Radiolabelled bisphosphonates

4.1.1 Radiopharmaceuticals

• [^99mTc]Tc-Hydroxy-methylene-diphosphonate ([^99mTc]Tc-HMDP)
• [^99mTc]Tc-Hydroxy-diphosphonate([^99mTc]Tc-HDP)
• [^99mTc]Tc-2,3-dicarboxypropane-1,1-diphosphonate ([^99mTc]Tc-DPD)

4.1.2 Uptake mechanism / biology of the tracer

The radiolabelled bisphosphonates are incorporated into the surface of hydroxyapatite crystals in proportion with local bone vascularization and osteoblastic activity. After intravenous administration, the plasma clearance of bisphosphonates is biexponential; it is also a function of skeletal uptake and urinary elimination. Four hours after injection, approximately 60% of the injected amount will be fixed to the skeleton, the unbound fraction (34%) is excreted in the urine, and only 6% remains in circulation. Tracer elimination through the gastro-intestinal tract is insignificant. Maximum bone accumulation is reached 1 h after tracer injection and remains practically constant up to 72 h. Clearance of activity from the surrounding soft tissue shows a somewhat slower continuous course that reaches a more optimal bone-soft tissue-ratio between 2 and 3 h post injection.

4.1.3 Indications

The indications for bone scintigraphy are numerous and can generally be classified into three distinct clinical scenarios: confirmation or exclusion of specific bone diseases, exploration of unexplained symptoms, metabolic assessment of the skeleton before or under treatment. Non-exhaustive examples are outlined below [86].

Confirmation or exclusion of specific bone disease

• Oncology: breast and prostate cancer, lung and renal cancers, bone tumours and bone dysplasia, and paraneoplastic syndromes (e.g. hypertrophic pulmonary osteoarthropathy, algodystrophy, polymyalgia rheumatica, poly(dermato)myositis, osteomalacia).
• Rheumatological and osteoarticular infections: osteomyelitis, septic arthritis, spondylodiscitis or spondylitis, septic loosening of a prosthesis, especially of hip and knee, avascular necrosis, osteoarthritis, complex regional pain syndrome, Tietze’s syndrome (costochondritis), and Paget’s disease.
• Orthopaedics, sports & traumatology: periostitis (i.e. shin splints), enthesopathies (i.e. plantar fasciitis, Achilles tendinitis or bursitis, spondylolisthesis), radiological occult fractures and insufficiency fractures (i.e. osteoporotic vertebral fractures, sacral fracture, femoral head or neck fractures, tibial plateau fractures, tarsal or metatarsal fractures), pseudarthrosis (non-unions) (e.g. spinal fusion surgery), periarticular exostosis, viability of bone graft, and suspected aseptic loosening of prosthesis.
• Paediatrics: osteochondritis of the hip (Legg-Calve-Perthes disease) transient synovitis of the hip, osteoid osteoma, battered child syndrome, bone infarction (i.e. sickle cell disease and thalassemia).

Exploration of unexplained symptoms:

Sub-acute / chronic musculoskeletal or bone pain with normal clinical examination and radiographs. Further exploration of abnormal biochemical (e.g. phosphate or calcium metabolism) or radiological findings.

Metabolic assessment prior to therapy initiation:

• Assessment of bone remodelling prior to radionuclide therapy ([²²³Ra]RaCl₂, [⁸⁹Sr]SrCl₂, [¹⁵³Sm]Sm-EDTMP, [¹⁸⁶Re]Re-HEDP) as palliative treatment for painful bone metastases.
• Evaluation of the activity of arthropathies prior to synovectomy or before infiltration with corticosteroids of facet joints.
• Evaluation of osteoblast activity in (suspected) Paget’s disease before starting bisphosphonates.
• Assessment of benign or malignant vertebral compression fracture prior to vertebroplasty or kyphoplasty.

4.1.4 Specific indications for SPECT/CT imaging

• Oncology: in abnormal or equivocal planar scintigraphy to increase lesion localization and characterization or in normal planar scintigraphy with high suspicion of pathology to increase sensitivity;
• Suspected traumatic injuries of the axial or appendicular skeleton;
• Assessment of lesions in the tarsal or carpal small bones, particularly after trauma;
• Suspicion of axial or peripheral osteoid osteoma;
• Assessment of the spine and sacroiliac joints;
• Diagnosis of osteonecrosis and bone infarction;
• Diagnosis of infectious lesions, such as osteomyelitis and spondylodiscitis (complemented with infection imaging);
• Evaluation of painful prosthesis;
• Evaluation of residual pain after orthopaedic surgery on the axial or peripheral skeleton;
• Assessment of malignant or pseudo-malignant lesions;
• Exploration of extra-skeletal pathology or uptake.

4.1.5 Contra-indications

Pregnancy is a relative contra-indication.
It is not recommended to interrupt breast feeding although an interruption of 4 h during which one meal is discarded can be advised to be on the safe side [86].

Bone scintigraphy has a low sensitivity for purely osteolytic lesions (e.g. multiple myeloma) and is therefore not routinely recommended to evaluate multiple myeloma or similar disease. ‘Purely’ should not be mistaken for ‘predominantly’ though.

4.1.6 Clinical performance

Bone scintigraphy is a diagnostic imaging technique used to evaluate the distribution of active bone formation in the skeleton using a radioactive tracer. Bisphosphonate molecules labelled with Technetium-99m exhibit favourable tracer characteristics with good localization in the skeleton after intravenous injection. Tracer deposition occurs in proportion to local blood flow and bone remodelling activity (dependent on osteoblast- osteoclast activity). Unbound tracer is rapidly cleared from surrounding soft tissues.

