Semi-quantitative interpretation of the bone scan in metabolic bone disease: definition and validation of the metabolic index.

Certain easily recognisable features are commonly seen in the bone scans of patients with metabolic bone disorders. Seven such features have been numerically graded by three independent observers in the scans of 100 patients with metabolic bone disease and of 50 control subjects. The total score for each patient is defined as the metabolic index. The mean metabolic index for each group of patients with metabolic bone disease is significantly greater than that for the control group (P less than 0.001).     

The role of bone scanning in osteomalacia

The presence of eight "metabolic features" was assessed on the bone scintigrams of ten patients with osteomalacia. In all of these bone images, sufficient features were present to strongly suggest a metabolic disorder. There scintiphotos were included in a controlled blind study using 30 normal bone scans and 20 scans of metastatic disease. Nine of the ten metabolic bone images were correctly identified by two independent observers. Skeletal uptake of radiotracer, expressed as bone-to-soft tissue ratio, was significantly higher in the osteomalacic patients than in a group of 80 controls.     

The hot skull sign on bone scans of obese patients resulting from disparate soft tissue attenuation

We have frequently observed diffusely increased skull activity on bone scans of obese patients, who do not have evidence of metabolic or metastatic bone disease. Skull activity of 25 obese patients were compared to that of age and sex-matched nonobese 25 patients visually and quantitatively. The results clearly indicated that diffusely increased skull activity is significantly more common on bone scans of obese patients because of disparate attenuation of overlying soft tissues. This knowledge will help obviate the need for additional radiologic and/or laboratory tests in search of other conditions associated with hot skull, ie, Paget's disease and metabolic bone disorders such as renal osteodystrophy and primary hyperparathyroidism.     

Quantification of diphosphonate uptake based on conventional bone scanning

Up to now there has been no routinely used and easy-to-perform method for the quantification of bone uptake. Therefore, we have evaluated the clinical practicability of a new and simple method for the measurement of bone uptake based upon conventional three-phase bone scanning. In 13 patients with normal bone scans, whole-body scintigrams were obtained at 3 min and 1, 2, 3, 4, 5, 6 and 24 h after injection of 600 MBq technetium-99m hydroxymethylene diphosphonate (HMDP). Using a conventional region of interest technique, fitted time-activity curves of soft tissue and urinary excretion were established, and bone uptake was calculated from these data as the total whole-body activity minus both soft tissue activity and urinary excretion. Subsequently, the new method was tested in routine patient management: 32 healthy patients and five patients with different types of metabolic bone disease were investigated, measurements being performed only at 3 min and 3–4 h p.i. during conventional three-phase bone scanning. In the multi-imaged patient subset, soft tissue activity decreased exponentially, reaching a plateau after 6 h with a residual activity of about 14% of initial total whole-body activity. Bone uptake reached quite a stable plateau of about 27% as early as 3 h p.i., with no significant changes up to 24 h. Healthy patients of the two-scan group showed no differences in bone uptake (mean uptake values were 24.1% in women and 26.9% in men), whereas in patients with metabolic bone disease bone uptake was significantly higher, with a mean of 48% (P <0.05). Thus, the results of this method are in good agreement with the findings of standard 24-h whole-body retention measurements. The new method, however, is easy to perform, allows assessment of pure bone uptake instead of whole-body retention, and permits calculation of bone uptake by only two measurements during routine three-phase bone scanning. Received 5 February and in revised form 27 June 1997     

A critical assessment of bone scan quantitation (bone to soft tissue ratios) in the diagnosis of metabolic bone disease

Accurate quantitation from the bone scan image of skeletal uptake of radiopharmaceutical would be of value in the assessment of patients with metabolic bone disease. Repeat measurements of bone to soft tissue (B/ST) ratios on the one set of images were made for 103 subjects, a) by the same observer using lumbar vertebra 2 for the area of bone; b) by the same observer using lumbar vertebra w then lumbar vertebra 4; c) by two observers both using lumbar vertebra 2. The median difference between repeat measurements by the same observer was well under 1% but the 5–95 percentile range was -13 to +14%. Between the two observers there was a median difference of 10.6% with a 5–95 percentile range of -11 to +44%.We also measured B/ST ratios in 150 control subjects and 139 patients with various metabolic bone disorders. While statistically significant differences for B/ST ratios were found between the osteomalacia, renal osteodystrophy, Paget's groups, and the control population (P<0.001 in all cases), there was appreciable overlap between individual patient results and the control range.It is concluded, therefore, that measurement of B/ST ratios for the individual is of limited value in clinical practice.     

