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Bone Rep. 2019 Mar 16;10:100200. doi: 10.1016/j.bonr.2019.100200. eCollection 2019 Jun.

Calcium isotope ratios in blood and urine: A new biomarker for the diagnosis of osteoporosis.

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GEOMAR Helmholtz Centre for Ocean Research Kiel, 24148 Kiel, Wischhofstr.1-3, Germany.
OSTEOLABS GmbH, c/o GEOMAR Helmholtz Centre for Ocean Research Kiel, 24148 Kiel, Wischhofstr.1-3, Germany.
University Medical Center Schleswig-Holstein (UKSH), Arnold-Heller-Str. 3, 24105 Kiel, Germany.
Sektion Biomedizinische Bildgebung, Klinik für Radiologie und Neuroradiologie, Am Botanischen Garten 14, 24118 Kiel, Germany.
Klinik für Neuroradiologie und Radiologie, (UKSH), Arnold-Heller-Str. 3, 24105 Kiel, Germany.
Clinical Research Center Kiel GmbH, Schauenburgerstraße 116, 24118 Kiel, Germany.
Medistat, GmbH, Kieler Straße 15, 24119 Kronshagen, Germany.
Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, United Kingdom of Great Britain and Northern Ireland.


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.


Bone biomarkers; Bone mineral density (BMD); Calcium isotopes; Dual energy x-ray absorptiometry (DXA); Mass-spectrometry; Osteoporosis

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