Bone Mineral Metabolism in Cancer: Recent Results in Cancer Research

Recent Results in Cancer Research

Bone Mineral Metabolism in Cancer

Janusz Szymendera

Springer-Verlag

Table of Contents

Cover image

Title page

Recent Results in Cancer Research

Copyright

Introduction

Foreword

Chapter 1: General Outlines of Bone Tissue Metabolism

Publisher Summary

1 Structure and Function of Bone Cells

2 Structure and Function of Bone Matrix

3 Bone Mineral

Chapter 2: General Outlines of a Clinical Approach to Bone Tissue Metabolism

Publisher Summary

1 Calcium Metabolism

Inorganic Phosphate Metabolism

3 Collagen Metabolism and Urinary Hydroxyproline

4 Pyrophosphate Metabolism and Urinary Pyrophosphate

Chapter 3: Methods of Studying Bone Mineral Metabolism

Publisher Summary

1 Plasma State and Renal Handling of Calcium and Phosphate

2 Kinetics of Calcium Metabolism

3 Kinetics of Inorganic Phosphate Metabolism

4 Multicompartmental Analysis of Calcium and Phosphate Kinetics

5 Urinary Pyrophosphate

6 Other Methods

Chapter 4: The Metabolism of Bone Mineral in Malignancy without Evidence of Bone Destruction

Publisher Summary

1 Metabolism of Calcium and Inorganic Phosphate

2 Effects of Castration on Plasma State and Renal Handling of Calcium and Inorganic Phosphate

3 Discussion

Chapter 5: The Metabolism of Bone Mineral in Malignancy with Bone Lesions

Publisher Summary

1 Patients with Plasmacytoma

2 Patients with Cancer of the Breast

3 Discussion

General Summary

Appendix: An Analytical Solution of the Parallel Three-Compartment Open System Model

References

Subject Index

Monographs already Published

Recent Results in Cancer Research

Fortschritte der Krebsforschung Progrès dans les recherches sur le cancer

27

Edited by

V. G. Allfrey, New York · M. Allgöwer, Basel · K. H. Bauer, Heidelberg I. Berenblum, Rehovoth · F. Bergel, Jersey · J. Bernard, Paris · W. Bernhard, Villejuif · N. N. Blokhin, Moskva · H. E. Bock, Tübingen · P. Bucalossi, Milano · A. V. Chaklin, Moskva · M. Chorazy, Gliwice · G. J. Cunningham, Richmond · W. Dameshek†, Boston · M. Dargent, Lyon · G. Della Porta, Milano · P. Denoix, Villejuif · R. Dulbecco, La Jolla · H. Eagle, New York R. Eker, Oslo · P. Grabar, Paris · H. Hamperl, Bonn · R. J. C. Harris, London E. Hecker, Heidelberg · R. Herbeuval, Nancy · J. Higginson, Lyon W. C. Hueper, Fort Myers · H. Isliker, Lausanne · D. A. Karnofsky †, New York · J. Kieler, København · G. Klein, Stockholm · H. Koprowski, Philadelphia · L. G. Koss, New York · G. Martz, Zürich · G. Mathé, Villejuif O. Mühlbock, Amsterdam · W. Nakahara, Tokyo · V. R. Potter, Madison A. B. Sabin, Rehovoth · L. Sachs, Rehovoth · E. A. Saxén, Helsinki W. Szybalski, Madison · H. Tagnon, Bruxelles · R. M. Taylor, Toronto A. Tissières, Genève · E. Uehlinger, Zürich · R. W. Wissler, Chicago T. Yoshida, Tokyo

Editor in chief

P. Rentchnick, Genève

1970

Springer-Verlag Berlin · Heidelberg · New York

William Heinemann Medical Books Ltd., London

Copyright

JANUSZ SZYMENDERA, M. D., Research Assistant in Nuclear Medicine, Department of Isotopes, Institute of Oncology, Warsaw 22, Poland

Sponsored by the Swiss League against Cancer

SBN 433 31980 1

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks.

Under § 54 of the German Copyright Law where copies are made for other than private use, a fee is payable to the publisher, the amount of the fee to be determined by agreement with the publisher.

© by Springer-Verlag Berlin · Heidelberg 1970. Library of Congress Catalog Card Number 75-104194. Printed in Germany. The use of general descriptive names, trade names, trade marks, etc. in this publication, even if the former are not especially identified, is not to be taken as a sign that such names, as understood by the Trade Marks and Merchandise Marks Act, may accordingly be used freely by anyone.

