Download Chapter III. Practical Bone scan, SPECT and PET

Chapter III.
Practical
Bone scan,
SPECT and PET
Update of clinical application of bone scan, bone SPECT, and
bone PET
Sung June Jang, M.D.
National Medical Center
Won Woo Lee, M.D., Ph.D.
Seoul National University
Introduction
Bone is a specialized form of connective tissue, with hardness as its characterizing feature. Bone is a dynamic
organ, a metabolically active structure where bone formation and resorption occur continuously, and which
processes can be visualized by bone scan using several bone targeting radiopharmaceuticals.
Bone scan is the most popular of all the studies performed in nuclear medicine department. As the chest X-ray
is considered as the most common examination in radiology department, bone scan is also regarded as the mostwidely used study in nuclear medicine department. The study is relatively simple, no specific patient preparation
is required, and the imaging procedure is well standardized throughout diagnostic imaging departments. Modern
equipments have greatly enhanced the ease of operation and permit bone imaging in planar and tomographic
mode as well.
The bone metabolic rates can be regionally increased when foreign tissues such as cancer trigger reactive bone
formation, which processes are readily seen in bone scan. Diffusely increased uptake of bone scan agents in
whole skeleton are the trademark of metabolic bone disease. Sometimes low degree uptake of bone scan agents
is the only manifestation of certain bone diseases. Bone scan is not only a sensitive procedure for evaluating a
variety of skeletal disorders, but can be applied to certain soft tissue abnormalities such as calcifications,
hematoma, or contusion.
One of the major reasons for bone scan referral is bone metastasis screening of cancer patients. Additionally, in
cases of trauma, orthopedic problems, sports injuries, endocrine and rheumatologic disorders, bone scan plays
an important role for proper management of the patients.
Scintigraphic bone imaging started as 18F positron imaging in 1960’s. However, the bone PET has not been
widely used due to lack of highly sophisticated PET scanners. Instead, since Subramanian and McAfee invented
99m
Tc-labeled polyphosphate complexes in 1971, gamma camera imaging has played a big part in clinical bone
scan imaging because gamma cameras have been optimized for 99mTc, and a high dose activity can be
administered. In the near future to come, with the advent of state-of-the-art PET/CT scanners, we can see the
evolution of bone scintigraphy from easy-to-use bone scan to highly accurate bone PET.
Radiopharmaceuticals
1. Technetium complexes
Currently, 99mTc-labeled diphosphonates are the radiopharmaceuticals of choice for bone scan. They are MDP
(methylene diphosphonate), HMDP (hydroxymethylene diphosphonate), and DPD (dicarboxypropane
diphosphonate). Generally, the clearance of the bone scan agents from the vascular compartment is fast, with
half times of 2–4 min. Peak uptake varies for the different agents, but is usually around 1 h. The bone-tobackground ratio also varies due to the different clearance and uptake rates of other tissues and, therefore, the
maximum ratio occurs much later at 4–6 h. However, other factors like radionuclide decay and patient
compliance constrain the optimal acquisition time at 2–4 h after tracer administration. At this time point about
one third of the administered activity is bound to bone, one third is excreted in the urine and the remainder is
associated with other tissues, about 10% of which is bound to blood proteins.
2. 18F
18
F is obtained directly from cyclotron as sodium fluoride (Na18F). No more chemical modification is required
to be used as bone imaging agent. The decay half time is as short as 110 min. The high bone-to-background ratio
can be obtained as early as 30 min post injection because the renal excretion is very fast and protein-binding is
negligible. The mechanism of bone uptake is ion exchange between hydroxyl group of hydroxyapatite crystal
and fluoride ion. The greater the bone metabolism, the higher the uptake of 18F. Bone PET holds promise as
bone imaging modality because 18F has excellent pharmacokinetics and tomographic imaging is inherently
obtained. Furthermore, CT images are readily available in current hybrid PET-CT system. Thus, bone PET using
18
F is a very promising tool for evaluation of bone diseases.