An unusual scintigraphic pattern in sickle cell patients

We reviewed the nuclear medicine files of all patients enrolled in the sickle cell disease clinic who had had scans performed within the previous 5 years. We specifically looked for patterns of tracer uptake in these scans that would correlate with the severe anemia and consequent bone marrow hyperactivity of sickle cell patients. Thirtythree patients were included (21 men and 12 women) with a mean age of 26.8 years (range 17–48 years). The appearance of each of these patients' most recent scans was examined in the areas of the distal femurs, the proximal tibias and the distal tibias; a distinct triangular shaped pattern of increased activity was identified in these areas in a majority of patients. Thirty-three patients without sickle cell disease served as age-matched controls. This pattern was seen in 65.1% (95 out of 146 images) of the sickle cell patients' delayed images and 80.4% (82 out of 102 images) of their blood pool images. In contrast, the control patients demonstrated the triangular pattern in none of their blood pool studies (0%) and only 10.9% of their delayed bone images (P<0.001). The mean age of sickle cell patients with this pattern is 25.6 years which was significantly lower than that of those without this pattern (mean=37.5 years, P<0.05). Given the high prevalence of this unique scintigraphic pattern in a group of patients with known accelerated bone marrow function, these findings may be scintigraphic evidence of bone marrow expansion. The patient's age appears to be an important factor in visualization of this pattern.Presented in part at the annual meeting of the Association of University Radiologists, April 17–21, 1988, New Orleans, Louisiana, USA     

Mastocytosis: magnetic resonance imaging patterns of marrow disease

Objective. To report the bone marrow MRI findings of patients with mastocytosis and correlate them with clinical, pathologic, and radiographic features. Design and patients. Eighteen patients with mastocytosis had T1-weighted spin echo and short tau inversion recovery MRI of the pelvis at 0.5 T. In each patient the MR pattern of marrow disease was classified according to intensity and uniformity and was correlated with the clinical category of mastocytosis, bone marrow biopsy results, and radiographic findings. Results. Two patients had normal MRI scans and normal bone marrow biopsies. One patient had a normal MRI scan and a marrow biopsy consistent with mastocytosis. Fifteen patients had abnormal MRI scans and abnormal marrow biopsies. There were several different MR patterns of marrow involvement; none was specifically associated with any given clinical category of mastocytosis. Fifteen of the 18 patients had radiographs of the pelvis; of those, 13 with abnormal MRI scans and abnormal marrow biopsies had the following radiographic findings: normal (nine); sclerosis (three); diffuse osteopenia (one). Conclusion. While radiographs are very insensitive for the detection of marrow abnormalities in mastocytosis, MRI is very sensitive and may display several different patterns of marrow involvement.     

Techetium 99m methylene diphosphonate bone scanning in osteoarthritic hands

In this prospective study, the radiological features characteristic of osteoarthritis of the hand were compared with the radionuclide bone scan images. A total of 32 patients was assessed at 6-monthly intervals for 18 months. Microfocal radiographs were taken at each visit. The high magnification and resolution of this technique permitted direct measurement of joint space width, subchondral sclerosis, osteophyte number and area and juxta-articular radiolucency area for each joint in the hand. Four-hour technetium 99m methylene diphosphonate bone scans were taken at 0 and 12 months and the activity of tracer uptake at each joint scored. The latter was compared with each X-radiographic feature at every visit and the changes between visits analysed. The scan scores did not correlate with any of the X-radiographic features other than osteophyte size. During the study the size of growing and remodelling osteophytes increased significantly at joints with raised or increased isotope uptake. Offprint requests to: J.C. Buckland-Wright, Department of Anatomy, Guy's Hospital Medical School, London Bridge, London SE1, 9RT, UK     

