Assessing bone mineral changes in response to vitamin D supplementation using natural variability in stable isotopes of Calcium in Urine

Abstract

Osteoporosis is a chronic disease of public health importance, particularly in low and middle income countries. Measuring the bone mineral balance (BMB) in a non-invasive manner, and its response to different interventions, is critical to the definition of optimal strategies for its prevention and management. In this study, we demonstrate the usefulness of natural variability in calcium isotopes (δ44/40Ca) of urine and the derived BMB estimates as a biomarker of bone health and its responsiveness to interventions. Vitamin D3 is commonly used as a supplement for the prevention and treatment of osteoporosis, along with calcium supplements. We studied the effect of a short term vitamin D3 supplementation on changes in urine δ44/40Ca and the derived BMB. δ44/40Ca before and after the vitamin D3 supplementation yielded a statistically significant change (p = 0.050) with a positive δ44/40Ca enrichment. The mean derived BMB was net positive (0.04 ± 0.05) in comparison to a net negative value for the control group (−0.03 ± 0.01). These results indicate the potential usefulness of urinary natural δ44/40Ca and the derived BMB, which, along with bone mineral density could be used as a sensitive marker for precision in the prevention and treatment of osteoporosis.

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

“…(30,52) We could not determine Ca absorption, which is strongly influenced by an individual's vitamin D status. (53) Indeed, we found that participants who were 25OHD deficient had the lowest δ 44/42 Ca serum levels irrespective of Ca intake (confirming findings by Rangarajan and colleagues (27) ); this may of course reflect 25OHD effects on bone, too, (54) and requires further study. The δ 44/42 Ca urine showed a significant albeit lower degree of correlation than with δ 44/40 Ca serum with most measures, likely due to individual changes in Ca isotope fractionation occurring in the kidneys as previously described.…”

“…( 19 ) Finally, in a group of healthy young men, Rangarajan and colleagues showed an increase in Ca isotope ratios after 3 weeks of vitamin D supplementation. ( 27 ) Importantly, these interventional studies have shown that Ca isotope ratios in blood and urine change within days in response to bone demineralization and therefore provide a sensitive tool to monitor disease processes or treatments that affect bone homeostasis.…”

“…(18) In a study in older women, those with osteoporosis confirmed by dual-energy X-ray absorptiometry (DXA) scan had significantly lower δ 44/42 Ca serum and δ 44/42 Ca Urine values compared with agematched controls without osteoporosis. (19) The sensitivity of natural Ca isotope fractionation measures has been further studied in animal models (14,17,24) and healthy adults, (16,20,22,23,(25)(26)(27)(28) where δ 44/42 Ca in serum and urine closely reflected the interventions to alter bone homeostasis.…”

Assessment of coupled Zn concentration and natural stable isotope analyses of urine as a novel probe of Zn status

“…Investigations are limited to using (i) Cu stable isotope analysis of dried urine spots on filter paper by laser ablation MC-ICP-MS 30 as a biomarker for Wilson's disease and (ii) the association between the Ca stable isotope composition of urine and changes in bone mineral balance 31 in a new biomarker for osteoporosis. 32 Both cases highlight the potential of isotopesensitive techniques to improve diagnosis.…”

Calcium isotope fractionation by osteoblasts and osteoclasts, across endothelial and epithelial cell barriers, and with binding to proteins

“…Biochemical markers such as bone-specific alkaline phosphatase, NTX, P1NP, CTX only qualitatively reflect bone formation or bone resorption but do not provide a measurement of net BMB [5] [8]. Bone biopsies to determine the mineralization status of the bone are invasive and infrequently performed [8][9][10].In contrast, natural occurring Ca isotopes (CaI) measured in blood serum and urine have been shown to be a potential biomarker for the quantification of mineralization and demineralization processes in the human body [11][12][13][14][15] and may even serve as a sensitive diagnostic tool for the early prediction of osteoporosis [13] [16].…”