**10. Osteoarthritis**

118 12 Chapters on Nuclear Medicine

lesions on PET study represents active tumor itself. Bone scintigraphy is more sensitive than FDG-PET for detection of blastic/sclerotic lesion, whereas FDG-PET is more sensitive for lytic lesions and bone marrow disease. The latter has the additional ability to assess extraskeletal metastatic disease. Hybrid PET/CT imaging improves the specificity of FDG-PET for skeletal metastases (Dasgeb et al., 2007; as cited in Even-Sapir, 2005). An additional finding from scanning the peripheries, particularly in patients with bronchogenic carcinoma, may be the observation of hypertrophic osteoarthropathy secondary to cortical periostitis, that typically appears as symmetrical, nonuniform, irregular cortical uptake involving the long bones, most often seen in the femora, tibiae and wrists, and giving rise to the "tramline sign" (Gnanasegaran et al., 2009; Love et al., 2003; as cited in Ernstoff & Meehan, 2000). In patients with bone metastases who have received chemotherapy, reparative osteoblastic reaction that occurs after this treatment may lead to the appearance of bone areas with intense uptake during the first 3 months (flare phenomenon). As healing progresses, uptake in the lesion disminishes and by 6 months it should generally be possible to differentiate response from

18F-FDG-PET has become a routine imaging modality for staging and monitoring the response to therapy in patients with lymphoma. There are accumulating data indicating that 18F-FDG-PET may detect early marrow infiltration and may add clinically relevant information when performed in patients with primary or secondary lymphomatous bone involvement. FDG-PET can detect early marrow infiltration and therefore is more sensitive than planar scintigraphy or CT for assessment of early skeletal involvement in lymphoma (Dasgeb et al., 2007). A pattern of heterogeneous patchy marrow activity should raise the suspicion of marrow involvement in an 18F-FDG-PET study prior to therapy, while a pattern of diffuse uptake, mainly in Hodgkin's Lynphoma, is more commonly associated

Metastatic disease occasionally manifests as a solitary abnormality, usually in the spine, although other causes such as fractures, avascular osteonecrosis, primary bone tumors and infections must be previously ruled out. The location and/or characteristics of the lesion may guide the diagnostic suspicion but, especially if it is a solitary lesion, it must be studied with other imaging techniques such as CT or/and MRI (Schneider, 2006). Approximately 50% of cases in which scintigraphy detect a solitary focal uptake in a patient with a history of cancer, it is a metastasis. In patients with breast cancer, the sternum is a relatively common site to be affected often as a solitary lesion and probably results from local spread from the involved internal mammary lymph nodes. If a sternal lesion is situated distant from the manubriosternal junction, is irregular, asymmetric, or eccentric, then malignant involvement should be suspected. In a retrospective study of patients with breast cancer, 3.1% presented with an isolated sternal lesion and 76% of these were found to represent metastatic disease (Gnanasegaran et al., 2009; as cited in Kwai et al., 1988). Vertebral body fractures have a characteristic appearance on bone scintigraphy, showing a horizontal linear pattern of increased tracer accumulation. However, it is usually not possible to differentiate fractures due to benign diseases, such as osteoporosis from malignant collapse. In such cases, further evaluation with MRI is often the most informative. However, multiple linear abnormalities of varying intensity favour a benign etiology with presumed osteoporotic fracture occurring at different time points. Also, a follow-up bone scan after a few months that shows reducing activity at a vertebral fracture site, suggests a benign cause and a healing fracture. SPECT technique improves the localization and characterization of the vertebral lesions, due to its ability to delineate the body, pedicles, and spinous process:

with reactive hematopoietic changes or myeloid hyperplasia (Even-Sapir, 2007).

progression (Love et al., 2003).

Osteoarthritis (OA) is the most prevalent chronic joint disease and it has the greatest health economic impact. Conventional radiography is still the first and most commonly used imaging technique for evaluation of a patient with a known or suspected diagnosis of OA (Guermazi, 2009). MRI is an appropriate tool for describing changes in cartilage volume and concomitant soft-tissue alterations. But for qualitative cartilage imaging, MRI has, to date, not been fully validated. Bone scan allows the differentiation of inflammatory from degenerative joint affections and may add information on the activity of the subchondral bone, which may develop to a prognostic marker of OA (Zacher et al., 2007). Another pronostic marker of slower progression that can help us deciding the most appropriate management is the imaging of the joints that show up as "cold" (Colamussi et al., 2004). Radionuclide joint imaging is more sensitive than clinical or radiographic techniques in detecting early joint involvement but usually it must be supplemented by other techniques to establish a specific diagnosis (Hoffer & Genant, 1976).