Most pathological bone conditions, whether of infection, traumatic, neoplastic or other origin, are often associated with an increase in vascularization and local bone remodelling.

This accompanying bone reaction is reflected on a bone scan as a focus of increased radioactive tracer uptake. Bone scintigraphy is a sensitive technique that can detect significant metabolic changes very early, often appearing several weeks before they become apparent on conventional radiological images. In addition, the technique provides an overview of the entire skeleton with relatively modest radiation exposure.

Conventional X-ray images and CT will show the net effect of increased osteoblastic and/or osteoclastic activity through increased sclerosis (dominance of osteoblastic activity) or osteolysis (dominance of osteoclastic activity). However, this is revealed in a much later stage of a disease compared to a bone scan. Also, it is standard protocol to image the entire skeleton, which is cumbersome to do with conventional X-ray images and may produce a high radiation burden with CT. With recent low dose protocols being applied in diagnostic CT imaging the latter argument is no longer valid. MRI is usually preferred for bone lesion characterization, because of its capability to characterize soft tissue tumour components at the same time. However, MRI and bone scans allow visualization of different types of lesions. The two techniques lead to divergent lists of differential diagnoses and are therefore often complementary.

The introduction of hybrid SPECT/CT bone imaging has added sensitivity and specificity as well as complexity to this technique, increasing the need for standardization and experience.

4.1.7 Activities to administer

The suggested activities to administer for adults range from 300 MBq to 740 MBq (8-10 MBq/Kg for adults) [86]. 

In paediatric nuclear medicine, the activities should be modified according to the EANM paediatric dosage card (https://www.eanm.org/publications/dosage-calculator/). The minimum recommended activity is 40 MBq.

4.1.8 Dosimetry

The effective dose per administered activity is 4.9 µSv/MBq for normal uptake and excretion [3]. The range of the effective doses for the suggested activities is 3-4 and in children 2.5 mSv [86].

Caveat

“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but  it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."

4.1.9 Interpretation criteria/major pitfalls

In three-phase scans the blood flow and blood pool aspect of identified lesions should be compared. To assess whether a skeletal lesion has by itself increased vascularity the blood flow and blood pooling of the surrounding soft-tissue should be assessed as well. Skeletal asymmetry result from diffusely increased blood flow in the area of interest (soft-tissue inflammation) or decreased contralateral supply (arterial insufficiency). Increased skeletal uptake, whether focal or diffuse, can be objectively assessed by comparing with the contralateral bone or soft tissue. Still, symmetrical increased activity can also be pathological as in sacroiliitis. The localization, size, shape, intensity, homogenous/heterogeneous aspect and number of abnormal findings should be assessed. Sufficient resolution and counts statics are a prerequisite for properly evaluating these characteristics. Some osteolytic skeletal lesions are seen as a region of reduced tracer uptake, either surrounded by a rim of increased tracer deposition or, conversely, with a punched-out appearance. Bone scintigraphy has a low sensitivity for this last category of purely osteolytic lesions (e.g. multiple myeloma) and is therefore not routinely indicated to evaluate multiple myeloma or similar disease.

Lesions detected on bone scintigraphy can take an extended time to normalize because of the protracted course of bone healing which could take multiple months. Therefore, it is rarely useful to repeat the investigation within 4 to 6 months.

An increase in the intensity or the number of foci on scans performed less than 6 months apart might represent disease progression but could also be associated with a flare phenomenon after therapy.

The renal system and urinary tract are normally visualized. Both diffuse and focal tracer uptake can occur in soft tissue. Diffusely increased soft-tissue uptake can be caused by drug interference, failed Technetium-99m labelling, severe osteoporosis, renal failure, dehydration, or an insufficiently long interval between tracer injection and image acquisition. Conversely, reduced or absent tracer uptake in soft tissue may be caused by excessive avidity of the osteoblasts populating the axial skeleton, resulting in a super scan appearance (i.e. due to diffuse metastatic infiltration, severe metabolic bone condition, etc.) or excessively long interval between tracer injection and imaging.

Clinical data should be taken into account when interpreting skeletal or joint abnormalities

Sources of errors:

• Focal soft tissue hot spots have a wide range of causes and could lead to an incorrect diagnosis of skeletal disease on planar imaging. Attenuation artefacts caused by metal objects or motion artefacts are generally obvious. The same holds true for tracer extravasation at the injection site due to (partly) paravenous injection.
• The most common artefacts are related to urinary tracer contamination. This could be due to dilatation, stasis or an anatomical variant of the urinary tract, especially after urological surgery, or due to contamination during urination.
• Bone lesions may be purely or predominantly lytic and, therefore, barely visible on planar bone scintigraphy, particularly when <2 cm, e.g. multiple myeloma, infarction, osteonecrosis, haemangioma, or lytic bone metastases. These artefacts and sources of error can generally be intercepted with an additional SPECT/CT acquisition or with a planar image of higher resolution and greater count statistics.

4.1.10 Patient preparation

No special preparations are required. Unless contraindicated, patients should be well hydrated and instructed to drink at least 0.5 L of water between the time of injection and delayed imaging and to void their bladder frequently.

4.1.11 Methods

The detailed recommendations are available in the EANM Bone & Joint Guidelines.