Calcium Disorders

Butterworths International Medical Reviews: Clinical Endocrinology

David Heath, Stephen J. Marx

• Publisher: Butterworth-Heinemann
• Year: 2013
• Print ISBN: 9780407022737
• eBook ISBN: 9781483192109
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Clinical Endocrinology 2: Calcium Disorders presents an extensive examination of the treatment of postmenopausal and senile osteoporosis. It discusses the acquired disorders of vitamin D metabolism. It addresses the prevention of osteoporosis.Some of the topics covered in the book are the classification of rickets; mechanisms of homeostasis; transepithelial transport of phosphate anion; definition of mendelian rickets; treatment of; classification of androgens and synthetic anabolic agents; and assessment of parathyroid function. The measurement of parathyroid hormone is fully covered. An in-depth account of the indirect assessment of parathyroid activity is provided. The acquired disorders of Vitamin D metabolism are completely presented. A chapter is devoted to the aetiological views of rickets and osteomalacia. Another section focuses on the treatment and prevention of rickets and osteomalacia. The analysis of renal osteodystrophy, hypercalcemia, and familial hypocalciuric hypercalcemia are briefly covered.The book can provide useful information to doctors, endocrinologists, students, and researchers.

1

Hereditary rickets

C.R. Scriver, D. Fraser and S.W. Kooh

Publisher Summary

This chapter provides an overview of hereditary rickets disorder of mineral deposition in the preosseous cartilage of growth plates and the matrix of growing bone. The heritability of rickets has been increasing in modern man because environmental causes have abated. Parathyroid hormone and vitamin D are the principal hormone products of vertebrate evolution that regulate extracellular phosphorus and calcium homeostasis. Calmodulin¹⁵⁶ and vitamin D-dependent calcium-binding protein are the principal intracellular gene products controlling calcium activity. One of the intrinsic factors controlling the transport of the vitamins is the plasma vitamin D-binding protein. The appearance of rickets with increasing vitamin D deficiency depends on the occurrence of hypophosphatemia. In calcipenic rickets, it is the controlling response (parathyroid hormone secretion) that causes hypophosphatemia. While in phosphopenic rickets, the controlled response loop involves phosphate directly and is inadequate to restore phosphate homeostasis. The primary repair of calcium homeostasis with vitamin D or calcium is indicated in calcipenic rickets. Three mechanisms have been suggested to explain vitamin D dependency: (a) a poor absorption of vitamin D, (b) an inadequate conversion of vitamin D to 1,25(OH)D, and (c) the inability of target tissues to respond satisfactorily to physiological concentrations of the active metabolites. An affected individual has 50% probability of having affected children. With appropriate therapy, all biochemical and radiographic abnormalities revert to normal; deformities disappear and normal growth returns. However, the defect in vitamin D metabolism is permanent and treatment must be continued into adulthood to prevent the recurrence of osteomalacia.

INTRODUCTION

Since the first description of ‘vitamin D-resistant osteomalacia’ by Albright et al.¹, in 1937, it has become obvious that there exists an increasingly large and diversified list of heritable rachitic conditions. The early classifications^{33, 50} of the various syndromes were descriptive. However, as more discrete conditions are added to the list, and as more information is acquired about the pathogenetic mechanisms of the human diseases and their animal analogues, it becomes clear that the individual conditions represent paradigms of genetic phenomena.

Our approach in this paper will be to look first at the evolutionary steps through which phosphate has become central to the energetics of all cell processes and calcium has become a key mediator of cellular function. In the evolutionary scheme, genes determine enzymes and hormones which in turn establish homeostatic mechanisms. Accordingly, we will examine mechanisms of phosphate and calcium homeostasis, and consider how they can be targets for mutation leading to various rachitic syndromes. With this background, we will describe specific forms of rickets and osteomalacia,^* examine how they fit in with the present knowledge of cell control and function, and finally indicate how the understanding of pathogenetic mechanisms can be used to design logical therapies.