Introduction

The introduction of new methods for studying the plasma state, renal handling, and kinetics of calcium and inorganic phosphate has rendered possible a more efficient and appropriate approach to the problems of bone-tissue metabolism and more adequate investigation of the pathogenesis of its miscellaneous abnormalities. Used to study the metabolism of bone mineral in osteoporosis, hypo- and hyperparathyroidism, and other metabolic bone diseases, the new methods have given much valuable information. In malignancy they also promise to supplement the scantiness of the existing information better than the routine examination procedures, yet they have been used far more rarely in this field.

The material presented in this work represents an attempt to marshal the facts and to answer, by the aid of recent techniques, some still open problems of bone-mineral metabolism in patients with cancer. Since the new techniques involve an entirely new approach, the first two chapters are devoted to it and details of these techniques are presented in the third chapter.

I realize the shortcomings of this work, but the never-ending and continuously increasing search for new discoveries makes some data obsolete at the moment of their presentation. Nevertheless, I hope that this work will give some information which will be useful in interpreting disturbances of bone-tissue metabolism in patients, both without any evidence of bone secondaries, and with widespread osseous metastases.

Warsaw, February 1970

JANUSZ SZYMENDERA

Foreword

SKI, M. D., for his suggestion about the study, for his interest in it, and for his kindness in placing the facilities of the Department at my disposal.

SKI, Ph. D., for his valuable suggestions and help in the mathematical treatment and presentation of the results, and CZESŁAW SMARSZ, Ph.D., for kind supply and informations on the use of ultrafiltration devices, and for helpful discussions during the present work.

I am grateful to MAURICE E. SHILS, M. D., Sc. D., Associate Member of the Sloan-Kettering Institute for Cancer Research, for advice on metabolic balance investigations and for kindly supplying a brillant blue dye.

I owe my sincerest thanks to the members of the metabolic team, STEFAN MADAJEWICZ, M. B., JANUSZ NOWOSIELSKI, M. Sc., Mrs. CHRISTINA ROGALSKA, technical assistant, and Mrs. SOPHIE MOZER, dietitian, for their collaboration and technical assistance, without which the work would have been impossible.

I am also greatly indebted to Assistant Professor ADAM MICHAŁOWSKI, M. D., who helped me in preparing the English manuscript.

This study was supported by grants from the International Atomic Energy Agency, the Polish Academy of Sciences and the Medical Academy of Warsaw.

Chapter 1

General Outlines of Bone Tissue Metabolism

Publisher Summary

This chapter focuses on bone tissue metabolism. Bones are organized on two levels: (1) as organs and (2) as a tissue. As organs, they are particular elements of the skeleton adapted to withstand stresses; as a tissue, they form a highly specialized connective tissue composed of cells embedded in an interstitial substance, which includes the organic framework or matrix and the mineral. The chapter discusses the molecular structure and metabolism of the major parts of bone, namely, cells, organic matrix, and inorganic salts. Bone cells are organized in three compartments: (1) proliferating, (2) functional, and (3) a final-stage compartment. The interstitial organic substance or matrix consists of two major components: (1) collagen and (2) ground substance. The degradation of bone collagen to peptides and amino acids is mediated by proteolytic enzymes. The ground substance in which the cells and collagen are embedded consists of proteoglycans and glycoproteins. The time-dependent changes in the content of proteoglycans are because of their half-lives. The catabolism of sulphated glycosaminoglycans depends on the desulphation processes, followed by the degradation of the desulphated polymer. The inorganic portion of bone contains two major mineral phases: (1) amorphous or noncrystalline calcium phosphate and (2) crystalline bone apatite. Both the amorphous calcium phosphate and crystalline apatite are strongly hydrated; the volume of hydration shell is several times greater than that of mineral.

Bones are organized on two levels: as organs and as a tissue. As organs, they are particular elements of the skeleton adapted to withstand stresses; as a tissue, they form a highly specialized connective tissue composed of cells embedded in an interstitial substance, which includes the organic framework or matrix and the mineral. A brief account of what is known about the molecular structure and metabolism of the major parts of bone—cells, organic matrix and inorganic salts—seems advisable.

