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Calcium-41 ( t = 10 years) can be used after a single dose to follow calcium metabolism over a subject's lifetime. The aims of this study were to expand a Ca kinetic model and estimate bone resorption in women with stable bone loss, compare the rates with those calculated with classical isotope studies, and to use the model to simulate dynamic changes in urinary Ca:Ca ratios and bone balance for the design and interpretation of Ca studies. Forty-two women >5 years post-menopause were given Ca intravenously. Bone mineral content and bone mineral density of total body were measured by dual-energy X-ray absorptiometry at the beginning of the study. Urine collections were made periodically for up to ∼5 years while subjects were free living. Urinary Ca:Ca ratios were measured using accelerator mass spectrometry. The isotope data were analyzed by compartmental modeling. Four compartments were necessary to fit the urinary tracer data and total bone calcium. The final model included pathways for absorption, distribution, urinary excretion, and endogenous excretion and was used to calculate rates of bone turnover. Estimates of bone resorption in a subset of the women ( n = 13), studied previously in a 3-week balance and full kinetic study with Ca, agreed with those using Ca methodology. Thus, rates of bone resorption can be estimated from Ca urinary data in stable post-menopausal women. The model was used to simulate dynamic changes in urinary Ca:Ca ratios and bone balance, as a result of interventions that perturb calcium metabolism to aid in study design and interpretation. [ABSTRACT FROM AUTHOR]

Summary: Urinary excretion of tritiated tetracycline (H-TC) and Ca tracers was validated as reflecting skeletal disappearance of these bone-seeking tracers as a direct measure of bone turnover following ovariectomy in rats. Introduction: Tritiated tetracycline (H-TC) and Ca tracers have been used to measure bone resorption in animal models, but urinary excretion of these labels has not been directly compared to skeletal turnover. We aimed to evaluate the use of bone-seeking labels by comparing label release into urine with label in the skeleton when bone turnover was perturbed following ovariectomy. Methods: Sixty-four 6-month-old ovariectomized (OVX) rats were randomized to one of eight groups in a 2 × 4 design that differed in time of H-TC and Ca administration following ovariectomy (1 month, when bone turnover would be accelerated following estrogen depletion or 3 months when bone loss due to OVX had slowed down) and time of euthanasia (1 week, 1 month, 3 months, and 6 months post-dose). Twenty-four-hour urine pools over two to four consecutive days and total skeleton were collected and recovered for the assessment of H-TC and Ca. Results: Urinary H-TC levels reflected skeletal H-TC levels ( r = 0.93; p < 0.0001) over a wide range of bone turnover rates in response to an intervention. Urinary Ca and H-TC excretion were highly correlated ( r = 0.95, p < 0.0001). Conclusion: This study confirms that bone-seeking label excretion into the urine directly measures bone turnover. [ABSTRACT FROM AUTHOR]

Urinary excretion of bone labels can be used to monitor bone resorption. Here we investigate the effects of dosing frequency on label incorporation of various sites when bone turnover was perturbed by ovariectomy. We compared tritiated tetracycline (3H-TC) and 45Ca in two studies. Nine-month-old rats were given single or multiple injections of 3H-TC and 45Ca and sacrificed after 7 or 14 days. Six-month-old OVX rats were given 3H-TC and 41Ca tracers 1 or 3 months following ovariectomy (OVX + 1 mo or OVX + 3 mo, when bone turnover was higher or lower, respectively) and sacrificed 1 week, 1 month, 3 months, or 6 months postdose. Twenty-four-hour urine pools over 2–4 consecutive days as well as the proximal tibia, femur midshaft, lumbar vertebrae (L1–L4), and remaining skeleton were analyzed for 3H, 45Ca, and calcium content. Bone turnover as assessed by urinary 3H-TC was greater in OVX + 1 mo compared to OVX + 3 mo rats up to 6 months postdose. 45Ca labeling efficiency (% dose/g Ca) was significantly higher than for 3H and labeling was higher in trabecular-rich than cortical-rich bone. This study affirms that a single administration of either 3H-TC or 45Ca is a useful approach to measuring bone turnover directly. The amount of label incorporation into bone was greater in bone sites that were more metabolically active and in all sites when closer vs farther from OVX. [ABSTRACT FROM AUTHOR]

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]