Excretion Levels of Metal Ions in
Patients Undergoing Total Hip Replacement with a
Porous-Coated Prosthesis: Preliminary Results
Quantitative Characterization and Performance of Porous Implants
for Hard Tissue Applications, ASTM STP 953
by Lynne C. Jones,1 David S. Hungerford,2
Robert V. Kenna,3
Guy Braem,4 and Virginia Grant5
associate, Orthopaedic Surgery, Johns Hopkins University School
of Medicine, Baltimore, MD 21239.
Orthopaedic Surgery, Johns Hopkins University School of Medicine,
Chief, Division of Arthritis Surgery, Good Samaritan Hospital,
Baltimore, MD 21239.
3Research associate, Orthopaedic Surgery, Good
Samaritan Hospital, Baltimore, MD 21239.
4Research technician, Johns Hopkins University
School of Medicine, Baltimore, MD 21239.
5Staff chemist, Chesapeake Bay Institute of the
Johns Hopkins University School of Medicine, Baltimore, MD
Jones, L. C.. Hungerford, D. S., Kenna, R. V., Braem, G.,
and Grant, V., "Urinary Excretion Levels of Metal
Ions in Patients Undergoing Total Hip Replacement with a Porous-Coated
Prosthesis: Preliminary Results," Quantitative
Characterization and Performance of Porous Implants for Hard
Tissue Applications, ASTM STP 953, J. E. Lemons, Ed.,
American Society for Testing and Materials, Philadelphia,
1987, pp. 151162.
prostheses implanted without bone cement are currently being
evaluated for use in patients undergoing total joint replacement
(TJR). One parameter under study is the potential release
of metal ions from these prostheses. In order to determine
if there is a systemic increase in cobalt, chromium, or nickel
levels within the body subsequent to total joint replacement
with a porous-coated prosthesis, 24-h urine specimens were
collected from patients prior to and subsequent to TJR with
a PCA total hip prosthesis. Metal ion analysis was achieved
using flameless atomic absorption spectroscopy. Increases
in urinary cobalt and nickel excretion were detected in several
patients at six months and in most patients at one year after
surgery. However, these differences were not statistically
significant. No differences between the preoperative and postoperative
time periods (one week, six months, and twelve months) were
detected for urinary levels of chromium. Although the metal
ion levels for all of the patients studied appear to be in
the range handled by the bodys systemic compensatory
mechanisms, which adjust levels of trace elements, continued
follow-up is needed to determine the patterns and the long-term
significance of metal ion release.
WORDS: porous implants, biocompatibility, corrosion,
total hip replacement, porous-coated prostheses, flameless
atomic absorption, metal ion release
issue of biocompatibility of orthopedic implants, although
not new, has come recently to the fore in orthopedic surgery
with the introduction of porous-coated prostheses, which can
be used in the cementless application of total joint arthroplasty.
Although all metallic implants are subjected to corrosive
forces within the body, these forces may have a larger impact
on porous-surfaced prostheses. Porous-coated implants have
an increased total surface area, as well as intimate contact
with bone. It has been suggested that these two factors may
contribute to an accumulation of corrosion products retained
in the body, which, if given sufficient quantities and time,
may lead to potential immunological, toxicological, or carcinogenic
effects . Due to the limited clinical experience
with porous-coated prostheses, there is a paucity of information
available pertaining to metal ion release from these implants
principal objective of our investigation was to determine
if there were increased levels of the metal ions which constitute
the metallic components retained by patients undergoing total
hip arthroplasty. Analysis of metal ion levels in urine samples
has been shown to give an accurate assessment of the total
body load [713J. A long-term study was instituted
in which 24-h urine samples from patients undergoing total
hip replacement (THR) with a PCA total hip prosthesis were
collected at various time intervals prior to and subsequent
to surgery and were analyzed for changes in total metal ion
content. Levels of the metals that comprise this prosthesiscobalt,
chromium, and nickelwere determined using flameless
atomic absorption spectroscopy. The following is a report
of our preliminary findings for up to twelve months after
study population included 30 patients who were scheduled for
cementless total hip replacement with a PCA total hip system
(Howmedica, Inc., Rutherford, NJ). Participation in this clinical
study, approved by the Institution Review Board, was on a
volunteer basis; consent was obtained only after the study
had been fully explained to each individual. At the time of
this writing, information was available for various time periods
up to one year for 17 patients. The following descriptive
information was collected from each patient: occupation, location
of residence, alcohol consumption, and level of tobacco smoking.
