The influence of therapeutic radiation on the patterns of bone remodeling in ovary-intact and ovariectomized mice.

Our purpose was to characterize changes in bone remodeling associated with localized radiation that models therapeutic cancer treatment in ovary-intact (I) and ovariectomized (OVX) mice and to evaluate the influence of radiation on the pattern of bone mineral remodeling. Young adult, female BALB/c mice, I and OVX, were used (n = 71). All mice were intravenously injected with 15 µCi (45)Ca. Thirty days post-(45)Ca administration, the hind limbs of 17 mice were exposed to a single dose of 16 Gy radiation (R). The time course of (45)Ca excretion, serum CTx and osteocalcin markers, and cancellous bone volume fraction (BV/TV) and cortical thickness (Ct.Th) of the distal femur were assayed. Cellular activity and dynamic histomorphometry were performed. Irradiation resulted in rapid increases in fecal (45)Ca excretion compared to control groups, indicating increased bone remodeling. CTx increased rapidly after irradiation, followed by an increase in osteocalcin concentration. BV/TV decreased in the I mice following irradiation. Ct.Th increased in the OVX groups following irradiation. I+R mice exhibited diminished osteoblast surface, osteoclast number, and mineral apposition. Our murine model showed the systemic effects (via (45)Ca excretion) and local effects (via bone microarchitecture and surface activity) of clinically relevant, therapeutic radiation exposure. The I and OVX murine models have similar (45)Ca excretion but different bone microarchitectural responses. The (45)Ca assay effectively indicates the onset and rate of systemic bone mineral remodeling, providing real-time assessment of changes in bone histomorphometric parameters. Monitoring bone health via a bone mineral marker may help to identify the appropriate time for clinical intervention to preserve skeletal integrity.

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

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.