In vivo skeletal imaging of 18F-fluoride with positron emission tomography reveals damage- and time-dependent responses to fatigue loading in the rat ulna

The skeletal response to damaging fatigue loading is not fully understood. We used 18F-fluoride PET to describe the time course of the skeletal response following the creation of increasing levels of in vivo, fatigue-induced damage. The right forelimbs of 40 adult rats were loaded in vivo in cyclic compression to four levels of subfracture, fatigue displacement: 30, 45, 65, or 85% of fracture displacement. Rats were injected with a bone-seeking radionuclide (18F-fluoride) on days 0 (4 h), 2, 4, 7, 9, 11, 18, 24, and 30, and imaged using a small animal positron emission tomography (PET) scanner. We quantified fluoride uptake in the central 50% of the right (loaded) and left (control) forelimbs. There were significant increases in fluoride uptake in loaded forelimbs compared to control on day 0 for all displacement groups. Normalized uptake (loaded/control) reached peak levels 4 to 9 days after loading. Normalized uptake depended significantly on the level of fatigue displacement. Normalized uptake increased progressively from the 30 to the 45% displacement level (P < 0.001), and from the 45 to the 65% level (P < 0.001) but did not differ between 65 and 85% (P = 0.41). Histologically, we observed a rapid periosteal response with increased vascularity as early as day 1 and abundant woven bone formation between days 3 and 7. Periosteal and woven bone thicknesses were greater in bones subjected to more fatigue displacement. We conclude that a single bout of fatigue loading leads to a transient increase in the uptake of 18F-fluoride, that the uptake is in proportion to the level of initial damage and is associated with increased vascularity and woven bone formation in the first week after loading.