Background/Purpose: Bone toxicity during drug development can arise from intended pharmacologic mechanisms or off-target effects. Standard histopathological evaluation often fails to detect early skeletal alterations, especially in short-term studies. Early detection is crucial for mitigating risks in compounds affecting skeletal remodeling, growth, or maintenance.

Methods: Data was compiled from naïve Sprague-Dawley rats typically used in early exploratory and chronic toxicity studies. Naïve male Sprague-Dawley rats were treated with prednisolone (7.5 mg/kg/day) for 14 or 28 days. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA), and microCT analysis assessed trabecular microarchitecture. Serum biomarkers related to bone turnover were also evaluated.

Results: Prednisolone treatment significantly reduced femoral BMD in the 28-day group, with a decreasing trend in the 14-day group. MicroCT showed compromised trabecular microarchitecture with decreased thickness and increased separation. Histology revealed thinning of the physis, indicating impaired growth. Serum biomarkers such as P1NP, osteocalcin, and CTX-1 showed reduced bone formation and resorption.

Conclusion: Integrating serum biomarkers and imaging assays with routine histopathology improves detection and characterization of skeletal toxicity. This multimodal approach enhances nonclinical safety assessments’ sensitivity and supports including bone-specific endpoints in early toxicology studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multimodal-preclinical-screening-of-glucocorticoid-induced-disruption-of-bone-remodeling-in-rat/