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Objective: The superiority of sodium F-fluoride PET (F-PET)/computed tomography (CT) over planar and single field-of-view single-photon emission computed tomography (SPECT) bone scintigraphy with Tc-methylene diphosphonate in bone metastases detection has been established. The present study prospectively compares whole-body Tc-methylene diphosphonate SPECT (WB-SPECT) and F-PET performance indices for the detection of bone metastases in breast cancer., Methods: A total of 41 pairs of studies in female breast cancer patients (average age 58 years, range 30-75) were included. Half-time WB-SPECT and F-PET/CT were performed at a 4-day average interval (range 0-36 days), with subsequent fusion of CT to WB-SPECT. Two readers independently interpreted the studies, with differences resolved by consensus. Composite gold standard included the CT component of the F-PET/CT study with follow-up CT, MRI, F-fluoro-deoxyglucose-PET/CT, and bone scans., Results: On patient-based analysis, metastases were diagnosed in 21 patients, with 19 patients detected by WB-SPECT and 21 with F-PET, the latter being the only modality to detect a single metastasis in two patients. The sensitivity of WB-SPECT and F-PET was 90 and 100% (P=NS), and the specificity were 95 and 85%, respectively (P=NS). On lesion-based analysis, 284 total sites of increased uptake were found. WB-SPECT detected 171/284 (60%) and F-PET 268/284 (94%) lesions, with good interobserver agreement for WB-SPECT (κ=0.679) and excellent agreement for F-PET (κ=0.798). The final analysis classified 204 lesions as benign and 80 as metastases. WB-SPECT identified 121 benign and 50 malignant sites compared with 192 and 76, respectively, for F-PET. WB-SPECT and F-PET had a sensitivity of 63 vs. 95%, P-value of less than 0.001, and a specificity of 97 vs. 96% (P=NS), respectively, on lesion-based analysis., Conclusion: F-PET had higher sensitivity for the diagnosis of bone metastases from breast cancer compared with WB-SPECT, showing a statistically significant 32% increase on lesion-based analysis.

Rationale: The isotope bone scan is routinely used in the management of prostate cancer as the skeleton is the second most common area of metastasis after lymph nodes. A classic site of involvement in the pelvis is the ischium, and the aim of this study was to assess the value of single-photon emission computed tomography/computed tomography (SPECT/CT) imaging in patients with focal ischial uptake on the planar scan., Materials and Methods: This was a retrospective study of consecutive 150 patients with prostate cancer who were referred for a whole-body bone scan between August 2007 and 2008. Two experienced nuclear medicine consultants along with a musculoskeletal radiologist reviewed the scans., Results: Sixty-eight patients were diagnosed with widespread metastases and 46 patients showed typical degenerative disease changes on planar whole-body imaging. SPECT/CT imaging was done in 36 patients to clarify the diagnosis in areas of indeterminate uptake noted on planar whole-body imaging. Ten of these 36 patients who had focal increased ischial uptake were included in the study. Only three of these 10 patients were diagnosed as having a metastatic lesion with the presence of an enthesopathy, a common finding., Conclusion: Isolated focal uptake in the ischium is a relatively common finding in patients with prostate cancer and there is concern that this, on occasion, could be misinterpreted as metastasis. SPECT/CT imaging has an important role in differentiating a benign from a malignant lesion.

Purpose: The purpose of this study was to investigate the additional value of single photon emission computed tomography/computed tomography (SPECT/CT) over whole-body planar bone scintigraphy and SPECT in prostate cancer patients in terms of diagnostic confidence, inter-reviewer agreement and the possible impact on the clinical management., Methods: This was a retrospective review of 40 consecutive prostate cancer patients (mean age 71 years) who underwent (99m)Tc-methylene diphosphonate (MDP) whole-body planar bone scintigraphy, SPECT and SPECT/CT between April 2006 and April 2008. The images were evaluated by two independent reviewers; inter-reviewer agreement was evaluated using a weighted kappa score. Each focus of abnormal increased tracer uptake was recorded using a 4-point diagnostic confidence scale. Institutional Review Board approval was obtained., Results: Fifty lesions on planar bone scintigraphy in the 40 patients were evaluated. On reporting the planar study and SPECT scans, reviewers rated 61% of lesions as equivocal. On reporting the SPECT/CT scans only 8% of lesions were rated as equivocal, 24% were rated as malignant and 68% as benign. Weighted kappa scores for inter-reviewer agreement were 0.43 for bone scintigraphy, 0.56 for SPECT and 0.87 for SPECT/CT. All were significant at p < 0.0001. Follow-up imaging confirmed the SPECT/CT diagnoses in 14 patients., Conclusion: The addition of SPECT/CT resulted in a significant reduction of equivocal reports; a definitive diagnosis was given in the majority of the patients due to the improved diagnostic confidence compared to planar or SPECT imaging alone in prostate cancer patients with suspected bone metastases.

