Chapter 48: Agents Affecting Mineral Ion Homeostasis and Bone Turnover

INTRODUCTION

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.

ABBREVIATIONS

PHYSIOLOGY OF MINERAL ION HOMEOSTASIS

Calcium

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.

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.

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.