1 Structure and Function of Bone Cells

Bone cells are organized in three compartments: a proliferating, a functional, and a final-stage compartment (OWEN, 1963). The first compartment cells, the preosteoblasts, are reproducing themselves, and the second compartment cells may be either osteoblasts or osteoclasts. The final-stage cell of an osteoblast is the osteocyte (OWEN, 1963).

Osteoblasts and osteocytes have much the same fine structure and reveal the cytoplasmatic features of intense metabolic activity: they control the metabolism of collagen, proteoglycans and glycoproteins, as well as the mineral elements of bone tissue (BAUD, 1966). Osteoclasts, giant cells with a variable number of nuclei, produce organic acids, the agents of the solubilization of bone mineral, as well as acid hydrolases—the enzymes that digest organic matrix (VAES, 1966). There is good evidence to suggest that bone cells of all functional states stem from the preosteoblast (OWEN, 1963).

The differences in structure and metabolic activities of bone cells are associated with their specific function: osteoblasts with formation, osteocytes with maintenance, and osteoclasts with resorption of bone (BAUER et al., 1961).

2 Structure and Function of Bone Matrix

The interstitial organic substance or matrix consists of two major components: collagen and ground substance.

2.1 Collagen

Composition and Structure of Collagen

The collagenous framework of the bone tissue is composed of typical fibres having characteristic low-angle X-ray diffraction patterns and banded patterns in the electron microscope with a periodicity of 64—70 nm (RAMACHANDRAN, 1963). Each collagen fibre is composed of basic tropocollagen molecules having a molecular weight of 300,000 (BORNSTEIN and PIEZ, 1964), a length of 300 nm, and a diameter of 1.5—1.6 nm in the wet state (BEAR, 1952).

Tropocollagen is composed of three polypeptide alpha chains having the same molecular weight of about 100,000 The alpha 2 chain differs in its amino acid composition and chromatographic behaviour from the two alpha 1 chains (BORNSTEIN and PIEZ, 1964). The amino acid composition of alpha 1 and alpha 2 chains of human skin collagen—there are about 1,100 amino acid residues in each chain—is shown in Fig. 1.

Fig. 1 A comparison of the amino acid composition of alpha chains from human skin collagen. The values used for constructing this diagram were taken from BORNSTEIN and PIEZ (1964). 1° = 2.78 amino acid residues per 1000 total residues; I = Imino acids; II = Hydroxy amino acids; III = Acidic amino acids; IV = Basic amino acids; V = Aromatic amino acids

Significant differences may be found in the contents of proline, hydroxyproline, alanine, lysine and glutamic acid (more in alpha 1 chain) and hydroxylysine, histidine, leucine, isoleucine, valine and tyrosine (more in alpha 2 chain) in comparing both chains (BORNSTEIN and PIEZ, 1964). The findings that collagen from codfish skin contains three different, chromatographically separable alpha chains (PIEZ, 1964), that the fragments produced by cleavage of the methionyl bonds in the alpha 1 chains demonstrate large variations in their amino acid composition (BORNSTEIN and PIEZ, 1965), and that the primary structure of collagen is heterogeneous as a consequence of the incomplete hydroxylation of individual prolyl residues in collagen (BORNSTEIN, 1967)—all indicate that alpha 1 chains are not identical. Moreover, the finding of large variations in amino acid composition in the fragments produced by cleavage of the methionyl bonds indicates that the amino acid sequence of each of the alpha chains is unique throughout its length (BORNSTEIN and PIEZ, 1965). It contradicts the model of collagen structure proposed by PETRUSKA and HODGE (1964) based on identical intrachain subunits.

The alpha chains of the tropocollagen molecule have a discernible recurrence of certain similar sequences of amino acids. These sequences are found in the crystalline or non-polar regions. The non-polar regions alternate with a large polypeptide run, the amorphous or polar region. The non-polar regions which form 50—60 per cent of an alpha chain are visualized as interbands in the electron micrographs, while the alternating polar regions are visualized as bands (SEIFTER et al., 1965). The attack of bacterial collagenase on non-polar sequences gives 5—6 dialysable tripeptides Gly-Pro-R, in which R represents any amino acid residue (GRASSMANN et al., 1963). The polar segments give rise to non-dialysable peptides containing from 11 to 15 residues, in which every third one is the glycyl residue, and among the other residues there are those from acidic and basic amino acids (FRANZBLAU et al., 1964). The model of the alpha chain