Methods
1. General
The mechanism of image acquisition is under base of scintillation detection. Thallium-dopted NaI crystal is
most commonly used as scintillation element in the current gamma camera, whereas other different crystals
(BGO, LSO, LYSO, etc) are used in PET system. The photopeak (140 keV) of 99mTc is ideally fit for the NaI(Tl)
crystal of a gamma camera, and allows for administration of higher doses (e.g. 700-1,000 MBq) of 99mTc. There
is no special patient preparation required for a bone scan. After the tracer administration, the patient is just
advised to drink plenty of fluids and to void frequently. Thus, excretion of tracer from the soft tissue is enhanced
and the radiation exposure to the bladder minimized. Just before scanning, the patient is asked to empty the
bladder. Several geometric configurations have been designed for the gamma cameras. Bone scan images can be
acquired using the single-head gamma camera, which has one detector that can be tilted, angled or moved to
image patients in the supine, sitting or standing position. Using two-head gamma camera, whole body images
can be scanned more easily head-to-feet or vice versa. Three-head gamma cameras are particularly adequate for
SPECT acquisition. Contrary to standard gamma camera system, PET detectors are arranged to cover full 360°
aspects around the long axis of the patients, which allows just ~20cm axial field of view per acquisition.
Therefore several acquisitions are necessarily required to cover whole body.
2. Bone scan (planar whole body)
The prototype of bone scan is planar whole body imaging using 99mTc-labeled diphosphonates. The detectors
of gamma camera scan the body at anterior and posterior aspects. Detectors are set to move at a speed (i.e. 13
cm/min). The slower the detector speed is set, the nicer the image quality can be obtained. However, it takes
longer time instead, which may inadvertently provoke patient motion. Additional spot images (0.5~1 million
counts per image) are usually obtained after the whole body scanning in order to clarify the suspicious bone
lesions that have been noted at the whole body scan.
3. Three phase bone scan
The three phase bone scan consists of flow, blood pool, and delay images after the administration of the bone
imaging agents. The flow images are obtained immediately after the agent injection and are practically
equivalent to radionuclide angiography. For the flow phase, images of 2-4 s duration are acquired for a total
time of 60-90 s. The blood pool images are the second phase images that are obtained around 3~5 min postinjection. The blood pool phase needs to be completed within 10 min in order to limit the signal contribution
from the bony uptake. Soft tissue inflammation can be revealed by high uptake at the blood pool images. After
2-3 h the delay images are obtained, which are basically same with the routine bone scan images.
The number one utility of the three phase bone scan lies in the discrimination between soft tissue inflammation
(i.e. cellulitis) and osteomyelitis. The uptake pattern of the bone scan agent in the osteomyelitis is intense,
persistent, localized uptake over the suspicious bone lesion area in all of the three phases (Fig.1), while the
uptake pattern in the cellulitis is relatively mild, diffuse uptake in only the first and second phases. However, it
is of importance to keep in mind that the two conditions (celluitis vs. osteomyelitis) are not always clearly
differentiated. Pure osteomyelitis is hardly seen in clinic, as some degree of overlying soft tissue inflammation
is usually accompanying the osteomyelitis. On the other hand, due to the enhanced blood flow and subsequently
increased delivery of the bone imaging agent, mildy increased bone uptake at delay phase is common finding in
the cellulitis.
Inflammatory arthritis such as septic arthritis is also readily revealed by three phase bone scan. Increased
uptake around the involved joint in whole three phases is the typical finding of the septic arthritis (Fig.2).
Another indication of the three phase bone scan is for the diagnosis of complex regional pain syndrome type I,
which is a new internationally accepted term for the reflex sympathetic dystrophy syndrome. Diffusely
increased uptake of the bone imaging agent can be seen in all the three phases, particularly at the third delay
phase. Peri-articular increased uptake in the terminal extremity (hands/feet) small joints at the delay phase
seems to be the pathognomonic finding of CRPS type I in the three phase bone scan (Fig.3).