Aim: F-18 fluor choline-positron emission tomography/computed tomography (FCH-PET/CT) has emerged as a new diagnostic tool for the imaging of prostate cancer. In this study, we have evaluated the potential role of FCH-PET/CT for the assessment of bone metastases in patients with prostate cancer. Furthermore, we assessed the pattern of metabolic uptake by FCH in relation to morphologic changes on CT., Methods: Seventy men with biopsy-proven prostate cancer underwent FCH-PET/CT for preoperative staging or follow-up evaluation. Thirty-two patients were evaluated preoperatively, and 38 patients were referred for postoperative evaluation of suspected recurrence or progression based on clinical algorithms. PET imaging consisted of a dynamic PET/CT acquisition of the pelvic region during 8 min (1 min frames) starting 1 min after i.v. injection of 4.07 MBq/kg/bw FCH, which was followed immediately by a semi-whole body acquisition., Results: Overall, 262 lesions showed increased uptake on FCH-PET. Two hundred ten lesions (210 of 262) were interpreted as bone metastases. The mean of maximum standardized uptake value (SUV(max)) in all malignant lesions was 8.1 +/- 3.9. Forty-nine lesions (24%) had no detectable morphological changes on CT-probably due to bone marrow metastases. Fifty-six sclerotic lesions (having a Hounsfield unit (HU) level of more than 825) were interpreted as highly suspicious for metastatic bone disease on CT and/or other imaging modalities such as the bone scan, but showed no FCH uptake. There was a significant correlation between tracer uptake as assessed by SUV and the density of sclerotic lesions by HU (r = -0.52, p < 0.001). The sensitivity, specificity, and accuracy of FCH-PET/CT in detecting bone metastases from prostate cancer was 79%, 97%, and 84%, respectively., Conclusion: FCH-PET/CT showed promising results for the early detection of bone metastases in prostate cancer patients. We have found that a HU level of above 825 is associated with an absence of FCH uptake. Almost all of the FCH-negative sclerotic lesions were detected in patients who were under hormone therapy, which raises the possibility that these lesions might no longer be viable. However, clarification and the prognostic value of such lesions require further research.

Nuclear medicine has entered a new era of multimodality imaging. Dedicated multislice single-photon emission computed tomography/computed tomography (SPECT/CT) cameras are relatively new additions to the diagnostic armamentarium in nuclear medicine. The integration of SPECT and CT provides precise anatomical localization and may enable characterization of abnormalities identified on planar or SPECT imaging by providing structural information by CT. The evidence in support of SPECT/CT is rapidly amounting but still relatively limited. To date, studies have suggested improved diagnostic confidence and specificity in the diagnosis of bone pathology. The combination of functional information and anatomical localization has the potential to influence medical practice with newer imaging algorithms. This review presents the current evidence and potential indications of SPECT/CT bone imaging in the assessment of benign and malignant conditions.

Aim: F-18 fluor choline-positron emission tomography/computed tomography (FCH-PET/CT) has emerged as a new diagnostic tool for the imaging of prostate cancer. In this study, we have evaluated the potential role of FCH-PET/CT for the assessment of bone metastases in patients with prostate cancer. Furthermore, we assessed the pattern of metabolic uptake by FCH in relation to morphologic changes on CT., Methods: Seventy men with biopsy-proven prostate cancer underwent FCH-PET/CT for preoperative staging or follow-up evaluation. Thirty-two patients were evaluated preoperatively, and 38 patients were referred for post operative evaluation of suspected recurrence or progression based on clinical algorithms. PET imaging consisted of a dynamic PET/CT acquisition of the pelvic region during 8 min (1-min frames) starting 1 min after i.v. injection of 4.07 MBq/kg/bw FCH which was followed immediately by a semi whole body acquisition., Results: Overall, 262 lesions showed increased uptake on FCH-PET. Two hundred ten lesions (210/262) were interpreted as bone metastases. The mean standardized uptake values (SUV) in all malignant lesions was 8.1 +/- 3.9. Forty-nine lesions (24%) had no detectable morphological changes on CT-probably due to bone marrow metastases. Fifty-six sclerotic lesions (having a Hounsfield unit (HU) level of more than 825) were interpreted as highly suspicious for metastatic bone disease on CT and/or other imaging modalities such as the bone scan but showed no FCH uptake. There was a significant correlation between tracer uptake as assessed by SUV and the density of sclerotic lesions by HU (r = -0.52, p < 0.001). The sensitivity, specificity, and accuracy of FCH-PET/CT in detecting bone metastases from prostate cancer was 79%, 97%, and 84%, respectively., Conclusion: FCH-PET/CT showed promising results for the early detection of bone metastases in prostate cancer patients. We have found that a HU level of above 825 is associated with an absence of FCH uptake. Almost all of the FCH-negative sclerotic lesions were detected in patients who were under hormone therapy, which raises the possibility that these lesions might no longer be viable. However, clarification and the prognostic value of such lesions require further research.

