Comparison of the Distribution of 3H-Alendronate and 3H-Etidronate in Rat and Mouse Bones

Abstract Alendronate and etidronate are bisphosphonates used clinically to treat diseases associated with increased bone resorption. Etidronate is less potent and was reported to cause osteomalacia. This study examines if differences in distribution of alendronate and etidronate in the skeleton can explain differences in efficacy and in effects on mineralization between the two drugs. Eight-day old rat pups were injected s.c. with 3 H-alendronate or 3 H-etidronate both at either 1.3 μmol/kg or at their respective pharmacological effective doses in the growing rat of 0.12 μmol/kg for alendronate and 72.8 pmol/kg for etidronate. Twelve hours after administration, at 1.3 μmol/kg both drugs showed a three- to fourfold higher localization on osteoclast vs. osteoblast surface. At the pharmacologically effective doses, 3 H-alendronate labeled eightfold more osteoclast surface than osteoblast surface. In contrast, 3 H-etidronate labeled approximately equal fractions of osteoclast and osteoblast surface. When similar doses of 3 H-etidronate and 3 H-alendronate (0.24 μmol/kg 3 H-etidronate vs. 0.20 μmol/kg 3 H-alendronate; 1.5 μmol/kg 3 H-etidronate vs. 1. μmol/kg 3 H-alendronate; and 14.6 μmol/kg 3 H-etidronate vs. 12.0 μmol/kg 3 H-alendronate) were injected intravenously into adult mice at similar specific activities, 3 H-etidronate labeled 1.5–2.5 times more osteoclast surface than 3 H-alendronate, but 3 to 15 times more osteoblast surface. Consequently, the ratio between the fraction of labeled osteoclast surface and the fraction of labeled osteoblast surface ranged for 3 H-alendronate from 9 to 24, whereas for 3 H-etidronate the range was from 4 to 7, due to more extensive labeling of osteoblast surface by 3 H-etidronate. In a third experiment, we confirmed in adult mice the previous observation made in rat pups that normal bone formation occurs over alendronate-covered bone surfaces, and found that it occurred over etidronate-covered surfaces as well. Forty nine days after s.c. administration of alendronate at 0.12 μmol/kg or etidronate at 1.3 μmol/kg or 55.3 μmol/kg into adult mice bone formed over drug label. The distance from incorporated label to bone surface for both drugs (12.7 μm for alendronate and 8.7 and 9.2 μm for etidronate) was similar to wall width (defined by cement line) in controls (10.6 μm). In conclusion, alendronate, especially at pharmacologically active doses, shows higher uptake on resorption vs. formation surfaces than etidronate. The extent of bone formation on surfaces containing alendronate or etidronate is similar and is comparable to the “wall width” in controls.