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 45Ca. Thirty days post-45Ca administration, the hind limbs of 17 mice were exposed to a single dose of 16 Gy radiation (R). The time course of 45Ca 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 45Ca 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 45Ca excretion) and local effects (via bone microarchitecture and surface activity) of clinically relevant, therapeutic radiation exposure. The I and OVX murine models have similar 45Ca excretion but different bone microarchitectural responses. The 45Ca 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.

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The Influence of Therapeutic Radiation on the Patterns of Bone Marrow in Ovary-Intact and Ovariectomized Mice

With over 30 years' development, accelerator mass spectrometry (AMS) technology has been applied in almost all domains of science and technology. In this article, we first provide a brief description of the basic principles of AMS and then a review of recent technical developments. Selected examples of applications are given to show the impact and potential of AMS in earth and environmental sciences, archeology, art authentication, biomedical sciences, nuclear astrophysics and nuclear environmental safeguards. Finally, the trends and challenges of AMS development are briefly discussed.

Development of Accelerator Mass Spectrometry and Its Applications

Our aim was to determine if zoledronic acid (ZA) changes 45Ca 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 45Ca. 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 45Ca assay, measured by liquid scintillation. A group of nonirradiated, intact mice were used for the longitudinal evaluation of 45Ca biodistribution. Distal femur bone histomorphometric parameters were measured using microCT at 50 days post–ZA intervention. Most 45Ca 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 45Ca excretion. There was a significant difference in 45Ca 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 45Ca was slower in the OVX + ZA compared to the I + ZA group (P = 0.064). 45Ca 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.

Skeletal Remodeling Following Clinically Relevant Radiation-Induced Bone Damage Treated with Zoledronic Acid

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.

/pdf/the-influence-of-therapeutic-radiation-on-the-patterns-of-4soxlg9hzk.pdf

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

The rare, long-lived radiotracer, 41Ca, measured by accelerator mass spectrometry in the urine or serum following incorporation into the bone provides an ultra-sensitive tool to assess changes in bone calcium balance in response to an intervention. Changes in bone balance can be followed for years with one small dose that is both radiologically and biologically non-invasive. Sequential interventions can be compared, with greater precision than they can with biochemical markers of bone turnover and with greater power than with bone densitometry. This method is especially useful to screen interventions over a period of weeks. The development and validation of this tool and its applications are reviewed. Mini abstract: Use of 41Ca measured in the urine or blood by accelerator mass spectrometry to assess bone balance provides a tool to compare the relative efficacy of multiple interventions. This perspective provides insights in the use of this novel method and comparisons with more traditional methods for evaluating the efficacy of interventions.

Calcium-41: a technology for monitoring changes in bone mineral.

The mechanisms governing calcium fluxes during bone remodeling processes in perimenopausal women are poorly known. Despite higher, albeit erratic, estradiol levels in perimenopause, spine bone loss is greater than during the first five years past the final menstrual flow when estradiol becomes low. Understanding changes during this dynamic transition are important to prevent fragility fractures in midlife and older women. The exploration of long-lived 41 Ca ( T 1/2  = 1.04 × 10 5  yrs) tracer measurements using accelerator mass spectrometry (AMS) leads to the possibility of monitoring bone remodeling balance. With this new technology, we explored a pilot long-term feasibility study of bone health by measuring the 41 Ca trace element in urine for six years from premenopausal to later perimenopausal phases in one midlife woman. We measured bone mineral density in parallel.

B.C. Lentle

Papers

A pilot study of the feasibility of long-term human bone balance during perimenopause using a 41Ca tracer