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.
Highlights
Calcium is an essential mineral in the body, controlling the formation and maintenance of bones and teeth (Boskey, 2008), muscle contraction, neural signal transmission, cell apoptosis and the coagulation of blood
The remaining 80 subjects were divided into 2 groups based on dual-energy X-ray absorptiometry (DXA) scans (Table 1): 14 women with osteoporosis (≤−2.5 T-score) and 66 without osteoporosis (> −2.5 Tscore) as controls
Statistical analyses show that the receiver operating characteristics (ROC) optimized sensitivity is 100% corresponding to a negative predictive value (NPV) of ~100% for δ44/ 42CaBlood
Summary
Calcium is an essential mineral in the body, controlling the formation and maintenance of bones and teeth (Boskey, 2008), muscle contraction, neural signal transmission, cell apoptosis and the coagulation of blood. Three organs control the Ca homeostasis: the gastrointestinal tract (GI), where Ca is absorbed from the diet, the skeleton which is the main Ca reservoir, and the kidneys where Ca is reabsorbed from the urine back into the blood and controlled amounts are excreted. Physiological ageing processes as well as intestinal, bone, kidney and endocrine disorders interfere with Ca homeostasis. Osteoporosis is the most widely prevalent condition, mainly affecting postmenopausal women. It is a systemic disorder characterized by low BMD, increased fragility and predisposition to fractures (Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis, 1993). In clinical practice osteoporosis is diagnosed when BMD is reduced on DXA, after exclusion of other causes (Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis, 1993; Kanis, and WHO, Scientific, Group, 2007)
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