Bone Scan: Indications Revisited

Introduction

Skeletal scintigraphy or bone scan is a well-established imaging technique in the nuclear medicine department. It is performed using technetium 99m-methylene diphosphonate (Tc99m MDP) on a gamma camera or single-photon emission computed tomography single-photon emission computed tomography (SPECT)- or fluorine-18 sodium fluoride (F-18 NaF) on a positron emission tomography-CT (PET-CT) scanner. Since the discovery of Tc-99m MDP by Subramanian and McAfee in 1971[1] and its superiority over other bone-seeking radiopharmaceuticals,[2] it is one of the most used radiotracers for bone imaging and bone scan, per se, remains one of the most commonly performed investigations in any nuclear medicine department. The changes in the indications of bone scans over the past three decades and the various causes behind them are discussed.

Materials and Methods

This study was conducted in a nuclear medicine center situated in a tertiary care university hospital which is operational since 1987. It is a retrospective analysis of the various indication with which the referring clinician had sent the patients for skeletal imaging. The data were collected from the departmental records.

Randomly, 1 year was selected from different decades, and bone scan indications were evaluated. The years selected were 1998, 2012, and 2021. All the bone scans done in that 1 year from January 1 to December 31 were evaluated for the referring physician indications. For analysis purposes, the result of the bone scan was not taken into account. The diagnosis, made by the referring physician, and clinically relevant history were considered for determining the indication for the bone scan. The indications were broadly divided into metastatic and nonmetastatic indications. The nonmetastatic indications were further divided into the infection-related, metabolic bone scan, i.e., renal osteodystrophy, hyperparathyroidism, osteoporosis (including insufficiency fracture), occult fracture evaluation, arthritis evaluation, pain related i.e., nonspecific body pain, low backache, limb pain, etc., prosthesis-related, and miscellaneous indications such as Paget's disease, fibrous dysplasia, and vascularity. In case of overlap of indication, like prosthetic evaluation presenting with pain, whose final diagnosis was an infection-related complication, the indication was considered under prosthesis related. Similarly, when a known case of Paget's disease presented with pain and bone scan was done to look for multiple sites of involvement, the indication was considered under the miscellaneous category.

The F-18 NaF bone scans were not included in the study for analysis because they were not performed in 1998 and 2012 at our institute.

Results

The number of Tc99m-MDP bone scans performed in 1998, 2012, and 2021 was analyzed in this study. In 1998, a total of 1003 bone scans were performed, of which 605 (60.3%) were for metastatic or malignancy workup while 398 (39.7%) were for the nonmetastatic cause. Similarly, in 2012, 978 bone scans were performed, of which 545 (55.7%) were for metastatic/malignancy workup and 433 (44.3%) were for the nonmetastatic cause. In 2021, a total of 530 bone scans were performed, out of which 82 (15.5%) were for metastatic or malignancy workups, and the rest 448 patients (84.5%) had a bone scan done for nonmetastatic work-up [Figure 1]. The number in 2021 was less due to the COVID-19 pandemic.

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Figure 1 Bone scan indications, depicted in percentages, in the years 1998, 2012, and 2021 with trendlines

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In the nonmetastatic category [Figure 2], the most common indication in 1998 was pain-related, accounting for 45.5% with 181 patients out of 398 getting a bone scan done for pain. This was reduced to 11.5% in 2012 (50 patients out of 433) and further reduced to 10.5% in 2021 (47 patients out of 448) [Figure 3], due to advancements in other imaging modalities such as musculoskeletal (MSK) magnetic resonance imaging (MRI), and Ultrasonography (USG). The second largest indication in the nonmetastatic category was arthritis-related indications, accounting for 33% in 1998 (131 patients out of 398 patients) which remained fairly stable in 2012 at 30% (130 patients out of 433) and 35.3% in 2021 (158 patients out of 448) [Figure 4]. Similarly, indications for fracture evaluation were 7.5% in 1998 (30 patients in 398) which increased to 11.4% in 2012 (49 patients in 433) and 4.2% in 2021 (19 patients in 448). The major change was seen in infection-related indications, which increased from 4% in 1998 (16 patients out of 398) to 24.9% in 2012 (108 patients out of 433) and 26.3% in 2021 (118 patients out of 448) [Figure 5]. Similarly, prosthesis-related indications increased from 2% (8 patients out of 398) in 1998-2.5% in 2012 (11 patients out of 433) and 9.6% in 2021 (43 patients out of 448) [Figure 6]. The indications for metabolic bone scan and insufficiency fracture were 3% in 1998, increased to 16.2% in 2012, and in 2021, it accounted for 8.5% of all nonmetastatic indications [Figure 7]. The miscellaneous causes, which included all other indications, not present in other categories, as described above, are fairly stable at 5% in 1998, 3.5% in 2012, and 5.6% in 2021 [Figures 8 and 9].