Precision of measurement of bone density with a special purpose computed tomography scanner

A new, special purpose, low-dose computed tomography scanner has been developed for the precise measurement of bone density in the distal radius. The instrument includes an 125I source and four scintillation detectors which are scanned across a section of the forearm to produce a cross-sectional image. A number of innovative features have been included to improve patient comfort and scanner precision. The reproducibility for trabecular bone measurement was 0.5% for repeated scans in 22 subjects. The long-term precision in a group of normal subjects was better than 5 mg cm-3. The high precision and the separate measurement of trabecular bone make this technique suitable for the longitudinal study of bone density in metabolic bone disease.     

Deconvolution analysis of 99mTc-methylene diphosphonate kinetics in metabolic bone disease

The kinetics of ^99mTc-methylene diphosphonate (MDP) and ⁴⁷Ca were studied in three patients with osteoporosis, three patients with hyperparathyroidism, and two patients with osteomalacia. The activities of ^99mTc-MDP were recorded in the lumbar spine, paravertebral soft tissues, and in venous blood samples for 1 h after injection. The results were submitted to deconvolution analysis to determine regional bone accumulation rates. ⁴⁷Ca kinetics were analysed by a linear two-compartment model quantitating short-term mineral exchange, exchangeable bone calcium, and calcium accretion. The ^99mTc-MDP accumulation rates were small in osteoporosis, greater in hyperparathyroidism, and greatest in osteomalacia. No correlations were obtained between ^99mTc-MDP bone accumulation rates and the results of ⁴⁷Ca kinetics. However, there was a significant relationship between the level of serum alkaline phosphatase and bone accumulation rates (R=0.71, P<0.025). As a result deconvolution analysis of regional ^99mTc-MDP kinetics in dynamic bone scans might be useful to quantitate osseous tracer accumulation in metabolic bone disease. The lack of correlation between the results of ^99mTc-MDP kinetics and ⁴⁷Ca kinetics might suggest a preferential binding of ^99mTc-MDP to the organic matrix of the bone, as has been suggested by other authors on the basis of experimental and clinical investigations.     

Quantification of pulmonary uptake of indium-111 labelled granulocytes in inflammatory bowel disease

This study describes a method for quantifying the pulmonary trapping of indium-111 labelled polymorphonuclear (PMN) cells in patients with inflammatory bowel disease (1131) in comparison to non-inflamed controls. Twenty patients with extensive IBD were studied by ¹¹¹In-PMN scintigraphy. Gamma-camera images were obtained at 2.5–4 h (early) and 20–25 h (late) after the injection of autologous PMNs labelled in plasma with ¹¹¹In-tropolonate. Local uptake in the chest, iliac bone marrow, spleen and liver was quantified as the counts per pixel per second per MBq of injected ¹¹¹In for both early and late scans. Fourteen subjects without inflammatory disease were studied as controls. IBD patients showed significantly greater loss of splenic activity between early and late scans compared with controls (mean ± SD: –35.7% ± 16.6% versus –4.5% ± 6.1%, P < 0.001). There was no significant difference between control and IBD groups with respect to liver and bone marrow uptake on both early and late scans. Chest uptake was significantly higher in patients with 11313 on both early (6.4 ± 1.6 cps/MBq/pix) and late (5.6 ± 1.5cps/MBq/pix) scans, compared with the controls (4.8 ± 1.3 cps/MBq/pix, P < 0.005 and 3.4 ± 1.0 cps/MBq/pix, P < 0.001 respectively). The chest uptake in the control group on the late scans demonstrated a significant linear correlation with iliac uptake (y=0.23x + 0.41, r=0.87, n=14). Assuming in controls that there is no parenchymal uptake of ¹¹¹In, this regression enables an estimate to be made, based on iliac counts, of the count rate from bone marrow in the chest wall. After subtraction of this from the total chest count rate, the true parenchymal uptake was derived, which averaged (2.86 ± 0.91) cps/MBq/pix in the IBD group compared to zero assumed in the control group. The higher lung ¹¹¹In-PMN uptake on the early scans in IBD compared to controls is suggested to reflect a combination of increased margination, compared to controls, and early migration, whilst the excess ¹¹¹In-PMN retention on late scans represents extravascular migration only. The bone marrow correction technique for quantification of pulmonary migration of ¹¹¹In-PMNs should prove useful for the evaluation of PMN kinetics in disease. Correspondence to: A.M. Peters     

