Stable Calcium Isotopes in Urine as a Biomarker of Bone Mineral Balance in Spaceflight

Long duration human spaceflight leads to loss of bone mass. As a consequence, there is a need for techniques to sensitively detect changes in the net rate of bone formation or resorption (i.e., changes in "bone mineral balance") and to assess the effectiveness of countermeasures. We have documented, in bed rest experiments, that measurements of the Ca isotope composition of urine using mass spectrometry can be used to monitor rapid changes in net bone mineral balance that are not directly observable by other means (1, 2). We propose to extend these experiments to the International Space Station (ISS), in order to demonstrate the utility of Ca isotopes as a tool for monitoring bone mineral balance and countermeasures to bone resorption in space. This proposal builds on a successful existing collaboration between researchers at Arizona State University (ASU) and Johnson Space Center (JSC) to study and apply the Ca isotope method as a bone biomarker (2, 3). The proposed project paves the way for future development of capability to measure Ca isotopes in-flight, to monitor bone health during exploration-class space missions where in situ evaluation of countermeasure effectiveness will be required to assure crew health and safety. The project will also have broad clinical application for Earth-based populations. Our proposal falls under the Spaceflight Biochemical Profile Human Research Program (HRP) research emphasis, and addresses Integrated Research Plan (IRP) Gap N3: How do nutritional status/nutrition requirements change during spaceflight?

References:

(1). Morgan JL, Skulan JL, Gordon GW, Romaniello SJ, Smith SM, Anbar AD (2012). Rapidly assessing changes in bone mineral balance using natural stable calcium isotopes. Proc. Natl. Acad. Sci. USA 109, 9989-9994;

(2). Skulan J, Bullen T, Anbar AD, Puzas JE, Shackelford L, LeBlanc A, Smith SM (2007). Natural calcium isotopic composition of urine as a marker of bone mineral balance. Clin. Chem. 53,1155-1158;

(3). Morgan JLL, Skulan JL, Gordon GW, Romaniello SJ, Smith SM and Anbar AD (2011). High-precision measurement of variations in calcium isotope ratios in urine by multiple collector inductively coupled plasma mass spectrometry. Anal. Chem. 83, 6956–6962.

Our research has demonstrated that changes in the natural Ca isotope composition of blood and urine reflect changes in net bone mineral balance (BMB) within days of the onset of disruption of BMB. By contrast, changes in BMB require months or years to produce changes in bone mineral density large enough to be detected by radiological techniques such as dual-energy x-ray absorptiometry (DXA), which currently are the only clinically practical methods of determining BMB. By permitting rapid measurements of changes in BMB, Ca isotopes allow disruptions in BMB to be detected before they have caused significant skeletal damage, and the effectiveness of countermeasures to abnormal bone loss or gain to be quickly evaluated in individual people.

The usefulness of this technique extends beyond measuring bone loss in spaceflight to the detection and evaluation of treatment for any disease involving disruption in BMB, including osteopenia/osteoporosis, cancer, and Paget’s disease. For example, we currently are exploring the application of the Ca isotope technique to the early detection of osteolytic lesions in multiple myeloma. The potential usefulness of Ca isotopes supports their widespread clinical application. We are exploring the possibility of using laser fluorescence, rather than conventional mass spectrometry, to build small, compact Ca isotope measurement instruments suitable to both spaceflight and clinical use.

Beyond the numerous potential clinical applications of Ca isotopes per se, our research on Ca isotopes has been a driving force behind international research into biomedical application of other isotope and elemental systems, including Fe, Zn, and Cu. Collectively, these efforts hold the promise of the development of an entirely new and powerful class of disease biomarkers.

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