Seminars in Nuclear Medicine
Volume 40, Issue 1 , Pages 52-61, January 2010

Miscellaneous Indications in Bone Scintigraphy: Metabolic Bone Diseases and Malignant Bone Tumors

  • Gary J.R. Cook, MBBS, MSc, MD, FRCR, FRCP

      Affiliations

    • Department of Nuclear Medicine and PET, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
    • Corresponding Author InformationAddress reprint requests to Gary J.R. Cook, MBBS, MSc, MD, FRCR, FRCP, Department of Nuclear Medicine and PET, The Royal Marsden NHS Foundation Trust, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom
    • ,
  • Gopinath Gnanasegaran, MD

      Affiliations

    • Department of Nuclear Medicine, Guys and St Thomas' NHS Foundation Trust, London, United Kingdom
    • ,
  • Sue Chua, MBBS, BSc, FRCR

      Affiliations

    • Department of Nuclear Medicine and PET, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom

Article Outline

The diphosphonate bone scan is ideally suited to assess many global, focal or multifocal metabolic bone disorders and there remains a role for conventional bone scintigraphy in metabolic bone disorders at diagnosis, investigation of complications, and treatment response assessment. In contrast, the role of bone scintigraphy in the evaluation of primary malignant bone tumors has reduced with the improvement of morphologic imaging, such as computed tomography and magnetic resonance imaging. However, an increasing role for 18F-fluorodeoxyglucose positron emission tomography and positron emission tomography/computed tomography is emerging as a functional assessment at diagnosis, staging, and neoadjuvant treatment response assessment.

 

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Metabolic Bone Disorders 

Metabolic bone disorders represent a heterogeneous group of skeletal pathologies that can lead to global or focal changes in bone metabolism. These are often associated with biochemical and microscopic or macroscopic morphologic changes. While some features of metabolic bone disorders or their complications can be detected with plain film radiography, the superior sensitivity of bone scintigraphy can be valuable for diagnosis, detection of complications, and monitoring of treatment response.

The continuous improvement in gamma camera hardware and software with the addition of single-photon emission computed tomography (SPECT), and more recently, hybrid SPECT/computed tomography (CT), has maintained a role for nuclear medicine methods in bone disease despite the improvements seen in morphologic imaging techniques, such as CT and magnetic resonance imaging (MRI). In addition to conventional single photon bone imaging agents, such as the 99mTc-labeled diphosphonates, there is also a resurgence of interest in positron emission tomography (PET) imaging with the bone-specific agent, 18F-sodium fluoride. The superior quantitative characteristics of PET make 18F-fluoride bone imaging an attractive technique for measuring and monitoring parameters reflecting different aspects of bone metabolism in the metabolic bone disorders.

The exact mechanism of localization of bone tracers is not fully understood, but it is probable that they bind to hydroxyapatite crystals. Accumulation in bone is dependent on local blood flow but is influenced more strongly by the degree of osteoblastic activity, and hence bone formation.1 Most pathologic processes that involve bone result in increased bone turnover, with both osteoblast and osteoclast activity being accelerated. In a normal subject, approximately 30% of an injected dose of 99mTc-methylene diphosphonate (99mTc-MDP) remains in the skeleton, with most uptake being within the first hour, but this may be significantly higher in subjects with metabolic bone diseases.2 Scintigraphic techniques with bone tracers can therefore produce a functional map of bone turnover, displaying pathology that may involve the skeleton focally or globally.

Osteoporosis 

Osteoporosis is defined as a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue, with an increase in bone fragility and susceptibility to fractures. Despite an increase in bone turnover that is usually present in osteoporosis, uncomplicated osteoporosis is not associated with a visibly abnormal bone scan. Even quantitative 24 hour whole body retention measurements of labeled diphosphonate were unable to differentiate osteoporotic subjects from normal subjects,3 although using the same method it was possible to differentiate the reduced bone turnover in oophorectomized women on estrogen supplements from those on no treatment, and to predict the increased rate of bone loss in untreated subjects.4 A method using quantitative SPECT bone scintigraphy was first described by Front et al.5 Knowing about the time and amount of injected activity and with correction for radioactive decay, it was possible to express a quantitative index in units of percentage injected dose per milliliter of bone tissue. In a study of the regional measurement of bone turnover, higher turnover, as measured by the quantitative bone index, was found in the femoral neck and shaft of osteoporotic patients compared with a control population.6 Although vertebral quantitative bone index values were higher in the osteoporotic group, the difference did not reach statistical significance.

