Labeling the human skeleton with 41Ca to assess changes in bone calcium metabolism

Abstract

Bone research is limited by the methods available for detecting changes in bone metabolism. While dual X-ray absorptiometry is rather insensitive, biochemical markers are subject to significant intra-individual variation. In the study presented here, we evaluated the isotopic labeling of bone using 41Ca, a long-lived radiotracer, as an alternative approach. After successful labeling of the skeleton, changes in the systematics of urinary 41Ca excretion are expected to directly reflect changes in bone Ca metabolism. A minute amount of 41Ca (100 nCi) was administered orally to 22 postmenopausal women. Kinetics of tracer excretion were assessed by monitoring changes in urinary 41Ca/40Ca isotope ratios up to 700 days post-dosing using accelerator mass spectrometry and resonance ionization mass spectrometry. Isotopic labeling of the skeleton was evaluated by two different approaches: (i) urinary 41Ca data were fitted to an established function consisting of an exponential term and a power law term for each individual; (ii) 41Ca data were analyzed by population pharmacokinetic (NONMEM) analysis to identify a compartmental model that describes urinary 41Ca tracer kinetics. A linear three-compartment model with a central compartment and two sequential peripheral compartments was found to best fit the 41Ca data. Fits based on the use of the combined exponential/power law function describing urinary tracer excretion showed substantially higher deviations between predicted and measured values than fits based on the compartmental modeling approach. By establishing the urinary 41Ca excretion pattern using data points up to day 500 and extrapolating these curves up to day 700, it was found that the calculated 41Ca/40Ca isotope ratios in urine were significantly lower than the observed 41Ca/40Ca isotope ratios for both techniques. Compartmental analysis can overcome this limitation. By identifying relative changes in transfer rates between compartments in response to an intervention, inaccuracies in the underlying model cancel out. Changes in tracer distribution between compartments were modeled based on identified kinetic parameters. While changes in bone formation and resorption can, in principle, be assessed by monitoring urinary 41Ca excretion over the first few weeks post-dosing, assessment of an intervention effect is more reliable approximately 150 days post-dosing when excreted tracer originates mainly from bone.

Precise and direct determination of the half-life of 41Ca

“…in nuclear technology 41 Ca is one of several long-lived nuclides that determine the long-term safety of final depositories for nuclear waste (Hou, 2005;Warwick et al, 2009). In biological and medical research, it is used as a tracer for various processes (Freeman et al, 2000;Jiang et al, 2004;Denk et al, 2006). For all these applications, the reliable and accurate knowledge of the nuclide's half-life is of crucial importance.…”

Review on Application of Biosystem Modeling: Introducing 3 Model-based Approaches in Studying Ca Metabolism

“…Because of these advantages, calcium kinetic modeling has been used in studying the effect of specific conditions on calcium metabolism such as subject characteristics (Bryant et al, 2003;Wastney et al, 1996), dietary intervention (Spence et al, 2005), and calcium source (Shahnazari et al, 2010;Weaver et al, 2009). As long-term assessment of calcium and bone metabolism became possible with 41 Ca, a calcium kinetic model that fits 41 Ca data collected over years were developed (Denk et al, 2006) and used to estimating bone resorption rates (Lee et al, 2011b). The procedures and contexts of calcium kinetic modeling are well summarized with suitable software, WinSAAM, by Wastney et al (Wastney, 1999).…”

Oral Vitamin D Supplements Increase Serum 25-Hydroxyvitamin D in Postmenopausal Women and Reduce Bone Calcium Flux Measured by 41Ca Skeletal Labeling

“…Dietary and lifestyle interventions may be effective in preventing bone loss, but assessing their subtle impact on bone structure is challenging. Current techniques, such as measuring bone mineral density (BMD) 11 and serum biomarkers of bone metabolism, are limited by their low sensitivity and/or high variability (3). Labeling the skeleton with 41 Ca to monitor bone calcium flux is a promising technique to evaluate bone metabolism (3,4).…”

“…Current techniques, such as measuring bone mineral density (BMD) 11 and serum biomarkers of bone metabolism, are limited by their low sensitivity and/or high variability (3). Labeling the skeleton with 41 Ca to monitor bone calcium flux is a promising technique to evaluate bone metabolism (3,4). This method can detect small changes in bone calcium flux with high sensitivity and precision over a short period of time, making it an ideal tool for assessing dietary and lifestyle interventions in small groups (3,4).…”