Continuing Education Activity
Nuclear medicine imaging is a valuable tool in the diagnosis of musculoskeletal system disorders and pathology. It is commonly utilized to diagnose soft tissue and bony infections, neoplasms, and traumatic injury. This activity reviews the modalities and interpretation of nuclear medicine imaging in the evaluation of musculoskeletal disorders and will highlight the role of the interprofessional team in the use of nuclear medicine imaging.
- Describe common nuclear medicine imaging modalities available for musculoskeletal evaluation.
- Identify the indications for musculoskeletal nuclear medicine imaging tests.
- Summarize the diagnostic significance of the findings of these tests.
- Outline the preparation required for common nuclear medicine imaging tests.
The use of radioactive substances in the evaluation of the musculoskeletal system has a relatively long history. Early researchers explored the metabolic activity of bone using phosphorus-32 and autoradiography. Further research explored the uptake of radiogallium by various skeletal tissues, including bone tumors, and demonstrated increased uptake before radiographic changes were visible. In 1971, 99mTc 99m polyphosphate was introduced as a readily available and inexpensive bone scanning agent. This became the basis of many tracers, including 99mTc-methylene diphosphonate and hydroxymethylene diphosphonate.
Bone scan, or bone scintigraphy, uses radiopharmaceuticals consisting of a radionuclide bound to members of the phosphate family, the most common form being 99mTc-methylene diphosphonate (99mTc-MDP). Bone scintigraphy is exquisitely sensitive to bone turnover, detecting as little as a 5% change. In specific instances, this can provide evidence of bone disease or dysfunction before bony changes are appreciated on conventional radiography.
Uptake can be seen with multiple conditions, including fracture, malignancy, and infection. Other disorders of bone turnover can also be seen, such as fibrous dysplasia and avascular necrosis. Soft tissue conditions such as cellulitis and complex regional pain syndrome can be seen in certain phases of the scan. “Cold spots” may be caused by areas of decreased bone turnover seen with certain tumors and bone abscesses or caused by decreased blood flow such as in frostbite, gangrene, or avascular necrosis.
Single-photon emission computed tomography (SPECT), which can also be combined with conventional CT images (known as SPECT/CT), is an adjunct to bone scintigraphy and typically allows for more accurate anatomic localization of lesions.
Gallium – 67 Scintigraphy
Gallium-67 citrate emerged as one of the earliest tracers used in musculoskeletal tumor and infection imaging. It was commonly used in combination with bone scintigraphy, and results are based on the uptake patterns of the two tracers. Gallium-67 imaging is a well-established imaging modality with a sensitivity of 65 to 80% for osteomyelitis when combined with bone scintigraphy. This radionuclide has a half-life of 78 hours, requiring a 2 to 3-day delay between administration and imaging, making imaging logistically difficult. Ga-67 in combination with SPECT is currently used to diagnose spondylodiscitis, although more recent literature suggests the superiority of fluorine-18 2'-deoxy-2-fluoro-D-glucose PET (FDG/PET) scans in this indication. Gallium-67 is currently infrequently used.
In Vitro Labeled Leukocytes and Bone Marrow Imaging
The radiolabeling of leukocytes to localize musculoskeletal infection has been used for the past three decades with great success. Indium-111 and 99mTc labeled hexamethylpropylene amine oxime (99mTc-HMPAO) are the most commonly used radiotracers. There are several differences between the two isotopes used for labeled leukocyte scintigraphy. Advantages of In are a limited normal distribution and stability of the label, which allows delayed imaging. 99mTc-HMPAO, in contrast, has a large normal distribution, including liver, lungs, spleen, gastrointestinal system, and urinary tract, but offers higher resolution images. Radiation exposure to the patient is significantly lower when using 99mTc-HMPAO.
Variability in intramedullary bone marrow distribution from fractures or hardware can lead to difficulty differentiating infection from normal active marrow when investigating infection of the bone. In these instances, utilizing a 99mTc-Sulfur Colloid scan can differentiate the two. Both labeled leukocytes and 99mTc-sulfur colloid will show activity in the normal bone marrow. Still, infection changes the intraosseous environment so that 99mTc-sulfur colloid is not taken up by phagocytes and is cleared from the marrow in these areas, therefore showing no activity in areas of infection.
