist in contact simultaneously. The protective
surface oxide layer on the implants is in a continuous process
of partial dissolution and reprecipitation10. Dissolution is
favored by contact with proteins and amino acids leading to
corrosion. In addition, macrophages that ingest released
particles are stimulated by inflammatory mediators such as TNF-α
to release reactive oxygen species such as superoxide (O2-) and
hydrogen peroxide (H2O2). These products can be metabolized into
products such as hypoclorous acid, capable of damaging
extracellular matrix components and increasing degradation by
High serum and urine metal ion concentrations have been
associated with both first and second generation MOM bearings.
Jacobs et al.12 found that serum chromium concentration was
9-fold higher and cobalt concentration 3-fold higher in patients
with McKee-Farrar THAs than the control patients without
implants. Second generation implants showed similar increases in
metal ions. Savarino et al.13 reported 4-to-5-fold higher cobalt
concentrations and 7-fold higher chromium concentrations in
patients with the Metasul THAs than in control patients without
There is concern over metal ion release in the growing
population of young and active patients that receive THAs.
Heisel et al.14 compared cobalt and chromium levels in patients
with MOM THAs as a function of varying levels of activity. They
found a 2.7% and 3.0% serum concentration increase in cobalt and
chromium, respectively when the patients increased their mean
activity by 28% as measured by a 2-dimensional accelerometer
worn on the ankle. During treadmill running, mean activity
increased by 1621% while serum cobalt and chromium
concentrations increased by 3.0% and 0.8%. Based on the accuracy
of the tests and the small relative size of serum metal ion
changes, the data did not demonstrate statistically significant
correlation between activity level and serum metal ions.
Release of metal ions from MOM THAs has clinical significance
for child-bearing females. Ziaee et al.15 collected blood from
the mother and umbilical cord after five deliveries, four of
which involved MOM THAs. The chromium and cobalt levels were an
average of 50% lower in the cord than in maternal blood and
there was a strong correlation between levels of trace elements
in the cord and maternal blood.
Biology of Ions
Metal ion toxicity can occur if the ion binds with a biomolecule.
Titanium ions are very active and immediately bind to water or
inorganic anions within the tissue. On the other hand, inactive
ions such as copper and nickel remain as ions for long durations
and have a greater chance of combining with biomolecules to
express toxicity10. Trace elements that show similar
high-reactive ion binding qualities to titanium, such as
zirconium, niobium, and tantalum, hold promise as alloys that
could decrease bonds between metal ions and biomolecules.
Released ions would instead bind harmlessly to water and
inorganic anions in the tissue.
Metal ion toxicity can lead to local tissue inflammation,
fibrosis, and necrosis. Mathiesen et al.16 reported extensive
periprosthetic tissue necrosis due to metal ion toxicity in 4 of
9 patients with MOM THAs. Metal particles can also be found
beyond the periprosthetic tissue to regional lymph nodes, liver,
and spleen12, 17, 18. These particles can interfere with
osteoblasts and osteoclasts, inducing bone resorption and cause
toxicity to macrophages and fibroblasts19, 20.
Several recent studies have documented evidence of
hypersensitivity to metal wear particles in patients with
painful and failed MOM THAs. Park et al.21 reported a
significantly higher prevalence of hypersensitivity to cobalt
(p=0.03) in patients with early osteolysis when compared to
control patients. The cohort consisted of 169 THAs with
second-generation MOM bearings, with ten reported cases of
osteolysis. Histiologic analysis of periprosthetic tissue from
two patients with osteolysis revealed a perivascular
accumulation of CD3-positive T-cells and CD68-positive
macrophages. Immunohistochemical analysis demonstrated the
presence of bone-resorbing cytokines such as IL-1β and TNF-α.
These findings suggest that delayed hypersensitivity in MOM THAs
may cause early osteolysis. Milosev et al.22 reported similar
evidence of osteolysis from hypersensitivity to metal wear
particles. He analyzed a cohort of 591 patients with MOM THAs at
a mean of seven years postoperatively and showed a survival rate
91% at ten years (95% confidence interval 0.88 to 0.95). The
major cause of failure was aseptic loosening, which occurred in
25 patients. Histological analysis of 17 of the revision THAs
showed a hypersensitive reaction in 13 patients (2%), with
perivascular infiltration of lymphocytes and aseptic
Neoplasia Associated with Metallic Debris and Ions
Metal ions have been linked to increased cancer rates. Visuri et
al.23 reported a standardized incidence ratio (rate of
occurrence in the cohort compared to the general population) of
3.0 (95% confidence interval 1.1-6.6) for hematopoietic cancers
in a cohort of 433 patients with McKee-Farrar MOM THAs. The
standardized incidence rate of leukemia was also elevated at 3.2
(95% confidence interval 1.0-7.4).