Bone scintigraphy as a new imaging biomarker: the relationship between bone scan index and bone metabolic markers in prostate cancer patients with bone metastases

Objective

A computer-aided diagnosis system for bone scintigraphy with a semiquantitative index from the Bone Scan Index (BSI) has been used to quantify the spread of bone metastases. However, few papers have made clear associations among BSI, bone metabolic markers, and prostate-specific antigen (PSA). This retrospective study aimed to examine these relationships in prostate cancer patients with bone metastases.

Methods

A total of 158 scans from 52 patients (number of median examinations/person 3, range 1–8; median age 71 years, age range 46–86) were included. The intervals between bone scans and blood examinations were 0–16 days (median 0 day). The serum markers of PSA, pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (1-CTP), bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) were examined. Subjects were divided into 4 groups according to BSI; Group A: 0 to <2, Group B: 2 to <4, Group C: 4 to <8, and Group D: over 8. BSI, which corresponded to the amount of metastatic lesion, was automatically calculated by BONENAVI^® software (FUJIFILM RI Pharma, Co. Ltd., Tokyo, Japan; Exini Bone, Exini Diagnostics, Sweden).

Results

All bone scans showed high uptake with bone metastases. BSI was correlated significantly with the serum 1-CTP, serum BAP, serum TRACP-5b, logBAP, logTRACP-5b, and logPSA (r = 0.39, 0.66, 0.69, 0.71, 0.62 and 0.41, respectively). BSI did not correlate significantly with the serum PSA. The statistical F value was 11 in the serum 1-CTP, 31 in serum BAP, 29 in logBAP, 19 in serum TRACP-5b, 14 in logTRACP-5b, 3 in serum PSA, and 9 in logPSA by analysis of variance. Comparison by Dunnett’s test showed significantly higher values in Group D for all original bone metabolic markers and the logPSA, Group C for the serum BAP, logBAP, serum TRACP-5b, and logTRACP-5b, and Group B for the logTRACP-5b compared with Group A.

Conclusion

The changes in BSI showed a close relationship with all bone metabolic markers but not with the serum PSA. The BSI is confirmed to reflect the activity and extent of bone metastases, and can be used as an imaging biomarker.     

Radioimmune imaging of bone marrow in patients with suspected bone metastases from primary breast cancer

Radioimmune imaging of bone marrow was performed by technetium-99m- (99mTc) labeled antigranulocyte monoclonal antibody BW 250/183 (AGMoAb) scans in 32 patients with suspected bone metastases from primary breast cancer. AGMoAb scans showed bone marrow defects in 25/32 (78%) patients; bone invasion was subsequently confirmed in 23 (72%) patients. Conventional bone scans performed within the same week detected bone metastases in 17/32 (53%) patients (p less than 0.001). AGMoAb scans detected more sites indicating metastatic disease than bone scans in 12 of these 17 patients (71%). All patients with bone metastases in the axial skeleton had bone marrow defects at least at the sites of bone metastases. Of 15 patients with normal, or indicative of, benign disease bone scans, 8 patients (53%) presented with bone marrow defects in the AGMoAb scans. Bone invasion was confirmed in six of them. AGMoAb bone marrow scans provide a method for the early detection of bone metastatic invasion in patients with breast cancer and suspected bone metastases.     