When the labeled WBC scan shows activity that is absent on the 99mTc-sulfur colloid scan, the test is positive. Drawbacks to leukocyte scintigraphy include delayed results and in-vitro blood handling for the labeling process. This is described in more detail below.
FDG PET - Fluorodeoxyglucose F 18 (FDG)
Positron emission tomography (PET) is a nuclear medicine imaging modality that uses 18F-FDG (or FDG) as a tracer. It is based on the detection of photons that are produced during radionuclide decay. Positrons are emitted from the nucleus of the radionuclide during decay, producing two annihilation photons which are detected by the scanner. After administration, the tracer enters cells by glucose transporters (GLUTs) and is phosphorylated to FDG-6-phosphate. Uptake is primarily dependent on glucose transporter concentration and cellular metabolic activity. FDG-6-phosphate is unable to be further metabolized in the glycolytic pathway and therefore accumulates in the cell.
Glucose-6-phosphatase normally dephosphorylates FDG allowing it to leave the cell. Tumor cells commonly exhibit decreased glucose-6-phosphatase concentrations, which may cause cells to retain tracer for longer periods, leading to detection on the delayed scan technique.
FDG is a non-specific tracer, showing uptake in many tissues with increased glucose transporters such as the muscles, heart, GI tract, urinary tract, and brain. Uptake in other organs and the bony skeleton is normally low. Normal bone marrow does not exhibit significant uptake; therefore, active inflammatory infiltrates can be easily distinguished from hematopoietic marrow. States of active inflammation will show increased uptake due to the increased concentration of glucose transporters in active inflammatory cells.
FDG/PET provides some advantages to other forms of nuclear musculoskeletal imaging. It provides prompt results, typically around two hours after tracer injection. It is not distorted or affected by metal implants and offers a relatively high resolution of 4 to 5 mm. When in the form of PET/CT, three-dimensional localization and anatomic correlation improve.
Anatomy and Physiology
99mTc-methylene diphosphonate complexes used in bone scintigraphy bind to the hydroxyapatite crystal in bone and quickly clear from soft tissue. The rate of uptake of these radiotracers is primarily dependent on bone turnover and secondarily dependent on local blood flow.
Normal findings on bone scintigraphy include uniform uptake throughout the bony skeleton. Intense uptake at the kidneys and bladder (due to urinary excretion), sacroiliac joints, nasopharynx, sternum, and joint surfaces is also considered normal. Increased uptake will also be seen at the physes of skeletally immature individuals due to increased osteoblast activity.
Gallium-67 citrate binds to transferrin in the plasma resulting in increased concentrations in areas of inflammation and increased local perfusion. In infection, increased concentrations of lactoferrin secreted from leukocytes bind Ga-67 at the inflammatory foci. Bacteria also produce Siderophores which bind Ga-67 and are transported into the bacterium.
Uptake of Indium-111 and 99mTc-exametazime labeled leukocytes is dependent on several prerequisites, including intact chemotaxis mechanism, an adequate number of labeled cells, and a baseline leukocyte count of at least 2000/microliter. The sensitivity of these tests is higher in neutrophil-mediated infections. Labeled leukocytes accumulate in the bone marrow due to phagocytosis by macrophages, and distribution within the marrow can be affected by age, fractures, hardware, or neoplasm.
All the nuclear medicine imaging modalities described above may be used in the evaluation of osteomyelitis. When bone scintigraphy is used, it is typically in the form of a three-phase bone scan. When osteomyelitis is present, the bone scan will demonstrate hyper-perfusion, hyperemia, and increased levels of bone turnover at the site of infection. The sensitivity of this imaging test for post-traumatic osteomyelitis is good, ranging from 89 to 100%; however, specificity is less than 10% in this setting.
The three-phase bone scan also offers differentiation between osteomyelitis and cellulitis. Cellulitis shows strong uptake in phases one and two, followed by weak uptake in the third phase, while osteomyelitis shows uptake in all phases. There is some evidence that adding a fourth phase to the scan may increase specificity, particularly in patients with peripheral vascular disease or diabetes mellitus. Labeled leukocyte scintigraphy is also commonly used to diagnose osteomyelitis. The Indium-111 labeled leukocyte scan has a sensitivity of 91% and specificity of 97% for the detection of osteomyelitis.