The superior quantitative accuracy of 18F-fluoride PET has also been explored in the investigation of bone metabolism in osteoporotic subjects. This method also allows kinetic parameters to be calculated from dynamic scan acquisitions of different skeletal regions.7 The long-term precision of quantitative 18F-fluoride PET for measurement of regional indices of bone metabolism is equivalent to biochemical markers of global metabolism,8 and the relationship between changes in bone mineral density at the lumbar spine and regional bone turnover measured with 18F-fluoride PET is similar to that seen with biochemical markers of global skeletal turnover.9 However, a dissociation of regional lumbar spine turnover, as measured by 18F-fluoride PET, and global skeletal turnover, as measured by biochemical markers, has been reported with relatively reduced regional bone formation in the lumbar spine in osteoporotic women.10, 11 Additionally, this technique is able to measure regional changes in bone metabolism because of antiresorptive therapy for osteoporosis, recording a reduction of 18% in net plasma clearance of tracer to bone mineral.12

The 99mTc-MDP bone scan has no routine clinical role in the diagnosis of osteoporosis per se but is most often used in established osteoporosis to diagnose fractures, particularly at sites that are difficult to image with plain film radiography (eg, sacrum, ribs), and may be particularly useful in the diagnosis and timing of vertebral fractures. The characteristic appearance of this type of fracture is of intense, linearly increased tracer uptake at the affected vertebral level. Although the bone scan may become positive soon after a fracture, it can take a maximum of 2 weeks for the scan to become abnormal, especially in elderly people. Subsequently, there is a gradual reduction in tracer uptake, with the scan normalizing between 3 and 18 months after the incident, the average being between 9 and 12 months.13 With regard to this, the bone scan also is extremely useful in assessing the age of fractures (Fig. 1). If a patient complains of back pain with multiple previous vertebral fractures noted on radiographs, and the bone scan is normal, then this essentially excludes recent fracture as the cause of symptoms. Other causes of pain should then be considered. Currently, a vertebral fracture is defined on the basis of morphometry, but morphometric abnormalities are not specific to fracture and, for example, may be due to congenital vertebral anomalies.14 The bone scan may therefore have a role in deciding whether a morphometric abnormality is related to a fracture, provided that it is acquired within several months of the start of symptoms. Ryan and Fogelman,15 by comparing vertebral fractures identified with scintigraphy with morphometric radiographic changes, concluded that only in vertebrae with morphometric deformities >3 standard deviations below the normal mean, can fractures be confidently diagnosed. However, to date, this approach has not been used in clinical practice.

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  • Figure 1. 

    A posterior 99mTc-MDP bone scan showing abnormal linear activity of different intensities at a number of levels in the lower thoracic and lumbar spine, indicating previous vertebral fractures of different ages.

Because of its great sensitivity, the bone scan also is useful in identifying unsuspected osteoporotic fractures at other sites, such as ribs, pelvis, and hip. It also has an important role in assessing suspected fractures where radiography is unhelpful, either because of poor sensitivity related to the anatomical site of the fracture (eg, sacrum; Fig. 2) or because adequate views are not obtainable because of the patient's discomfort.16

An isotope bone scan also may be valuable in patients in whom back pain persists for longer than one would expect after vertebral fracture. It is common to find that there has been additional unsuspected vertebral fracture. In addition, it is becoming increasingly apparent that osteoporotic patients with chronic back pain may have unsuspected abnormalities affecting the facet joints.16, 17 It is not known whether this is related to physical disruption of the joint at the time of vertebral collapse or is caused by subsequent secondary degenerative or inflammatory changes. SPECT imaging is essential (Fig. 3) to identify abnormalities in the facet joints. On planar imaging alone, it is not possible to separate activity in the facet joints from associated activity in the vertebral body caused by fracture, and the 3-dimensional properties of this technique allow confident anatomical placement of abnormal foci of increased activity. In the osteoporotic patient, it is also important to exclude secondary causes for pain, such as metastatic disease, infection, Paget's disease, among others.