In prostate cancer, bone is the second most common site of metastatic disease after lymph nodes. This is related to a poor prognosis and is one of the major causes of morbidity and mortality in such patients. Early detection of metastatic bone disease and the definition of its extent, pattern, and aggressiveness are crucial for proper staging and restaging; it is particularly important in high-risk primary disease before initiating radical prostatectomy or radiation therapy. Different patterns of bone metastases, such as early marrow-based involvement, osteoblastic, osteolytic, and mixed changes can be seen. These types of metastases differ in their effect on bone, and consequently, the choice of imaging modalities that best depict the lesions may vary. During the last decades, bone scintigraphy has been used routinely in the evaluation of prostate cancer patients. However, it shows limited sensitivity and specificity. Single-photon emission computed tomography increases the sensitivity and specificity of planar bone scanning, especially for the evaluation of the spine. Positron emission tomography is increasing in popularity for staging newly diagnosed prostate cancer and for assessing response to therapy. Many positron emission tomography tracers have been tested for use in the evaluation of prostate cancer patients based on increased glycolysis ((18)F-FDG), cell membrane proliferation by radiolabeled phospholipids ((11)C and (18)F choline), fatty acid synthesis ((11)C acetate), amino acid transport and protein synthesis ((11)C methionine), androgen receptor expression ((18)F-FDHT), and osteoblastic activity ((18)F-fluoride). However, there are presently no accurate imaging modalities to directly, reproducibly, and effectively delineate bone metastases in prostate cancer.

Purpose: To assess (18)F-fluorodeoxyglucose (FDG) uptake in bone metastases in patients with and without previous treatment, and compare positive positron emission tomography (PET) with osteolytic or osteoblastic changes on computed tomography (CT)., Methods: One hundred and thirty-one FDG-PET/CT studies were reviewed for bone metastases. A total of 294 lesions were found in 76 patients, 81 in untreated patients and 213 in previously treated patients. PET was assessed for abnormal FDG uptake localised by PET/CT to the skeleton. CT was evaluated for bone metastases and for blastic or lytic pattern. The relationship between the presence and pattern of bone metastases on PET and CT, and prior treatment was statistically analysed using the chi-square test., Results: PET identified 174 (59%) metastases, while CT detected 280 (95%). FDG-avid metastases included 74/81 (91%) untreated and 100/213 (47%) treated lesions (p<0.001). On CT there were 76/81 (94%) untreated and 204/213 (96%) treated metastases (p NS). In untreated patients, 85% of lesions were seen on both PET and CT (26 blastic, 43 lytic). In treated patients, 53% of lesions were seen only on CT (95 blastic, 18 lytic). Of the osteoblastic metastases, 65/174 (37%) were PET positive and 98/120 (82%), PET negative (p<0.001)., Conclusion: The results of the present study indicate that when imaging bone metastases, prior treatment can alter the relationship between PET and CT findings. Most untreated bone metastases are PET positive and lytic on CT, while in previously treated patients most lesions are PET negative and blastic on CT. PET and CT therefore appear to be complementary in the assessment of bone metastases.

Diagnostic imaging has played a major role in the evaluation of patients with bone metastases. The imaging modalities have included bone scintigraphy, computed tomography, magnetic resonance imaging, and most recently PET/CT, which can be performed with different tracers, including fluorodeoxyglucose (FDG), 18F-fluoride, 18F-choline (FCH), and 18F-DOPA (dihydroxyphenylalanine). For most tumors the sensitivity of FDG in detecting bone metastases is similar to bone scintigraphy; additionally it can be used to monitor the response to chemotherapy and hormonal therapy. 18F-Fluoride may provide a more sensitive "conventional" bone scan and is superior for FDG nonavid tumors, but, nevertheless, FDG in "early disease" often has clear advantages over 18F-fluoride. Although more data need to be obtained, it appears that FCH is highly efficient in preoperative management regarding N and M staging of prostate cancer once metastatic disease is strongly suspected or documented. For neuroendocrine tumors and in particular in medullary thyroid cancer, DOPA is similar to 18F-fluoride in providing high quality information regarding the skeleton. Nevertheless, prospective studies with large patient groups will be essential to define the exact diagnostic role of FCH and DOPA PET in different clinical settings.