All patients underwent cementless implantation of a PCA total
hip prosthesis, an implant with an ultrahigh-molecular-weight
polyethylene (UHMWPE) surface articulating with a cobalt-chromium
hour urine samples were collected at the following time periods:
preoperatively, and postoperatively at one week, six months,
and twelve months. [Urine specimens are continuing to be collected
for each of these patients on an annual basis.] Urine collection
was achieved using sterile Medi-Flex specimen containers (Tn-State
Hospital Supply Corp., Howell, MI) and Medi 24-h urine containers
(Medi, Inc., Holbrook, MA). The patients were asked not to
ingest any vitamins (particularly B-complex vitamins) 48 h
prior to collection of urine. They were also asked not to
contaminate the collection vessels by rinsing or wiping the
surfaces. At the time of receipt, the total 24-h urine output
was measured and recorded. The samples were then agitated,
and two 50-mL aliquots were drawn into sterile Corning centrifuge
tubes (Corning, Corning, NY). These tubes were stored in a
Revco ultralow-temperature freezer (West Columbia, SC) at
-70°C until the time of analysis. An additional 10-mL sample
was taken and used for analysis of specific gravity.
standards were evaluated in order to determine the accuracy
of the methodology for each of the ions under analysis. Each
of the standards was prepared from reference solutions purchased
from the Fisher Scientific Co. (Fairlawn, NJ). Solutions ranging
from 5 to 50 parts per billion (ppb) were analyzed.
The diluent used was ultrapure deionized water (Millipore
Milli-Q System, Bedford, MA). In addition, Standard Reference
Material (SRM) No. 2670 (National Bureau of Standards, Washington,
DC) was analyzed for normal and elevated chromium and nickel
levels in urine. Both calibration evaluations yielded reproducible,
the time of analysis, all the urine samples were removed from
the freezer and placed in a warm-water bath until thawed.
The tubes were then centrifuged at 200 rpm for 10 mm. If a
precipitate had formed, determinations of the volume of the
supernatant and the recipitate were made. A concentration
of approximately 60-pt of ultrapure nitric acid (Ultrex grade,
J. T. Baker Chemical Co., Philipsburg, NJ) for each 10 mL
of supernatant was added to the pellet only. The dissolved
pellet was then returned to the supernatant.
determinations of the cobalt, chromium, and nickel content
of the urine samples were made using the "method of additions"
. This involves analysis of three aliquots per
specimen under study: these aliquots were (1) undiluted, (2)
spiked with 2 ppb cobalt and 2 ppb chromium, and (3) spiked
with 10 ppb nickel. All the specimens were analyzed using
a Perkin-Elmer Model 4000 atomic absorption spectrometer with
a Model HGA 500 lectrothermal source (Perkin-Elmer, Norwalk,
CT). This technique included the use of pyrolyzed graphite
furnace tubes and deuterium background correction. The analytic
program was optimized for each phase (drying, ashing, and
atomization) and for each metal wavelengths and slit widths)
was taken to minimize all possible sources of contamination.
This included subjecting all containers, laboratory glassware,
and equipment to acid washing with 10% nitric acid. In addition,
all triplicate values were reviewed to detect possible decreases
in analytic efficiency, as well as periodic sampling error
or contamination. If the three values were inconsistent, the
specimen was reanalyzed.
analysis of the results was achieved using analysis of variance
techniques for elated measurements, and the comparisons were
made using linear contrast methods. All methods of analysis
stressed the value of comparing the variability of the data
for an individual patient, as well as the variability between
this time, we are reporting only the preliminary findings
obtained. As this is a very early stage of a long-term investigation,
the information available involves only a fraction of the
30 patients to be included (17 evaluated preoperatively, 14
at six months postoperatively and 4 at one year postoperatively).
