is Professor of Nuclear Medicine and Radiology, Albert Einstein
College of Medicine, Bronx, and Chief of the Division of Nuclear
Medicine, Long Island Jewish Medical Center, New Hyde Park, NY.
is a Research Scientist, Division of Nuclear Medicine and
is an Associate Chairman, Department of Orthopedic Surgery, Long
Island Jewish Medical Center, New Hyde Park, NY.
Although most of the nearly 500,000 joint replacements performed
annually in the United States are successful, complications do
occur. While many such complications are easily diagnosed,
differentiating aseptic loosening from infection can be a daunting
task since these 2 entities are remarkably similar, clinically and
histopathologically. This article reviews the clinical aspects of
prosthetic joint failure, the appearances of aseptic loosening and
infection on various radionuclide imaging studies, and the
advantages and disadvantages of these procedures.
The era of modern joint replacement surgery is <50 years old.
The modern hip prosthesis, the prototype of which was developed in
the late 1950s, is a modular appliance that permits the surgeon to
modify the components to suit an individual patient's needs. A
total hip arthroplasty consists of femoral and acetabular
components. An arthroplasty in which the femoral component
articulates with the native acetabulum is a hemiarthroplasty.
The predecessor of the modern knee replacement, developed in the
mid-1970s, was a fixed-bearing implant consisting of a 1-piece
metallic femoral component, a polyethylene patellar component, and
a polyethylene tibial tray with a central peg. Its modern,
mobile-bearing descendants offer superior joint mobility with less
In addition to polymethylmethacrylate (PMMA), or surgical
cement, there are several ways by which these devices, composed of
metal (cobaltchromium and titanium), and an ultra-high
molecular-weight (UHMW) polyethylene plastic, can be secured to
native bone. Cementless, porous-coated prostheses depend on bony
ingrowth into a porous coating applied to the surface of the
device. Some prostheses are coated with hydroxyapatite compound,
which stimulates new bone formation and serves as an attachment for
newly formed osseous tissue around the hardware. Acetabular
components can be forced (press-fit) into the acetabulum or secured
with orthopedic screws.
By 10 years after implantation, rough- ly half of all prostheses
exhibit radio-graphic evidence of loosening and up to 30% require
In many cases, loosening results from an inflammatory or immune
A synovial-like pseudomembranous structure develops. The cellular
composition of the pseudo-membrane is varied: histiocytes are seen
most often (95% of specimens), followed by giant cells (80%), and
lymphocytes and plasma cells (25%). Neutrophils are present in
<10% of the cases.
Particulate debris produced by component fragmentation attracts and
activates local tissue phagocytes. This debris is impervious to
enzymatic destruction, leading to re-peated, unsuccessful, attempts
at phagocytosis, which, in turn, stimulate secre- tion of
proinflammatory cytokines and proteolytic enzymes that damage bone
and cartilage and activate immune cells. This process leads to
osteolysis with loss of supporting osseous tissues and prosthetic
Infection affects <2% of primary and <5% of revision
arthroplasties. Bacteria readily bind to the materials used in
joint arthroplasties, and, once attached to the implant, some
bacteria produce a surface glycocalyx that protects them from the
host inflammatory response. About one third of prosthetic joint
infections develop within 3 months, another third within 1 year,
and the remainder >1 year after surgery. The inflammatory
reaction accompanying the infected prosthesis is similar to that of
aseptic loosening, with one important difference: neutrophils,
usually absent in aseptic loosening, which are invariably present
in large numbers in infection.
Treatment of prosthetic infection often requires multiple
admissions. An excisional arthroplasty is performed, followed by
antimicrobial therapy, and eventually, revision arthroplasty.
Aseptic loosening, in contrast, is usually managed with a
single-stage exchange arthroplasty that requires only 1 hospital
admission and 1 surgical intervention.
Because their treatments are so different, the importance of
distinguishing infection from aseptic prosthetic loosening cannot
be overstated. This distinction, unfortunately, can be difficult.
Clinical signs of infection are often absent and laboratory tests
are unreliable. The results of joint aspiration have been
disappointing, with large numbers of false-positive and
false-negative results reported. Radio-graphs are neither sensitive
nor specific, and hardware-induced artifacts limit the utility of
cross-sectional imaging modalities. Radionuclide or functional
imaging studies are not hindered by metallic hardware and are very
useful for evaluating the painful joint replacement.
Bone scintigraphy is widely available, easily performed, and
extremely sensitive. A normal study-ie, one in which periprosthetic
uptake is indistinguishable from surrounding nonarticular
bone-rules against a prosthetic abnormality (Figure 1). The
significance of increased periprosthetic uptake, however, is less
certain. Several early investigations found that the test could
identify the failed joint replacement, but could not determine the
cause of failure.
Merely confirming prosthetic failure is not sufficient; the cause
of the failure must be determined if appropriate treatment is to be
instituted. This is especially true today, when many patients are
referred to nuclear medicine specifically to differentiate aseptic
loosening from infection. Some investigators have suggested that
aseptic loosening of hip prostheses can be distinguished from
infection by analyzing periprosthetic up-take patterns. Williamson
reported that focal periprosthetic uptake was as-sociated with
loosening, while diffuse uptake around both the femoral and
ace-tabular components was associated with infection. Williams et
however, found that diffusely increased activity was associated
with both aseptic loosening and infection (Figures 2 and 3).
