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BACKGROUND: Skeletal metastases of bone sarcomas are indicators of poor prognosis. Various imaging modalities are available for their identification, which include bone scan, positron emission tomography/CT scan, MRI, and bone marrow aspiration/biopsy. However, there is considerable ambiguity regarding the best imaging modality to detect skeletal metastases. To date, we are not sure which of these investigations is best for screening of skeletal metastasis. QUESTION/PURPOSE: Which staging investigation—(18)F-fluorodeoxyglucose positron emission tomography/CT ((18)F-FDG PET/CT), whole-body MRI, or (99m)Tc-MDP skeletal scintigraphy—is best in terms of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in detecting skeletal metastases in patients with osteosarcoma and those with Ewing sarcoma? METHODS: A prospective diagnostic study was performed among 54 of a total 66 consecutive osteosarcoma and Ewing sarcoma patients who presented between March 2018 and June 2019. The institutional review board approved the use of all three imaging modalities on each patient recruited for the study. Informed consent was obtained after thoroughly explaining the study to the patient or the patient’s parent/guardian. The patients were aged between 4 and 37 years, and their diagnoses were proven by histopathology. All patients underwent (99m)Tc-MDP skeletal scintigraphy, (18)F-FDG PET/CT, and whole-body MRI for the initial staging of skeletal metastases. The number and location of bone and bone marrow lesions diagnosed with each imaging modality were determined and compared with each other. Multidisciplinary team meetings were held to reach a consensus about the total number of metastases present in each patient, and this was considered the gold standard. The sensitivity, specificity, PPV, and NPV of each imaging modality, along with their 95% confidence intervals, were generated by the software Stata SE v 15.1. Six of 24 patients in the osteosarcoma group had skeletal metastases, as did 8 of 30 patients in the Ewing sarcoma group. The median (range) follow-up for the study was 17 months (12 to 27 months). Although seven patients died before completing the minimum follow-up, no patients who survived were lost to follow-up. RESULTS: With the number of patients available, we found no differences in terms of sensitivity, specificity, PPV, and NPV among the three staging investigations in patients with osteosarcoma and in patients with Ewing sarcoma. Sensitivities to detect bone metastases for (18)F-FDG PET/CT, whole-body MRI, and (99m)Tc-MDP skeletal scintigraphy were 100% (6 of 6 [95% CI 54% to 100%]), 83% (5 of 6 [95% CI 36% to 100%]), and 67% (4 of 6 [95% CI 22% to 96%]) and specificities were 100% (18 of 18 [95% CI 82% to 100%]), 94% (17 of 18 [95% CI 73% to 100%]), and 78% (14 of 18 [95% CI 52% to 94%]), respectively, in patients with osteosarcoma. In patients with Ewing sarcoma, sensitivities to detect bone metastases for (18)F-FDG PET/CT, whole-body MRI, and (99m)Tc-MDP skeletal scintigraphy were 88% (7 of 8 [95% CI 47% to 100%]), 88% (7 of 8 [95% CI 47% to 100%]), and 50% (4 of 8 [95% CI 16% to 84%]) and specificities were 100% (22 of 22 [95% CI 85% to 100%]), 95% (21 of 22 [95% CI 77% to 100%]), and 95% (21 of 22 [95% CI 77% to 100%]), respectively. Further, the PPVs for detecting bone metastases for (18)F-FDG PET/CT, whole-body MRI, and (99m)Tc-MDP skeletal scintigraphy were 100% (6 of 6 [95% CI 54% to 100%]), 83% (5 of 6 [95% CI 36% to 100%]), and 50% (4 of 8 [95% CI 16% to 84%]) and the NPVs were 100% (18 of 18 [95% CI 82% to 100%]), 94% (17 of 18 [95% CI 73% to 100%]), and 88% (14 of 16 [95% CI 62% to 98%]), respectively, in patients with osteosarcoma. Similarly, the PPVs for detecting bone metastases for (18)F-FDG PET/CT, whole-body MRI, and (99m)Tc-MDP skeletal scintigraphy were 100% (7 of 7 [95% CI 59% to 100%]), 88% (7 of 8 [95% CI 50% to 98%]), and 80% (4 of 5 [95% CI 28% to 100%]), and the NPVs were 96% (22 of 23 [95% CI 78% to 100%]), 95% (21 of 22 [95% CI 77% to 99%]), and 84% (21 of 25 [95% CI 64% to 96%]), respectively, in patients with Ewing sarcoma. The confidence intervals around these values overlapped with each other, thus indicating no difference between them. CONCLUSION: Based on these results, we could not demonstrate a difference in the sensitivity, specificity, PPV, and NPV between (18)F-FDG PET/CT, whole-body MRI, and (99m)Tc-MDP skeletal scintigraphy for detecting skeletal metastases in patients with osteosarcoma and Ewing sarcoma. For proper prognostication, a thorough metastatic workup is essential, which should include a highly sensitive investigation tool to detect skeletal metastases. However, our study findings suggest that there is no difference between these three imaging tools. Since this is a small group of patients in whom it is difficult to make broad recommendations, these findings may be confirmed by larger studies in the future. LEVEL OF EVIDENCE: Level II, diagnostic study.