The use of 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the evaluation and management of patients with malignancy continues to increase. However, its role in the identification of bone metastases is far from clear. FDG has the advantage of demonstrating all metastatic sites, and in the skeleton it is assumed that its uptake is directly into tumor cells. It is probable that for breast and lung carcinoma, FDG-PET has similar sensitivity, although poorer specificity, when compared with the isotope bone scan, although there is conflicting evidence, with several articles suggesting that it is less sensitive than conventional imaging in breast cancer. There is convincing evidence that for prostate cancer, FDG-PET is less sensitive than the bone scan and this may be tumor specific. There is very little data relating to lymphoma, but FDG-PET seems to perform better than the bone scan. There is an increasing body of evidence relating to the valuable role of FDG-PET in myeloma, where it is clearly better than the bone scan, presumably because FDG is identifying marrow-based disease at an early stage. There are, however, several other important variables that should be considered. The morphology of the metastasis itself appears to be relevant. At least in breast cancer, different patterns of FDG uptake have been shown in sclerotic, lytic, or lesions with a mixed pattern, Furthermore, the precise localization of a metastasis in the skeleton may be important with regard to the extent of the metabolic response induced. Previous treatment is highly relevant and it has been found that although the majority of untreated bone metastases are positive on PET scans and have a lytic pattern on computed tomography (CT), after treatment, incongruent CT-positive/PET-negative lesions are significantly more prevalent and generally are blastic, which presumably reflects a direct effect of treatment. Finally, the aggressiveness of the tumor itself may be relevant. The most important question, however, is irrespective of whether a lesion is seen on x-ray, CT, or bone scan and irrespective of lytic of blastic morphology: if the FDG-PET study is negative, what is the clinical relevance of that lesion?

The nuclear medicine bone scan has historically been one of the most common investigations to stage and monitor skeletal malignancy. Current guidelines for using radiographs to assess the response of skeletal metastases to systemic therapy are limited in their ability to give a timely result. Despite some minor limitations caused by the flare phenomenon, skeletal scintigraphy remains widely used for this purpose, both clinically and in trials of new cancer treatments. Nuclear medicine has also played an important role in the posttherapy evaluation of primary bone tumors, both with bone agents and nonspecific tumor agents, such as 201Tl. In the future, it is possible that positron emission tomography radiopharmaceuticals such as 18F-fluorodeoxyglucose may prove to be superior in predicting and measuring treatment response in primary and metastatic bone and bone marrow disease, but further work is required in this area.

The use of positron emission tomography (PET) in clinical oncology continues to increase and although there is now a large literature on the use of PET with various tracers in a wide variety of cancers, there has previously been relatively little use specifically in the evaluation of skeletal metastases. However, a number of reports on PET in this area of oncology are now becoming available. The potential advantages of PET over conventional nuclear medicine techniques, including improved spatial resolution, absolute quantitation and the acquisition of tomographic studies as a routine, are also of potential benefit in this area. The bone agent, 18F-fluoride and the tumour agent 18F-fluorodeoxyglucose, have been used to evaluate both benign and malignant skeletal disorders qualitatively and quantitatively and the current knowledge with respect to the skeleton in cancer patients is summarised in this article.

Background: Positron emission tomography (PET) is a nuclear medicine technique that only recently has been widely used in clinical oncology. PET, as a metabolic imaging technique, demonstrates advantages over and complements structural imaging methods and also demonstrates differences from conventional nuclear medicine, all of which has led to its enormous growth in clinical applications in recent years., Methods: There is now a large body of literature on the use of PET with various tracers, especially (18)F-fluorodeoxyglucose ((18)FDG), in large numbers of patients with carcinoma. In the assessment of the skeleton in patients with carcinoma, early reports of PET imaging are now available with the use of (18)F-fluoride as a bone agent and the use of (18)FDG as a tumor agent, and the current knowledge is summarized in this report., Results: High-quality tomographic PET bone scans are possible with (18)F-fluoride with possible advantages in sensitivity and specificity over conventional bone scintigraphy. With (18)FDG, it is possible to image tumor metabolism directly, and early studies have demonstrated a high sensitivity for the detection of skeletal metastases, although the demonstration of osteoblastic metastases may be less satisfactory., Conclusions: The clinical role of PET in the evaluation of patients with bone metastases is not yet defined; however, as described in this report, there is emerging evidence that this imaging method also may aid patient management in this area with the use of either (18)FDG or (18)F-fluoride ion.