For the 17 patients included in the preoperative evaluation,
the diagnosis at presentation was primarily osteoarthritis
(n = 11), although a few patients had
diagnoses of avascular necrosis of bone (n =
3) and rheumatoid arthritis (n = 3). This group included
11 males and 6 females. The age of the patients ranged from
14 to 77 years with a mean of 58 years. Most of the
patients resided in Maryland (n = 13),
primarily in Baltimore and its suburbs (n =
7); the others lived in New York (n =
2), Pennsylvania (n = 1), and Illinois
(n = 1). The majority of the patients
were not smokers or excessive alcohol consumers. All but 1
patient had jobs in which occupational exposure is not known
to occur; 1 patient was a machinist.
values for urinary metal ion excretion are reported as the
mean plus or minus the standard error. All the statistical
analyses weighted the comparison of each individual to himself.
As no significant differences were seen in the specific gravities
of the samples for each individual patient, no conversion
of the results from micrograms per litre was attempted.
and one-week-postoperative specimens were collected and analyzed
for 17 of the study patients (Fig. 1). For these patients,
the average urinary levels of the preoperative samples were
0.95 ± 0.28 µg/L for cobalt, 1.41 ± 0.24 µg/L
for chromium, and 4.31 ± 1.14 µg/L for nickel. These
averages and variances are similar to those reported by previous
investigators [1013,16,17]. Postoperatively (at
one week), values of 1.08 ± 0.28 µg/L for cobalt, 2.85
± 1.34 µg/L for chromium, and 11.8 ± 6.74 µg/L
for nickel were determined.
1Mean control values for urinary metal
ion levels for 17 patients scheduled to undergo total hip
replacement. The bar lines indicate the 95% confidence limits.
increases were seen for each metal ion, these increases were
not statistically significant. The urinary chromium and nickel
levels for one patient were significantly elevated one week
postoperatively (17.3 and 85.2 µg/L, respectively).
As these values are considerably outside the range seen for
the other patients, it was suggested that these results may
have been due to contamination of the specimen. As is shown
in Table 1, this patient had normal levels at the six- and
twelve-month time periods. The average values, if this patient
is excluded, are 1.53 ± 0.27 µg/L for chromium and 5.08
± 1.00 µg/L for nickel. Three patients underwent subsequent
THR for the contralateral hip and those results are not included
in the six- and twelve-month results reported herein.
1 - Urinary metal ion rsults determined for
four patients followed up to one year subsequent to
total hip replacement.a
+ standard error
1.78 + 0.70
4.87 + 2.44
5.67 + 3.92
26.06 + 19.87
2.12 + 0.86
15.03 + 4.84
1.20 + 0.41
13.58 + 2.33
values are in micrograms per litre.
bPossible contamination is not ruled out.
The mean nickel value for one week postoperatively is
6.35 + 3.04 µg/L when this value is deleted.
The mean chromium value is 1.79 + 0.84 µg/L
when excluding this value.
2 graphically illustrates the results for these patients evaluated
at six months (n = 14). At six months, a slight increase
was detected for cobalt (1.57 ± 0.50 µg/L) and
chromium (1.52 ± 0.27 µg/L), while a larger average
increase was found for nickel (11.43 ± 2.92 µg/L).
This elevation in nickel ion level is primarily a reflection
of the elevated values found for two patients (29.2 and 41.0
µg/L). One of the patients returned to normal levels
(10.6 µg/L) by one year. The one-year follow-up for
the other patient is not available at this time. However,
using statistical methods that allow comparison of the variance
within one patient to that of all patients (that is, ANOVA
for related measurements), it was determined that these differences
were not statistically significant. No relationships between
the elevated values and age, occupation, alcohol consumption,
or cigarette smoking were detected.
this time, results are available for only 4 patients for the
one-year follow-up period (Table 1). This group included 2
males and 2 females with an average age of 68 years (the range
was 61 to 74). None of the patients was a smoker and their
alcohol consumption ranged from abstinence to one drink per
day. No change in the level of urinary chromium (1.20 ± 0.41
µg/L) was detected. Cobalt was observed to increase
in 3 of the 4 patients, with an average value of 2.90 ±
0.92 µg/L (Fig. 3). With respect to nickel, an average
value of 13.58 ± 2.33 µg/L was seen, also reflecting
an increase in 3 of the 4 patients. Although these data reflect
a threefold increase for cobalt and nickel in comparison with
the preoperative values, this increase was not found to be
- Six-month follow-up results for 14 THR patients, demonstrating
no increase in urinary cobalt or chromium content, in comparison
with preoperative levels, and an elevation in nickel content
due, in part, to large increases observed in 2 patients. Excluding
these 2 patients, the average urinary nickel level was 7.49
+ 1.16 µg/L at six months. The bar lines encompass
the 95% confidence limits.
