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In Zusammenarbeit mit dem Universitätsklinikum Schleswig-Holstein in Kiel, dem GEOMAR – Helmholz Zentrum, Prof. Eisenhauer und osteolabs GmbH in Kiel wurden mehrere klinische Studien durchgeführt:
Die Beurteilung von Calcium Isotopenverhältnissen wurde bereits in mehreren Studien zur Beurteilung des Knochenumsatzes verwendet. (Rangarajan et al. 2018), (J.Skulan et al 2007)
2010: Bone 46 (2010) 889: A pilot study on the use of natural calcium isotope (44Ca/40Ca) fractionation in urine as a proxy for the human body calcium balance.
Abstract
We explored the possibility of using natural calcium (Ca) isotope variations in the urine (delta(44/40)Ca(urine)) as a proxy for the Ca balance in the human body. We chose two test persons extremely different in their health status, gender and age (4-year-old healthy boy and a 60-year-old woman known to suffer from osteoporosis). During a 5 day interval the Ca isotope composition of the individual diet (delta(44/40)Ca(diet)) was monitored for both test persons to be in general agreement to the Ca isotope composition of the normal western European diet ( approximately -1.02+/-0.1 per thousand). However, measurements showed that (1) delta(44/40)Ca(urine) of both test persons are approximately 1.37 and approximately 2.49 per thousand, respectively, heavier than delta(44/40)Ca(diet) and that (2) the delta(44/40)Ca(urine-boy) is approximately 1.1 per thousand heavier when compared to the value of the woman. The individual offset between diet and test persons is interpreted to reflect individual Ca reabsorption rates in the kidneys being the result of Rayleigh type Ca isotope fractionation related to the partitioning of Ca between the glomerular filtrate and filtered residue. The relative difference between delta(44/40)Ca(urine-boy) and delta(44/40)Ca(urine-woman) of approximately 1.1 per thousand may reflect individual differences in the balance of bone mineralization and demineralization processes related to age, gender and health status. By arbitrarily defining an equilibrium value for Delta(44/40)Ca(diet-urine) of -1.93 per thousand being the arithmetic mean of delta(44/40)Ca(urine) for both test persons the measured delta(44/40)Ca(urine) values may be applied to model the individual bone mineralization and demineralization processes in a qualitative way. Note, second order influences of intestinal Ca absorption during sequestration of Ca between intestine and blood have to be subject of further studies.
2016: Isotopes in Environmental and Health Studies 52 (2016) 1-16: Biological fractionation of stable Ca isotopes in Göttingen minipigs as a physiological model for Ca homeostasis in humans.
Abstract
In order to investigate fractionation of calcium (Ca) isotopes in vertebrates as a diagnostic tool to detect Ca metabolism dysfunction we analyzed the Ca isotopic composition (δ(44/40)Ca = [((44)Ca/(40)Ca)sample/((44)Ca/(40)Ca)reference]-1) of diet, faeces, blood, bones and urine from Göttingen minipigs, an animal model for human physiology. Samples of three groups were investigated: 1. control group (Con), 2. group with glucocorticosteroid induced osteoporosis (GIO) and 3. group with Ca and vitamin D deficiency induced osteomalacia (-CaD). In contrast to Con and GIO whose average δ(44/40)Cafaeces values (0.39 ± 0.13‰ and 0.28 ± 0.08‰, respectively) tend to be lower than their diet (0.47 ± 0.02‰), δ(44/40)Cafaeces of -CaD (-0.27 ± 0.21‰) was significantly lower than their δ(44/40)Cadiet (0.37 ± 0.03‰), but also lower than δ(44/40)Cafaeces of Con and GIO. We suggest that the low δ(44/40)Cafaeces of -CaD might be due to the contribution of isotopically light Ca from gastrointestinal fluids during gut passage. Assuming that this endogenous Ca source is a common physiologic feature, a fractionation during Ca absorption is also required for explaining δ(44/40)Cafaeces of Con and GIO. The δ(44/40)Caurine of all groups are high (>2.0‰) reflecting preferential renal reabsorption of light Ca isotopes. In Göttingen minipigs we found a Ca isotope fractionation between blood and bones (Δ(44/40)Cablood-bone) of 0.68 ± 0.15‰.
2019: Bone Reports 10 (2019) 100200: Calcium isotope ratios in blood and urine: A new biomarker for the diagnosis of osteoporosis.