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Figure 2 Changes in various nonmetastatic indications, depicted in percentages, in the years 1998, 2012, and 2021

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Figure 3 A 35-year-old male presented to orthopedics OPD with low back ache for the past 6 months, which started as a dull pain, but now increased in intensity since 1 month associated with loss of appetite and mild malaise. The patient also developed pain in the left shoulder region for the past 1 month. A radiograph of lumbar spine done 5 months back showed subtle sclerosis and end plate of L4 vertebra. Bone scan and MRI Lumbo-sacral (LS) spine were advised. A 3-phase bone scan using Tc99m-MDP tracer was performed. The flow phase of the lumbar region showed increased vascularity near the lower border of the kidneys at the site of L3-4 vertebrae (a). The static blood pool (b. 1) and delayed (b. 2) images of the lumbar region showed increased tracer pooling and delayed tracer uptake in the same region at L3-4 level. The whole-body blood pool image (c) and delayed images (d) taken after 3 h showed increased uptake in L3-4 vertebrae, left sternoclavicular joint, and manubrium sternum. The SPECT-CT images of L4 (e) vertebra showed destructive lesion with pre and paravertebral soft tissue and similar findings of destruction and fluid collection were noted in left sternoclavicular joint (f). Button sequestrum (Black arrow) is noted in the vertebral lesion. MRI done 2 days later confirmed Spondylodiscitis of L3 and L4 vertebrae and the patient was started on anti-tubercular drugs with dramatic improvement in 2 weeks. OPD: Outpatient department, MRI: Magnetic resonance imaging. MDP: Methylene diphosphonate, CT: Computer tomography, Tc99m-MDP: Technetium 99 m-methylene diphosphonate, SPECT: Single-photon emission computed tomography, LS: Lumbar spine

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Figure 4 A 72-year-old male, known case of seropositive rheumatoid arthritis for the past 5 years, taking biologics for the past 1 year. The patient was having neck pain and MRI cervical spine showed signal changes in atlantoaxial joint with edema and was reported as possible infection. The patient underwent 3-phase bone scan using Tc99m-MDP tracer. The whole-body blood pool image (a) showed increased tracer pooling in both shoulder joints, right sternoclavicular joint, both wrist joints, right knee joint, and small joints of hands and feet. Delayed whole body image (b) showed increased tracer concentration in the same regions showing increased tracer pooling. The SPECT-CT of the head and neck region showed increased tracer uptake in left facetal joint between C1 and C2 vertebra (c) and in right sternoclavicular joint (d), all due to active rheumatoid arthritis. MRI: Magnetic resonance imaging. MDP: Methylene diphosphonate, CT: Computer Tomography, Tc99m-MDP: Technetium 99 m– methylene diphosphonate, SPECT: Single-photon emission computed tomography, MRI: Magnetic resonance imaging

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Figure 5 A 7-year-old female presented to Orthopedic OPD with pain and swelling in right ankle joint, The radiograph of ankle joint was reported as normal study. The ESR of the patient was 50 mm/1^st h while CRP was positive (48 mg/1000 ml). Rest all blood parameters were within normal limits. The patient underwent 3-phase bone scan using Tc99m-MDP tracer. The flow image of ankle joint (a) showed increased flow to the right ankle. The blood pool static images of ankle (b. 1. and b. 2) showed increased tracer pooling in the right ankle joint while delayed static images (b. 3 and b. 4) showed mild increased tracer uptake in right tibiotalar joint with relatively normal tracer uptake in the bones suggesting cellulitis. The whole-body blood pool image (c) showed mild increased tracer pooling in the skull (right frontal and left parietal), both shoulders, few right-sided ribs apart from the right ankle. The same regions showed increased tracer uptake in delayed whole-body images (d) taken after 3 h of tracer injection. The diagnosis of multifocal osteomyelitis was made and the patient underwent fluid aspiration from the right ankle joint which showed tubercular bacilli. The patient was started on antitubercular drugs and is doing fine now. OPD: Outpatient department, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein, MDP: Methylene diphosphonate, Tc99m-MDP: Technetium 99 m-methylene diphosphonate

