Metabolic Bone Disease

Volume 1

Louis V. Avioli, Stephen M. Krane

• Publisher: Academic Press
• Year: 2013
• Print ISBN: 9780120687015
• eBook ISBN: 9781483216317
• Topic: Medizin
• Subtopic: Klinische Medizin

Metabolic Bone Disease, Volume I covers the approach to a variety of disorders of mineral metabolism. The book discusses bone metabolism and calcium regulation; kidney function in calcium and phosphate metabolism; as well as the role of alkaline phosphatase in metabolic bone disorders. The text also describes the diagnostic value of bone biopsies; the etiology, clinical aspects, therapy, and the main syndromes of vitamin D deficiency, rickets, and osteomalacia; and the pathogenesis and therapy of osteoporosis. The pathogenesis and treatment of nephrolothiasis are also encompassed. Orthopedic doctors, physicians, endocrinologists, and people involved in the research of metabolic bone diseases will find the book invaluable.

1

Bone Metabolism and Calcium Regulation

LAWRENCE G. RAISZ

Publisher Summary

This chapter reviews the most salient features of calcium regulation and the roles of the major regulatory hormones, parathyroid hormone, calcitonin, and the active metabolites of vitamin D. The maintenance of a constant calcium ion concentration in extracellular fluid plays a central role in the control of bone metabolism. Bone is also important in the regulation of magnesium, phosphate, sodium, and hydrogen ions, and under certain circumstances, the control systems depends on these ions and on calcium as well. Parathyroid hormone increase the entry of calcium into the cells, and its earliest effect is a transient lowering of serum ionized calcium concentration. Thus, the hormone helps maintain intracellular calcium, which is essential for secretion, muscular contraction, and many other cell functions. Calcium ion concentration is largely responsible for feedback control of parathyroid hormone synthesis and secretion. Magnesium has a similar acute effect on the release of preformed hormone; however, low magnesium is less effective than low calcium in stimulating hormone synthesis and gland hyperplasia.

I. Introduction

II. General Problem of Calcium Regulation

III. General Description of Skeletal Structure and Function

A. Bone Histology

B. Bone Chemistry

IV. Distribution and Transport of Calcium and Phosphate

A. Distribution

B. Factors Controlling Entry and Exit of Calcium and Phosphate!

V. Regulation of Bone Formation

VI. Regulation of Bone Resorption

A. Parathyroid Hormone and Bone Resorption

B. Vitamin D and Bone Resorption

C. Calcitonin and Bone Resorption

D. Other Hormones That Affect Bone Resorption

E. Nonhormonal Influences on Bone Resorption

VII. Cellular Calcium Regulation

General References

References

I INTRODUCTION

More than a quarter century ago, Albright and Reifenstein (1948) were able to summarize briefly the fragmentary and conflicting information then available on bone metabolism and its role in calcium regulation. Ten years later, the physicochemical background against which biological regulation must play its part was described by Neuman and Neuman (1958). Since that time the problem appears to have received more than its share of fallout from the information explosion in biomedical science of the 1950’s and 1960’s. These 25 years have seen the following:

1. A clear definition of the feedback system which maintains serum calcium concentration constant by changes in parathyroid hormone secretion mediated through control of bone resorption as well as renal and intestinal calcium transport

2. Chemical characterization of parathyroid hormone and the beginning of studies on its complex metabolism

3. The identification of early effects of parathyroid hormone on production of cyclic 3′,5′-adenosine monophosphate (cAMP) and on mineral translocation in kidney and bone

4. The discovery of calcitonin and the remarkably rapid elucidation of its chemistry and of an entirely new feedback system, regulating calcium and affecting bone. Except in the area of mechanism of action, our knowledge of calcitonin is at least as extensive as that for parathyroid hormone

5. The discovery of the activation of vitamin D by multiple-step metabolic transformation, which has led to the concept that vitamin D is really a third calcium-regulating hormone

6. Analysis of the chemical composition, biosynthesis, and degradation of bone and cartilage matrix, particularly collagen. In the description of bone matrix in Albright and Reifenstein’s book the word collagen does not appear.