Abstract
We assessed the potential of Calcium (Ca) isotope fractionation measurements in blood (δ44/42CaBlood) and urine (δ44/42CaUrine) as a new biomarker for the diagnosis of osteoporosis. One hundred post-menopausal women aged 50 to 75 years underwent dual-energy X-ray absorptiometry (DXA), the gold standard for determination of bone mineral density. After exclusion of women with kidney failure and vitamin D deficiency (<25 nmol/l) 80 women remained in the study. Of these women 14 fulfilled the standard diagnostic criteria for osteoporosis based on DXA. Both the δ44/42CaBlood (p < 0.001) and δ44/42CaUrine (p = 0.004) values were significantly different in women with osteoporosis (δ44/42CaBlood: -0.99 ± 0.10‰, δ 44/42CaUrine: +0.10 ± 0.21‰, (Mean ± one standard deviation (SD), n = 14)) from those without osteoporosis (δ44/42CaBlood: -0.84 ± 0.14‰, δ44/42CaUrine: +0.35 ± 0.33‰, (SD), n = 66). This corresponded to the average Ca concentrations in morning spot urine samples ([Ca]Urine) which were higher (p = 0.041) in those women suffering from osteoporosis ([Ca]Urine-Osteoporosis: 2.58 ± 1.26 mmol/l, (SD), n = 14) than in the control group ([Ca]Urine-Control: 1.96 ± 1.39 mmol/l, (SD), n = 66). However, blood Ca concentrations ([Ca]Blood) were statistically indistinguishable between groups ([Ca]Blood, control: 2.39 ± 0.10 mmol/l (SD), n = 66); osteoporosis group: 2.43 ± 0.10 mmol/l (SD, n = 14) and were also not correlated to their corresponding Ca isotope compositions. The δ44/42CaBlood and δ44/42CaUrine values correlated significantly (p = 0.004 to p = 0.031) with their corresponding DXA data indicating that both Ca isotope ratios are biomarkers for osteoporosis. Furthermore, Ca isotope ratios were significantly correlated to other clinical parameters ([Ca]Urine, ([Ca]Urine/Creatinine)) and biomarkers (CRP, CTX/P1NP) associated with bone mineralization and demineralization. From regression analysis it can be shown that the δ44/42CaBlood values are the best biomarker for osteoporosis and that no other clinical parameters need to be taken into account in order to improve diagnosis. Cut-off values for discrimination of subjects suffering from osteoporosis were - 0.85‰ and 0.16‰ for δ44/42CaBlood and δ44/42CaUrine, respectively. Corresponding sensitivities were 100% for δ44/42CaBlood and ~79% for δ44/42CaUrine. Apparent specificities were ~55% for δ44/42CaBlood and ~71%. The apparent discrepancy in the number of diagnosed cases is reconciled by the different methodological approaches to diagnose osteoporosis. DXA reflects the bone mass density (BMD) of selected bones only (femur and spine) whereas the Ca isotope biomarker reflects bone Ca loss of the whole skeleton. In addition, the close correlation between Ca isotopes and biomarkers of bone demineralization suggest that early changes in bone demineralization are detected by Ca isotope values, long before radiological changes in BMD can manifest on DXA. Further studies are required to independently confirm that Ca isotope measurement provide a sensitive, non-invasive and radiation-free method for the diagnosis of osteoporosis.
2019: Anwendung von Calciumisotopenfraktionierungen zur Diagnostik der Osteoporose
Eine wichtige Rolle in der leitliniengerechten Diagnostik der Osteoporose spielt die Knochendichtemessung (BMD) unter Verwendung der “Dual-Energy-Röntgen-Absorptiometrie, DXA”. Das DXA-Verfahren wird durch Laborparameter unterstützt, um Differenzialdiagnosen ausschließen zu können. Alternativ zur DXA-Messung wird die “Quantitative Computertomographie, QCT” verwendet und in geringerem Maße auch die “Ultraschall”-Methode. Obwohl DXA und QCT das Potenzial haben, Osteoporose zu erkennen, sind beide Methoden gegenüber BMD-Zu-/Abnahme relativ unempfindlich, da der Substanzverlust schwerwiegend sein muss, bevor DXA und QCT ihn erkennen können. Somit liefern beide Methoden nur eine beschränkte Momentaufnahme, ohne die Möglichkeit, auch Osteoporose-Therapien begleiten zu können.