4. Pin hole image
Pin hole images are useful for identification of photon defect area in case of avascular necrosis of femur head
(Fig4). By the zooming effect inherent to the pin hole collimation, very high resolution of bone scan can be
realized by just obtaining extra images without further injection of the imaging agent. If the avascular necrosis
involves the whole area of femur head, total hip replacement surgery is recommended as a type of treatment in
the patient. Therefore, pin hole imaging can play a very essential role in the patient management. Recently,
some argues that pin hole images are not recommended any more in the ear of high sensitivity and resolution of
the current gamma cameras, because it takes extraordinarily long time to get pin hole images of high quality.
Furthermore, changing of the collimators is a tricky procedure at institutes where automatic collimator changing
systems are not installed. However, pin hole collimation can provide the usual bone scan images with extremely
high resolution. Therefore, in selective cases of minute bone lesions, pin hole imaging is very essential for
patient management.
5. Bone SPECT (single photon emission computed tomography)
Tomographic sections of a certain body part can be reconstructed with SPECT imaging acquisition.
Tomography greatly enhances contrast and eliminates superimposed activity by providing three-dimensional
images, i.e. in axial, coronal and sagittal planes (Fig.5). Disease involving knee joints, shoulder joints, and
spines are good candidates for SPECT application. Three-head detector gamma cameras are particularly useful
for SPECT acquisition because of its shorter acquisition time. But, dual-head or even single-head gamma
camera can be used as well. Best results are obtained with a 360° acquisition, 128×128 matrix for high
resolution, 3-6° angular steps and 20-30 s per view. This results in a 30-45 min total acquisition time for a single
head camera, which is shorter for dual or even shorter for triple-head gamma cameras.
Radiation Dosimetry
According to ICRP-53 (International Commission on Radiological Protection 1987), the effective dose
equivalent (EDE) for a routine whole body bone scan with 99mTc-MDP is 0.008 mSv/MBq, whereas the EDE for
an 18F whole body survey is 0.027 mSv/MBq. The higher radiation dose of 18F is related to the higher uptake of
fluoride compared to the diphosphonates. The only exception is the bladder, where the radiation dose from
99m
Tc is 0.05 mSv/MBq compared to 0.022 mSv/MBq from 18F, related to the longer half-life of 99mTc. As
mentioned earlier, the radiation burden can be decreased significantly by drinking ample fluids and voiding
frequently, increasing the elimination of tracer from the body.
Image Interpretation
Knowledge of normal uptake in the skeleton is mandatory. This experience is usually gained through training
and interpreting sessions with experts. Fortunately, skeletal scintigraphy is a routine procedure, so that each
practicing specialist can easily get acquainted and become proficient. Normal variants, however, may be tricky
and many an atlas is devoted to these.
The first step is to check for focal or diffuse abnormalities, i.e. areas of increased and/or decreased uptake, the
next step is to compare left vs. right. In pediatric patients, the growth plates are active, which translates into
increased uptake. Additional information may be retrieved from the different phases, e.g. increased uptake
during the flow phase, indicating hyperemia. Multi-phase imaging is important to differentiate increased uptake
in the soft tissues from the bone uptake.
A distinctive feature of bone scintigraphy is its high sensitivity to detect abnormalities such as fractures,
infection, degenerative changes, metabolic bone disorders, metastases, but the test is non-specific at large. Many
disease entities present with abnormal uptake on the bone scan. However, certain patterns may favor one
diagnosis over another. For instance, a linear array of hot spots in the consecutive ribs suggests fractures.
Multiple irregularly scattered areas of focally increased uptake are highly suspicious for metastatic disease.
Slightly-moderately increased uptake in a diffuse pattern in adjacent endplates of joint suggests degenerative
changes, especially when it is also observed in neighboring joints. Common pitfalls are: unparalleled patient
body position obscuring the symmetry, genitourinary contamination, dental implants or disease, or
radiopharmaceutical problems.
The clinical context as given in the form of patient past history or reason for bone scan referral is important for
the readers to derive proper conclusions from the bone scan findings. The clinical history, signs and symptoms
should be available in every bone scan studies. Other imaging study information is also very important for
proper interpretation of bone scan images. We can say that it is highly recommended to refer to other imaging
study (i.e. conventional radiography, CT, MR or US) results whenever they are available. Specialized
procedures or management change are usually awaiting the bone scan report, to be guided by the detected
abnormalities. In most cases, correlative interpretation of the bone scan results with all other imaging modalities
available will lead to the proper diagnosis.
