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Diagnostic Imaging of Musculoskeletal Diseases:
A Systematic Approach
Akbar Bonakdarpour, MD · William R.
Reinus, MD · Jasvir S. Khurana, MD
Editors

Diagnostic Imaging
of Musculoskeletal Diseases

A Systematic Approach

13
Editors
Akbar Bonakdarpour William R. Reinus
Department of Radiology Department of Radiology
Temple University Hospital Temple University Hospital
3401 N. Broad Street 3401 N. Broad Street
Philadelphia, PA 19140-5189 Philadelphia, PA 19140-5189
USA USA
[email protected] [email protected]

Jasvir S. Khurana, MD
Department of Pathology
Temple University Hospital
3401 N. Broad St.
Philadelphia, PA 19140-5189
USA
[email protected]

ISBN 978-1-58829-947-5 e-ISBN 978-1-59745-355-4

DOI 10.1007/978-1-59745-355-4
Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2009935060

© Springer Science+Business Media, LLC 2010

All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the
publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief
excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and
retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter
developed is forbidden.
The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified
as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.
While the advice and information in this book are believed to be true and accurate at the date of going to press, neither
the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may
be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Preface

We dedicate this text to Drs. Ernest E. Aegerter, a pathologist, and John A. Kirkpatrick Jr.,
a radiologist. They were among the principal founders of the field of skeletal pathology and
radiology. During their time, their residents and colleagues knew them as great educators with
a dedication and a passion for their work. Their textbook, Orthopedic Diseases, published
initially in 1958 was among the first interdisciplinary works devoted to this field. Dr. Aegerter
and Dr. Kirkpatrick illuminated many aspects of the field of radiology. Today, with the advent
of new technologies, this field has grown to include not only diseases that affect the skeleton
but also those that affect muscles, ligaments, tendons, and also the cartilaginous structures
within joints.
With this text we intend to carry on Dr. Aegerter and Dr. Kirkpatrick’s tradition. We have
recruited only well-known musculoskeletal radiologists and pathologists to participate in the
writing of this book. Each author has been carefully selected for his expertise on the topic about
which he’s been asked to contribute. Each author is known as an experienced and seasoned
teacher. Each author has made a mark on the field.
With this talent we aim to lay the foundation of a useful and worthy teaching text. Our
goal is to create a textbook that is at once readable by the radiology resident experiencing
musculoskeletal radiology for the first time and thorough enough to be used by the practicing
radiologist. We do not intend, however, to present an exhaustive reference work. We leave that
task to other authors.
Instead we aim to provide a text that not only conveys important information about com-
mon and some less common musculoskeletal diseases, but more importantly provides a practi-
cal and systematic approach to analyzing diseases of bones, muscles, tendons, ligaments, and
joints. We will provide with each category a means by which to conceptualize and analyze how
pathology changes their appearance on medical images.
To meet these goals we have organized this text according to major categories of disease:
trauma, infection, tumors and tumor-like conditions, metabolic diseases, endocrine disorders,
dysplastic diseases, and arthritis. Where disease categories overlap, e.g., intraosseous tophus
or brown tumor of bone, we discuss those points under each appropriate heading. Where there
is debate as to the etiology of a disease, we also discuss these issues guiding the reader, to the
best of our ability, to what current thinking has to say about that disease.
We also include a chapter that examines basic interventional techniques that apply to mus-
culoskeletal imaging. Again, the idea is not to provide an exhaustive reference on any one
technique, but instead to give the reader a primer on these techniques and their indications
with guidance for finding further information.
Finally, in recognition of the importance of orthopedic procedures, we include information
on the use, imaging appearance, and pathology affecting prostheses and fixation devices. This
information is essential to the practice of modern radiology.
We hope that the reader will both enjoy reading this text and find the experience profitable
to their knowledge base, both in fact and in concept. We look forward to receiving readers’
impressions, criticisms, and suggestions to improve this text in future editions.