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  • Figure 3. 

    Sagittal (A) and transaxial (B) SPECT 99mTc-MDP images of a patient with previous vertebral fractures clearly seen as varying degrees of abnormal uptake on the sagittal images. A transaxial image in the lower thoracic spine also shows increased activity in the position of the facet joints.

Paget's Disease 

Most patients with Paget's disease have polyostotic disease. The bone scan is a convenient way to evaluate the whole skeleton and has shown a greater sensitivity for detecting affected sites in symptomatic patients in comparison with radiographic skeletal surveys.18 Characteristically, affected bones show intensely increased activity, extending from the end of a bone and spreading either proximally or distally, often showing a “V”-shaped leading edge. Another sign that a scintigraphic abnormality is due to Paget's disease rather than other focal skeletal pathology is that a whole bone is often involved (Fig. 4). This appearance is frequently seen in the pelvis, scapula, and vertebrae. The characteristic appearance of vertebral Paget's disease is of abnormal tracer accumulation throughout the vertebra, affecting the body and posterior elements, as well as the spinous and transverse processes. Many different patterns describing vertebral uptake have been reported as being specific for pagetic involvement, including clover, heart,19 and Mickey Mouse signs.20 The skull may show a different pattern with a ring of increased activity only in the margins of the lesion, representing what is recognized radiologically as osteoporosis circumscripta (Fig. 5).

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  • Figure 4. 

    Anterior and posterior 99mTc-MDP images showing typical pagetic involvement of the right hemipelvis and left upper femur. A right hip replacement is also seen.

Because effective treatments for Paget's disease have become available in recent years, it is increasingly being recognized that preventive treatment with regard to possible complications is desirable, rather than simply treating symptomatic cases. Because of this, it is important to be able to accurately evaluate the extent of disease and the response to treatment. In performing bone scintigraphy after treatment, it is recognized that pagetic lesions may often respond in a heterogeneous manner, even in individual patients (Fig. 6).21 After intravenous bisphosphonate therapy, some bones may completely normalize, whereas the majority show some improvement, and a small proportion remain unchanged. Persistent active disease evident on bone scan may be an indication for more aggressive therapy in selected cases to achieve an optimal clinical result, and this is one of the reasons why it is argued that scintigraphic evaluation may add extra information to simply measuring alkaline phosphatase levels alone. It is also argued that bone scintigraphy may be a valuable method to monitor treatment response in patients with monostotic disease in whom alkaline phosphatase levels are relatively normal.22 Subsequently, the bone scan may also act as a sensitive measure of reactivation of disease, influencing decisions on further treatment. The bone scan appearances can be unusual after successful bisphosphonate treatment, resultant heterogeneous uptake sometimes mimicking metastatic disease.21, 23 Many authors have used quantitative, semiquantitative or qualitative semiquantitative, or qualitative methods with bone scintigraphy to measure treatment response in Paget's disease, generally finding good correlation with other biochemical and clinical markers of disease activity.21, 22, 24, 25, 26, 27, 28, 29, 30 The superior quantitative accuracy of PET using 18F-fluoride ion has been described with significant differences in kinetic and semiquantitative indices between pagetic and normal bones,31 and this method has also been described to measure response to bisphosphonate treatment.32 It was found that simpler quantitative methods, such as standardized uptake value (SUV), correlated with more complex dynamic kinetic indices (eg, Ki-PAT, Ki-NLR) and would simplify the use of PET in this situation. An increase in 18F-fluorodeoxyglucose (18F-FDG) uptake has also been reported in pagetic bone,33 correlating with disease activity. However, to our knowledge, it has not been used to monitor treatment response.