Clinical considerations
1. Oncology
1) Metastatic bone lesion
Bone scan with technetium complexes is indicated for screening purposes in various cancers, such as prostate,
breast, etc. The intent here is to detect occurrence and extent of malignant disease, presenting as hot or
sometimes as cold spots. The whole body mode is ideal for surveying the skeleton, and is superior to
conventional radiography. Since the study is not specific, sometimes a combination of scintigraphy and
radiography is necessary. For the spine, especially vertebrae, bone SPECT is useful to delineate metastatic
lesions, or MR imaging is recommended to confirm presence or absence of bone metastases.
In general, bone metastases appear as an increased uptake [1] (Fig.6). The increased uptake usually turns out to
be reactive change of normal bone responding to the invasive metastatic lesion. In most cases, bone metastasis
starts from the bone marrow, thus cortical bone involvement of metastasis indicates more progressive diseases.
On the other hand, low degree of uptake may also indicate the presence of bone metastasis. This is in part
because in highly aggressive and fast expanding tumors, there is no time long enough for the bone to respond
and the regional bone blood flow may be jeopardized to such an extent that the tracer cannot be delivered. Cold
metastatic lesions have been reported for leiomyosarcoma, ductal breast cancer, and multiple myeloma (Fig7).
The feasibility of whole body imaging with 18F for oncologic disorders has been reported by several
investigators [2]. Although just as in bone scan using technetium complexes, there was considerable overlap
between benign and malignant lesions, high lesion-to-background ratio, early image acquisition post injection,
inherent nature of tomographic imaging are merits of 18F bone PET. Of course, cost-effectiveness may be one
hurdle for the bone PET to be widely accepted in the clinic.
Single benign bone lesion on the bone scan is of considerable clinical interest. Widely varying frequencies of
the single benign lesion have been reported: 15%–35% in the patient without malignancy, and 40%–80% in
patients with known malignancy [1]. The benign lesion should be differentiated from single bone metastasis, but
it is not always clear-cut to identify benign or malignant single lesion. Lesion distribution is sometimes a clue.
In breast cancer, distant metastasis is rare in the absence of lesions in the thorax, i.e. ribs, sternum, and thoracic
spine [3].
An interesting finding is the so-called flare phenomenon, paradoxically increased uptake in metastatic lesions
after initiation of chemotherapy, hemi-body radiation or high dose radionuclide therapy. In general, this is
related to the enhanced blood flow to the responsive bone and indicates the presence of a therapeutic effect.
2) Primary bone lesion
Without high degree of uptake on bone scan, it is very hard to regard any bone lesion as malignant. Bone scan
is indicated to evaluate the extent of the malignant primary bone tumor and screening for metastases. In the
diagnosis and screening of osteogenic sarcoma (Fig8), Ewing’s sarcoma, and chondrosarcoma, bone scan plays
a major role for the patient management. Benign bone tumors usually show moderate or little uptake on bone
scan except osteoid osteoma, fibrous dysplasia, Paget’s disease.
2. Infection and inflammation
Inflammatory bone lesion such as osteomyelitis has intense uptake on the involved bone area. Inflammatory
arthritis like septic pyogenic arthritis also shows high uptake on the joint involved. The increased uptake is
attributed to the enhanced blood flow to some extent. Thus three phase bone scan is primarily recommended to
evaluate the flow and blood pool over the bone or joint area. As mentioned earlier, absent or mild uptake on the
delay phase with increased flow and blood pool indicates cellulitis rather than osteomyelitis. Increased bone
uptake at delay phase (2-4 hrs post injection) may become clearer in late delay images like 24 h post injection
(fourth phase image). More straightforward diagnosis of bone infection can be established using other nuclear
medicine studies. 67Ga is taken-up by both bacteria and leukocytes, and so can be used in both sterile abscess
and leukopenic patients. However its long half life of 78 hrs limits the injected dose as low as 5mCi, which may
hamper the image quality. Furthermore, 67Ga is not easily obtainable because it is produced by a cyclotron.