The heritability^† of rickets has, in general, been increasing in modern man because environmental causes have abated. Accordingly, our emphasis on intrinsic causes of rickets is appropriate. Our goal is to encourage the physician to anticipate and prevent the consequences of rickets by the application of genetic principles to the patient.

THE COMPONENTS OF MINERAL METABOLISM: THE EVOLUTIONARY PERSPECTIVE

Earth cooled and solidified during her first billion years of geochemical evolution, and phosphate was trapped in igneous rocks of the lithosphere⁶⁷. Since molecular oxygen was also present in the lithosphere, phosphorus occurred as phosphate. The anion became available to biological evolution when leaching by oceans produced sedimentary deposits of inorganic phosphates. Phosphate became sufficiently abundant to support evolution of prokaryotes at least 1.5 billion years ago and probably as long ago as 3 billion years. When cellular energy metabolism became irrevocably coupled with phosphate and oxygen in solution, evolution of eukaryotes and multicellular organisms could be sustained¹¹⁹.

Vertebrate evolution began about 400 million years ago. The skeleton of later vertebrate evolution is bone, a tissue with adaptive advantages over cartilage. Attainment of a stable internal phosphate pool was necessary for the evolution of mineralization. Thus, cells and organisms became dependent on phosphate long ago, and those that possessed mechanisms to capture the anion from the environments to compartmentalize it and to control its cellular content were more fit in the Darwinian sense. Phosphate transport systems in membranes were the phenotype, and genes to control them were the genotype that conferred advantage. Mutant phenotypes with disturbed phosphate transport are found throughout evolution, from prokaryotes to man, and are the price paid for the selective advantage attached to the normal genes at the relevant loci.

The case for calcium is somewhat similar. Biologists consider calcium to be so important ‘that evolution simply could not help bestowing upon it one role after another’⁸⁸. Calcium was available in primeval oceans but whereas phosphate was first selected for the energetics of biological systems, calcium seems to have been selected initially for its role in excitation–response coupling in cells. Later, during vertebrate evolution, it was readily stored in chemical union with phosphate, as hydroxyapatite (Ca₁₀(PO₄)₆(OH₂), in the skeleton from whence it could be recalled to maintain calcium pools in biological fluids and be controlled within narrow limits by hormones.

Parathyroid hormone and vitamin D are the principal hormone products of vertebrate evolution that regulate extracellular phosphorus and calcium homeostasis. Calmodulin¹⁵⁶ and vitamin D-dependent calcium-binding protein¹⁵⁵ are the principal intracellular gene products controlling calcium activity. The role of calcitonin is less well understood and some consider it a vestigial hormone in man⁵. Parathyroid hormone and vitamin D both expose mineral pools in bone. The former also acts on kidney to conserve calcium and reject the attendant phosphate anion in glomerular filtrate; the latter also acts on the intestine to enhance absorption of both calcium and phosphate.

Parathyroid hormone is synthesized, processed, and secreted by the parathyroid chief cell; the signal for control of hormone release is the activity of calcium ion on the parathyroid cell. The hormone acts on target cells by binding to a specific plasma membrane r...

Table of contents

• Cover image
• Title page
• Table of Contents
• Butterworths International Medical Reviews
• Copyright
• Preface
• List of Contributors
• Chapter 1: Hereditary rickets
• Chapter 2: The prevention of osteoporosis
• Chapter 3: The treatment of postmenopausal and senile osteoporosis
• Chapter 4: The assessment of parathyroid function
• Chapter 5: Bisphosphonates
• Chapter 6: Acquired disorders of vitamin D metabolism
• Chapter 7: Renal osteodystrophy
• Chapter 8: Asymptomatic hypercalcemia and primary hyperparathyroidism
• Chapter 9: Familial hypocalciuric hypercalcemia
• Chapter 10: Hypercalcaemia of malignancy
• Chapter 11: Hypocalcemia and other abnormalities of mineral homeostasis during the neonatal period
• Index