v
vi Preface

Ernest E. Aegerter John A. Kirkpatrick

Akbar Bonakdarpour
Philadelphia, PA William R. Reinus
Jasvir S. Khurana
Contents

1 Bone Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Fayez F. Safadi and Jasvir S. Khurana
2 Systematic Approach to Metabolic Diseases of Bone . . . . . . . . . . . . . . 15
Akbar Bonakdarpour
3 Systematic Approach to Radiology of Endocrine Disorders Affecting
the Musculoskeletal System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Akbar Bonakdarpour and Colleen Veloski
4 Circulatory Diseases of Bone and Adjacent Soft Tissues . . . . . . . . . . . . 99
Wilfred C.G. Peh and Seoung-Oh Yang
5 Imaging Approach to Musculoskeletal Trauma . . . . . . . . . . . . . . . . . 125
William R. Reinus
6 Imaging and Understanding Fracture Fixation . . . . . . . . . . . . . . . . . 203
Bahman Rafiee
7 Systematic Approach to Tumors and Focal Lesions of Bone . . . . . . . . . . 241
Shigeru Ehara and Jasvir S. Khurana
8 Systematic Approach to Tumors and Tumor-Like Conditions
of Soft Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Theodore T. Miller, Carolyn M. Sofka, Paul Zhang,
and Jasvir S. Khurana
9 Imaging Approach to Hemoglobinopathies . . . . . . . . . . . . . . . . . . . . 351
Avneesh Chhabra and William R. Reinus
10 Imaging Approach to Musculoskeletal Infections . . . . . . . . . . . . . . . . 363
William R. Reinus
11 Systematic Approach to Arthropathies . . . . . . . . . . . . . . . . . . . . . . 407
William R. Reinus
12 Imaging of Prostheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Sayed Ali and William R. Reinus
13 Systematic Approach to Skeletal Dysplasias with Emphasis
on Non-lethal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
Akbar Bonakdarpour
14 Interventional Procedures in Musculoskeletal Radiology . . . . . . . . . . . . 599
Jamshid Tehranzadeh, Scott Seibert, and Afshin Gangi
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635

vii
Contributors

Sayed Ali, MD Assistant Professor, Department of Radiology, Temple University School

of Medicine, Philadelphia, PA, USA, [email protected]
Akbar Bonakdarpour, MD, MS (Radiology), FACR∗ W. Edward Chamberlain Professor of
Radiology, Emeritus Professor of Radiology and Former Chief of Musculoskeletal Radiology,
Former Professor of Orthopedic Surgery, Temple University School of Medicine, Philadelphia,
PA, USA, [email protected]
Avneesh Chhabra, MD Assistant Professor, Department of Radiology, Johns Hopkins
School of Medicine, Baltimore, MD, USA, [email protected]
Shigeru Ehara, MD∗ Professor and Chair, Department of Radiology Iwate Medical Univer-
sity School of Medicine, Morioka, Japan, [email protected]
Afshin Gangi, MD, PhD Professor of Radiology, University Hospital of Strasbourg, Stras-
bourg, France
Jasvir S. Khurana, MD∗ Associate Professor, Department of Pathology, Temple University
School of Medicine, Philadelphia, PA, USA, [email protected]
Theodore T. Miller, MD, FACR∗ Professor of Radiology, Weill Medical College of Cornell
University, New York; Attending Radiologist, Department of Radiology and Imaging, Hospital
for Special Surgery, New York, USA, [email protected]
Wilfred C.G. Peh, MBBS, MHSM, MD, FRCPG, FRCPE, FRCR∗ Clinical Professor,
National University of Singapore, Singapore, Republic of Singapore; Senior Consultant Radi-
ologist, Alexandra Hospital, Singapore, Republic of Singapore, [email protected]; wil-
[email protected]
Bahman Rafiee, MD Assistant Professor, Musculoskeletal Division, Department of Radiol-
ogy, University of Pittsburgh, Pittsburgh, PA, USA, [email protected]; [email protected]
William R. Reinus, MD MBA FACR∗ Vice Chairman and Professor, Department of Radio-
logy; Chief, Musculoskeletal Radiology Temple University, Temple University School of
Medicine, Philadelphia, PA, USA, [email protected]
Fayez F. Safadi, PhD Associate Professor, Department of Anatomy and Cell Biology, Temple
University School of Medicine, Philadelphia, PA; Adjunct Associate Professor, Department of
Cell and Developmental Biology, Weill Cornell Medical College in Qatar, Education City,
Doha, Qatar, [email protected]
Scott Seibert, MD St. Mary’s Medical Center, San Francisco Orthopaedic Residency Pro-
gram, San Francisco, CA, [email protected]