3 - One-year results for 5 THR patients, showing
increases in urinary cobalt and nickel, in comparison with
preoperative levels, for 3 of the 4. No changes were seen
in the urinary chromium levels over time. The 95% confidence
limits are shown by the bar lines.
a variety of metals have been inserted into patients since
the late 1700s, there remains a paucity of information available
on the biological effects of these implants on the human body.
Evaluation of retrieved specimens, as well as experimental
findings, indicates that metallic implants exhibit corrosive
behavior . With the advent of metal-on-metal
prostheses, accumulation of wear debris surrounding the joint
has also been observed [22,23]. The development of
ultrahigh-molecular-weight polyethylene (UHMWPE) for plastic-to-metal
articulating surfaces has reduced the quantities of metallic
products observed in the evaluated joints . However,
an unacceptable rate of loosening of the components of the
prosthesis in patients with total knee and total hip arthroplasty
has been seen with the use of methacrylate cement for implant
fixation. It is for this reason that porous-coated prostheses,
which allow biologic ingrowth for implant fixation, were developed.
Renewed concerns about the toxicity and carcinogenicity of
implant material have been primarily related to the increased
surface area of the prosthesis, the intimate contact between
the bone and the metal, and the technology involved in the
sintering of the beads. It is important to relate these concerns
to the clinical situation.
issue of biocompatibility of orthopedic implants involves
the study of potential local and systemic effects of the metal
ions released from the surfaces of each prosthetic component.
In the laboratory, corrosion products of Co-Cr alloy prostheses
have demonstrated cytotoxic or carcinogenic potential .
Concerns pertaining to cytotoxicity are usually in reference
to the local reaction of the biologic tissue in juxtaposition
with the implant material. Not as well studied are the possible
toxic effects on the metabolic functions of other tissues
in the body. Carcinogenesis may be either a local or a systemic
effect. The evaluation of the possible local carcinogenic
effect is dependent on the collection of retrieved specimens
from deceased patients. Although this project has been initiated
at our institute, the results are not available for report.
In order to assess, indirectly, the level of corrosion and,
directly, the level of systemic response to potential corrosion
products of orthopedic implants, serum and urine samples have
been monitored by previous investigators [14,2528].
Both methods of biological monitoring have been validated
for use as indicators of exposure to cobalt, chromium, and
nickel 1713]. Collection and analysis of urine samples
offer the advantages of ease of collection, minimum discomfort
to the patient, and a minimum of matrix complications. For
these reasons, we enlisted patient volunteers for the evaluation
of 24-h urine specimens subsequent to THR with a PCA total
hip system. There is an increased risk of specimen contamination
during collection of urine samples; however, care was taken
to minimize possible contamination by supplying uncontaminated
containers to each patient and by increasing the awareness
of each patient of possible sources of contamination.
studies have indicated that there is an increase in urinary
metal ion levels subsequent to implantation of a metal substrate.
Using Sprague-Dawley rats, Wapner et al. evaluated urine chromium
levels in animals implanted with Co-Cr microspheres [ASTM
Specification for Cast Cobalt-Chromium-Molybdenum Alloy for
Surgical Implant Applications (F 75-82)] of several surface
areas . They saw a significant increase in urine
chromium only in the animals implanted with spheres having
300 times the basic ratio of surface area to body weight.
This increase was most dramatic at 10 days, returning to slightly
elevated levels at 100 days. Woodman et al. found a significant
elevation of urinary nickel levels in rabbits implanted with
porous cast Co-Cr alloy at six months (63.01 ± 1.94 ng/ mL)
in comparison with solid implants (39.23 ± 1.23) and controls
(28.51 ± 1.52) . However, limitations in the experimental
design and in animal models make it difficult to assess the
clinical relevancy of these experiments. Metallic microspheres
implanted loosely in bone are not an adequate representation
of the clinical situation. Animals, which have diets, metabolisms,
and kinematics that are different from those of humans may
not sufficiently model the human situation. As porous-coated
prostheses are being implanted in humans, biological monitoring
of humans appears to be the best alternative.