When intramedullary infection is suspected, this test should be performed with a 99mTc sulfur colloid scan to differentiate between active marrow and sites of infection. Labeled leukocytes have no inherent affinity for bone; therefore, this scan does not differentiate between bone and soft tissue infection. Single-photon emission tomography/computed tomography, or SPECT/CT, is a useful adjunct in investigating osteomyelitis, particularly with surrounding soft tissue infection. This imaging improves anatomic localization, providing better differentiation between osseous and soft tissue infections. SPECT/CT has similar overall sensitivity to triple-phase bone scan and labeled leukocyte scans but improves the accuracy of both exams when evaluating for osteomyelitis.
FDG-PET is most useful in spinal osteomyelitis, demonstrating high sensitivity and specificity and excellent anatomic localization when performed as PET/CT. FDG-PET offers much higher sensitivity than labeled leukocytes in spinal osteomyelitis and higher specificity than combined Gallium/Bone scintigraphy protocols. In the workup of spinal osteomyelitis, FDG-PET offers a useful adjunct to MRI in patients with non-diagnostic MRI findings or contraindications to MRI such as metallic implants.
Peri-prosthetic Joint Infection (PJI)
Bone scintigraphy is limited in utility due to the inability to distinguish aseptic loosening and PJI. Postoperative increased uptake on technetium-99m bone scintigraphy after total hip arthroplasty and total knee arthroplasty may also be normal for up to two years due to bony remodeling around the implant. Bone scintigraphy is sensitive but not specific for PJI and therefore is best used as a screening tool. Bone scintigraphy has been combined with gallium-67 scintigraphy or labeled leukocyte scans with variable results.
Labeled leukocyte scintigraphy, when combined with 99mTc sulfur colloid scans, offers higher sensitivity and specificity for PJI when compared with bone scintigraphy. Delayed or late imaging, typically at 24 hours or more, is preferred when chronic PJI is suspected. The bacterial biofilm produced around implants slows the migration of leukocytes to the infected area, and the overall sensitivity and accuracy of the exam for PJI may be increased with delayed imaging.
Implantation of arthroplasty hardware may cause an abnormal distribution of hematopoietic bone marrow, complicating the interpretation of results. Adding a 99mTc-Sulfur Colloid scan may offer better discrimination of normal bone marrow, and reactive leukocyte infiltrates in infection. Three-phase bone scintigraphy combined with labeled leukocyte/sulfur colloid marrow scintigraphy is the current gold standard nuclear medicine imaging for PJI and offers high sensitivity, specificity, and diagnostic accuracy for PJI.
Diabetic Foot Infection
The most common nuclear medicine modalities used in diabetic foot infections are bone scintigraphy and labeled leukocyte scintigraphy, with the latter being the current gold standard. Loss of skin integrity in the form of a pedal ulcer can rapidly lead to underlying osteomyelitis. As seen with other forms of osteomyelitis, bone scans are highly sensitive but poorly specific. Attempts have been made to improve the accuracy of bone scans in diabetic infection, such as adding a late 4 phase which demonstrates uptake in woven bone, common in osteomyelitis but seen in other conditions such as fractures and degenerative changes.
Neuropathic conditions such as Charcot joint may also mimic osteomyelitis by demonstrating focal hyperperfusion, hyperemia, and bony uptake, making diagnosis challenging. In addition, fractures and degeneration are an integral part of the Charcot joint. Labeled leukocyte imaging also demonstrates increased uptake in the neuropathic Charcot joint, which has been attributed to increased conversion of fatty to hematopoietic marrow activity. Sulfur colloid imaging is a useful adjunct in these instances. Single Photon Emission Computed Tomography or SPECT/CT may assist in differentiating soft tissue and bony infectious lesions. However, due to the proximity of these structures in the foot, clear differentiation may be challenging.
Bone scintigraphy is sensitive for detecting bone remodeling, periostitis, and microfractures associated with bone stress injury. These changes result in increased uptake on bone scintigraphy before changes can be seen on radiographs. Stress fractures of the tibia, metatarsals, the scaphoid, tarsal bones, and spine are the more common indications for a bone scan. Although MRI is the most common modality used to diagnose tibial stress fractures and is comparable to bone scintigraphy sensitivity, bone scintigraphy can provide prognostic information by determining whether active bone turnover is present at the fracture site.