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  • Figure 6. 

    (A) 99mTc-MDP scan showing Paget's disease of the right humerus. (B) After intravenous bisphosphonate therapy, there has been some response showing a residual heterogeneous pattern of uptake.

The radionuclide bone scan may occasionally identify complications of Paget's disease. An incremental fracture on the convex surface of a bowed long bone may be shown as a linear area of increased activity running perpendicular to the cortex (Fig. 7). Although osteosarcoma complicating Paget's disease is very rare, signs that sarcomatous change may have occurred include a change to heterogeneous and irregular uptake within an area of bone, perhaps with some photon-deficient areas corresponding to bone destruction. However, the bone scan may be misleading in the event of fracture or sarcomatous change, as one attempts to identify focally increased tracer uptake against a high background of activity, and it is important to perform radiographs of any symptomatic site in this situation.

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  • Figure 7. 

    A 99mTc-MDP bone scan showing Paget's disease affecting the left humerus, mid-thoracic and lower lumbar spine, sacrum, right 11th rib, left pelvis, left femur and tibia, and the right tibia. Focal linear activity in the right tibia indicates an incremental fracture.

Hyperparathyroidism 

Most cases of primary hyperparathyroidism are asymptomatic and are unlikely to be associated with changes on bone scintigraphy. The diagnosis is made biochemically and therefore bone scintigraphy has no routine role in diagnosis. Bone scans are often used to help differentiate the causes of hypercalcemia, in particular, hyperparathyroidism vs malignancy, so that typical features of metabolic bone disorders may be recognized. In hyperparathyroidism there is increased skeletal turnover, and in the more severe cases, commonly seen as part of renal osteodystrophy, this will be evident scintigraphically. A bone scan may show several features in hyperparathyroidism, but the most important is the generalized increased uptake throughout the skeleton that may be identified because of increased contrast between bone and soft tissues. This is commonly termed the metabolic superscan to differentiate from superscans caused by widespread bone metastases (Fig. 8). Other typical features that have been described in bone scans in metabolic bone diseases include a prominent calvarium and mandible, beading of the costochondral junctions, and a “tie” sternum.34

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  • Figure 8. 

    A 99mTc-MDP bone scan showing features of a metabolic superscan with a diffuse increase in skeletal activity compared with soft tissues in a patient with hyperparathyroidism.

Severe forms of hyperparathyroidism may be associated with ectopic calcification, which can lead to uptake of bone radiopharmaceuticals into soft tissue, the most dramatic example being that of microcalcification in the lungs (Fig. 9). Focal skeletal abnormalities may represent associated brown tumors, although these are relatively uncommon.

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  • Figure 9. 

    A 99mTc-MDP bone scan in a patient with severe hyperparathyroidism as part of renal osteodystrophy showing a typical metabolic superscan and diffuse uptake in the lungs.

Renal Osteodystrophy 

Renal osteodystrophy is due to a combination of bone disorders as a consequence of chronic renal dysfunction, and often demonstrates the most severe cases of metabolic bone disease. It may comprise osteoporosis, osteomalacia, adynamic bone, and secondary hyperparathyroidism in varying degrees. The commonest bone scan appearance is similar to a superscan from other metabolic bone disorders, and uptake of diphosphonate in areas of ectopic calcification also may be seen (Fig. 9). A clue in differentiating this type of scintigraphic pattern from others is that there may be a lack of bladder activity in view of renal failure. Although rarely seen now, aluminum toxicity from hemodialysis causes a poor quality bone scan with reduced skeletal uptake and increased soft-tissue activity, as aluminum blocks mineralization and hence the uptake of tracer. This pattern is applicable to other forms of adynamic bone disease.

Quantitative measurements of bone metabolism in renal osteodystrophy using 18F-fluoride have been compared with bone histomorphometry35 and have shown a close relationship between the net plasma clearance of 18F-fluoride to bone mineral and the histomorphometric indices of bone formation. The method was able to differentiate low turnover from high turnover states of renal osteodystrophy.