a few laboratories have attempted to analyze the concentrations
of metal ions in urine in patients subsequent to arthroplasty
in which metallic components have been used. Coleman et al.
evaluated the metal concentrations in the urine, blood, and
hair of patients with hip arthroplasties . They
found that, preoperatively, the average value for urinary
cobalt excretion was 0.5 µg/L, with 0.4 µg/L
for urinary chromium excretion. In patients with metal-to-metal
THR prostheses, Coleman et al. detected increases in urinary
cobalt and chromium levels (24.0 and 6.2 µg/L, respectively),
with a very high increase in cobalt (73.0 µg/L) and
chromium (26.0 µg/L) in one patient. This is in contrast
to their findings for patients with metal-to-plastic THR prostheses
(0.7 µg/L of cobalt, 1.2 µg/L of chromium). Jones
et al. found an increase in urinary levels ranging from 20
to 55 µg/L in hypersensitive individuals with
loosened metal-to-metal THR prostheses . In a study that
evaluated the urinary content of cobalt in patients with cementless
porous and nonporous Austin-Moore prostheses, Jorgenson et
at. found no significant difference between the two groups
. However, the level in both groups appeared to
be slightly elevated when compared with those values accepted
as the normal range . In a retrospective study
of patients undergoing total knee replacement, we found no
significant difference in urinary cobalt or chromium in patients
with cementless as opposed to cemented PCA total knee prostheses
in comparison with controls . The results of this
study lend support to the possibility of increases in urinary
cobalt excretion in some patients by six and twelve months.
We were unable to detect any difference in urinary chromium
excretion between our preoperative and postoperative specimens,
regardless of the time that had elapsed. However, none of
our patient results for urinary cobalt or chromium were in
the range of the elevations detected by Coleman et al. or
Jones et al. for metal-to-metal prostheses [25,31].
nickel levels for patients after THR have not been documented
by previous investigators. However, our six-month and one-year
averages for urinary nickel are within the range established
by Adams et al. for normal values in a comparison of the results
of seven laboratories (10.5 ± 5.1 µg/L) .
Despite this, urinary nickel levels at six months for
two patients were in the range seen in some individuals exposed
occupationally (5.0 to 36.0 µg/L)a high-risk group
for carcinogenesis . However, in one of the two
patients this level returned to the preoperative level by
one year. The one-year result for the other patient is not
available at this time.
difficulty of documenting a statistically significant increase
in urinary cobalt and nickel levels may be due to the relatively
small number of patients included. It is also a reflection,
however, of the variability of response from individual to
individual. The finding of elevations in 3 of the 4 patients
studied at one year lends support to the importance of continuing
biologic effect of a systemic increase in cobalt and nickel
at the levels we have seen is unknown. Cobalt supplementation
in patients at levels of 20 to 50 mg/day may result in polycythemia,
transient hyperglycemia, and hyperplasia of bone marrow .
Increases of nickel in the diet have lead to dermatitis
and hypersensitization . Allergy to nickel has
been documented by Deutman et al. to occur in 5.8% of patients
prior to THR . In addition, these authors also
suggest that THR with a nickel-containing prosthesis may trigger
hypersensitivity reactions in some patients. There is a lack
of information on abnormal accumulation of cobalt, chromium,
and nickel in specific tissues throughout the body. Accumulations
of metal ions in the soft tissue and bone surrounding metal-on-metal
prostheses have been reported [22,23]. No information
is available clinically as to the level of exposure of the
bone cells in juxtaposition with porous implants. However,
Woodman et al. were unable to detect increases in metal ion
levels in cortical bone surrounding solid implants of several
alloy types in an animal model . It is clear that
analysis of various tissues at autopsy is warranted in order
to determine the full extent of the consequences of metal
PCA total hip prosthesis is made of 63.0% cobalt, 28.0% chromium,
and 0.7% nickel. The increase of nickel in some patients despite
the low amounts present in the composition of the prosthesis,
is not easily explained. The differences in the changes of
excretion of these metal ions may be due to differences in
(1) corrosion processes, (2) solubility coefficients, (3)
binding to proteins, or (4) excretion mechanisms. Additional
in vitro and in vivo research is necessary to
elucidate this enigma.
results suggest that there is an increase in metal ions released
from porous-coated total hip implants. However, the location
and mechanism of release is not known. In order to distinguish
whether the increase is a consequence of wear of the articulating
surfaces or a result of increased corrosion of the porous
surfaces, a comparison of our results with those obtained
from cemented porous-coated prostheses, where the implant
design is the same but the porous surface is not exposed to
bone, is necessary.
response of the body to porous-coated cobalt-chromium prostheses
needs to be defined. Because of the limited number of clinical
trials, little is known about the variables affecting biologic
ingrowth and possible metal ion release from these prostheses.