The diphosphonate space: a useful quantitative index of disease activity in patients undergoing hexamethylene diphosphonate (HMDP) bone imaging for Paget's disease

Comparison between the plasma levels of intravenously injected technetium 99m hexamethylene diphosphonate (^99mTc-HMDP) and chromium 51 ethylene diamine tetra-acetic acid (⁵¹Cr-EDTA) reflects the uptake of diphosphonate into bone (the diphosphonate space). This can be used as an index of skeletal function in metabolic bone disease. In a series of 49 patients with Paget's disease the diphosphonate space (DPS) correlated well with other indicators of disease activity such as alkaline phosphatase and urinary hydroxyproline levels. The DPS is a good predictor of the volume of skeletal involvement as estimated from bone images. The DPS also provides a sensitive indicator of response to treatment with intravenously administered bisphosphonate. The DPS is simple to perform and is a useful adjunct to routine bone imaging. Offprint requests to: A. Evans     

Iodine-131-metaiodobenzylguanidine and bone scintigraphy for the detection of neuroblastoma.

The purpose of this study was to compare the utility of bone and metaiodobenzylguanidine (MIBG) scintigraphy for the detection of primary and metastatic deposits of neuroblastoma. 99mTc methylene diphosphonate (MDP) bone and 131I-MIBG scans performed within 1 mo of each other in 85 patients with known or suspected neuroblastoma were evaluated for evidence of skeletal and extraskeletal disease. In 77 of 77 patients with confirmed neuroblastoma, the MDP and MIBG scans were concordant for the presence or absence of skeletal disease. A nearly twofold greater number of skeletal lesions were evident on MIBG scanning. No patients with normal bone scans had MIBG studies indicating bone involvement. In patients with histologic evidence of bone marrow involvement, each study suggested skeletal lesions in approximately 70%. In patients with extraskeletal disease demonstrated by CT, there was soft-tissue uptake of MIBG in 80% and MDP in 39%. We conclude that both MIBG and MDP are useful for the detection of skeletal neuroblastoma. MIBG is the better agent for characterizing the extent of disease, and MDP is a valuable adjunctive agent that provides skeletal landmarks for comparison. MIBG is clearly superior for the detection of extraskeletal neuroblastoma.     

The pathology of metabolic bone disease

The skeletal manifestations of the diverse group of metabolic bone diseases are mediated through the altered function of osteoblasts and osteoclasts and abnormal rates of mineralization. Appropriate understanding of their pathologic conditions requires familiarity with the normal anatomy and physiology of the skeleton. The accurate identification of metabolic bone disease frequently demands histologic confirmation and sophisticated analysis of undecalcified bone specimens labeled with tetracycline by histomorphometric techniques. These procedures allow the assessment of many morphologic features that characterize specific disease states. The most common types of metabolic bone diseases are acquired disorders; nonetheless, rare forms frequently are genetically based and cause intrinsic alterations in the bone-cell populations.     

Rationale for the use of bone scans in selected metastatic and primary bone tumors

Since the introduction of bone scans in 1951, there have been many studies comparing biologic and physical characteristics of new bone-imaging agents and the results of scintigraphy and radiology in large numbers of patients. Relatively speaking, there have been fewer studies detailing the health benefits and financial cost associated with the use of skeletal scintigraphy. This review concerns these aspects in patients with malignancies of various sites and stages. About 2% of patients with stage I or II breast cancer have bone metastases at the time they first present, whereas nearly 28% of patients with stage III disease have bone metastases. A large percentage of patients with initially negative scans develop bone metastases during the first 3--4 yr; many of them develop them within the first 12--18 mo after initial diagnosis. For patients with lung cancer, the use of bone scans in staging their disease is somewhat controversial. Several studies indicate that the yield of positive bone scans may range from as low as 2% to as high as 35%. Data on the use of bone scans in staging prostatic cancer initially are similar to those in patients with breast cancer, that is, yields of 7% in patients with stage I or II disease and a yield of about 20% with stage III disease. Children with osteosarcoma or Ewing's sarcoma rarely have bone disease distant from the site of their primary bone lesion at presentation. However, a large percentage of them (30%--40% or so) develop bone metastases during the follow-up period. As in the case with patients with breast cancer, about half of these bone metastases are evident by 12--18 mo.     

