Purpose: 1) To ascertain whether a) first-order statistical features from 18F-fluoride and 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography / computed tomography (PET/CT), or b) non-invasive measurement of changes in plasma clearance of 18F-fluoride (Ki) to bone mineral on 18F-fluoride PET/CT could provide incremental value in response assessment of breast cancer bone metastases compared with maximum standardised uptake value (SUVmax). 2) To ascertain whether for 18F-fluoride PET, mean SUV (SUVmean), metabolic tumour volume (MTV) or total lesion metabolism (TLM) parameters for whole skeletal (WS) could differentiate between progressive disease (PD) and non-PD better than the average of 5 target ROIs, the biggest or hottest lesions, and if any of the WS parameters were able to predict survival. 3) To ascertain the robustness of a clinical reference standard for response assessment of breast cancer bone metastases in order to determine its reliability. Methods: 18F-FDG and 18F-fluoride PET/CT scans were acquired before and 8 weeks after commencing treatment. Percentage changes in SUV parameters, Ki, MTV, TLM, standard deviation (SD), entropy, uniformity and absolute changes in kurtosis and skewness, from the same ≤ 5 index lesions, were measured. Associations were made between parameters and progression free survival (PFS) and overall survival (OS). Venous blood samples were taken at 55 and 85 minutes post-injection of 18F-fluoride to calculate Ki in individual bone metastases. Clinical response up to 24 weeks was used as a reference standard. 3-D segmentation of the skeleton on 18F-fluoride PET was performed using semi-automatic methods. An anonymised questionnaire was formulated containing all the relevant clinical patient information at 8, 12 and 24 weeks. Results: In patients with PD, 18F-fluoride PET/CT TLM and kurtosis predicted PD better than SUVmax on a per-patient basis (4, 4 and 3 out of 4, respectively) and TLM, entropy, uniformity and skewness on a lesion basis (18, 16, 16, 18 and 15 out of 20, respectively). Kurtosis was independently associated with PFS (p = 0.033) and OS (p = 0.008). In patients with PD, mean 18F-fluoride Ki significantly increased (>25%) in all, SUVmax in 3 and SUVmean in 2. In non-PD patients, Ki decreased or remained stable in 7, SUVmax in 5 and SUVmean in 6. A significant mean percentage increase in Ki from baseline occurred in patients with PD compared with SUVmax and SUVmean (89.7% vs 41.9% and 43.8%, respectively; p<0.001). Using the ROC cut-offs, in all 19 patients; WS SUVmean, performed better than 5 ROIs, biggest and hottest lesions (16, 15, 14, 14 out of 19, respectively). Generally, in all patients, correlations were present between WS and 5 ROIs and WS and the hottest lesion for SUVmax {(r=0.847, p=0.001), (r=1.00, p<0.001) respectively}, SUVmean {(0.779, p<0.001), (0.467, p=0.044), respectively} and TLM {(0.686, p=0.001), (0.535, p=0.018), respectively). In the 4 patients with PD, correlations were seen between WS and 5 ROIs for SUVmax (1.00, p<0.001) and SUVmean (1.00, p<0.001), respectively. In WS, the median % changes in TLM and MTV were statistically significantly higher in patients with PD than non-PD {171.4% vs 5.2% (p=0.002), 141.8 vs 3.5% (p=0.004) compared to median % changes in SUV parameters. Using 5 ROIs, median % changes in SUVmax, SUVmean, TLM and MTV were not significantly different in patients with PD or non-PD. None of the parameters for the WS were able to predict survival. When clinical responses were classified as PD and non-PD, the strength of agreement was highest (very good) at 24 weeks, κ=0.87 (CI=0.64, 1.0). The median OS and PFS was higher in patients with PD than non-PD, though not statistically significant. Conclusion: 1) With 18F-fluoride PET/CT, some first-order features provide incremental value over SUVmax in predicting clinical response and survival in breast cancer bone metastases treated with endocrine therapy. 18F-fluoride Ki more reliably differentiates PD from non-PD than SUVmax and SUVmean. 2) Overall, WS tumour burden assessment on 18F-fluoride provides no incremental value over methods such as the average of 5 ROIs; the biggest and the hottest lesions in predicting response to treatment in breast cancer bone metastases. 3) Using a clinical reference standard derived from standard clinical, imaging and biochemical tests at 24 weeks to differentiate PD from non-PD categorisation is reproducible.