Osteomalacia 

Patients with osteomalacia usually demonstrate similar features of a bone scan as described in hyperparathyroidism, although in the early stages of the disease it may appear normal.36 The reason that osteomalacia shows these features is not fully understood. Tracer avidity may reflect diffuse uptake in osteoid, although more likely it is due to the degree of secondary hyperparathyroidism that is present. In addition, the presence of focal lesions may represent pseudofractures or true fractures (Fig. 10). Pseudofractures are characteristically found in the ribs, the lateral border of the scapula, the pubic rami, and the medial femoral cortices. Although osteomalacia is usually a biochemical and/or histologic diagnosis, the typical bone scan features can be helpful in suggesting the diagnosis. The detection of pseudofracutures with this technique is more sensitive than that with radiography.37

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  • Figure 10. 

    A 70-year-old Asian man with bone pain showing multiple rib lesions and increased uptake in the left lesser trochanter. The kidneys and soft tissues are only faintly visualized. The vitamin D levels were almost unrecordable indicating osteomalacia. The patient responded well to vitamin D therapy.

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Primary Malignant Bone Tumors 

The role of bone scintigraphy in the diagnosis and management of primary malignant bone tumors has diminished with the continual improvement in morphologic imaging techniques, including multislice CT and MRI, but a few specific clinical applications remain. In contrast, a larger role is developing for 18F-FDG-PET/CT for staging and response assessment, and will be included in this section.

Bone Scintigraphy in Malignant Bone Tumors 

Bone scintigraphy is useful when an incidental radiographic skeletal lesion cannot be characterized, helping to determine whether it is solitary or multiple. When a lesion is solitary, the bone scan is limited in its ability to characterize the lesion. A negative bone scan increases the probability of a benign lesion, and increased uptake and blood flow and/or blood pool are more frequent in malignant lesions. Characteristic patterns of uptake have been described in some primary bone tumors,38 but in practice there is enough overlap in the scintigraphic characteristics of solitary bone lesions, making it not a reliable enough test.39 Dynamic bone scintigraphy with a 3-phase bone scan may add information on the vascularity of a lesion. Although malignant bone tumors are characteristically associated with increased vascularity, several benign bone tumors may show similar features, such as aneurysmal bone cyst and osteoid osteoma. The differential diagnosis of a solitary bone lesion will usually depend more on morphologic imaging techniques, including radiographs, CT, and MRI, which may be very specific, and ultimately on expert histologic analysis.

After a diagnosis of a malignant primary bone lesion is made, the use of bone scintigraphy to define the extent of tumor before surgical resection is controversial. Although some studies have reported a good correlation between increased bone tracer uptake and true anatomical extent,40, 41, 42 this is not supported by other studies.43 Discrepancies between surgical tumor extent and bone scintigraphy may be due to peritumoral reactive changes overestimating extent or underestimations due to inability to detect marrow and soft-tissue involvement. For these reasons, currently MRI is often the most accurate noninvasive assessment of tumor extent.

The predominant role of the bone scan in primary malignant bone tumors is to detect skeletal metastases (Figure 11, Figure 12). Although the bone scan cannot be relied on to detect soft-tissue metastases, these are occasionally seen, especially in osteosarcoma.44

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  • Figure 12. 

    A young girl with a previous osteosarcoma of the left femur which was resected and a prosthesis implanted subsequently showed evidence of bone metastases in the thoracic spine and right upper femur on bone scintigraphy.

