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INTRODUCTION

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This chapter presents a primer on mineral ion homeostasis and the endocrinology of Ca2+ and phosphate metabolism, then some relevant pathophysiology, and finally pharmacotherapeutic options in treating disorders of mineral ion homeostasis.

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ABBREVIATIONS

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Abbreviations

BMD: bone mineral density

CaSR: calcium-sensing receptor

CGRP: calcitonin gene–related peptide

CKD-MBD: chronic kidney disease–mineral bone disease

CTR: calcitonin receptor

CYP: cytochrome P450

DHT: dihydrotachysterol

ERK: extracellular signal–regulated kinase

FGF: fibroblast growth factor

FGF23: fibroblast growth factor 23

FGFR: FGF receptor

FGFR/KL: FGF receptor/Klotho

FRS2α: FGFR substrate 2α

HRT: hormone replacement therapy

HVDDR: hereditary 1,25-dihydroxyvitamin D resistance

Ig: immunoglobulin

IL-1: interleukin 1

IP3: inositol triphosphate

KL: klotho

MTC: medullary thyroid carcinoma

NF-κB: nuclear factor kappa B

25-OHD3: 25-OH-cholecalciferol

OPG: osteoprotegerin

NPT2: Sodium-dependent phosphate transport protein 2

PDDR: pseudovitamin D–deficiency rickets

Pi: inorganic phosphate

PKC: protein kinase C

PLC: phospholipase C

PTH: parathyroid hormone

PTHR: PTH receptor

PTHrP: PTH-related protein

RANK: receptor for activating NF-κB

RANKL: RANK ligand

RDA: recommended daily allowance

REMS: Risk Evaluation and Mitigation Strategy

SERM: selective estrogen receptor modulator

SGK1: serum and glucocorticoid–regulated kinase 1

TK: tyrosine kinase

TRPV6: Transient receptor potential cation channel V6

VDDR-1: vitamin D–dependent rickets type I

VDR: vitamin D receptor

XLH: X-linked hypophosphatemia

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PHYSIOLOGY OF MINERAL ION HOMEOSTASIS

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Calcium

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Elemental calcium is essential for many biological functions, ranging from muscle contraction and intracellular signaling (see Chapter 3) to blood coagulation and supporting the formation and continuous remodeling of the skeleton.

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Extracellular Ca2+ is in the millimolar range, whereas intracellular free Ca2+ is maintained at submicromolar levels. Different mechanisms evolved that regulate Ca2+ over this 10,000-fold concentration span. Changes in cytosolic Ca2+ (whether released from intracellular stores or entering via membrane Ca2+ channels) can modulate effector targets, often by interacting with the ubiquitous Ca2+-binding protein calmodulin. The rapid association-dissociation kinetics of Ca2+ permit effective regulation of cytosolic Ca2+ over the range of 100 nM to 1 μM.

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The body content of calcium in healthy adult men and women, respectively, is about 1300 and 1000 g, of which more than 99% is in bone and teeth. Ca2+ in extracellular fluids is stringently regulated within narrow limits. In adult humans, the normal serum Ca2+ concentration ranges from 8.5 to 10.4 mg/dL (4.25–5.2 mEq/L, 2.1–2.6 mM) and includes three distinct chemical forms: ionized (50%), protein bound (40%), and complexed (10%). Thus, whereas total plasma Ca2+ concentration is about 2.5 mM, the concentration of ionized Ca2+ in plasma is about 1.2 mM. The various pools of Ca2+ are illustrated schematically in Figure 48–1.

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Figure 48–1

Pools of calcium in serum. Concentrations are expressed as milligrams per deciliter (top axis) and as millimoles per liter (bottom axis). The total serum calcium concentration is 10 mg/dL ...

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