Mountford et al
found that this pattern was reasonably specific, but not sensitive
for infection. Aliabadi et al
reported that bone scintigraphy was moderately sensitive and very
specific for diagnosing loosening with or without infection, but
could not distinguish the loosened uninfected from the loosened
infected prosthesis. Lieberman et al
reported that bone scintigraphy was sensitive and specific for
identifying loosened hip replacements but excluded infected devices
The age of the prosthesis, together with the introduction of new
types of prostheses, further complicates interpretation of bone
scintigraphy. During the first year after prosthetic hip
implantation, periprosthetic uptake patterns are variable and only
a normal bone scan is reliable. In cemented hip replacements >1
year old, persistent periprosthetic uptake is present in up to 10%
of asymptomatic devices.
Persistent uptake beyond 1 year is even more frequent in cementless
or porous-coated hip replacements.
Few, if any data are available about the evolution of
periprosthetic uptake patterns in other types of hip
Evaluating knee replacements is even more problematic, as
increased periprosthetic activity can persist for some time after
Hofman et al
studied asymptomatic knee replacements with serial bone scans over
2 years. They concluded that, although periprosthetic activity
generally decreased over time, there was considerable
patient-to-patient variation, and sequential scans are needed to
determine the significance of increased periprosthetic uptake
Further complicating matters is the fact that most joint
replacement infections occur within 1 year after implantation when
periprosthetic uptake is so variable that only a normal bone scan
contributes useful information, regardless of the type or location
of the prosthesis. Three-phase bone scintigraphy does not improve
the accuracy of bone scintigraphy, which is approximately 50% to
70% (Figure 5).
In summary, bone scintigraphy is sensitive, with a high negative
predictive value, and is useful as a screening test.
Gallium-67 citrate imaging is often performed together with bone
scintigraphy to diagnose musculoskeletal infection. Uptake
mechanisms of the diphos- phonates and gallium are different, and
each study provides complementary information about different
aspects of a disease process. The combined study is positive for
infection when the distribution of the 2 radiotracers is spatially
incongruent, or when their distribution is spatially congruent
the intensity of gallium uptake exceeds that of the diphosphonate
(Figure 6). The combined study is equivocal for infection when the
distribution of the 2 tracers is spatially congruent
the relative intensity of uptake of each tracer is similar (Figure
7). The combined study is negative for infection when gallium
images are normal, regardless of the bone scan findings, or when
the spatial distribution of the 2 tracers is congruent
the relative intensity of gallium uptake is less than that of the
diphosphonate (Figure 8).
Although Tehranzadeh et al
reported 95% accuracy for the combined study, other investigators
have reported less satisfactory results. Merkel et al
found that the sensitivity, specificity, and accuracy of the
technique for diagnosing joint replacement infection in a canine
model were 61%, 71%, and 67%, respectively. In 130 patients with
painful orthopedic prostheses, these investigators reported that
bone/gallium imaging was 66% sensitive, 81% specific, and 77%
accurate for diagnosing infection.
Gomez-Luzuriaga et al
reported a sensitivity, specificity, and accuracy of 70%, 90%, and
80%, respectively, for bone/gallium imaging. Kraemer et al
reported 38% sensitivity and 100% specificity for bone/gallium
imaging for diagnosing prosthetic hip infection. With an accuracy
that ranges from roughly 60% to roughly 80%, bone/gallium
scintigraphy offers only a modest improvement over bone
Labeled leukocyte scintigraphy
The accuracy of labeled leukocyte (white blood cell [WBC])
imaging for diagnosing prosthetic joint infection has been the
subject of controversy. Some investigators have found the study to
be reasonably sensitive and specific.
Other investigators have reported that the test is specific, but
not sensitive, attributing poor sensitivity to the chronicity of
Still other investigators have found that labeled leukocyte imaging
is sensitive but not specific, attributing poor specificity to
The accuracy of WBC imaging is related to the presence of
neutrophils. The paucity of neutrophils in the aseptically loosened
prosthesis, together with their invariable presence in infected
hardware, rules against chronicity and nonspecific inflammation as
explanations for the poor results reported by some investigators.
The explanation is, in fact, related to image interpretation. WBC
images are interpreted as positive for infection when the intensity
of uptake in the region of interest exceeds that in some reference
point, or when activity outside the normal distribution of the
tracer is observed (Figure 9). The intensity of labeled leukocyte
uptake in a focus of infection-as well as the normal distribution
of labeled leukocytes-is variable.
In one investigation, the sensitivity and specificity of WBC
imaging for diagnosing infected hip replacements varied with the
interpretive criteria used. When any periprosthetic activity was
considered positive for infection, the test was 100% sensitive and
23% specific. When only activity more intense than the
contralateral side was considered positive for infection,
specificity rose to 61% and sensitivity fell to 65%.
