Introduction

Bone seeking radiopharmaceuticals have been available since the early days of nuclear medicine. An example is phosphonates which were originally studied by Subramanian et al. in 1971.[1] Technetium 99m-methylene diphosphonate (Tc99m-MDP) was developed in 1975 and is the predominant radiotracer used in skeletal scintigraphy.[2] Researchers have studied the utility of these agents in a variety of medical situations like infection, tumor, and hardware complications.[3][4][5] Most commonly, a clinician injects Tc99m-MDP intravenously, and technologists obtain images approximately 2 to 4 hours later. However, there are certain instances where additional imaging at 2 earlier time points provides the needed information to identify pathology better.  These additional imaging points are a triple-phase bone scan.

Procedures

Healthcare providers should contact the patient ahead of imaging and instruct them to arrive well hydrated, in clothes without metallic objects, and plan for the procedure to last 3 to 6 hours.[6] The patient should void immediately before the study, or if the patient has a Foley catheter in place, the catheter should not be clamped to allow urine to flow freely and reduce artifact from a full bladder.

The intravenously-injected, bone-seeking agent is usually a diphosphonate, most commonly methyl diphosphonate (MDP) or hydroxydiphosphonate (HDP) with initial deposition thought attributable to chemisorption on the bone surface. The agent is complexed with Technetium 99m, a relatively short-lived radiotracer with good spatial resolution, a good target to background ratio, and favorable imaging characteristics. The typical patient dose is 20 to 30 millicuries (mCi) or 740 to 1110 megabecquerel (MBq) for adults and 0.2 to 0.3 mCi/kg or 9 to 11 MBq/kg for children with the maximum dose not exceeding the administered activity for an adult. The minimum dose for pediatric patients is 0.05 to 1.0 mCi or 20 to 40 MBq.

Before injection of the radiotracer, the patient is positioned on the gamma camera so the area of interest can be imaged. The technologist starts imaging and injects the patient. Images are obtained at 1 to 3 seconds per frame (when using digital images) for a video clip lasting 60 seconds which is referred to as "dynamic imaging." Each frame is a summation of the radioactivity counts for the obtained image.  This dynamic imaging demonstrates and characterizes relative perfusion to a particular area and is called the "flow phase" or "angiographic phase." 

Following this step, a second image is obtained in the same field of view and is termed the "blood pool" phase. This characterizes blood pool accumulation in the soft tissues and bone (or lack thereof) as a result of flow and capillary dilatation.

Two to 3 hours after initial injection, the third phase, termed "delayed," includes images of the same location as the earlier phases and will also include either the whole body or the lower half of the body. There will be anterior and posterior projections of the whole body or lower body images while the body part imaged in the earlier phases likely contains views from different projections to characterize the accumulation (or lack thereof) of radiotracer in the osseous structures. The clearing of the radiotracer from the soft tissues (or lack thereof) can be assessed as well. If there are any areas with abnormal radiotracer activity, they can also obtain "spot" images of the area of interest. Multiple projections of the spot images may be useful to improve anatomic localization. In areas of complex anatomy, newer gamma cameras have an advanced rotating imaging capability called single-photon emission computed tomography (SPECT).  This is a 3-dimensional compilation of images and can be viewed alone or fused to conventional computed tomography (CT) scan.  Often, SPECT and CT imaging capabilities are combined in a single machine. The fusion of these 2 datasets allows for precise anatomic localization.

Indications

Three-phase bone scanning has a narrower scope than traditional single delayed phase imaging. These indications include but are not limited to the following:

• Evaluation for osteomyelitis: Skeletal scintigraphy has an approximately 95% overall sensitivity for detection of osteomyelitis and can detect changes days or weeks before osseous changes are visualized on standard radiographs.[7] The exam will usually demonstrate increased activity in all 3 phases with localization to the bone on delayed phase imaging.
• Differentiation between osteomyelitis and cellulitis: Cellulitis shows increased perfusion and diffusely increased soft tissue activity on early images without increased bony activity on delayed images. Osteomyelitis will demonstrate increased activity on the flow, blood pool, and osseous uptake on the delayed phase.
• Complex regional pain syndrome (previously referred to as reflex sympathetic dystrophy): This entity consists of pain, tenderness, swelling, and vasomotor instability in the affected limb, usually precipitated by trauma.[8] Although the diagnostic performance of a three-phase bone scan is highly variable, ranging from 14% to 100% sensitivity and 50% to 100% specificity,[8] the scan will usually demonstrate the affected limb to have increased perfusion, asymmetrically increased blood pool, and a characteristic diffusely increased juxta-articular pattern around the joints of the affected extremity on delayed phase imaging.[7]
• Evaluation of inflammatory arthritides: Angiogenesis has been found to be an essential event in maintaining inflammatory and immune responses, resulting in increased blood flow to the area. The addition of perfusion and blood pool phases in skeletal scintigraphy improves the diagnostic accuracy of the exam.[9]
• Evaluation of orthopedic prosthetic infection versus loosening: –The overall accuracy of skeletal scintigraphy in the evaluation of orthopedic prosthetic joints is about 50% to 70%, but is a useful screening tool due to its high negative predictive value.[10] Infection generally shows a more generalized increase, while aseptic loose implants will demonstrate a localized, limited focal response on the flow and blood pool phases.[11]
• Evaluation of myositis ossificans (also known as heterotopic ossification): Non-specific increased uptake on flow and blood pool images is seen early in the development of the lesion and gradually decreases as the lesion matures.[12] Increased uptake on the delayed phase is typical. Evaluation of maturity is crucial as there is a higher risk of recurrence if the lesion is removed before reaching maturity.