2020: Early effects of androgen deprivation on bone and mineral homeostasis in adult men: a prospective cohort study
Abstract
Objective: and mineral homeostasis are less known. Therefore, we aimed to phosphate homeostasis and bone turnover.
Design: Prospective cohort study.
Methods: to the endocrine outpatient clinic, received cyproterone acetate. Changes in blood markers of calcium/phosphate homeostasis and bone turnover between Results: Of 26 screened patients, 17 were included. The median age was 44 (range 20–75) years. The median time s. Compared to baseline, an 81% decrease was observed for median total testosterone (to 3.4 nmol/L (0.4–12.2); P < 0.0001) and free testosterone (to 0.06 nmol/L (0.01–0.18); P < 0.0001). Median total estradiol decreased by 71% (to 17.6 pmol/L (4.7–35.6); P < 0.0001). Increased serum calcium (P < 0.0001) and phosphate (P = 0.0016) was observed, paralleled by decreased PTH (P = 0.0156) and 1,25-dihydroxyvitamin D3 (P = 0.0134). The stable calcium isotope ratio (δ44/42Ca) decreased (P = 0.0458), indicating net steocalcin decreased (P < 0.0001 and P = 0.0056, respectively), periostin tended to decrease (P = 0.0500), whereas sclerostin increased (P < 0.0001), indicating suppressed bone formation. Serum bone resorption markers (TRAP, CTX) were unaltered.
Conclusions: In adult men, calcium release from the skeleton occurs early f early bone resorption. The increase of sclerostin and reduction of bone formation markers, without changes in formation in the acute phase.
2020: Serial Bone Density Measurement and Incident Fracture Risk Discrimination in Postmenopausal Women
Abstract
Importance Repeated bone mineral density (BMD) testing to screen for osteoporosis requires resources. For patient counseling and optimal resource use, it is important for clinicians to know whether repeated BMD measurement (compared with baseline BMD measurement alone) improves the ability to discriminate between postmenopausal women who will and will not experience a fracture.
Objective To assess whether a second BMD measurement approximately 3 years after the initial assessment is associated with improved ability to estimate fracture risk beyond the baseline BMD measurement alone.
Design, Setting, and Participants The Women’s Health Initiative is a prospective observational study. Participants in the present cohort study included 7419 women with a mean (SD) follow-up of 12.1 (3.4) years between 1993 and 2010 at 3 US clinical centers. Data analysis was conducted between May 2019 and December 2019.
Main Outcomes and Measures Incident major osteoporotic fracture (ie, hip, clinical spine, forearm, or shoulder fracture), hip fracture, baseline BMD, and absolute change in BMD were assessed. The area under the receiver operating characteristic curve (AU-ROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD were calculated to assess incident fracture risk discrimination during follow-up.
Results Of 7419 participants, the mean (SD) age at baseline was 66.1 (7.2) years, the mean (SD) body mass index was 28.7 (6.0), and 1720 (23%) were nonwhite individuals. During the study follow-up (mean [SD] 9.0 [3.5] years after the second BMD measurement), 139 women (1.9%) experienced hip fractures, and 732 women (9.9%) experienced major osteoporotic fracture. In discriminating between women who experience hip fractures and those who do not, AU-ROC values were 0.71 (95% CI, 0.67-0.75) for baseline total hip BMD, 0.61 (95% CI, 0.56-0.65) for change in total hip BMD, and 0.73 (95% CI, 0.69-0.77) for the combination of baseline total hip BMD and change in total hip BMD. Femoral neck and lumbar spine BMD values had similar discrimination for hip fracture. For discrimination of major osteoporotic fracture, AU-ROC values were 0.61 (95% CI, 0.59-0.63) for baseline total hip BMD, 0.53 (95% CI, 0.51-0.55) for change in total hip BMD, and 0.61 (95% CI, 0.59-0.63) for the combination of baseline total hip BMD and change in total hip BMD. Femoral neck and lumbar spine BMD values had similar ability to discriminate between women who experienced major osteoporotic fracture and those who did not. Associations between change in bone density and fracture risk did not differ by subgroup, including diabetes, age, race/ethnicity, body mass index, or baseline BMD T score.
Conclusions and Relevance The findings of this study suggest that a second BMD assessment approximately 3 years after the initial measurement was not associated with improved discrimination between women who did and did not experience subsequent hip fracture or major osteoporotic fracture beyond the baseline BMD value alone and should not routinely be performed.