99m
Tc-HMPAO-WBC (white blood cell) scan is a useful alternative of 67Ga scan.
3. Orthopedics
The bone scan is very sensitive in detecting trauma (Fig.9) and, in general, will be positive within 24 hrs after a
traumatic bone event. Fractures will show increased uptake up to 1 year in about two-thirds of cases [4]. Nuclear
medicine in sports injuries is an emerging field, a trend that can be expected to continue. Stress fractures in
athletes are not infrequent, and routine radiographic evaluation often provides negative or questionable results,
especially in the early stages. Stress fractures are most common in the lower extremities. Ultrasound is a
possible adjunct to physical examination. Stress fractures occur more frequently in female athletes than males. A
stress fracture is a fatigue fracture, related to repetitive stresses to normal bone [5] (Fig10). Accurate and timely
diagnosis is required to prevent possible costly and disabling complications. Bone scan is used to differentiate
stress fractures from shin splints or periostitis. In shin splints there is micro-trauma to the bone, which still has a
sufficient reparative ability and healing response, whereas in a stress fracture there is a “critical mass” of injured
bone leading to mechanical failure. Since the therapy is so different for these entities, i.e., decreasing but
continuing exercise at a lower level in shin splints and “active-rest” plus immobilization in stress fractures, it is
important to make the correct diagnosis.
Another referral for a bone scan is to differentiate the loosening from the infection of an orthopedic prosthesis.
Bone uptake is increased during the first year after prosthesis (hip, knee, shoulder or elbow implant) insertion.
The bone scan shows increased uptake postoperatively up to a few months after the surgery and the duration of
positive bone scan is somewhat longer for non-cemented than cemented prostheses [6]. After that period,
increased uptake around the stem and tip usually heralds loosening. The diagnosis of periprosthetic infection
needs to be double-checked by performing an infection survey with 67Ga or 99mTc-labeled WBC.
SPECT has provided new indications for bone scan. A frequent referral is low back pain with normal
radiographs. Facet joint abnormalities, occult fracture of spine, spondylolysis or spondylolisthesis can be easily
evaluated using the bone SPECT. In addition, SPECT is helpful to delineate the lesion of avascular necrosis.
4. Others
Renal osteodystropy is one of long-term manifestations of end-stage renal disease. Bone scan can provide
objective evidence of bony abnormality as it shows diffuse increased uptake in whole skeleton and relatively
decreased uptake in soft tissue. Kidneys and bladder are not visualized because renal excretion of the technetium
compounds is severely impaired. So-called “beautiful bone scan” is a typical bone scan finding of renal
osteodystrophy. The enhanced bone uptake in the renal osteodystrophy results in 2~3 times the whole body
counts of normal bone scan.
Rhabdomyolysis is skeletal muscle disease induced by heavy exercise, drug abuse, or infection. Damaged
skeletal muscle is contaminated by intra-or extra cellular calcium, and technetium-labeled phosphates readily
bind to the calcium ion in the injured muscle area (Fig11).
Plantar fasciitis is an inflammatory or degenerative change involving plantar fascia. Athletics or heavy weight
patients often suffer from the disease. Bone scan shows typically increased uptake on the plantar side of
calcaneus (Fig12).
Non-union of fracture has different prognosis according to the vascularity at the fracture site. If the
vascularity is good enough, bone scan shows high uptake of the technetium-labeled diphosphonates
(hypertrophic non-union). Hypertrophic non-union predicts good prognosis without any other surgical
treatment (Fig13). To the contrary, atrophic non-union is devoid of blood supply to the fracture site, which
means prognosis is so detrimental that further surgical treatment is required (Fig14).
Summary
Bone scintigraphy, either as positron or gamma imaging, is an extremely sensitive test to evaluate a large
spectrum of abnormalities related to the bone. The study findings may be non-specific sometimes and other
imaging modalities, i.e. plain radiography, CT, MR, US are required to reduce the number of diagnostic
possibilities. The addition of sophisticated imaging modalities provides the opportunity of correlative imaging,
which will yield the final diagnosis in the vast majority of patients.
