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Background: Postmenopausal estrogen depletion is a major contributing factor to bone loss. Soy isoflavones have variable effects on the prevention of postmenopausal bone loss, which is possibly related to the specific isoflavone content or the variable equol-producing capacity of individuals., Objective: We aimed to determine the effects of the content of isoflavones in a soy supplement and the equol-producing ability of the individual on postmenopausal bone calcium retention., Design: The study was a blinded, randomized, crossover intervention trial in 24 postmenopausal women who were prescreened for their ability to convert daidzein to equol. Women were equilibrated with (41)Ca before the intervention. Interventions were 5 soy isoflavone oral supplements (2 doses of a genistein-rich soy supplement and 3 doses of mixed isoflavones in various proportions) and a bisphosphonate (risedronate). Each intervention was given sequentially for 50 d followed by a 50-d washout period. The percentage of bone calcium retention was determined from the change in urinary (41)Ca:calcium., Results: Interventions that ranged from 52 to 220 mg total isoflavones/d increased bone calcium retention between 3.4% and 7.6% (P < 0.05), which was a moderate effect compared with that of risedronate at 15.3% (95% CI: 7.1%, 22.7%; P = 0.0014). The most-effective soy intervention delivered 105.23 mg total isoflavones/d as genistein, daidzein, and glycitein in their natural ratios and increased bone calcium retention by 7.6% (95% CI: 4.9%, 10.2%; P < 0.0001). Genistein, at 52.85 mg/d, increased bone calcium retention by 3.4% (95% CI: 0.5%, 6.2%; P = 0.029); but there was no benefit at higher amounts (113.52 mg/d). There was no difference (P = 0.5) in bone calcium retention between equol producers and nonproducers., Conclusion: Soy isoflavones, although not as potent as risedronate, are effective bone-preserving agents in postmenopausal women regardless of their equol-producing status, and mixed isoflavones in their natural ratios are more effective than enriched genistein. This trial was registered at clinicaltrials.gov as NCT00244907., (© 2015 American Society for Nutrition.)

Background: Dietary soluble corn fiber (SCF) significantly improves calcium absorption in adolescents and the bone strength and architecture in rodent models. Objective: In this study, we aimed to determine the skeletal benefits of SCF in postmenopausal women. Design: We used our novel technology of determining bone calcium retention by following the urinary appearance of 41Ca, a rare long-lived radioisotope, from prelabeled bone to rapidly and sensitively evaluate the effectiveness of SCF in reducing bone loss. A randomized-order, crossover, double-blinded trial was performed in 14 healthy postmenopausal women to compare doses of 0, 10, and 20 g fiber from SCF/d for 50 d. Results: A dose-response effect was shown with 10 and 20 g fiber from SCF/d, whereby bone calcium retention was improved by 4.8% (P < 0.05) and 7% (P < 0.04), respectively. The bone turnover biomarkers N-terminal telopeptide and osteocalcin were not changed by the interventions; however, a significant increase in bone-specific alkaline phosphatase, which is a bone-formation marker, was detected between 0 and 20 g fiber from SCF/d (8%; P = 0.035). Conclusion: Daily SCF consumption significantly increased bone calcium retention in postmenopausal women, which improved the bone calcium balance by an estimated 50 mg/d. This study was registered at clinicaltrials.gov as NCT02416947. [ABSTRACT FROM AUTHOR]

Background: Ensuring adequate vitamin D status in older adults may reduce the risk of osteoporosis. The serum 25-hydroxyvitamin D [25(OH)D] concentration is the recommended biomarker of vitamin D status, but the optimal serum 25(OH)D concentration for bone health in postmenopausal women remains unclear. Objective: The aim of this study was to apply the highly sensitive (41)Ca skeletal labeling technique and the measurement of urinary (41)Ca:(40)Ca ratios to determine the serum 25(OH)D concentration that has greatest benefit on bone calcium flux in postmenopausal women. Methods: We administered a mean intravenous (41)Ca dose of 870 pmol to healthy postmenopausal women [n = 24, age (mean ± SD): 64 ± 6.0 y] without osteoporosis. After 6 mo, at the nadir of their wintertime serum 25(OH)D status, each of the women sequentially consumed daily oral cholecalciferol supplements of 10, 25, and 50 μg/d (in this order), each for 3 mo. We assessed serum 25(OH)D concentrations monthly and urinary (41)Ca:(40)Ca ratios biweekly. (41)Ca:(40)Ca ratios were measured with low-energy accelerator mass spectrometry. With the use of pharmacokinetic analysis, we determined the effect of varying serum 25(OH)D concentrations on (41)Ca transfer rates. Results: At baseline, the mean (95% CI) serum 25(OH)D concentration was 16.2 (13.5, 18.8) μg/L. After the first, second, and third intervention periods, mean (95% CI) serum 25(OH)D increased to 29.8 (27.2, 32.4), 36.9 (34.2, 39.7), and 46.6 (41.2, 52.0) μg/L, respectively. Supplementation was associated with a downward shift in the urinary (41)Ca:(40)Ca ratio compared with the predicted (41)Ca:(40)Ca ratio without vitamin D supplementation. In the model, the most likely site of action of the increase in serum 25(OH)D was transfer from the central compartment to a fast exchanging compartment. At this transfer rate, predicted values were a concentration with half-maximal effect of 2.33 μg/L and an estimate of the maximal effect of 31.7%. After the first, second, and third intervention periods, the mean changes in this transfer rate were +18.0%, +25.7%, and +28.5%, respectively. Conclusion: In healthy postmenopausal women, increasing serum 25(OH)D primarily affects calcium transfer from the central compartment to a fast exchanging compartment; it is possible that this represents transfer from the extracellular space to the surface of bone. A serum 25(OH)D concentration of ~40 μg/L achieves ~90% of the expected maximal effect on this transfer rate. This trial was registered at clinicaltrials.gov as NCT01053481. [ABSTRACT FROM AUTHOR]