ix
x Contributors

Carolyn M. Sofka, MD∗ Associate Professor of Radiology, Weill Medical College of Cor-
nell University, New York; Associate Attending Radiologist, Department of Radiology and
Imaging, Hospital for Special Surgery, New York, USA
Jamshid Tehranzadeh, MD∗ VA Long Beach Health Care System, DMM Health Care Group
# 05/114, 5901 E. 7th Street Long Beach, CA 90822 USA, [email protected]
Colleen Veloski, MD Assistant Professor, Department of Endocrinology and Metabolism,
Temple University School of Medicine, Philadelphia, PA, USA, [email protected]
Seoung-Oh Yang, MD, PhD Professor, Department of Radiology, Eulji University School
of Medicine, Daejeon, South Korea, [email protected]
Paul Zhang, MD Associate Professor of Pathology, Hospital of the University of Pennsylva-
nia, Philadelphia, PA, USA

∗ Denotes member of the International Skeletal Society

Chapter 1

Bone Structure and Function

Fayez F. Safadi and Jasvir S. Khurana

Abstract This chapter discusses the normal structure and Introduction

function of the skeleton and the various ways it is regu-
lated. The skeleton is both an organ and a type of con-
The Skeleton
nective tissue. Knowledge of its various identifiable parts
greatly facilitates an understanding of skeletal function and
also the disease processes that can occur. Normally, the major Apart from functioning as a major endocrine, hematopoi-
skeletal processes of resorption and formation are tightly etic, and reticuloendothelial organ, the skeleton serves as
coupled. This feature plays a role in the normal function the body’s structural support and locomotion system. It has
of skeletal renewal. Disturbances of the remodeling cycle mechanisms to grow and change in shape and size to suit
can be seen in a number of generalized skeletal disorders varying stressors including the ability to resist mechanical
including metabolic bone disease and conditions such as forces. It is also a major organ in the homeostasis of cal-
Paget disease. This chapter discusses the macroscopic and cium/phosphate balance and in the detoxification of heavy
microscopic anatomy of the skeleton as well as its bio- metals.
chemical makeup. It introduces the emerging information Bone tissue is continuously formed and remodeled
about the molecular control of bone cells and the skeletal throughout life. This is necessary since otherwise it would
processes. fatigue with the daily repetitive stress and torsion of motion
and weight bearing.
Keywords Remodeling • Coupling • Formation • Resorp- Initially, the bone achieves its increase in size and shape
tion • Mineralization • Cortical • Trabecular • Epiph- through growth (increase in size) and modeling. In late child-
ysis • Metaphysis • Diaphysis • Periosteum • Endosteum • hood and adulthood there is continuous renewal of the skele-
Woven • Lamellar • Osteoblasts • Osteoclasts • Receptor ton, by a process termed remodeling. Both modeling and
activator of nuclear factor kappa B (RANK) • Transform- remodeling require two separate processes, namely bone
ing growth factor-beta (TGF-β) • Bone morphogenetic pro- resorption and bone formation, to occur in coordination and
teins (BMPs) • Platelet-derived growth factors (PDGFs) • simultaneously to be effective. This phenomenon is known
Insulin-like growth factors (IGFs) • Calcium hydroxyap- as “coupling.”
atite • Collagen • Alkaline phosphatase • Glycosaminogly-
cans • Proteoglycans • Non-collagenous proteins • Osteo-
pontin • Osteocalcin • Vitamin D • Vitamin A • Estrogen • Bone Formation and Degradation
Androgen • Parathyroid hormone • Wolff’s law
The major functions of bone cells include matrix forma-
tion (osteogenesis), mineralization, and degradation (resorp-
tion). Because formation and resorption are antagonistic
processes that proceed simultaneously, bone metabolism
must be tightly regulated at all times. During the first two
decades of life when the skeleton is growing, there is a net
increase in bone mass such that bone formation exceeds its
degradation. Once the skeleton has reached maturity, the
F.F. Safadi ()
skeleton maintains a constant balance between formation
Department of Anatomy and Cell Biology, Temple University School
of Medicine, Philadelphia, PA 19140, USA and resorption to ensure that there is no net gain or loss of
e-mail: [email protected]; [email protected] bone; this regulated balance is called coupling. Uncoupling