For the foreseeable future the status of bone scan may remain the same. Clinical demand for quantitative
imaging needs to be further investigated. In single photon imaging, new tracers will be developed with faster
uptake and/or clearance from the vascular compartment. Thus, the time interval between tracer administration
and imaging may be shortened, enhancing patient convenience. New equipment may further increase spatial
resolution, so that even smaller abnormalities can be detected. Development of specialized image reconstruction
and processing techniques will produce higher contrast in tomograms and improve image quality.
The combination of anatomic and functional imaging, e.g. SPECT/CT, is the newest addition to our diagnostic
armamentarium, providing ease of localization and enhanced specificity to lesion characterization.
Suggested Readings
1. Freeman LM, Blaufox MD: Metabolic bone disease. Semin Nucl Med 1997;27:195-305.
2. Freeman LM, Blaufox MD: Orthopedic nuclear medicine (Part I). Semin Nucl Med 1997;27:307-389.
3. Freeman LM, Blaufox MD: Orthopedic nuclear medicine (Part II). Semin Nucl Med 1998;28:1-131.
4. Copnnolly LP, Strauss J, Conolly SA: Role of skeletal scintigraphy in evaluating sports injuries in
adolescents and young adults. Nucl Med Ann 2003;171-209.
5. Fournier RS, Holder LE: Reflex sympathetic dystrophy: diagnostic controversies. Semin Nucl Med
1998;28:116-123.
References
1. Brown ML, Collier BD, Fogelman I. Bone scintigraphy: part 1. oncology and infection. J Nucl Med 1993;34:2236–40.
2. Kang JY, Lee WW, So Y, Lee BC, Kim SE. Clinical usefulness of 18F-fluoride Bone PET. Nucl Med Mol Imaging
2010;44:55-61.
3. Goldfarb CR, Ongseng FO, Finestone H, Szakacs GM, Guelfguat M, Jonas D. Distribution of skeletal metastases in
patients with breast carcinoma. J Nucl Med 1998;39:114P
4. Collier BD, Fogelman I, Brown ML. Bone scintigraphy: part 2. orthopedic bone scanning, J Nucl Med 1993;34:2241–6.
5. Anderson MW, Greenspan A. Stress fractures. Radiology 1996;199:1–12.
6. Rahmy AI; Tonino AJ; Tan WD. Quantitative analysis of technetium-99m-methylene diphosphonate uptake in unilateral
hydroxy-apatite-coated total hip prostheses: first year of follow-up. J Nucl Med 1994;35:1788-91.
Fig.1. Three phase bone scan findings of acute osteomyelitis in right foot. (A) flow, (B) blood pool, (C) delay
phase.
Fig.2. Three phase bone scan findings of septic arthritis in right knee joint. (A) flow, (B) blood pool, (C) delay
phase.
Fig.3. Complex regional pain syndrome type I (reflex sympathetic dystrophy) in right hand revealed on three
phase bone scan. (A) blood pool, (B) delay phase.
Fig4. Osteonecrosis in left femur head. (A) whole body planar bone scan, (B) pin hole image.
Fig5. Knee SPECT. (A) planar regional view, (B) transaxial, (C) coronal, (D) sagittal planes
Fig6. Multiple bone metastases. (A) whole body planar, (B) regional images.
Fig7. Osteolytic bone metastasis from a multiple myeloma patient.
Fig8. Osteogenic sarcoma in right distal femur. (A) simple x-ray, (B) bone scan.
Fig9. Bone contusion. (A) no abnormal finding in simple x-ray, (B) anterior and (C) posterior regional images of
bone scan.
Fig10. Stress fracture in left fibular bone. (A) bone scan regional view, (B) MRI.
Fig11. Rhabdomyolysis of bilateral thigh muscles. (A) anterior, (B) posterior images of bone scan.
Fig12. Plantar fasciitis on bone scan. (A) medial, (B) plantar view images.
Fig13. Hypertrophic non-union. (A) tibio-fibular fracture at the time of injury, (B) non-union 1year later, (C)
hypertrophic non-union on bone scan.
Fig14. Atrophic non-union. (A) tibio-fibular fracture at the time of injury, (B) non-union 2 months later, (C)
atrophic non-union on bone scan.