Fractures of the pars interarticularis, or spondylolysis, are a common pediatric stress fracture, and early bony changes may not be evident on radiographs or computed tomography. SPECT/CT allows for early diagnosis and prognostic information by assessing bone metabolism at the fracture site. Patients with a positive SPECT/CT may have better outcomes following surgical repair of symptomatic spondylolysis. Currently, MRI has replaced bone scintigraphy and SPECT/CT as the imaging of choice for these injuries.
Acute occult bony or soft tissue injuries in children, such as a toddler’s tibia fracture, may be quickly and easily diagnosed with bone scintigraphy. Radiographic changes may take 2 or 3 weeks to become evident in these injuries, and MRI is logistically challenging in young children due to the requirement that the patient lay still. In cases of suspected child abuse where missed injury can endanger the patient, bone scintigraphy can provide prompt evidence of musculoskeletal injury before radiographic changes are evident.
Occult insufficiency fractures of the spinal column, sacrum, pelvis, and femoral head or neck may also be evaluated with bone scintigraphy, demonstrating increased uptake at the fracture site in delayed phases. SPECT/CT provides more precise anatomic localization. MRI has largely replaced these tests in this indication. However, bone scintigraphy provides a useful adjunct when MRI would be otherwise contraindicated or affected by metallic artifacts from implanted hardware at the site in question.
Bone scintigraphy has historically been the most common nuclear medicine imaging modality used in the workup of metastatic musculoskeletal disease. It is most commonly used to evaluate bony metastasis but is limited in specificity and anatomic localization. FDG-PET and PET/CT are now the mainstay nuclear medicine modalities for identification and workup of both soft tissue and bony metastases and provide useful information for biopsy guidance, staging, response to therapy, and anatomic localization.
FDG-PET offers several advantages over bone scintigraphy and SPECT/CT. FDG is taken up directly by tumor cells, in contrast to 99mTc-MDP, which reflects changes in bone metabolism by a tumor. This direct uptake of FDG allows for more precise differentiation of active and healing lesions, giving a clearer picture of response to therapy. FDG has no inherent affinity for bone and, therefore, can also detect soft tissue metastases. FDG has a high affinity for osteolytic lesions such as renal and thyroid carcinoma, detecting these metastases with high sensitivity. It also identifies both skeletal and extraskeletal lesions in multiple myeloma, where bone scintigraphy is poorly sensitive.
Bone scintigraphy, in contrast, offers better sensitivity for detecting osteoblastic tumors and metastases such as prostate and small cell lung carcinoma. Patients with mixed lesions such as in breast carcinoma should therefore undergo both imaging tests. FDG-PET is now ubiquitous in the staging and surveillance of essentially all types of lymphoma and detects intramedullary bony metastases with more accuracy than bone scintigraphy and bone marrow biopsy.
Other less common indications for nuclear medicine imaging include the following:
Bone scintigraphy may be used to assess bone vascularity in cases of a suspected bone infarct. Bone scintigraphy is typically used to evaluate the femoral head, femoral condyles, and jaw. Changes seen on bone scintigraphy occur quickly compared to radiographs or MRI and can be seen in less than 72 hours. Changes include the absence of uptake in affected areas, which also may include a ring of high uptake around the necrotic lesion indicating reactive hyperemia. Labeled leukocyte scintigraphy and FDG-PET have little clinical utility in this condition.
Paget Disease/Fibrous Dysplasia
Bone scintigraphy may demonstrate well-delineated areas of intense bony uptake and hyperemia. The main indication for bone scintigraphy in this condition is the diagnosis of polyostotic involvement of fibrous dysplasia—Paget disease results in diffuse intense uptake in affected bones. There is little evidence to support the utilization of bone scan to follow disease progression for either Paget disease or fibrous dysplasia.
Complex Regional Pain Syndrome
Bone scintigraphy results in a characteristic finding of diffuse intense hyperemia of the affected area in the flow and blood pool phases, followed by a less common finding of peri-articular bony uptake in delayed phases. The presence of peri-articular uptake in the delayed phases is highly suggestive of the diagnosis.
