Naturally Occurring Stable Calcium Isotope Ratios in Body Compartments Provide a Novel Biomarker of Bone Mineral Balance in Children and Young Adults

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.Ca-42 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 (delta Ca-44/42) 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).Ca-44 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. delta(44/42)Ca(serum)and delta(44/42)Ca(urine)were higher in children (n= 66, median age 13 years) compared with adults (n= 51, median age 28 years;p< 0.0001 andp= 0.008, respectively). delta(44/42)Ca(serum)increased with height in boys (p< 0.001, R-2= 0.65) and was greatest at Tanner stage 4. delta(44/42)Ca(serum)correlated positively with biomarkers of bone formation (25-hydroxyvitaminD [p< 0.0001, R-2= 0.37] and alkaline phosphatase [p= 0.009, R-2= 0.18]) and negatively with bone resorption marker parathyroid hormone (PTH;p= 0.03, R-2= 0.13). delta(44/42)Ca(serum)strongly positively correlated with tibial cortical BMDZ-score (n= 62;p< 0.001, R-2= 0.39) but not DXA. Independent predictors of tibial cortical BMDZ-score were delta Ca-44/42(serum)(p= 0.004, beta = 0.37), 25-hydroxyvitaminD (p= 0.04, beta = 0.19) and PTH (p= 0.03, beta = -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. (c) 2020 The Authors.Journal of Bone and Mineral Researchpublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).