A. Bonakdarpour et al. (eds.), Diagnostic Imaging of Musculoskeletal Diseases: A Systematic Approach, 1

DOI 10.1007/978-1-59745-355-4_1, © Springer Science+Business Media, LLC 2010
2 F.F. Safadi and J.S. Khurana

a b

Fig. 1.1 (a and b) Bone is calcified. The crystal structure of calcium bone developing on fibrous tissue is called intramembranous ossifica-
hydroxyapatite makes bone growth more difficult as compared to other tion and that on cartilage is enchondral (or endochondral) ossification.
organs. Large volumetric growth of bone is achieved by having an inter- (a) shows vertebrae of an embryo that are still cartilage. They will even-
mediate non-mineralized structure (or model) which can grow and then tually be replaced by bone (endochondral ossification). (b) shows the
later mineralize. This model can be of either fibrous tissue or cartilage – mandible forming from fibrous tissue (intramembranous ossification)

of formation and resorption is a common feature of most of long bones and flat bones form by endochondral and
metabolic bone diseases. Among the many effects of aging, intramembranous bone formation, respectively (Fig. 1.1a, b).
the rate of bone formation declines to a greater extent than Some bones, like the clavicle have both kinds of bone for-
the rate of resorption, resulting in progressive bone loss as mation. Both long and flat bones are organized with a hard,
bone remodels. but relatively thin, outer region composed of dense, com-
pact bone called the cortex or cortical bone. Inside the cor-
tex is the marrow cavity containing hematopoietic elements,
Bone Architecture fat, and spongy spicules of bone. The bone spicules are also
referred to as trabecular or cancellous bone (Fig. 1.2).
Bone is a composite tissue consisting of mineral, matrix,
cells, and water. The mineral is an analog of the natu-
rally occurring crystalline calcium phosphate, hydroxyap-
atite. The outer cortices of various bones are fashioned in the
Parts of a Long Bone
form of a hollow tube or a bilaminar plate. The architecture is
strengthened by internal “struts” of trabecular bone that are Epiphysis
oriented either along or perpendicular to the lines of stress.
This kind of design is known in engineering terms as “com- This term refers to the end of a tubular bone, located between
posite” and allows bone to take advantage of the strength of the physeal plate (in developing bone) and the articular carti-
components. Thus, bone resists mechanical compression and lage. In adults, the physeal plate is absent. The portion of the
can deform a great deal before failing. Indeed, it is this abil- bone that the epiphysis would have occupied in the growing
ity to deform that allows the skeleton to absorb the forces of skeleton is arbitrarily referred to by the same name (Fig. 1.3).
movement.

Physis or Epiphyseal Plate

Gross Morphology
The physis (growth plate) is the region of bone elongation in
There are four kinds of bones: long bones (femur, tibia, ulna, children. Injuries or other disruptions such as infections can
and radius), short bones (carpal and tarsal bones), flat bones seriously affect the subsequent size and shape of the bone.
(skull, sternum, and scapula), and irregular shaped bones Abnormally increased vascularity around the epiphysis in
(vertebra and ethmoid). These bones form through different certain inflammatory conditions, e.g., juvenile chronic arthri-
mechanisms during embryonic development. The majority tis and hemophilia, can cause elongation of the bone leading
1 Bone Structure and Function 3

Fig. 1.2 Adult long bone. Sagittal section through the proximal femur
showing the internal structure of the bone. The outer dense compact
bone (cortical bone) and the inner cancellous (trabecular or spongy)
bone are filled with spicules or trabeculae

to limb length discrepancies. Premature closure of the physis

may cause shortening and partial closure may cause an angu-
lar deformity of the bone. Fractures of the physeal plate
are classified using the Salter–Harris classification which is
based on the amount and kind of physeal disruption caused Fig. 1.3 Schematic of a tibia. The interior of a typical long bone show-
by the fracture. ing middle diaphysis, a growing proximal end (epiphysis) with a still
active epiphyseal growth plate, and a distal end with the epiphysis fused
to the metaphysic. The diaphysis (shaft) of a long bone contains a large
marrow cavity surrounded by thick-walled tube of compact bone. A
Metaphysis small amount of spongy bone lines the inner surface of the compact
bone. The proximal and distal ends, or epiphyses, of the long bone con-
sist of spongy bone with a thin outer shell of compact bone. The outer
This refers to the widened portion of bone occupying the area
surface of the bone is covered by a fibrous layer of connective tissue
between the cylindrical diaphysis and the physis/epiphysis. called the periosteum
This portion of long bones is rich in trabeculae that trans-
fer load from the articular plates into the bone’s cylindri-
cal cortex. Remodeling and modeling defects in this region with few trabeculae. The marrow space also contains reticu-
are frequent in conditions such as multiple hereditary osteo- loendothelial and hematopoietic elements and fat in varying
chondromatosis. Several tumors have an epicenter in the proportions that change with age.
metaphysis.

