Thesis

186 Part II Chapter 8 ALP and 59 ng/mL for P1NP in male adults and premenopausal females and 76 ng/ mL for P1NP in postmenopausal females. Quantitative analysis of Na[18F]F PET-CT: normal versus pathological bone Acquisition and analysis of Na[18F]F PET-CT was identical to our previous baseline study [4]. In short, total body PET-CT imaging (n=37 scans) was performed approximately (median; IQR) 49 min (44 – 67 min) after administration of 1.00 MBq/ kg (0.93-1.06 MBq/kg) Na[18F]F on a Philips Gemini TF TOF 64T (Philips Healthcare; Eindhoven, the Netherlands; n=33 scans in 11 patients) and, from July 2019 onward, on a GE Discovery MI PET-CT (GE Healthcare; Chicago, Illinois; n=4 scans in 4 patients). All image analyses were performed independently in Osirix version 11.0 (Pixmeo SARL, Geneva, Switzerland) by a nuclear medicine physician (WvdB) with 15 years of experience in reading PET-CT, taking both PET-CT and low-dose CT into account and who was blinded for the biochemical results and treatment. PET-CT images were quantified using the standardized uptake value (SUV, in g/mL) which is the local activity-concentration of the 18F-fluoride anion (in Bq/mL) normalized for the injected Na[18F]F activity (in Bq) per unit bodyweight (in g), as bodyweight seemed the optimal measure of volume of distribution for Na[18F]F-SUVs and normalizing for CT-based skeletal volume (SV) or lean body mass did not improve results [4, 11, 12]. The SUVcut-off to discern normal, healthy bone from pathological Na[18F]F-uptake strongly varied among patients and scans and was therefore individually defined as previously published [4, 12]. FD burden was measured by the volumetric parameter fluoride tumor volume (FTV), i.e. the volume of FD-affected bone, excluding accumulation not attributable to FD, with SUV≥SUVcut-off. This parameter was found superior to FD SUV or its derivative intensity measures including peak SUV (SUVpeak) defined as the mean SUV in a 1-cm3 spherical volume with highest uptake within the FTV [12]. We determined the ‘Fraction affected skeleton’ (FAS) by dividing the functional FTV, by the baseline anatomical SV (the volume of bone with a CTdensity between 150 and 2500 HU). This parameter thus represents the portion of the skeleton being pathologically metabolically active which is more analogous to SBS than FTV. We used baseline SV as we observed in the subset of current cohort with the largest treatment-induced change in FTV, that the SV determined on CT did not change on a per-patient analyses (mostly less than 1% change and all within 3% change, judged as within measurement error, data not shown). Statistical analysis Percentage change in parameters (∆) after start of denosumab or non-denosumab were quantified for SUVpeak, FTV, ALP and P1NP according to:

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