20 Chapter 1 Bone scintigraphy with SBS has several technical limitations in comparison to Na[18F]F-PET/CT: 1. SBS is based on planar imaging, while the human skeleton is a three-dimensional (3D) structure, and especially the thorax, spine and pelvis and are frequently affected by FD/MAS. The skeletal burden cannot be precisely visualized using planar (2D) imaging. 3D cross-sectional imaging provides more precise information on the extent of involved skeletal structures and thus skeletal burden. Although SPECT-imaging could benefit from this improvement over planar scintigraphy, whole body SPECT/CT is seldomly performed, as the acquisition would be very time-consuming. 2. The spatial resolution of both planar bone scintigraphy and SPECT are inferior to PET (roughly 8mm vs just above 3 mm full-width at half maximum). 3. Patient preparation of Na[18F]F-PET/CT is more patient friendly than [99mTc]Tc-HDP SPECT/CT since the used PET-radiopharmaceutical has a shorter incubation time: 3 to 4 hours for [99mTc]Tc-HDP to around 45 to 60 minutes for Na[18F]F-PET/CT. Secondly, acquisition of [99mTc]Tc-HDP plus one table position SPECT/CT takes approximately 35 minutes, compared to 12 to 15 minutes for acquisition and potentially much faster with modern PET/CT-scanners [20]. 4. SBS determination is semiquantitative, less precise, and is limited to a weighted sum of the per-segment estimation of the percentage of affected normal bone volume. The weighting factors used are based on average representation of that segment within the skeleton. Some FD-affected locations may cause disproportionate pain complaints, especially in expansile lesions. In these patients SBS might be an underestimation, for example in the ribs. Furthermore, the weighting factors of all skeletal segments as proposed by Collins, et al. sum up to 0.998, which remains unexplained [16]. Thus,Na[18F]F-PET/CTshouldtheoreticallyhave important advantagesover [99mTc]Tc-HDP including SBS and over serum BTMs. As far as we know after careful research of the literature, no study on FD/MAS using (quantitative) Na[18F]F-PET/CT had been performed at the time of our study. This thesis investigates the conceptualization for use of quantitative Na[18F]F-PET/CT and its (possible) role to improve both primary assessment of skeletal FD-burden and quantifying treatment response after bone remodeling therapy (Part II). This part of the dissertation discusses challenges in quantifying normal bone in relation of Na[18F]F- uptake, including factors that might influence bone metabolism, patient variation and which methodologies to consider when determining normal bone reproducibly