Bone Marrow
Diaphysis (Shaft)
The medullary cavity is filled with varying proportions of
This refers to the middle, cylindrical portion of a tubular hematopoietic marrow (red marrow) and fat (yellow mar-
bone. There is a thick cortex surrounding a marrow space row). Red marrow is most prevalent in younger age groups
4 F.F. Safadi and J.S. Khurana

and in the metaphyseal region of long bones. The diaphyses

mainly contain yellow marrow in adults. In comparison to the
appendicular (limb) skeleton, the axial skeleton has a greater
proportion of red marrow throughout life.

Periosteum

The periosteum is composed of an outer fibrous layer and an

inner cambium (cellular) layer. The cambium layer contains
osteoprogenitor cells and fibroblasts. When tendons insert
into bone, the collagen fibers (Sharpey’s fibers) pass through
the periosteum and then into the bone lamellae (see below).
Sharpey’s fibers contribute to the appositional growth of bone Fig. 1.4 Section from a fracture site. There is lamellar bone seen in
(see intramembranous bone formation). the bottom right of the picture from which streams of woven bone are
emanating toward the top left. Note the organized pattern of lamellae
seen in the compact, mature lamellar portion under polarized light and
contrast with the woven bone
Endosteum
Secondary organization is a hallmark of lamellar bone.
The endosteum is composed of a resting layer of marrow at In the cortex, the lamellae are arranged in circumferential
its interface with bone. This is not a morphologically rec- as well as tubular arrangements. The tubular arrangement is
ognizable layer of tissue at the light or electron microscopic called an osteon. Under the microscope, these tubes can look
level. It is, however, a convenient concept that explains the like circles or parallel sheets depending on how they are cut
functional changes seen in physiologic and pathologic alter- to make histologic sections. The central part of the tube is the
ations in bone at the bone medullary cavity interface. Haversian canal, which contains blood and lymphatic vessels
and nerves. Bone cells called osteocytes are located between
lamellae (see below). The osteons play an important role in
Microscopic Features of Bone the mechanical properties of cortical bone, since the long axis
of an osteon is parallel to the long axis of a long bone. Each
Microscopically too, bone tissue can be either compact (cor- osteon acts as a fiber that resists failure (fracture) with defor-
tical) or spongy (trabecular or cancellous) and can be classi- mation (stretch). The surrounding lamellae (circumferential)
fied based on collagen fibers arrangements into two different bone resists compressive forces.
types: woven bone and lamellar bone.

Blood Supply of Bone

Woven (streamer/immature) bone. This form of bone con-
sists of randomly oriented collagen fibers alongside
which reside large numbers of osteoblasts (osteoprogen- Bone has a rich vascular supply. It receives 10–20% of the
itor cells). Under polarized light woven bone can be cardiac output. Blood supply varies with different types of
recognized as having a haphazard structure. It contains rel- bones. Blood vessels are especially rich in areas contain-
atively more cells per unit area than mature bone. It occurs ing red bone marrow. The diaphyseal nutrient artery is the
in regions of rapid growth, such as in the immature skele- most important supply of arterial blood to a long bone. This
ton (especially in the embryo), fracture callus, fibrous dys- divides into ascending and descending branches that sup-
plasia, osteosarcoma, and several other tumors. ply the inner two-thirds of the cortex and medullary cav-
ity. Numerous metaphyseal and epiphyseal arteries that arise
Lamellar bone. Lamellar bone is the mature form of adult mainly from arteries that supply adjacent joints supply the
bone. It is readily identified on polarized light microscopy ends of bones. These arteries anastomose with the diaphy-
by parallel lines of mineralized bone (Fig. 1.4). Studies seal capillaries and terminate in bone marrow, cortical bone,
have shown that lamellar bone has well-organized colla- trabecular bone, and articular cartilage. In growing bones, the
gen fibers. Lamellar bone forms when the rate of depo- epiphyseal arteries are separated from the diaphyseal arteries
sition is slow and generally it forms only on pre-existing by the physeal cartilaginous plate. Finally, periosteal arteri-
bone. oles are vessels that supply the outer layer of cortical bone.
1 Bone Structure and Function 5

Blood is drained from bone through veins that accompany

the arteries and frequently leave through foramina near the
articular ends of the bones. Lymph vessels are abundant in
the periosteum.

