Microcolumnar CsI:Tl scintillator screens have been the gold standard in X-ray imaging for many years due to their high density, high atomic number, and scintillation efficiency. The structured screens provide an improvement in performance by channeling the light to the detector, improving detection efficiency and spatial resolution. We have taken this concept a step further by laser-machining the CsI:Tl scintillator to provide pixels that match the detector pixels. This allows for still thicker CsI:Tl layers up to 700 µm pixelated with pitch of 100 µm to match CMOS flat panel pixels, thus improving X-ray absorption and resolution. We are investigating the applications of CMOS detectors with pixelated scintillators for imaging of bone microarchitecture on diagnostic Cone Beam CT (CBCT) systems to provide improved quantitative metrics for diagnosis of osteoporosis and osteoarthritis. The scintillator design includes reflective coatings applied to the laser-cut grooves to improve optical isolation between pixels. Such coatings are created by atomic layer deposition (ALD), a unique approach, which permits formation of reflectors over inter-pixel grooves with aspect ratios as high as 140:1. Here we present initial results quantifying performance gains in CMOS detector resolution and their impact on the quality of bone microstructure segmentation. We demonstrate 77% gain in spatial resolution at 2 lp/mm and extension of the limiting resolution from 3 lp/mm to 4.5 lp/mm for the CMOS detector with a pixelated screen compared to a commercial sensor. In a bench-top CBCT study emulating diagnostic systems for orthopedic applications (extremity CBCT), we achieved >0.75 correlations in metrics of trabecular microarchitecture between pixelated CsI:Tl based CBCT and gold-standard micro-CT. The pixelated scintillator is expected to have significant impact for many other applications including mammography and digital radiography, where resolution and dose efficiency (DQE) of the detector are of critical importance.