Breast cancer is a disease that commonly metastasizes to bone, increasing morbidity, mortality, and health service costs. The 99m technetium (99mTc) diphosphonate bone scan historically has played a significant part in the evaluation of skeletal disease and continues to be one of the most clinically utilized investigations in the staging and follow up of breast cancer patients. More tumor-specific radiopharmaceuticals are now being evaluated and, in particular, 18-fluoro-2-deoxyglucose positron emission tomography (18FDG PET) may have a greater role in this disease in the future.

Purpose: 99mTechnetium methylene diphosphonate (99mTc MDP) bone scintigraphy is currently the method of choice for the detection of bone metastases, but 18F-fluoro-deoxy-D-glucose positron emission tomography (18FDG PET) offers superior spatial resolution and improved sensitivity. We have compared 18FDG PET with 99mTc MDP bone scintigraphy in patients with skeletal metastases from breast cancer and have analyzed the data in subgroups based on radiographic characteristics of lesions., Patients and Methods: Twenty-three women with breast cancer and confirmed bone metastases were studied with both 99mTC MDP bone scintigraphy and 18FDG PET, and the number of lesions detected and the quantitation of uptake (standardized uptake values [SUVs]) of 18FDG in osteolytic and osteoblastic metastases were compared. Survival was compared for both lytic and blastic bone metastases and for patients with high and low accumulation of 18FDG., Results: 18FDG PET detected more lesions than 99mTc MDP scintigraphy (mean, 14.1 and 7.8 lesions, respectively; P < .01). However, 18FDG detected fewer bone metastases compared with 99mTc MDP scintigraphy in a subgroup of patients with osteoblastic disease (P < .05). Higher SUVs were observed for osteolytic than osteoblastic disease (mean, 6.77 and 0.95, respectively; P < .01). Survival was lower in patients with osteolytic disease compared with the remainder (P=.01). A difference in survival was not found for those patients with high SUVs (> 3.6; P=.4)., Conclusion: 18FDG PET is superior to bone scintigraphy in the detection of osteolytic breast cancer metastases, which led to a poorer prognosis. In contrast, osteoblastic metastases show lower metabolic activity and are frequently undetectable by PET. The biologic explanation for this observation remains to be elucidated.

A case of osteoid osteoma in a young man is presented which evaded diagnosis for 9 years, and was eventually localized to the palmar aspect of the third carpometacarpal joint using the technique of registration bone scan to provide accurate localization. The lesion was removed with complete relief of pain.

One hundred and fourteen patients with painful bone metastases participated in this randomised, dose-controlled study of the efficacy and safety of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP), a systemically administered radiopharmaceutical. Fifty-five patients received single doses of 0.5 mCi/kg and 59 patients received single doses of 1.0 mCi/kg. Treatment with 153-Sm-EDTMP produced improvement from baseline in all patient-rated efficacy assessments, including degree of pain, level of daytime discomfort, quality of sleep and pain relief. During the first 4 weeks after dose administration, when the patients evaluated efficacy daily, there were statistically significant changes from baseline with the 1.0 mCi/kg dose but not with the 0.5 mCi/kg dose. The difference between doses in visual analogue pain scores was statistically significant at week 4 (P = 0.0476). Among subsets of patients examined, female patients with breast cancer receiving 1.0 mCi/kg had the most noticeable improvement. The physicians judged that approximately half of the patients in each dose group were experiencing some degree of pain relief by week 2. This value increased to 55% for the 0.5 mCi/kg group and 70% for the 1.0 mCi/kg group at week 4. More patients in the higher dose group (54%) than in the lower dose group (44%) completed the 16-week study. A predictable level of dose-related marrow suppression was the only toxicity associated with 153Sm-EDTMP treatment. Values for platelets and WBCs reached nadirs at 3 or 4 weeks with both doses and recovered by 8 weeks. Even at their lowest point, the values were generally higher than those associated with infectious or haemorrhagic complications. Myelotoxicity was no greater in female patients than in male patients. Long-term follow-up revealed longer survival among breast cancer patients who had received the higher dose than among those who had received the lower dose. The results suggest that the 1.0 mCi/kg dose of 153Sm-EDTMP is safe and effective for the treatment of painful bone metastases.