Normal and Critical Findings

In the initial phase of imaging, blood flow should be prompt and symmetric to the area of interest. In cases of infection and/or inflammation, there will be asymmetric blood flow preferentially to the affected area.

Blood pool imaging should show symmetric radiotracer activity. Once again, an area of inflammation and/or infection will exhibit disproportionate blood pool activity to the affected region.

In the delayed phase, the interpreter of the study must know the normal anatomic distribution of the radiotracer so he or she can appropriately interpret the images. Activity is generally seen throughout the osseous structures with the soft tissue activity predominately cleared by normal renal activity and is often referred to as "washout." This makes patient hydration and renal function of importance to improve the target to background activity. If the kidneys and bladder are not visualized, this raises suspicion for a "superscan," which implies diffuse malignant metastatic disease secondary to increased metabolic osteoblastic activity.[13] In children and young adults, intense activity is normally seen in the physes secondary to osteoblastic activity seen in bone growth. Activity in the area of the nasopharynx, sternum, sacroiliac joints, and articular surfaces is usually considered normal as well. Areas of intense, focal radiotracer activity not conforming to these areas is considered a positive finding and warrants further evaluation.

The various phases of a 3-phase scan can demonstrate positive findings at certain time points in the exam while being negative at other time points.

Osteomyelitis, complex regional pain syndrome, acute fractures, abnormalities of orthopedic prostheses, inflammatory arthritides, immature myositis ossificans, and aggressive tumors can all demonstrate three phase positivity.[11]

A 3-phase scan showing positive findings on the flow phase and the blood pool phase but negative uptake in the osseous structures is usually seen with soft tissue abnormalities, such as cellulitis or a soft tissue malignancy, such as a sarcoma. Of note, although the appearance on flow and blood pool imaging often appears indistinguishable in osteomyelitis versus cellulitis, in the case of cellulitis, the blood pool is more commonly increased secondary to venous congestion versus arterial activity that is usually seen in osteomyelitis.

When there are normal flow and blood pool imaging but increased activity on the delayed phases, the likely pathology has minimal to no soft tissue involvement and is confined to the bones. Some examples include shin splints, non-acute fractures, non-acute stress fractures, osteoblastic metastasis, and certain metabolic disorders.

Interfering Factors

Numerous factors can interfere with a 3-phase bone scan. If the patient has a medical condition that affects blood flow unilaterally, then the flow and blood pool phases can be adversely affected, demonstrating relatively abnormal activity to an area that may be normal for the patient. An example is a patient with advanced vascular atherosclerotic disease with decreased flow secondary to claudication or post-operative patients with bypass grafts of the extremities.

Additionally, poor renal function can cause continued activity within the soft tissues on the delayed phase imaging, as the radiotracer cannot be adequately cleared. This may limit the visualization of the bony structures. A 24-hour delayed acquisition (often referred to as the fourth phase) may be used to allow for clearance of soft tissue activity, although the 6-hour half-life of Technetium 99m means that approximately 94% of the radiotracer activity is degraded by the time the delayed imaging is acquired.

Urine contamination or a urinary diversion reservoir can interfere with the normalization algorithm as a focal area of increased radiotracer activity can result in apparent decreased activity within the osseous structures. The contamination can also appear as specious pathology if it overlies osseous structures.

Typically, the labeling efficiency of Technetium 99m to the bone-seeking agent is greater than 95%. Poor labeling results in a significant amount of unbound Technetium 99m-pertechnetate colloquially referred to as "free technetium." Free technetium can be seen with any Technetium 99m labeled agent. Free technetium is used in other imaging studies within the field of nuclear medicine but serves as a confounding agent in skeletal scintigraphy where it can localize to the salivary glands, thyroid, and stomach.

Complications

Although allergic reactions to radiopharmaceuticals may occur, they are rare and usually mild.  Care should be taken before administration, and the patient should be asked about any prior reactions to prior nuclear medicine exams.

As with any intravenous injection, there is always the risk of extravasation, which can cause pain, redness, and swelling. This also increases the risk of damage to cells secondary to radiation exposure.

Patient Safety and Education

The kidneys predominately clear the radiotracer, and the patient should be instructed to void frequently following radiotracer injection as to minimize the dose to the bladder. The average radiation dose the patient for skeletal scintigraphy is approximately 4.2 mSv, which is approximately half the dose of the average abdominal CT scan.

Although the incidence is unknown, methyl diphosphonate has been known to cause low blood pressure in certain patients.  As such, care should be taken to monitor the patient following injection and throughout imaging to ensure the patient is able to move safely following radiotracer administration.

Technetium 99m tagged radiotracers show excretion into breast milk. If the patient is breastfeeding, formula or stored breast milk should be used for a minimum of 24 hours.  The patient should be instructed to pump and discard her breast milk for the 24 hour following the study.

Clinical Significance

A 3-phase bone scan is a powerful tool within the nuclear medicine diagnostic toolkit. When properly indicated, it can help to differentiate between cellulitis and osteomyelitis, assist in the diagnosis of complex regional pain syndrome, evaluate inflammatory arthritides, assist with the evaluation of hardware loosening versus infection, as well as the evaluation of maturity of foci of heterotopic ossification. Clinicians should be familiar with the indications for a 3-phase scan and pre-procedure preparation of the patient.