Friday, 9 September 2005 - 4:00 PM

This presentation is part of: AMS in Low Dose Bioscience Workshop

41Ca non-invasively identifies at high sensitivity skeletal perturbations from bisphosphonate therapy and metastatic bone disease

Darren J. Hillegonds1, Douglas W. Burton2, Robert L. Fitzgerald2, Eberhard Denk3, Meng Yang4, Thomas R. Walczyk3, Leonard J. Deftos2, and John S. Vogel1. (1) Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, 7000 East Avenue, UC/LLNL L-397, Livermore, CA 94551, (2) VAMC-113, VA Healthcare System San Diego/University of California-San Diego, 3350 La Jolla Village Dr, San Diego, CA 92161, (3) Human Nutrition Laboratory, Institute of Food Science and Nutrition, Swiss Federal Institute of Technology Zurich, Schmelzbergstrasse 7 (LFV D19.3), CH-8092, Zurich, Switzerland, (4) AntiCancer Inc., 7917 Ostrow St., San Diego, CA 92111

The goal of this project is to develop 41Ca as a clinical tool for staging and monitoring skeletal tumor growth, assessing response to therapy, and detection of bone metastasis. We hypothesize that high precision assessment of bone turnover will enable improved clinical management in disorders affecting calcium metabolism.

Following administration of a radiologically benign 41Ca dose, body-wide 41Ca/Ca quickly decreases as the tracer is cleared from small and fast calcium pools, concentrating in the skeleton, from which it is slowly re-released. Due to low natural abundance (<10^-15), 41Ca remains above quantitation limits of accelerator mass spectrometry (AMS) for many years following a single <1ug dose. Low natural 41Ca/Ca variability (<10%) facilitates detection of small perturbations in bone turnover. We measured urinary 41Ca/Ca in 6 osteopenic postmenopausal women on weekly risedronate in a study conducted at ETH. Results show a consistent 41Ca/Ca decrease (53ą9)% (meanąSD) from baseline that is significant at each post-intervention measurement, making 41Ca more sensitive than available biomarkers.

We have also completed a preclinical study in 50 immunocompromised mice injected intra-tibially with a green fluorescent protein-expressing human prostate cancer cells (PC3-GFP) two weeks after an IP 41Ca dose. Five groups were treated monthly with vehicle or one of four bisphosphonates; six weeks later lesions were assessed via fluorometry and X-rays. AMS analysis showed high correlation of 41Ca/Ca and serum PTHrP, [Ca2+], and fluorimetry; animals with low bone destruction (via X-ray) had significantly lower serum 41Ca/Ca.

We have demonstrated that urinary 41Ca/Ca is consistently and significantly depressed from baseline with weekly risedronate in individual research subjects, making the 41Ca assay the most sensitive available marker of bone turnover. We have also shown that serum 41Ca/Ca identifies bone destruction and cancer proliferation in a preclinical model of metastatic prostate cancer.

This work was performed in part under the auspices of the U.S. Department of Energy by University of California Lawrence Livermore National Laboratory under Contract No. W-7405-Eng-48.


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