2020: Naturally Occurring Stable Calcium Isotope Ratios in Body Compartments Provide a Novel Biomarker of Bone Mineral Balance in Children and Young Adults
Abstract
Serum calcium (Ca), bone biomarkers, and radiological imaging do not allow accurate evaluation of bone mineral balance (BMB), a key determinant of bone mineral density (BMD) and fracture risk. We studied naturally occurring stable (non-radioactive) Ca isotopes in different body pools as a potential biomarker of BMB. 42 Ca and 44 Ca are absorbed from our diet and sequestered into different body compartments following kinetic principles of isotope fractionation; isotopically light 42 Ca is preferentially incorporated into bone, whereas heavier 44 Ca preferentially remains in blood and is excreted in urine and feces. Their ratio (δ44/42 Ca) in serum and urine increases during bone formation and decreases with bone resorption. In 117 healthy participants, we measured Ca isotopes, biomarkers, and BMD by dual-energy X-ray absorptiometry (DXA) and tibial peripheral quantitative CT (pQCT). 44 Ca and 42 Ca were measured by multi-collector ionization-coupled plasma mass-spectrometry in serum, urine, and feces. The relationship between bone Ca gain and loss was calculated using a compartment model. δ44/42 Caserum and δ44/42 Caurine were higher in children (n = 66, median age 13 years) compared with adults (n = 51, median age 28 years; p < 0.0001 and p = 0.008, respectively). δ44/42 Caserum increased with height in boys (p < 0.001, R2 = 0.65) and was greatest at Tanner stage 4. δ44/42 Caserum correlated positively with biomarkers of bone formation (25-hydroxyvitaminD [p < 0.0001, R2 = 0.37] and alkaline phosphatase [p = 0.009, R2 = 0.18]) and negatively with bone resorption marker parathyroid hormone (PTH; p = 0.03, R2 = 0.13). δ44/42 Caserum strongly positively correlated with tibial cortical BMD Z-score (n = 62; p < 0.001, R2 = 0.39) but not DXA. Independent predictors of tibial cortical BMD Z-score were δ44/42 Caserum (p = 0.004, β = 0.37), 25-hydroxyvitaminD (p = 0.04, β = 0.19) and PTH (p = 0.03, β = -0.13), together predicting 76% of variability. In conclusion, naturally occurring Ca isotope ratios in different body compartments may provide a novel, non-invasive method of assessing bone mineralization. Defining an accurate biomarker of BMB could form the basis of future studies investigating Ca dynamics in disease states and the impact of treatments that affect bone homeostasis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
2022: Naturally occurring stable calcium isotope ratios are a novel biomarker of bone calcium balance in chronic kidney disease
Abstract
Dysregulated calcium homeostasis is common in chronic kidney disease and causally associated with disorders of bone mineralization. However, radiological measures and biomarkers do not allow accurate evaluation of bone calcium balance. Non-radioactive calcium isotopes, 42Ca and 44Ca, are present in our diet and sequestered into body compartments following principles of kinetic isotope fractionation. Isotopically light 42Ca is preferentially incorporated into bone, while heavier 44Ca is excreted. The ratio (44/42Caserum) increases when bone formation exceeds resorption and vice versa, reflecting bone calcium balance. We measured these calcium isotopes by inductively coupled plasma mass-spectrometry in blood, urine and feces of 42 children with chronic kidney disease and 92 receiving dialysis therapy. We compared the isotope ratios with bone biomarkers and determined total bone mineral content by dual-energy x-ray absorptiometry and peripheral quantitative CT expressed as age-adjusted z-scores. The 44/42Caserum ratio positively correlated with serum calcium, 25-hydroxyvitamin D and alkaline phosphatases and inversely with serum parathyroid hormone and other bone resorption markers. The 44/42Caserum ratio positively correlated with age-adjusted z-scores of tibial trabecular bone mineral density and total bone mineral content measured by peripheral quantitative CT, and hip bone mineral density measured by dual-energy X-ray absorptiometry. Significant and independent predictors of total bone mineral content, measured by, were the 44/42Caserum ratio and parathyroid hormone. The 44/42Caserum ratio, repeated after four weeks, highly correlated with baseline values. When adjusted for calcium-containing medications and kidney impairment, the 44/42Caserum ratio in patients receiving dialysis was 157% lower than that of age-matched children and 29% lower than levels in elderly women with osteoporosis, implying significantly lower bone mineral content. Thus, calcium isotope ratios may provide a novel, sensitive and non-invasive method of assessing bone calcium balance in chronic kidney disease.