Current MOM THAs are made of alloy biomaterials consisting of
cobalt, chromium, titanium, aluminum, vanadium, and nickel. The
carcinogenic potential of cobalt and nickel have been reported
in animals. Intramuscular or intrathoracic injections of cobalt
metal powder produced fibrosarcomas and rhabdomyosarcomas at the
injection sites in mice while intratracheal instillation of
nickel metal powder in rats resulted in significant numbers of
squamos-cell carcinomas and adenocarcinomas of the lung24.
Osteosarcomas and fibrosarcomas have also been found in cats and
dogs with stainless-steel metallic composition internal fixation
devices25. However, Lewis et al.26 injected CoCrMo or TiAlV wear
debris powder into the knee joints in rats. They found no case
of neoplasia as a result of this exposure.
The exact mechanisms and association between neoplasia and
metallic trace elements remain to be defined. The association of
implant loosening and tumors around the implant site in rats
suggests that neoplasia resulted from a foreign-body reaction27.
This relationship has yet to be established in humans.
Macrophages binding to implants result in the generation of
reactive oxygen species (ROS)28, 29. ROS can cause alterations
in host DNA, most frequently causing guanine-to-thymine
transversions30. If these modifications are associated with
oncogenes or tumor suppressor genes, then metal ion release can
indirectly lead to the pathogenesis of neoplasia. Multiple
mutations in the p53 tumor suppressor gene have been reported as
guanine-to-thymine transversions31, 32 and oxidative DNA
modifications in cancer tissue from ROS have been reported33.
Reported cases of neoplasia
Since 1974, there have been 51 reported cases of malignant
tumors at the site of a THA in the English literature. These
include 20 cases of malignant fibrous histiocytoma, 10
osteosarcoma, 4 non-Hogkin lymphoma, 3 spindle cell sarcoma, and
2 cases each of pleoemorphic rhabdomyosarcoma, fibrosarcoma, and
leiomyosarcoma. Other individual cases were chondrosarcoma,
malignant peripheral nerve sheath tumor, synovial sarcoma,
multiple myeloma, liposarcoma, adenocarinoma and malignant
epithelioid hemangioma. The patients range in age from 39 to 88
years, with a mean age of 66 years. The mean time interval from
implantation to the diagnosis of neoplasia was 6.6 years with a
range of 0.5 to 20 years. 6 of these occurred around MOM THAs.
We will detail these 6 cases.
Penman and Ring34 reported a case of ostesarcoma in a
75-year-old woman with a cobalt-chromium MOM THA. The tumor was
discovered 5 years post-operatively on the lateral side of the
right femur. There was no history of Pagetís disease or
radiotherapy. The authors concluded that metal ion release could
have been associated with the development of the tumor.
Swann35 reported a case of malignant fibrous histiocytoma in a
63 year-old man that developed 3.5 years post-operative to a MOM
THA. Ryu et al.36 reported a case of soft tissue sarcoma in a 40
year-old man 1.5 years post-operative to a MOM THA. Stephenson
et al.37 reported a case of liposarcoma in a 57 year-old man 6
years post-operative to a MOM THA. In all 3 of these cases, the
tumors were not in direct contact with the metal implants. Metal
content was only measured in the liposarcoma patient and no
increased levels were found. This evidence suggested that the
tumors were not directly caused by the carcinogenic potential of
metal ions or debris from the implants.
Rushford38 reported a case of osteosarcoma in the acetabulum 5
months post-operative to a cobalt-chromium MOM THA in a
54-year-old woman. She had previously developed squamos cell
carcinoma in her cervix which was treated successfully with
radium insertion and external irradiation. The prosthetic cup
was found to be loose and the acetabulum bone quality was
abnormal. The authors concluded, based on the greater proportion
of bone radiation absorption, that the patientís previous
radiotherapy resulted in the subsequent development of
Arden and Bywater39 reported a case of fibrosarcoma 2.5 years
post-operative to a MOM THA in a 56-year-old patient. The
sarcoma was found to arise from the arthroplasty scar and extend
down to the pseudo-capsule, but did not involve the femur or
There is no
conclusive evidence to establish any direct link between metal
ion or debris with malignancy around THAs with MOM bearings. It
is however critical for these participants to be followed,
especially when MOM THAs are being done with greater frequency
and in younger patients.
Malignant Tumors at the Site of Total Hip Arthroplasty
(click to enlarge)
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