Several studies have reported the ability of bone scintigraphy to predict histologic response to preoperative chemotherapy in patients with primary malignant bone tumors. In a study of 27 patients with osteosarcoma, Ewing's sarcoma, and malignant fibrous histiocytoma, Ozcan et al45 reported that a reduction in hyperemia and extension were the most notable findings on 3-phase bone scintigraphy. A reduction in tumor blood flow of 58.7% was found in 15 responding patients compared with 19.9% in the nonresponders. A higher accuracy in assessing response was possible using all the information from 3-phase scintigraphy (88%), compared with static imaging alone (74%) where the blood flow and blood pool images showed a reduction in vascularity and extension (as predominantly assessed on blood pool) in responders independent of osteoblastic activity. In a similar study of 30 patients with osteosarcoma, Knop et al46 used parametric blood flow and plasma clearance images. Accuracy for predicting histopathologic response to chemotherapy was 88% for blood flow and 96% for plasma clearance by tumor bone. In a previous study by this group, it had been shown that a decrease in plasma clearance of > 20% was associated with histologic features of necrosis, but stable or increasing plasma clearance were associated with high residual tumor cell viability.47 A further study in osteosarcoma and Ewing's sarcoma showed conflicting findings in that the changes in perfusion and blood pool were not predictive, but uptake during the osseous phase predicted response to chemotherapy with an accuracy of 74%. Results with dynamic contrast-enhanced MRI were superior to bone scintigraphy in this study, with an accuracy of 86%.48

18F-FDG-PET in Malignant Bone Tumors 

The diagnosis of indeterminate bone lesions is limited with 18F-FDG-PET, but in general the greater the level of uptake as measured by SUV, the more likely a lesion is malignant in nature (Fig. 13). However, it has been reported that some giant cell tumors and fibrous dysplasia may show uptake equivalent to osteosarcomas and that some other benign bone lesions may show high 18F-FDG accumulation.49

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  • Figure 13. 

    18F-FDG-PET/CT scan of a patient with Ewing's sarcoma of the left pelvis showing a large FDG-avid mass with bone destruction and large soft-tissue component.

In a study of 83 patients with unclassified bone lesions (most of the 37 malignant lesions being primary or recurrent bone tumors), it was found that semiquantitative 18F-FDG-PET using SUV was less able to discriminate benign from malignant lesions (sensitivity 54%, specificity 91%, and accuracy 74%) than more complex parameters, including fractal dimension and transport constants from nonlinear regression analysis.50 A combination of SUV, fractal dimension, and transport constants revealed the best results with a sensitivity of 76%, specificity of 97%, and accuracy of 88%, concluding that 18F-FDG-PET has a high specificity for excluding malignant bone tumors but evaluation of full kinetics with discriminant analysis is required for best results. Recently, dual time point imaging and calculation of a retention index based on 1- and 2-hour SUVs for 18F-FDG showed improved discrimination of benign and malignant bone lesions compared with static measures but that some overlap was still present.51

With the advent of hybrid imaging, it is now possible to take advantage of the metabolic and morphologic information from 18F-FDG-PET/CT to enhance discrimination between benign and malignant bone lesions by dedicated interpretation of the CT characteristics.52

The sensitivity of 18F-FDG-PET in staging primary bone tumors appears to vary between different tumor types and location of metastasis. In general, 18F-FDG-PET or PET/CT would appear to have a complementary role to conventional staging procedures.53, 54, 55 18F-FDG-PET has been shown to be more accurate than bone scintigraphy in detecting bone metastases in patients with Ewing's sarcomas56, 57 but less in osteosarcoma (Fig. 14).58 In contrast, 18F-FDG-PET has limited sensitivity for detecting small pulmonary metastases compared with CT but has improved specificity.54, 58

Several studies report that serial 18F-FDG-PET assessment of primary bone tumors (predominantly osteosarcomas,59, 60 Ewing's sarcomas,61 or both62, 63) is a good noninvasive method to predict pathologic neoadjuvant chemotherapy response. Another earlier study also showed a correlation with pathologic response but described high 18F-FDG uptake in granulation and/or fibrotic tissue and in the fibrous pseudocapsule of treated tumors.64 A high baseline uptake of 18F-FDG in osteosarcoma has been reported as showing an inverse correlation with prognostic indicators and is associated with a poor outcome with similar results for patients with high post-treatment FDG activity.65, 66

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PII: S0001-2998(09)00068-3

doi:10.1053/j.semnuclmed.2009.08.002

Seminars in Nuclear Medicine
Volume 40, Issue 1 , Pages 52-61, January 2010

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