Nerve Supply of Bones

Periosteal nerves are sensory nerves, some of which are

pain fibers. Therefore, the periosteum is especially sensitive
to tearing or tension. Accompanying the arteries inside the
Haversian canals are vasomotor nerves that control vascular
constriction and dilation. Bone is also innervated by sym-
pathetic fibers. There is a possibility that a neurotransmitter
(such as dopamine and serotonin) may play a role in bone
metabolism [1]. There is also a possibility that cannabanoids Fig. 1.5 The picture shows a trabeculum of bone centrally with two
may play a role in bone integrity, since mutations of a canna- smaller interconnecting trabeculae above and below it on the right hand
side. The left-hand side of the picture shows fibrous tissue. On the left
banoid receptor produces osteopenia in experimental animals of the main trabeculum are three activated osteoclasts. Note the eroded
[2, 3]. bone adjacent to them. This erosive pit is called a Howship lacuna. On
the right-hand side of the trabeculum are a few active osteoblasts rim-
ming the bone. Within the trabeculum are tiny clear spaces containing
osteocytes
Bone Cells
for the production of collagen type I and glycosoaminogly-
The cells important in bone biology are osteoprogenitor can that comprise the osteoid, the non-mineralized organic
cells, osteoblasts, osteocytes, and osteoclasts. Osteoblasts matrix of bone. Osteoblasts and osteocytes are the principal
and osteocytes are thought to be derived from primitive mes- cells involved in mineralization of bone. They are thought
enchymal cells (the osteoprogenitor cells). Osteoclasts are to aid mineral deposition by increasing the local concen-
thought to owe their lineage to cells of the hematopoietic tration of calcium and phosphate in a complicated process
bone marrow related to macrophages/monocytes. using “matrix vesicles” [4, 5]. Both alkaline phosphatase and
parathyroid hormone (PTH) receptor have been discovered
on these cells. The phenotype and morphology of osteoblasts
Osteoprogenitor Cells
depend on their stage of development and differentiation.
Osteoblasts secrete the receptor activator of nuclear fac-
These are undifferentiated mesenchymal cells and have the tor kappa B (RANK) ligand. This ligand plays an impor-
properties of stem cells, that is, the potential for proliferation tant role in the differentiation of osteoclasts (see below).
and a capacity to differentiate. These cells can differentiate Osteoblasts also secrete variety of collagenous and non-
into osteoblasts, chondroblasts, bone marrow stromal cells, collagenous proteins such as osteocalcin, osteopontin, bone
or fibroblasts depending on the nature of the stimulus, and sialoprotein, and osteonectin, as well as a variety of cytokines
perhaps the local microenvironment. They are present in the and colony-stimulating factors (CSF), such as interleukin-6,
inner layer of the periosteum and the endosteum lining mar- interleukin-11, granulocyte-macrophage colony-stimulating
row cavities, osteonal (Haversian) canals, and the perforating factor (GM-CSF), and macrophage colony-stimulating fac-
(Volkmann’s) canals. Osteoprogenitor cells persist through- tor, and thus have a role in myelopoesis. Other sub-
out postnatal life as bone-lining cells; they are reactivated in stances secreted by osteoblasts include transforming growth
adults during the repair of bone fractures and other injuries. factor-beta (TGF-β), bone morphogenetic proteins (BMPs),
platelet-derived growth factors (PDGFs), insulin-like growth
factors (IGFs).
Osteoblasts Constant mechanical stress is essential for the mainte-
nance of bone mass and strength. Osteoblasts increase their
Osteoblasts are derived from the osteoprogenitor cells. activity in response to mechanical stimuli and so mediate
Osteoblasts have a cuboidal or columnar shape and vary in changes in bone size and shape. Perhaps this osteoblastic
size from barely detectable by light microscopy to up to response is modulated by the piezoelectric properties of the
50 μm when activated (Fig. 1.5). Osteoblasts are responsible calcium hydroxyapatite crystal.
6 F.F. Safadi and J.S. Khurana