Upper humeral cortical thickness as an indicator of osteopenia: diagnostic significance in solitary myeloma of bone

Solitary myeloma of bone is a form of plasma cell tumor, histologically indistinguishable from multiple myeloma but characterised by a single bony focus of disease. Most patients respond to local radiotherapy (median survival 10–12 years); however, many (>30%) rapidly develop multiple myeloma (median survival 2–4 years). Currently, no criteria exist for identifying these high-risk patients at the time of diagnosis.We have assessed the prognostic value of clinical features at presentation in 32 patients with solitary myeloma of bone. Only osteopenia at presentation (P<0.000003) and immunoparesis (P<0.00002) proved to be independent, significant prognosticators of decreased survival. Exclusion of patients with osteopenia or immunoparesis at presentation identified a group with an 80%–90% chance of surviving 10 years. Patients with either risk factor had a median survival of only 27 months.Osteopenia was assessed using measurements of combined cortical thickness in the upper humerus. This site has not previously been used, and normal values are presented for a control group (n=413).     

Computer-aided diagnosis system for bone scintigrams from Japanese patients: importance of training database

Aim

Computer-aided diagnosis (CAD) software for bone scintigrams have recently been introduced as a clinical quality assurance tool. The purpose of this study was to compare the diagnostic accuracy of two CAD systems, one based on a European and one on a Japanese training database, in a group of bone scans from Japanese patients.

Method

The two CAD software are trained to interpret bone scans using training databases consisting of bone scans with the desired interpretation, metastatic disease or not. One software was trained using 795 bone scans from European patients and the other with 904 bone scans from Japanese patients. The two CAD softwares were evaluated using the same group of 257 Japanese patients, who underwent bone scintigraphy because of suspected metastases of malignant tumors in 2009. The final diagnostic results made by clinicians were used as gold standard.

Results

The Japanese CAD software showed a higher specificity and accuracy compared to the European CAD software [81 vs. 57 % (p < 0.05) and 82 vs. 61 % (p < 0.05), respectively]. The sensitivity was 90 % for the Japanese CAD software and 83 % for the European CAD software (n.s).

Conclusion

The CAD software trained with a Japanese database showed significantly higher performance than the corresponding CAD software trained with a European database for the analysis of bone scans from Japanese patients. These results could at least partly be caused by the physical differences between Japanese and European patients resulting in less influence of attenuation in Japanese patients and possible different judgement of count intensities of hot spots.

     

Nuclear medicine studies in metabolic bone disease

The principal application of nuclear medicine in metabolic bone disease is the isotope bone scan. Often, it is not a diagnostic tool but can be useful in clarifying the nature of a clinical problem. The best-established role for the bone scan in metabolic bone disease is in Paget's disease, in which it is diagnostic, provides definition of the extent of disease, and probably reflects disease activity. The isotope bone scan is also important in osteoporosis, for which it is not diagnostic but may often provide useful information to confirm that fracture has occurred, determine the age of the fracture, identify unsuspected fractures, and identify other causes for pain, for example, facet joint disease. The bone scan is less useful in other metabolic bone diseases, for example, renal osteodystrophy and osteomalacia, but will often have a characteristic appearance, with several metabolic features. The degree of positivity of the scan generally relates to the severity of the hyperparathyroidism. In patients with metabolic bone disease, other specific clinical problems may arise, such as osteomyelitis or avascular necrosis, and the bone scan may be diagnostic in these conditions. Nuclear medicine techniques are also of value in hyperparathyroidism and to localize the site of the adenoma where surgical treatment is being considered; the use of technetium Tc 99m sestamibi is now routine. More recently, positron emission tomography (PET) scanning has been found to be helpful in the more difficult cases.