These investigators observed similar changes in spe-cificity when
these same criteria were applied to knee replacements.
Labeled leukocytes accumulate in the reticuloendothelial cells,
or fixed macro-phages of the bone marrow, the normal distribution
of which closely parallels that of the hematopoietically active
marrow, which is limited to the axial skeleton and proximal humeri
and femurs in normal adults. White blood cell activity outside
these regions is often interpreted as indicating infection.
There is, however, considerable individual-to-individual var-iation
in the distribution of hematopoietically active (and, hence, the
reticuloendothelial) marrow. Generalized marrow expansion is a
response to a systemic process, such as anemias, tumors, and other
myelophthisic states. Localized marrow expansion is a response to
local stimuli, such as fracture, inflammation, orthopedic hardware,
a Charcot joint, and even calvarial hyperostosis.
Generalized and localized marrow expansion alters the "normal"
distribution of marrow making it difficult to separate WBC
accumulation in atypically located, but otherwise normal, marrow
from uptake in infection.
Some investigators have found that interpreting WBC images
together with radionuclide bone images improves the accuracy of the
study. This improvement was the result of improved specificity,
which came at the expense of sensitivity.
Other investigators have found the technique less useful.
In one investigation of total knee replacements, the sensitivity
and specificity of WBC/bone imaging were no better than those of
WBC imaging alone
(Figure 10). Oswald et al
reported that WBC bone images were incongruent in 15% of
asymptomatic porous-coated hip arthroplasties. One problem with
WBC/ bone imaging is that while diphosphonates accumulate in bone,
labeled leukocytes accumulate in marrow. Conditions affecting
marrow may or may not affect bone and vice versa. Even when an
entity affects both bone and marrow, the effects may be
dramatically different on each.
Several investigators have used WBC imaging together with sulfur
colloid (marrow) imaging for diagnosing the infected joint replace-
The distribution of marrow activity on WBC and marrow images is
similar in normal individuals as well as in those with underlying
marrow abnormalities, ie, the images are spatially congruent. The
exception to this is osteomyelitis, which exerts opposite effects
on these 2 tracers. While stimulating the uptake of leukocytes,
osteomyelitis suppresses uptake of sulfur colloid. In
osteomyelitis, therefore, the distribution of activity on WBC and
marrow images is different. The WBC/marrow study is positive for
infection when there is activity on the WBC image without
corresponding activity on the marrow image-ie, the images are
spatially incongruent. When any other pattern is present, the study
is negative for infection (Figures 11 and 12).
The accuracy of WBC/marrow imaging ranges from 88% to 98%.
Meticulous technique is critical to the success of WBC/marrow
scintigraphy. When the study is performed with indium-111-labeled
leukocytes, marrow imaging can be performed either before or after
WBC imaging, or as a simultaneous dual isotope study. The use of
technetium (Tc)-labeled leukocytes neces- sitates modifications.
Since both parts of the study employ the same radionuclide,
Tc, at least 48 hours should elapse between the 2 tests. Sulfur
colloid should be prepared just before use. Using sulfur colloid
that is more than approximately 1 to 2 hours old may result in
images of inferior quality, including increased background and
urinary bladder activity, which is especially troublesome when
studying the hip.
In-vitro WBC labeling is labor-intensive, is not always
available, and requires direct contact with blood products. The
need for marrow imaging adds to the complexity and cost, and is
inconvenient for patients. Thus, investigators continue to search
for suitable alternatives. Although in-vivo WBC labeling techniques
have been explored, none of them are currently available in the
Although initial reports suggested that fluorodeoxyglucose
positron emission tomography (FDG-PET) could accurately identify
the infected joint prosthesis, recent studies are less encouraging.
Fluorodeoxyglucose PET does not ap-pear to be capable of
distinguishing the inflamed aseptically loosened prosthesis from
the infected prosthesis (Figure 13).
This is not surprising when one considers that FDG uptake depends
on tissue metabolism. Inflammation and infection are hypermetabolic
states, and both will manifest as areas of increased activity on
FDG PET images.
A novel approach to infection imaging is the use of radiolabeled
antibiotics. The most extensively investigated tracer in this group
is the radiolabeled fluoroquinolone,
Tc-ciprofloxacin. Although early investigations indicated that
Tc ciprofloxacin is moderately sensitive and very specific for
infection, more recent data suggest that, in orthopedic infections,
this agent may be more sensitive than specific.
Sarda et al
re-ported that, although the agent was sen- sitive, it could not
discriminate between infected and aseptic osteoarticular disease.
This study did not specifically address prosthetic joints, but the
findings are of concern and point to the need for focused
investigations in this area (Figure 14).
The primary role of nuclear medicine for a painful joint
replacement-differentiating aseptic loosening from infection of a
prosthetic joint- remains a daunting task. The relationship between
aseptic loosening and inflammation limits the role of nonspecific
indicators of inflammation, such as bone scintigraphy and FDG-PET,
to that of a screening test. For the moment at least, WBC/marrow
imaging, despite its disadvantages, remains the procedure of choice
for diagnosing infected joint replacement.