The isotope bone scan continues to be the most widely performed nuclear medicine investigation in the UK. The detection of skeletal metastases remains the most common clinical indication. However, the use of the bone scan is changing as it becomes subject to cost pressures, competing imaging modalities, and altering clinical indications. Overall, fewer studies are being performed for investigation of skeletal metastases, but this decrease in numbers has been compensated by increasing use in benign orthopaedic conditions. Advances such as correlative imaging and single photon emission computer tomography have increased its value and provided new clinical roles. Quantitation has still not achieved widespread usage, although it continues to be helpful to investigate sacroiliitis. Bone positron emission tomography imaging is now possible, although definite clinical roles have yet to be identified. Bone densitometry using dual x-ray absorptiometry is rapidly increasing in availability and usage throughout the UK, and this can be expected to continue to increase over the next few years.

Routine radionuclide bone scans have not been considered cost-effective for the routine follow-up after treatment of primary breast cancer. However subgroups of patients exist in whom early relapse in the skeleton is likely and this study examines again the role of the bone scan in routine follow-up. Serial radionuclide bone scans were performed every 6 months during the first 2 years of follow-up of 560 patients with breast cancer. Tumor characteristics which predict early relapse in bone were identified and the scan conversion rate from negative to positive determined for each prognostic group. A total of 199 (28%) of patients have relapsed, 50 (9%) with first recurrence in bone within two years of diagnosis. All were identified on the bone scan with a median lead time of 4 months over radiological evidence of bone involvement. The overall scan conversion rate was 2.8%. This was significantly higher in poor prognosis patients with T4 tumours (6.3%), more than four involved axillary lymph nodes (6.1%) and inoperable tumours (6.5%), than in good prognosis patients with T1 tumours (1.1%), negative axillary lymph node involvement (1.2%) or well-differentiated ductal grade tumours (1.1%). We do not recommend routine bone scans in the follow-up of all patients with breast cancer. In patients with a good prognosis after primary treatment they cannot be considered cost-effective. However, in those with features which predict early recurrence in the skeleton the frequency of scan conversion is sufficient to justify serial bone scanning during the first two years of follow-up.

In two patients with metastatic disease more lesions were detected on scintigraphs obtained with the 'low uptake' bone-scanning agent dimethyl-amino-diphosphonate. The results in these two patients provide practical support for the suggestion that bone-scanning agents with low uptake in normal bone, but high tumour-to-normal bone ratios, will allow better delineation of focal bone abnormalities.

The detection of focal pathology on a bone scan is dependent on the contrast between uptake in a lesion compared with the affinity of the scanning agent for the surrounding normal bone. Dimethyl-amino diphosphonate (DMAD) has a relatively low uptake in normal bone compared with methylene diphosphonate (MDP). We have compared the bone scan appearance with MDP and DMAD in 11 patients with multiple bone metastases from breast cancer. The median time between scans was 7 days (range 6 to 14). In two patients additional lesions were identified on the DMAD scan. No additional lesions were visible on the MDP scans. In five patients some lesions were visualized more clearly with DMAD and others with MDP. In six patients no differences were seen. Anatomical resolution was generally less clear with DMAD and precise anatomical localization was sometimes impossible. We have demonstrated superior lesion detection with DMAD. The clinical value of this for the detection of early relapse of disease in the skeleton requires further study.

Seventy-five women with clinical stage I or stage II carcinoma of the breast have had radionuclide bone scans at the time of presentation and at 6-monthly intervals during a mean follow-up period of 39 months. Patients with evidence of metastases on bone scan, either at the time of presentation or during follow-up, had significantly higher mortality and morbidity rates than those with persistently negative scans. Whatever the clinical stage, breast cancer patients with a positive bone scan have a very poor short term prognosis and local therapy to the breast is inadequate. A plan is outlined which incorporates the patient's bone scan status into the decision to introduce endocrine therapy or chemotherapy.

Baseline staging bone scans in 1,267 consecutive women with breast cancer attending a single clinic between 1980 and 1986 were reviewed. 0.3% of patients with T1, 3% with T2, 8% with T3, 13% with T4 tumors and none of those with Stage 1, 3% with Stage 2, 7% with Stage 3, and 47% with Stage 4 disease had a positive scan due to bone metastases. Two hundred eight-nine (23%) had bone scan abnormalities secondary to radiologically confirmed benign bone disease. In 20 patients, no cause for a bone scan abnormality could be found after a median follow-up of 3.50 yr, a false-positive frequency of 1.6%. The false-negative rate was 0.08%. It is concluded that patients with tumors less than 2 cm are most unlikely to have a positive scan. In this instance, scans are not required routinely. However, we recommend a baseline scan in all patients with Stage 2, 3, or 4 disease.

