Our purpose was to establish whether noninvasive measurement of changes in ¹⁸F-fluoride metabolic flux to bone mineral (K_i) by PET/CT can provide incremental value in response assessment of bone metastases in breast cancer compared with SUV_max and SUV_mean. Twelve breast cancer patients starting endocrine treatment for de novo or progressive bone metastases were included. Static ¹⁸F-fluoride PET/CT scans were acquired 60 min after injection, before and 8 wk after commencing treatment. Venous blood samples were taken at 55 and 85 min after injection to measure plasma ¹⁸F-fluoride activity concentrations, and K_i in individual bone metastases was calculated using a previously validated method. Percentage changes in K_i, SUV_max, and SUV_mean were calculated from the same index lesions (≤5 lesions) from each patient. Clinical response up to 24 wk, assessed in consensus by 2 experienced oncologists masked to PET imaging findings, was used as a reference standard. Of the 4 patients with clinically progressive disease (PD), mean K_i significantly increased (>25%) in all, SUV_max in 3, and SUV_mean in 2. Of the 8 non-PD patients, K_i decreased or remained stable in 7, SUV_max in 5, and SUV_mean in 6. A significant mean percentage increase from baseline for K_i, compared with SUV_max and SUV_mean, occurred in the 4 patients with PD (89.7% vs. 41.8% and 43.5%, respectively; P < 0.001). After 8 wk of endocrine treatment for bone-predominant metastatic breast cancer, K_i more reliably differentiated PD from non-PD than did SUV_max and SUV_mean, probably because measurement of SUV underestimates fluoride clearance by not considering changes in input function.