target="_blank" rel="nofollow" href="#ulink_b8031826-f381-584f-8834-2219b9bb1adc">33Boyce BF, Xing L: Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 2008;473:139–146.
34Takahashi N, Udagawa N, Takami M, Suda T: Cells of bone: osteoclast generation; in Bilezikian J, Raisz L, Rodan G (eds): Principles of Bone Biology. San Diego, Academic Press, 2002, pp 109–126.
35Panda DK, Miao D, Bolivar I, Li J, Huo R, Hendy GN, Goltzman D: Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem 2004;279:16754–16766.
36Xue Y, Karaplis AC, Hendy GN, Goltzman D, Miao D: Exogenous 1,25-dihydroxyvitamin D3 exerts a skeletal anabolic effect and improves mineral ion homeostasis in mice that are homozygous for both the 1alpha-hydroxylase and parathyroid hormone null alleles. Endocrinology 2006;147:4801–4810.
37Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T: PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol 2010;299:F882-F889.
38Lewin E, Wang W, Olgaard K: Rapid recovery of plasma ionized calcium after acute induction of hypocalcaemia in parathyroidectomized and nephrectomized rats. Nephrol Dial Transplant 1999;14:604–609.
39Fraser DR, Kodicek E: Regulation of 25-hydroxycholecalciferol-1-hydroxylase activity in kidney by parathyroid hormone. Nat New Biol 1973;241:163–166.
40Lieben L, Masuyama R, Torrekens S, Van Looveren R, Schrooten J, Baatsen P, Lafage-Proust MH, Dresselaers T, Feng JQ, Bonewald LF, Meyer MB, Pike JW, Bouillon R, Carmeliet G: Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 2012;122:1803–1815.
41Nguyen-Yamamoto L, Karaplis AC, St-Arnaud R, Goltzman D: Fibroblast growth factor 23 regulation by systemic and local osteoblast-synthesized 1,25-dihydroxyvitamin D. J Am Soc Nephrol 2017;28:586–597.
42Bai XY, Miao D, Goltzman D, Karaplis AC: The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem 2003;278:9843–9849.
43Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J: The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007;117:4003–4008.
44Krajisnik T, Bjorklund P, Marsell R, Ljunggren O, Akerstrom G, Jonsson KB, Westin G, Larsson TE: Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 2007;195:125–131.
Claudio Marcocci
Department of Clinical and Experimental Medicine, University of Pisa
via Paradisa 2
IT–56124 Pisa (Italy)
E-Mail [email protected]
Giustina A, Bilezikian JP (eds): Vitamin D in Clinical Medicine.
Front Horm Res. Basel, Karger, 2018, vol 50, pp 14–30 (DOI: 10.1159/000486062)
______________________
Daniel D. Bikle
VA Medical Center and University of California San Francisco, San Francisco, CA, USA
______________________
Abstract
The number of requests for vitamin D metabolite measurements has increased dramatically over the past decade leading commercial laboratories to develop rapid high throughput assays. The measurement of 25-hydroxyvitamin D (25[OH]D) and to a lesser extent 1,25-dihydroxyvitamin D (1,25[OH]2D) dominates these requests, but requests for multiple metabolite measurements in the same sample are also increasing. The most commonly used methods include immunoassays and liquid chromatography/mass spectrometry (LC-MS). Each method has its advantages and disadvantages, but with improvements in technology, especially in LC-MS, this method is gaining ascendance due to its greater precision and flexibility. The use of standards from the National Institutes of Standards and Technology has substantially reduced the variability from laboratory to laboratory, thereby improving the reliability of these measurements. Although the current demand is for measurement of total vitamin D metabolite levels, these metabolites circulate in blood tightly bound to vitamin D binding protein (DBP) and albumin with less than 1% free. The free concentration may be a more accurate indicator of vitamin D status especially in individuals with DBP levels that deviate from the normal population. Thus, methods to measure the free concentration at least of 25(OH)D are becoming available and may supplement if not replace measurements of total levels.
© 2018 S. Karger AG, Basel
Introduction
Nearly all, if not all, cells express the vitamin D receptor (VDR) at some stage in their development or activation, and many of these cells are also able to convert vitamin D to its active metabolites. As the appreciation that vitamin D affects numerous physiologic processes other than bone and mineral metabolism, and that these physiologic processes may have different optimal levels of vitamin D [1], interest in the measurement of the levels of vitamin D and its metabolites has soared. Moreover, disorders of vitamin D metabolism can be diagnosed by accurate measurement of these metabolites, and potential differences in ratios of vitamin D metabolites even in otherwise normal individuals can be predictive of differences in responses to dietary intakes of vitamin D in food and/or in supplements due to differences in metabolism [2]. However, the measurement of vitamin D metabolites is not trivial. These are lipophilic materials circulating in low concentrations tightly bound to proteins, vitamin D binding protein (DBP) and albumin in particular, making their measurements difficult. If one considers that only the free (i.e., non-protein bound) metabolite enters cells and is the biologically important concentration to consider [3], the requirements for sensitivity of measurement increase by several orders of magnitude. Moreover, distinguishing between the different metabolites that may differ only modestly chemically but with substantial differences biologically and quantitatively likewise contributes to the difficulties developers of assays have in providing a fast throughput assay at reasonable cost to meet the increasing demand for these measurements. In this review, the most common assays on the market today are described reviewing their advantages and limitations with a discussion of newer technologies including the development of assays intended to measure the free concentrations.
Vitamin D Production and