Serum osteocalcin (BGP) is an osteoblast product that probably reflects the rate of bone formation. It is a potential marker of skeletal metastases and, to investigate this, BGP was measured by radioimmunoassay in the serum of normal subjects and patients with breast or prostate cancer. Significantly higher levels were found in patients with metastatic bone disease in comparison to both normal subjects (P less than 0.001) and patients with non-metastatic cancer (P less than 0.05 for breast cancer and less than 0.001 for prostate cancer). The range of values was wide. Levels were higher in sclerotic than lytic bone metastases (P less than 0.01) and lower in patients with hypercalcaemia (P less than 0.001). Serial measurements of BGP were made in 53 patients with skeletal metastases from breast cancer receiving systemic therapy. At 1 month BGP rose by greater than 0.5 ng/ml in 15/16 responding patients compared with 7/23 patients with progressive disease (P less than 0.01). Responding patients also showed a rise in the bone isoenzyme of alkaline phosphatase and a paradoxical deterioration in the bone scan appearance, both reflecting a flare in osteoblast activity. The early increase in responding patients was followed by a gradual decrease over subsequent months as the osteoblast reaction induced by systemic therapy subsided. We conclude that BGP measurements reflect a wide variability of bone formation rates in metastatic bone disease. Bone formation was usually increased, particularly when metastases were sclerotic in appearance, but in patients with hypercalcaemia the low BGP levels suggest uncoupling of bone resorption and formation. Serial measurements of BGP may be useful in monitoring response to treatment.

The bone scan findings of 160 consecutive cases of breast cancer metastatic to bone presenting to Guy's Hospital between 1982-1987 were retrospectively assessed for number and distribution of lesions. Twenty-one percent of patients relapsed with a solitary bone metastasis. The spine was the commonest site for both solitary (52% of cases) and multiple (87%) metastases. Solitary bone metastases are more common than previously thought.

A comparison of 2 h and 4 h bone scan images obtained with technetium labelled H.E.D.P. in ten patients demonstrated no increase in lesion detection rate between the 2 h and 4 h scans. The 2 h bone scans were of sufficient quality to permit identification of tumours in all cases.

We have compared bone scintigrams made with Tc-99m-tagged HEDP (1-hydroxyethylidene diphosphonate)and MDP (methylene diphosphonate), the former at 4 hr after injection, the latter at both 2 and 4 hr. In 17 patients with skeletal metastases, there was no significant difference in lesion count or scan quality between the 4-hr images. The tumor-to-bone ratio (T/B) was significantly higher with Tc-HEDP (p less than 0.02). Lesion detection rate and T/B ratios were both lower with Tc-MDP at 2 hr when compared with the 4-hr values for both Tc-HEDP (p less than 0.02, p less than 0.005) and Tc-MDP (p less than 0.02, p less than 0.01). The 4-hr Tc-MDP scan was of significantly higher quality than the 2 hr Tc-MDP scan (p less than 0.01). Although Tc-HEDP produces a higher T/B ratio at 4 hr, the present study does not suggest that either agent is superior in clinical practice.

Some relations between metastatic bone disease and calcium homoeostasis were determined in a consecutive series of 81 patients with solid malignant tumours attending for radionuclide bone scans. Biochemical evaluation showed that bone resorption from metastatic disease was generally not enough to account for hypercalcaemia. While skeletal metastases were present in about half of the patients who developed hypercalcaemia, biochemical indices of bone resorption in these subjects were greatly increased and disproportionate to the extent of metastatic disease detected by the bone scans. Furthermore, a reduced renal phosphate threshold and increased tubular calcium reabsorption were generally observed in hypercalcaemic patients when compared with their normocalcaemic counterparts. These findings suggest that in most cases malignancy associated hypercalcaemia may be caused by the release of a humoral factor by tumour tissue which exhibits "parathyroid-hormone-like" activity with regard to bone resorption, renal phosphate threshold, and renal calcium handling. It may be postulated that this putative humoral mediator predisposes to hypercalcaemia both by stimulating generalised osteolysis and in most cases also by impairing the renal excretion of the resultant increase in filtered calcium load. While hypercalcaemia may arise as a result of metastatic bone disease alone, these data indicate that this may be the exception rather than the rule. Hence the term "metastatic hypercalcaemia" should probably be reserved for patients with extensive skeletal tumour disease in whom biochemical evaluation fails to yield evidence of an underlying humorally mediated cause.

