ALBERT

Description: 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.

Description: 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. 42Ca and 44Ca are absorbed from our diet and sequestered into different body compartments following kinetic principles of isotope fractionation; isotopically light 42Ca is preferentially incorporated into bone, whereas heavier 44Ca preferentially remains in blood and is excreted in urine and feces. Their ratio (δ44/42Ca) 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 DXA and tibial peripheral quantitative CT (pQCT). 44Ca and 42Ca 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. δ44/42Caserum and δ44/42Caurine were higher in children (n=66, median age 13 years) compared to adults (n=51, median age 28 years; p〈0.0001 and p=0.008 respectively). δ44/42Caserum increased with height in boys (p〈0.001, R2=0.65) and was greatest at Tanner stage 4. δ44/42Caserum 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 PTH (p=0.03, R2=0.13). δ44/42Caserum 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 δ44/42Caserum (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.