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Figure 6 Prosthesis evaluation. A 40-year-old man who had undergone hip replacement using an Austin Moore prosthesis 2 years back, now presented with dull pain in the left hip and mid-thigh. Radiograph of the left hip joint was reported as normal. The ESR was mildly elevated. Due to persistent left hip pain, the patient was referred for bone scan. The 3-phase bone scan using Tc99m-MDP tracer was performed. The flow images (1a) showed normal vascularity in both hip joints. The blood pool image (1b) of hip showed minimal increased tracer pooling in left hip joint, predominantly along acetabular surface while delayed static image (1c) and whole body (1d) image showed mild increased tracer uptake in left acetabular surface, focal tracer uptake in intertrochanteric region at the interface of bone-prosthesis surface. This case was diagnosed as aseptic loosening. A 58-year-old woman underwent total left knee replacement, now presented with pain at surgical site. The radiograph of the left knee was reported as normal. The ESR was mildly elevated. The patient underwent 3-phase bone scan using Tc99m-MDP tracer. The flow images (2a) showed increased vascularity in the left knee and the blood pool image (2b) showed increased tracer pooling in the left knee. The static delayed image of the knee joint (2c) and whole-body image (2d) showed diffuse increased tracer uptake at the interface of the bone-prosthesis surface in the tibial component of the prosthesis. This case was diagnosed as prosthetic infection and the patient was treated with antibiotics. MDP: Methylene diphosphonate, Tc99m-MDP: Technetium 99 m-methylene diphosphonate, ESR: Erythrocyte sedimentation rate

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Figure 7 A 17-year-old male, known case of CKD and rickets with wind-swept deformity of both lower limbs. His Sr. PTH is 204.5 pg/ml (10 – 65), Sr. calcium – 8.9 mg/dl (8.6 – 10.2), Sr. phosphorus - 4.8 mg/dl (2.5 – 4.5), and Sr. alkaline phosphatase – 821 U/L (≤ 30). The corrective surgery for deformity was planned. The patient also complained of pain in knees and ankles for which bone scan was advised to rule out any knee pathology. The bone scan using Tc99m-MDP tracer was performed. Delayed whole-body images showed diffusely increased tracer uptake in the entire skeleton with reduced soft-tissue tracer activity and nonvisualization of kidneys and bladder which are the physiological excretory pathway, all suggesting avid tracer uptake by the skeletal system. The bone scan was suggestive of superscan secondary to metabolic cause-CKD. CKD: Chronic kidney disease MDP: Methylene diphosphonate, Tc99m-MDP: Technetium 99 m-methylene diphosphonate, Sr.: Serum, PTH: Parathormone

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Figure 8 A 22-year-old female presented with left frontal swelling for the last 8 years which showed increase in size. There is redness of left eye with no visual disturbances and associated pain and headache episodes. Her blood parameters, Sr. PTH, Sr. total T3, Sr. total T4, Sr. TSH, Sr. calcium, Sr. phosphorus, and Sr. alkaline phosphatase are within normal limits. The radiograph and CT skull were suggestive of fibrous dysplasia of left frontal sinus. Bone scan was ordered to look for the multifocality of the lesion. A bone scan using Tc99m-MDP tracer was performed. The delayed images (a) showed focal intense tracer uptake in the skull over the left supraorbital margin. SPECT-CT images in axial (b), sagittal (c), and coronal (d) sections showed ground-glass opacity involving the posterior margin of enlarged left frontal sinus. Bone scan showed monostotic fibrous dysplasia. As the patient was symptomatic, she was referred for neurosurgical intervention. MDP: Methylene diphosphonate, CT: Computer tomography, Tc99m-MDP: Technetium 99 m-methylene diphosphonate, SPECT: Single-photon emission computed tomography, Sr.: Serum, PTH: Parathormone

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Figure 9 A 12-year-old boy presented with a history of fall while playing 2 years back and developed left SCFE. He was advised surgical management but deferred. The patient had been limping since then. He again sustained another fall 2 weeks back and presented to the orthopedic department with acute on chronic unstable left SCFE for which patient underwent “Modified Dunn's procedure” 3 days before. There was doubt on vascularity of femoral head post-procedure due to persistent pain for which bone scan was advised. A 3-phase bone scan using Tc99m-MDP tracer was performed. The flow images (a) showed mild increased flow to left hip. Same region showed increased tracer pooling in static (b. 1) and whole-body anterior blood pool (c) images. The delayed static image of hip (b. 2) and whole-body image (d) showed increased tracer activity in left femoral head and left acetabulum. The sagittal (e) and axial images (f) showed tracer uptake in the head of left femur thereby confirming that the vascularity was intact and tracer uptake by bone confirmed that it is viable. Note the reduced tracer uptake in neck of left femur due to peeling of periosteum in that region. MDP: Methylene diphosphonate, CT: Computer tomography, SCFE: Slipped capital femoral epiphysis, Tc99m-MDP: Technetium 99 m-methylene diphosphonate