Usefulness of molecular imaging for early diagnosis of OA is still a challenge. Cartilage damage in OA is being recharacterized as having an earlier dynamic phase, where cartilage damage is potentially reversible, followed by an irreversible pathologic phase that ultimately leads to joint pain and immobility (Hu & Du, 2009). The point at which cartilage damage is deemed irreversible has not been defined but probably depends on the size of the lesion, age of the patient, underlying cause, comorbid factors, activity level, use of joint stabilizers, genetic predisposition, and other factors. To detect early cartilage damage, molecular imaging research has focused on the identification of better ways to either visualize extracellular matrix depletion or measure events that are associated with cartilage damage, such as chondrocyte death and the elaboration of matrix-degrading enzymes. In OA, there is general acceptance that abnormal chondrocyte apoptosis is a pivotal event in the eventual destruction of articular cartilage (Biswal et al., 2007). A method for the study of cell death in living subjets is based on an endogenous protein, annexin V, whose function is not clearly understood but which is thought to play a role in coagulation (Biswald et al., 2007; as cited in Reutelinsperger & Van Heerde, 1997). This protein has an extremely strong affinity for the cell membrane phospholipid phosphotidylserine, which is expressed to the outer surface of the cell membrane during the apoptotic cascade. The use of annexin V, labelled with either a radioisotope or a fluorescent marker, provides an excellent opportunity to image programmed cell death. To date, annexin V has been labelled with 99mTc, iodine (125I, 124I, 123I), 111In, 11C, gallium (Ga-67, Ga-68), and 18F, making it appropriate for either SPECT or PET imaging (Biswald et al., 2007; as cited in Blankenberg, 1998; Glaser, 2003; Lahorte, 2004; Russell, 2002; Zijlstra, 2003). However Annexin V imaging has yet to be applied to the assessment of human OA. Another event associated with cartilage damage is the elaboration of matrix-degrading enzymes. In OA damaged cartilage appears to activate hibernating proteases such as matrix metalloproteinases and cathepsins. Using a cathepsin B–sensitive near-infrared fluorescent probe, researchers have found significant amounts of signal arising from an arthritic knee compared with normal knees in an animal model of OA (Biswald et al., 2007; as cited in Lai, 2004).

Nuclear Medicine in Musculoskeletal Disorders: Clinical Approach 121

skeleton) may be necessary, as commented in that section. Gallium-67 citrate uptake in HO is proportional to the uptake of 99m Tc-diphosphonates, in contrast to the relatively greater

A diagnostic-treatment algorithm of heterotopic ossification has been proposed, and threephase bone scintigraphy has been recommended, after clinical signs and laboratory test, for its diagnosis in patients without HO but with high risk factor. If clinical signs and symptoms are present but initial radiographic studies are normal, bone scan should be repeated after 4- 6 weeks, and when scintigraphic studies have displayed the HO, it should be made every three months during the first year. Bone scan has also been proposed during the follow-up

Following known injury, fractures are commonly demostrated by conventional radiography of most sites of trauma. In such circumstances bone scintigraphy has no major role, although unsuspected lesions may be identified. Acute fractures show increased perfusion on the radionuclide angiogram; intense, poorly marginated increased tracer accumulation representing relatively increased vascularity on the blood pool images; and intense poorly

Scintigraphy may be valuable in the diagnosis of occult fractures, which are true fractures not immediately obvious on clinical examination or plain radiography, and it is particularly useful to detect certain type of fractures that require urgent orthopedic treatment, such as femoral neck and intertrochanteric fractures, scaphoid fracture, and Lisfranc fracture. Occult femoral neck and intertrochanteric fractures are frequents in older females with continued hip pain following a fall. Shortly following the time of injury, there is an increase in perfusion to the fracture site which can be demonstrated during the rapid sequence flow study and blood pool phases of the so called three-phase bone scan. The time for first appearance of increased uptake on delayed 99mTc-diphosphonate images remains controversial, fluctuating between 24 hours and 2 weeks (Collier et al., 1993; as cited in Holder et al., 1990; Matin, 1979; Spitz, 1991). These problems are not encountered in the identification of scaphoid fracture which is readily visualized within 3 days of trauma. Bone scan demonstrates a focus of intense uptake usually centered in the scaphoid (Collier et al., 1993; as cited in Patel et al., 1992; Tiel-van-Buul et al., 1992). High-resolution bone scan images obtained with the wrist first in a neutral position and then in ulnar deviation are used to localize the scintigraphic abnormality to the scaphoid. With ulnar deviation there is movement and rotation of the scaphoid relative to adjacent bony landmarks such as the radial styloid (Collier et al., 1993). Premature imaging withing 48 hours must be avoided, particularly as the osseous scintigraphic changes may be obscured by the diffuse uptake resulting from superficial hyperemia or traumatic sinovitis. Prolonged delay of this study may also result in increased uptake associated with disuse and thus, masking the fracture (Murray, 1998). Scintigraphy is therefore of considerable value in identifying this lesion before X-ray change appears, especially as difficulty may be encountered in radiological diagnosis even after 2-3 weeks (Murray, 1998). Difficulties in identifying the exact anatomic localization of a focus of uptake can be overcome by the technique of a combined display of the scan and the X-ray (Murray, 1998; as cited in Hawkes, 1991). Other occult fracture that

gallium-67 citrate uptake characteristic of osteomyelitis (Shebab et al., 2002).

after HO removal to monitor possible recurrences (Medina et al., 2008).

defined increased tracer accumulation on delayed images (Holder, 1993).

**12. Fractures** 

**12.1 Occult fractures** 
