Skeletal remodeling following clinically relevant radiation-induced bone damage treated with zoledronic acid

Abstract

Our aim was to determine if zoledronic acid (ZA) changes (45)Ca pharmacokinetics and bone microstructure in irradiated, ovary-intact (I) and irradiated, ovariectomized mice (OVX), two groups with different patterns of skeletal damage. The hind limbs of I and OVX BALB/c mice received a single 16-Gy radiation dose, simulating pre- and postmenopausal female cancer patients undergoing radiation treatment. All I and OVX mice were radiolabeled with 15 μCi (45)Ca. Mice were treated with or without a 0.5 mg/kg injection of ZA. The time course of bone mineral remodeling was evaluated using a fecal (45)Ca assay, measured by liquid scintillation. A group of nonirradiated, intact mice were used for the longitudinal evaluation of (45)Ca biodistribution. Distal femur bone histomorphometric parameters were measured using microCT at 50 days post-ZA intervention. Most (45)Ca was incorporated into the skeleton and eliminated from the soft tissues within 3-5 days postirradiation, attaining a steady state of excretion at 25-30 days. ZA intervention in both groups resulted in a rapid decrease in fecal (45)Ca excretion. There was a significant difference in (45)Ca excretion in the OVX ± ZA (P = 0.005) group but not in the I ± ZA (P = 0.655) group. The rate of excretion of fecal (45)Ca was slower in the OVX + ZA compared to the I + ZA group (P = 0.064). (45)Ca assay is useful to monitor the time course of bone mineral remodeling after an antiresorptive intervention in irradiated mice, providing a basis to investigate bone effects of cancer therapy protocols. For equivalent doses of ZA, recovery may depend on the nature and degree of skeletal damage.