Abstract: Our group is interested in evaluating early effects of dietary interventions on bone loss. Postmenopausal women lose bone following reduction in estrogen which leads to increased risk of fracture. Traditional means of monitoring bone loss and effectiveness of treatments include changes in bone density, which takes 6 months to years to observe effects, and changes in biochemical markers of bone turnover, which are highly variable and lack specificity. Prelabeling bone with 41Ca and measuring urinary 41Ca excretion with accelerator mass spectrometry provides a sensitive, specific, and rapid approach to evaluating effectiveness of treatment. To better understand 41Ca technology as a tool for measuring effective treatments on reducing bone resorption, we perturbed bone resorption by manipulating dietary calcium in rats. We used 3H-tetracycline (3H-TC) as a proxy for 41Ca and found that a single dose is feasible to study bone resorption. Suppression of bone resorption, as measured by urinary 3H-TC, by dietary calcium was observed in rats stabilized after ovariectomy, but not in recently ovariectomized rats. [Copyright &y& Elsevier]

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 ∼150 days post-dosing when excreted tracer originates mainly from bone. [ABSTRACT FROM AUTHOR]

Abstract: The long-living radioisotope 41Ca could overcome current limitations in assessing the impact of interventions on bone health in controlled human studies. Changes in bone Ca metabolism can be identified directly via the induced changes in 41Ca excretion from 41Ca-labelled bones via the n(41Ca)/n(40Ca) ratio in urine. A 41Ca dose material (IRMM-3703), for use in human studies, was produced by IRMM within the EC funded project OSTEODIET. The 41Ca base material was purified and the purified solution is certified for both isotopic composition and amount content by isotope dilution mass spectrometry. The 44Ca-enriched isotope reference material, IM-6009, was used as spike and the natural Ca reference material, IM-6008, was used for correction of procedural bias. Isotope ratio measurements were performed using thermal ionisation mass spectrometry (TIMS). The certified n(41Ca)/n(40Ca) ratio in IRMM-3703 is 0.012789 (58). A set of synthetic isotope mixtures, IRMM-3701, was prepared from IRMM-3703. It enables comparability of 41Ca measurement results in different laboratories and by different techniques. The IRMM-3701 series is derived from gravimetric mixing of IRMM-3703 and a Ca solution of natural isotopic composition. It covers n(41Ca)/n(40Ca) ratios in the range of 1.0114(68)×10−6 to 1.0524(71)×10−13. [Copyright &y& Elsevier]

In order to develop 41Ca application in biomedicine science, we are now setting up and developing the method for the measurement of 41Ca with accelerator mass spectrometry (AMS) at the China Institute of Atomic Energy (CIAE). A sensitivity of about 10-14 (41Ca/Ca) was obtained in the first 41Ca AMS measurement trial. We are also developing this methodology to investigate fluctuation in Ca2+ concentration in the human cell when exposed to carcinogenic substances (CS). Both 41Ca AMS measurement and its tracing for cell messenger methods are introduced. The results indicate that 41Ca tracing can be used for investigation of Ca2+, an important member of cell messengers, and for studying Ca2+ messenger related cancer caused by CS, and it is suggested that other cell problems related with Ca2+ can also be studied with 41Ca tracing measured by 41Ca AMS. [Copyright &y& Elsevier]

An atom trap trace analysis system based on the technique of laser manipulation of neutral atoms is being developed to count individual 41Ca atoms present in natural samples with an isotopic abundance of 10−15. Trapping of all stable calcium isotopes has been demonstrated and single-atom counting has been realized. For the most abundant isotope, 40Ca (97% isotopic abundance), a magneto-optical trap loading rate of 2×1010 atoms/s has been reached at the overall capture efficiency of 1×10−4. System improvements could increase the efficiency by at least an order of magnitude. [Copyright &y& Elsevier]