Effects of Alfacalcidol on Mechanical Properties and Collagen Cross-Links of the Femoral Diaphysis in Glucocorticoid-Treated Rats

Bone fragility is increased in glucocorticoid (GC)-induced osteopenia even though GC-treated patients have higher bone mineral density (BMD), suggesting that the impaired bone quality may affect bone strength. This study was conducted to clarify the effects of GC on bone strength and collagen cross-links of adult rats and the effect of coadministration of alfacalcidol (ALF), a prodrug of active vitamin D₃. Six-month-old male Wistar-Imamichi rats (n = 32) were divided into the following four groups with equal average body weight: (1) 4-week age-matched controls, (2) 4-week GC (prednisolone, 10 mg/kg daily, i.m.) with concomitant administration of vehicle, (3) 4-week GC with concomitant administration of ALF (0.05 μg/kg daily, p.o.), and (4) 4-week GC with concomitant administration of ALF (0.1 μg/kg daily, p.o.). At the end of treatment, BMD, collagen cross-links, mechanical properties of the femoral midshaft, bone metabolic markers, and biochemical parameters were analyzed. In the GC group, femoral bone strength decreased without any change of BMD. This was accompanied by a decrease in the content of enzymatic cross-links. ALF (0.1 μg/kg) inhibited the GC-induced reduction in bone strength. The content of mature cross-links in the 0.1-μg/kg ALF group was significantly higher than that in the GC group. GC treatment caused a decrease in bone metabolic markers and serum calcium levels, which was counteracted by ALF coadministration. Preventive treatment with ALF inhibited the deterioration of bone mechanical properties primarily in association with the restoration of enzymatic cross-link formation and amelioration of the adverse effects of GC treatment on calcium metabolism.