The rate of metal ion release is not known, which thereby
clouds the issue of whether the patient will be subjected
to a level of metal ion concentration that could lead to potential
carcinogenic or toxicologic effects. Two approaches to this
problem include the monitoring of patients for tumor formation
and the monitoring of urinary metal ion levels. We found no
statistically significant increases in urinary metal ion levels
in any of the patient groups studied. Although increases in
metal ion levels have been detected in some of the patients
with cementless porous-coated total hip prostheses, the levels
seen are not sufficient to cause immediate alarm. Recent reports
of tumor formation juxtaposed to Co-Cr implants suggest that
these metals may create a carcinogenic environment in some
patients [37,38]. The prostheses of the two patients
cited were both of the metal-to-metal articulating type. This
leads to the generation of extremely fine particulate debris,
itself a chronic irritant, as well as exposure to a surface
area of metal many times that of the rigid implant. The reporting
of two cases that indirectly point to carcinogenesis out of
hundreds of thousands of cases suggests that this potential
exists for only a very small minority. Because of the seriousness
of this issue, however, it is important that these studies
have reported our preliminary findings in a long-term clinical
study of the urinary excretion of metal ions subsequent to
THR with a cementless porous-coated prosthesis. Based on the
study results available to date, there were no statistically
significant increases in urinary cobalt, chromium, or nickel
levels postoperatively (1, 26, and 52 weeks) in comparison
with preoperative levels. However, increases were detected
in several patients by six months and in 3 of the 4 patients
studied at one year for urinary cobalt and nickel. This suggests
that corrosion of the implant may be occurring and that it
can be detected in some patients one year postoperatively.
We would like to emphasize that this is a preliminary report
of our results. Only with longer term follow-up and an increased
number of patients recruited will these results be validated
and the implications of these findings determined.
wish to express our appreciation to A. Hester and K. Connor
for their technical assistance. We also wish to thank J. M.
Frazier for his guidance and the use of his laboratory during
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Glaser1 (written discussion)In regard to
the high nickel ion content in the urine of patients after implantation
of porous prostheses, is there a possibility that the source
of the nickel could be another implant or a dental bridge? Is
the body possibly excreting nickel from tissue or cells other
than the implant site?
Jones, D. S. Hungerford, R. V. Kenna, G. Braem, and V. Grant
(authors closure) As in vivo corrosion
of metallic orthopedic implants occurs at a very low rate, other
factors that may contribute to temporal changes in urinary metal
ion levels have been sought. In this study, only patients undergoing
a primary surgery were included (that is, no revisions). None
of the patients had any other orthopedic implants. It is somewhat
unlikely that corrosion and wear of dental implants contributed
to the increase demonstrated in some individuals. Wear debris
from dental implants would primarily be digested. Cobalt, chromium,
and nickel are poorly absorbed by the intestines. Therefore,
the contribution of this potential source would probably not
have a significant impact on the total urinary excretion of
these metal ions. No relationship between the epidemiological
data gathered (age, sex, occupation, health, and so forth) and
the urinary measurements was detected. However, this may be
partly due to the low numbers of patients evaluated at this
time. It is possible that nickel is released from the cells
at the implant site due to trauma. Increases in circulating
and excretory nickel levels have been correlated with other
types of trauma, including myocardial infarction, acute stroke,
and severe burns. The fact that increases in nickel have been
observed in the areas surrounding implants, which do not contain
nickel, lends support to this hypothesis. However, this hypothesis
remains to be tested. A likely source of metal ion release is
the debris from implantation of the components. This might vary
from patient to patient, depending on the extent of lavage of
the surgical site and the effectiveness of the individuals
body in removing this debris from the joint cavity and implant