Alendronate-induced morphological changes in osteoclasts and eroded pores during cortical bone remodeling in...

Bisphosphonates (BPs) are widely used to treat bone complications, yet their impact on the coupling between resorption and formation during cortical bone remodeling remains incompletely understood. We investigated associations between short-term alendronate treatment and osteoclast morphology, intracortical pore dynamics, and osteoprogenitor organization in a synchronized rat model of endo- and intracortical bone remodeling induced by lactation and dietary calcium restriction. Twenty-four lactating Sprague Dawley rats were randomized to vehicle, alendronate (28 μg/kg, twice weekly), or raloxifene (1 mg/kg, five times weekly) with raloxifene serving as a comparative control, for seven days under a low-calcium diet. Femurs were analyzed by micro-CT, histomorphometry, and multiplex RNA in situ hybridization combined with AI-driven image analysis. Alendronate was associated with a higher proportion of eroded pores (29% vs. 12% in controls) and lower density of formative pores (5.2 vs. 10.0 pores/mm²), indicating a prolonged reversal-resorption phase. Osteoclasts on endocortical surfaces were significantly larger (208 ± 37 μm²vs. 146 ± 46 μm²) and contained more nuclei (2.8 ± 0.40 nuclei vs. 2.2 ± 0.46 nuclei) under alendronate treatment, consistent with enhanced fusion. Osteoprogenitor abundance and spatial organization did not differ between treatment groups. Region-specific structural differences included increased midshaft porosity and larger distal metaphyseal cortical area in alendronate-treated rats. Raloxifene was associated with minimal differences on early remodeling events. Together, these findings support the interpretation that short-term bisphosphonate treatment is associated with early alterations in cortical remodeling dynamics under high-turnover conditions and highlight the importance of site-specific evaluation within defined physiological remodeling contexts.