Myositis Ossificans and Heterotopic Ossification
Early extraskeletal bone formation shows poorly delineated areas of increased uptake on bone scintigraphy that becomes less intense as the lesion matures. Myositis ossificans may continue to show increased uptake even after the lesion becomes stable enough for excision. Some evidence recommends against the exclusive use of bone scintigraphy to determine the timing of excision.
Sports or Overuse injuries
Bone scintigraphy may be used for various injuries, including plantar fasciitis, Achilles or peroneal tendonitis, Osgood-Schlatter disease, and medial tibial stress syndrome.
There are no absolute contraindications for bone scintigraphy. Relative contraindications exist, including pregnancy, physical size and weight limits of scanners, and recent nuclear medicine exams or therapy.
There are no absolute contraindications to labeled leukocyte scintigraphy. Relative contraindications to labeled leukocyte scintigraphy include neutropenia or concurrent use of immunosuppressive therapy that interferes with leukocyte chemotaxis.
There are no absolute contraindications to FDG-PET or PET/CT imaging. Relative contraindications include a blood glucose level of greater than 120 mg/dL, the inability to lie still for the exam, the inability to place arms above the head, patient greater than the size or weight limit of the scanner, history of claustrophobia, or recent chemotherapy less than ten days before the exam.
For bone scintigraphy, a single or dual-headed gamma camera with a high-resolution parallel hole collimator is required. A pin-hole collimator may be used to acquire high-resolution images and is routinely used with pediatric patients. Obtaining SPECT imaging requires that the gamma camera be oriented in a 180 deg geometry between detector heads, and images are then obtained over 360 degrees in approximately 10 to 30 seconds. SPECT/CT requires the addition of a CT scanner with a combined gamma camera. Refrigeration of the tracer at 4 to 8 deg C may be required, depending on the brand used. Intravenous access is necessary for the administration of radiotracer.
The radiolabeling of leukocytes for both In-111 and 99mTc-HMPAO scans requires a sterile field and appropriate sterile PPE. The labeling process is usually completed in a sterile laminar flow cabinet or isolator. Intravenous access for the withdrawal of patient blood and the administration of the labeled leukocytes is required. Imaging equipment is essentially the same as with bone scintigraphy, utilizing a planar gamma camera.
FDG-PET and PET/CT scans require the appropriate scanner, and the latter of the two uses a single system with a combined PET and CT scanner on a single table. In addition, intravenous access, a glucometer, and a patient scale is required. Images obtained from the scan must be processed using software approved for clinical use and evaluated on approved monitors with appropriate settings.
Radiology technologists that have completed training in the imaging modality to be performed are required to administer the radiotracers, operate the appropriate scanner with indicated protocols, and perform post-scan image reconstruction.
A radiologist or nuclear medicine physician must analyze the images obtained and provide a report for the ordering service or clinician.
Before the procedure, the patient should be advised on the risks and benefits of the imaging test and the intended purpose of the exam in their clinical condition. Clear instructions for the day of the procedure should be provided to the patient before arrival to avoid potential complications and delays. A brief interval history should be taken the day of the procedure to include any history of trauma, surgery, arthritis, pregnancy, cancer, bone disease, current medical conditions, prior imaging results, and any recent nuclear medicine therapy or imaging.
The patient should be well hydrated and should void immediately before the exam. The radiopharmaceutical is then prepared with sodium pertechnetate per manufacturer instructions and kept at the appropriate temperature. The radiopharmaceutical should not be exposed to air and should be injected within 6 hours of preparation. The tracer is administered intravenously.
The most commonly used protocol in bone scintigraphy is the three-phase bone scan. This begins with the injection of the tracer as described above, with the typical dose being 10 to 30 millicuries (mCi) for adults and 0.2 to 0.3 mCi per Kg for pediatric patients. The first phase is a dynamic imaging sequence or “flow phase” which is obtained from the moment of injection for approximately 60 seconds. This phase allows for the evaluation of the relative perfusion of the area of interest. This is immediately followed by a static imaging sequence or “pool phase” which includes soft tissue accumulation. The final phase or “bone phase” is typically scanned 2 to 5 hours after the initial injection, allowing for bony uptake and soft tissue clearance. In some instances, when peripheral vascular disease or diabetes mellitus is present, a final fourth phase can be imaged 24 hours after tracer injection to increase the accuracy of the exam.