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Discussion

Tc99m MDP skeletal scintigraphy or bone scan, one of the commonly performed investigations in the nuclear medicine department, has shown a paradigm shift in the indications for the scan due to various reasons, such as the development of other imaging modalities – PET-CT, MSK-MRI, and USG. The literature search yielded an article by Ryan and Fogelman[3] who also echoed a similar change in 1995 in the United Kingdom with a reduction in metastatic indication and an increase in benign orthopedic conditions. In the Indian scenario, this shift from metastatic to nonmetastatic indications was much later, primarily due to the delay in the launch of PET-CT. The first only PET scanner was established in India at Radiation Medicine Centre, Mumbai, in October 2002, which was followed by the first PET-CT scanner at Tata Memorial Hospital, Mumbai, in December 2004.[45] Since then, the number of PET-CT scanners has grown tremendously with more than 222 PET-CT centers in 2018.[4] As the PET-CT study provided much comprehensive information in terms of tumor size (T), nodal status (N), and other metastatic sites (M), it scores over bone scans which tells only about skeletal involvement in malignancy. This has been the biggest cause for the reduction in metastatic indications. Another major reason is the induction of PET-CT imaging in various cancer management guidelines such as NCCN Guidelines. Now, PET-CT imaging is part of Bone Cancer NCCN Guidelines and NCCN Evidence blocks ver. 1.2023 in bone lesions in age ≥40 years.[6] PET-CT imaging has been included in chordoma, Ewing sarcoma, and osteogenic sarcoma management.[6] The most common cause of skeletal metastases in males is prostate cancer and in females, breast cancer.[7] With the advent of theranostics and prostate-specific membrane antigen (PSMA)-based therapy with lutetium-177 and actinium-225 for prostatic carcinoma,[8] more and more patients are undergoing gallium-68 PSMA or fluorine-18 PSMA PET-CT scan, instead of conventional bone scan wherein if tracer localization is seen on these PET-CT studies, patients have an opportunity to be treated by the PSMA-based therapies.

In nonmetastatic indication, pain-related indication for skeletal scintigraphy was maximum, which showed a significant reduction in subsequent decades, mainly due to advancement in other imaging modalities such as multidetector CT, advancement in MSK-MRI techniques, HRUSG, and better workstations.[9] There has been a substantial increase in bone scan indications related to prosthesis evaluation. This has been due to manifold in numbers of prosthetic surgeries being performed, due to increased life expectancy, an aging population leading to more painful joints,[10] and better, much wider, availability of resources. In the Indian scenario, the number of total knee replacement (TKR) surgeries in 2006 was 1019, which increased to around 27,000 in 2019 with similar trends in total hip replacement surgeries.[10] Due to this increase in the absolute number of TKR surgeries, the number of revision TKR surgeries also showed an absolute increase in number with infection being the most common cause,[11] and a 3-phase bone scan is the preferred nuclear medicine study in patients of total joint arthroplasty presenting with pain,[12] leading to the total increase in many prosthesis-related cases presenting for the bone scan.

There is also an increase in other infection-related indications, such as vertebral spondylodiscitis and osteomyelitis, which accounted for 26.3% of all nonmetastatic indications in 2021, the reasons could be attributed to an aging population, increased surgical procedures in the older population, increased incidence of comorbidities such as diabetes mellitus leading to immunocompromised state, and improved detection rate due to better availability of imaging services.[13] There was an increase in the number of patients visiting the nuclear medicine department with a clinical diagnosis of metabolic bone disease, as described previously, from 3% to 16.2%, mainly attributed to a better understanding of these disease pathophysiology but then showed a decline to almost half to 8.5% in 2021. This decline is due to improved biochemical analysis and better imaging modalities, especially MRI, but most importantly development of multiple disease-related guidelines such as AACE/ACE 2016 – postmenopausal osteoporosis guidelines,[14] KDIGO 2017 guidelines for chronic kidney disease-mineral and bone disorder,[15] and many others. The indications for arthritis remained almost similar in the past 3 decades between 30% and 35%. The miscellaneous indications which included conditions such as osteoid osteoma, fibrous dysplasia, Paget's disease, and a few rarer conditions such as melorheostosis also remained the same at ~ 5%.

In conclusion, there has been a significant shift in the skeletal scintigraphy indications from metastatic to nonmetastatic ones due to advancements in technologies and a better understanding of the disease process. At present, the common orthopedic and rheumatological indications are arthritis evaluation, prosthesis-related complications, evaluation of radiologically occult fractures/infections, and metabolic bone diseases.