Assessment of response of skeletal metastases to systemic therapy is currently dependent on radiological evidence of bone healing. We have performed a prospective study of additional response criteria in patients with progressive bone metastases from breast cancer. Changes in these potential markers of response were correlated with the radiological response and the time to treatment failure (TTF). Successful systemic therapy typically led to a transient increase in osteoblast activity ('flare'), a reduction in osteoclast activity and symptomatic improvement. After 1 month a greater than 10% rise in serum osteocalcin (BGP) and alkaline phosphatase bone isoenzyme (ALP-BI) and a greater than 10% fall in urinary calcium excretion were seen in 14/16 patients with radiographic evidence of bone healing (UICC partial responders). In comparison similar biochemical changes at 1 month were seen in only 4/20 patients with progressive disease (P less than 0.001). The predictive value and diagnostic efficiency (DE) of changes at 1 month in biochemical measurements and symptom score has been calculated. The combination of a greater than 10% rise in ALPBI and BGP and a greater than 10% fall in urinary calcium excretion had a DE of 89% for discriminating response from progression, 88% for response from non-response (progressing + no change patients), and 76% for TTF of greater than 6 months from TTF of less than 6 months. Serum calcium, tartrate resistant acid phosphatase (TRP), urinary hydroxyproline excretion and bone scan changes were unhelpful in discriminating between patient groups. Independent confirmation is needed, but our results suggest there are reliable alternatives to plain radiography in the early assessment of response of bone metastases to treatment.

A single blood sample method was used to measure total skeletal activity during routine radionuclide bone scans in 114 patients with known carcinoma of the prostate. The method is based on the measurement of radioactivity in plasma after administration of 99mTc MDP and 51Cr EDTA, providing an assessment of total skeletal activity independent of renal function. The results showed a significant elevation of skeletal activity in patients with untreated bone metastases when compared with patients with no metastatic spread. Significant elevation with increasing extent of metastases was also shown, the highest activity being in patients with diffuse metastatic spread (superscan). Patients with treated metastatic disease showed significantly lower skeletal activity than patients with untreated bone metastases. The method requires the use of two radiopharmaceuticals injected as a mixture and potential errors may arise from pharmaceutical instability. In addition, elevation of total skeletal activity may be caused by coexistent metabolic bone disease. The results suggest that the measure may provide quantitative information in the assessment of the activity of bone metastases from prostatic carcinoma.

The bone scan is generally recognized to be an extremely powerful investigational tool in the evaluation of patients with skeletal disease. Currently 99mTc-methylene diphosphonate is the most widely used bone scanning agent, but recently several new diphosphonate compounds have been introduced which appear to have relatively higher skeletal affinity, leading to greater absolute uptake of tracer by bone. While the resulting improved contrast between bone and background soft-tissue may provide more pleasing scan images, it is not clear that increased bone uptake of tracer is equally desirable for identification of disease. Nevertheless, to date, no significant difference in lesion detection has been found in any comparative study of diphosphonate compounds. In this review the clinical studies evaluating diphosphonate bone scanning agents are summarized and the properties required of an ideal bone scanning agent in both benign and malignant disease discussed.

The relation between serum calcium and the extent of metastatic bone disease as judged by radionuclide bone scan was examined in a consecutive series of 195 patients with malignant disease. Of 87 patients with hypercalcaemia, 40% had no evidence of skeletal metastatic bone disease and serum calcium values. Of 160 patients judged to have bone-scan evidence of metastatic skeletal involvement, only 32.5% were significantly hypercalcaemic. Further, a negative correlation was found between the extent of metastatic bone disease and serum calcium value. The development of hypercalcaemia in malignancy is not directly related to the presence or extent of metastatic bone disease. It is suggested that the development of hypercalcaemia may depend on an alternative mechanism, such as the production of a humoral substance by tumour tissue, having its effect on calcium metabolism at sites or organs distant from local areas of tumor involvement.

Changes in osteoblast function, assessed by serial bone scans and serum alkaline phosphatase bone isoenzyme (ALP-Bl) and osteocalcin, have been studied in 53 patients receiving systemic therapy for bone metastases from advanced breast cancer. In 12/16 patients with healing of lytic disease on x-ray a paradoxical deterioration in the bone scan appearances after 3 mo treatment was seen. This was characterized by increased activity in baseline lesions and the appearance of new foci of tracer uptake; changes which are indistinguishable from progressive disease. After 6 mo successful treatment the bone scan improved with reduced tracer uptake and no new lesions since the 3-mo scan. New lesions appearing after 6 mo indicated progressive disease. These changes are attributed to a flare in osteoblast activity induced by successful systemic therapy and confirmed by a transient rise in osteocalcin and ALP-Bl. After 1 mo of treatment 15/16 responders showed a rise in both parameters compared with only 5/23 nonresponders (p = less than 0.001). The flare response is the rule rather than the exception after successful systemic therapy for bone metastases. The appearance of new lesions or increasing activity in known lesions during the first 3 mo is as likely to herald radiological response as disease progression.