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Purpose: We develop and validate a model-based framework for artifact correction and image reconstruction to enable application of Cone-Beam CT (CBCT) in quantitative assessment of bone mineral density (BMD). Compared to conventional quantitative CT, this approach does not require a BMD calibration phantom in the field-of-view during an object scan. Methods: The quantitative CBCT (qCBCT) imaging framework combined fast Monte Carlo (MC) scatter estimation, accurate models of detector response, and polyenergetic Poisson likelihood (PolyPL, Elbakri et al 2003). The underlying object model assumed that the tissues were ideal mixtures of water and calcium carbonate (CaCO3). Accuracy and reproducibility of qCBCT was evaluated in benchtop test-retest studies emulating a compact extremity CBCT system (axis-detector distance=56 cm, 90 kVp x-ray beam, ~16 mGy central dose). Various arrangements of Ca inserts (50 – 500 mg/mL) were placed in water cylinders of ~11 cm to ~15 cm diameter and scanned at multiple positions inside the fieldof- view for a total of 20 configurations. In addition, a cadaveric ankle was imaged in five configurations (with and without Ca inserts and water bath). Coefficient of variation (CV) of BMD values across different experimental configurations was used to assess reproducibility under varying imaging conditions. The performance of the model-based qCBCT framework (MC + PolyPL) was compared to FDK with water beam hardening correction and MC scatter correction. Results: The PolyPL framework achieved accuracy of 20 mg/mL or better across all insert densities and experimental configurations. By comparison, the accuracy of the FDK-based BMD estimates deteriorated with higher mineralization, resulting in ~120 mg/mL error for a 500 mg/mL Ca insert. Additionally, the model-based approach mitigated residual streaks that were present in FDK reconstructions. The CV of both methods was ~15% at 50 mg/mL Ca and less than ~8% for higher density inserts, where the PolyPL framework achieved 20-25% lower CV than the FDK-based approach. Conclusion: Accurate and reproducible BMD measurements can be achieved in extremity CBCT, supporting clinical applications in quantitative monitoring of fracture risk, osteoporosis treatment, and early osteoarthritis.
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