Labeled Leukocyte Imaging
Labeled leukocyte imaging requires special preparation of the leukocytes in a sterile field. The patient’s blood is collected and mixed in a vial with a citrate-dextrose anticoagulant. The blood is then centrifuged at 2000 g for 10 min. After separation of the pellet and blood-free plasma, the pellet is mixed with 10% HES and the erythrocytes are allowed to sediment. The remaining leukocyte-rich plasma is removed and re-centrifuged and the pellet is placed into the blood-free plasma obtained in an earlier step. In-oxine or 99mTc-HMPAO is then added to this mixture for labeling. The labeled leukocytes should be reinjected into the patient within 3 hours of labeling.
Dosing is variable, but a common dose of 111In-labeled leukocytes is 300 to 500 μCi, and a common dose of 99mTc-HMPAO–labeled leukocytes is 5 to 10 mCi. The timing of imaging is also variable, from 1 to 30+ hours after injection depending on the condition being investigated.
Patients should consume no food by mouth for at least 6 hours before the exam. Patients scheduled for morning exams should be instructed to remain NPO after midnight before the exam. Patients scheduled for afternoon tests should eat a light breakfast but should have no oral intake after 8 AM. Patients should arrive well hydrated having consumed at least 1 liter of water in the two hours before the exam. Blood glucose levels should be less than 120 mg/dl before administration of FDG. After injection, the patient should remain seated and still until the exam to minimize muscle activity. The patient should void 5 minutes before the start of the exam. The typical interval between FDG injection and image acquisition is 60 minutes. In combined systems, the PET and CT images are obtained concurrently. Reconstruction and processing are completed after the exam, and the images are evaluated using software to correlate areas of increased uptake with CT anatomy.
Complications are rare and are usually related to radionuclide administration, including venous extravasation or arterial injection. Allergic reactions are exceedingly rare but have been described.
Nuclear medicine imaging modalities can provide clinically useful information in the workup, diagnosis, and surveillance of many musculoskeletal conditions. In some instances, such as measuring tumor response to therapy or workup of infected implanted hardware, these nuclear medicine imaging tests offer advantages over conventional imaging. Nuclear medicine imaging provides the healthcare team with an alternative test when MRI or advanced conventional imaging is contraindicated. In many cases can be a complementary exam that offers an alternate source of clinical data for the practitioner. In general, nuclear medicine imaging is less specific than conventional imaging and requires correlation with a thorough history and physical in the context of the specific diagnosis being investigated.
Enhancing Healthcare Team Outcomes
The safe and successful utilization of any nuclear imaging modalities discussed above depends not only on expert knowledge from members of each discipline but also on careful communication among the healthcare team. This begins as early as the ordering of the exam. Channels for dialogue with a nuclear medicine physician should be established and accessible so an ordering physician can consider the diagnostic yield of a scan or patient appropriateness for a study in a given clinical scenario.
It is the responsibility of the ordering clinician or practitioner to ensure the appropriateness of the test before subjecting the patient to its associated risks. During the imaging process, the patient will inevitably encounter multiple handoffs of their care; the use of standardized handoff techniques is recommended, such as SBAR or an institution-specific model. Clear written instructions on preparing for the exam should be given to the patient before the exam day.
The highly technical nature of the exams also presents areas for interdisciplinary cooperation. For example, each radiotracer has a particular timeframe in which it must be administered following preparation. Coordination between the radiology technician preparing the radiotracer and the administering technician, who has insight on patient readiness for the exam, will ensure the tracers prepared are neither wasted nor administered inappropriately. Timing when obtaining imaging is often crucial to produce satisfactory and clinically useful results.
Depending on the purpose of the exam and the diagnosis being investigated, the timing of imaging may be variable even within an individual imaging modality. Clear communication between the ordering practitioner and the nuclear medicine physician about the indications for the exam and the information desired from the exam will allow for implementing the appropriate imaging protocol.
In the imaging suite, careful communication should continue between the radiology staff and the patient to ensure patient-centered care, patient safety, and patient satisfaction. Unique circumstances may arise regarding patient handling of trauma patients in the scanner, for example, which require additional caution. Time should be protected before the exam for a full explanation of the procedure and answering patient questions, and established protocols performed to confirm the correct patient and anatomical site being investigated.