Thirty years ago, Albright left open the question of whether parathyroid hormone acts primarily on bone or on kidney in regulating serum calcium; we can answer that question only with a thunderingly equivocal both! Now we must reevaluate the relative importance of parathyroid hormone and active metabolites of vitamin D in physiologic calcium regulation, and we still do not know the physiological function of calcitonin. Moreover, the processes of bone formation and resorption are understood only in general descriptive terms; the cellular and chemical events involved are largely unknown.

II GENERAL PROBLEM OF CALCIUM REGULATION

In this section, the most salient features of calcium regulation and the roles of the major regulatory hormones, parathyroid hormone, calcitonin, and the active metabolites of vitamin D, are briefly reviewed. A more detailed discussion of the regulatory hormones is presented in Volume II, Chapters 1–4.

The maintenance of a constant calcium ion concentration in extracellular fluid plays a central role in the control of bone metabolism. Bone is also important in the regulation of magnesium, phosphate, sodium, and hydrogen ions, and under certain circumstances the control systems may depend on these ions as well as on calcium. Even though feedback control appears to be exerted largely by extracellular calcium ion concentration, this is not the only purpose of regulation. Parathyroid hormone can increase the entry of calcium into the cells, and its earliest effect is a transient lowering of serum ionized calcium concentration (Parsons et al., 1971). Thus, the hormone could help maintain intracellular calcium, which is essential for secretion, muscular contraction, and many other cell functions. The subsequent increase of serum calcium concentration because of calcium mobilization from the skeleton and increased transport across the renal tubule or the intestinal mucosa is necessary to maintain this calcium supply. Moreover, extracellular regulation is essential because neuromuscular excitability depends on the concentration of calcium ion at the cell surface.

Calcitonin and vitamin D may be more important for maintaining calcium mass than concentration. Calcitonin secretion can be stimulated by calcium ingestion, with little increase in serum calcium concentration, and the formation of the most active metabolite of vitamin D- 1,25-dihydroxycholecalciferol-may not be regulated by changes in serum calcium concentration itself but by intracellular ion concentration or indirectly by other regulatory hormones.

Parathyroid hormone (see Volume II, Chapter 1) is initially synthesized as a larger prohormone, which is probably cleaved intracellularly to the classical 84 amino acid molecule prior to secretion. The secreted hormone is rapidly degraded to fragments that may be biologically active or inactive. These fragments can react with antibodies to bovine parathyroid hormone (PTH). Thus, immunoreactive PTH and biologically active PTH concentrations are not necessarily the same.

Calcium ion concentration is largely responsible for feedback control of parathyroid hormone synthesis and secretion. Magnesium has a similar acute effect on the release of preformed hormone, but low magnesium is less effective than low calcium in stimulating hormone synthesis and gland hyperplasia. Impairment of both hormone secretion and end organ response may be responsible for the hypocalcemia that occurs in magnesium deficiency. There are few factors other than calcium and magnesium which have been shown to influence PTH synthesis and secretion directly. Phosphate loading stimulates the gland, but this is probably entirely mediated by the associated decrease in serum calcium ion concentration. The role of hydrogen ion, catecholamines, and other factors is currently under study.

The discovery of calcitonin (Copp et al., 1962) was followed by a remarkably rapid elucidation of the chemistry, effects, and metabolism of this new hypocalcemic hormone secreted by cells of ultrabranchial origin located parafollicularly in the mammalian thyroid (see Volume II, Chapter 4). Unlike PTH, which is largely under direct divalent cation control, calcitonin secretion is stimulated not only directly by high calcium but also by gastrointestinal hormones, particularly gastrin (Cooper et al., 1972). The latter response may be the most important physiological mechanism for calcitonin secretion in mammals, and may explain why young, rapidly growing animals deficient in calcitonin develop hypercalcemia and hypercalciuria after oral ...

Table of contents

• Cover image
• Title page
• Table of Contents
• List of Contributors
• Copyright
• List of Contributors
• Preface
• Contents of Other Volumes
• Chapter 1: Bone Metabolism and Calcium Regulation
• Chapter 2: Kidney Function in Calcium and Phosphate Metabolism
• Chapter 3: Alkaline Phosphatase and Metabolic Bone Disorders
• Chapter 4: The Diagnostic Value of Bone Biopsies
• Chapter 5: Vitamin D, Rickets, and Osteomalacia
• Chapter 6: Osteoporosis: Pathogenesis and Therapy
• Chapter 7: Nephrolithiasis
• Index