Molecular Regulation of Osteoblast Differentiation: is close to the bone, there is a ring-like perimeter called
Osteoblast differentiation is regulated by many secreted clear zone or sealing zone. This zone contains abundant
growth factors, including transforming growth factor-beta microfilaments (actin filaments) but lacks other organelles.
(TGF-β), bone morphogenetic proteins (BMPs), and The formation of the sealing zone is a participation of actin
fibroblast growth factors (FGFs) [6, 7]. Furthermore, tran- filaments together with αv β3 integrin. Into the space bounded
scription factors play fundamental roles in osteoblast differ- by the ruffled border and bone, resorptive substances can be
entiation. Runx-2 (runt-related transcription factor 2)/cbfa-1 secreted [13, 14].
(core-binding factor a1) and osterix are essential transcrip-
tion factors for osteoblast differentiation [8, 9]. Also involved
with osteoblast regulation is leptin, a peptide synthesized Mechanism of Osteoclast-Mediated Bone Resorption
by adipocytes with binding affinity to its receptor in the
hypothalamus. This protein regulates bone formation by a Bone resorption involves protons (hydrogen ions) secreted
central mechanism [10]. by an ATP-driven proton pump in the ruffled border of osteo-
clasts. The enzyme carbonic anhydrase II is essential in the
generation of hydrogen ions. Simultaneously, acid hydro-
Osteocytes lases are released from lysosomes. This combination of the
acid created by the hydrogen ions and proteolytic enzymes
provides optimal conditions for the resorption of bone and
Osteocytes are cells within the substance of bone and are
degradation of collagen. Osteoclasts can move over the bone
derived from osteoblasts (Fig. 1.5). They are said to be
surface creating many such resorptive pits. These pits are
involved in cell signaling and maintaining the viability of the
well visualized by scanning electron microscopy and corre-
bone matrix. It is possible that these cells are important in
spond to the Howship’s lacunae in routine sections.
the translation of mechanical loads to cellular events such as
Osteoclasts have calcitonin (but not PTH or vitamin D)
bone formation.
receptors. They are stimulated by IL-6 (perhaps in combina-
tion with IL-1, IL-3, and IL-11) and RANK ligand. These
Osteoclasts cytokines are produced locally by cells of the osteoblast lin-
eage under the influence of PTH, vitamin D3 , TGF-β, IL-1,
and TNF. [11, 15–17]. The regulation of osteoclast differen-
These are multinucleated cells with 2–100 nuclei per tiation is a subject of intense ongoing study with implica-
cell. Most osteoclasts are closely related to the mono- tions for the treatment of a variety of diseases ranging from
cyte/macrophage hematopoietic progenitor cells. Their gene- osteoporosis to skeletal dysplasias such as osteopetrosis. It
sis requires the presence of osteoprogenitor cells along with a involves numerous cytokines including macrophages colony-
variety of hematopoietic cytokines, such as interleukins 1, 3, stimulating factor (M-CSF), RANK ligand (present on
6, and 11, tumor necrosis factor (TNF), M-CSF, and stem cell osteoblasts), RANK receptor (present on osteoclast precur-
factor. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin sors), and osteoprotegerin (OPG), a decoy protein [18–26].
D3 , transforming growth factor-alpha (TGF-α), and epider-
mal growth factor (EGF) act permissively in their formation,
whereas calcitonin inhibits the formation of osteoclasts [11].
Bone Matrix
Osteoclasts Are the Primary Bone Resorbing Cells
Bone matrix, consists of an organic and an inorganic or
Osteoclasts are mostly found at sites where resorption is tak- mineral component. Forty percentage of the dry weight is
ing place, within “eaten out” cavities in the surface of bone composed of the organic component, called osteoid. This
known as Howship’s lacunae (Fig. 1.5). The cells can also includes collagen, proteoglycans, glycoproteins, phospho-
tunnel through cortical bone creating channels. Osteoclasts lipids, and non-collagenous proteins (see Table 1.1). The
are polarized (the nuclei congregate away from the resorb- inorganic component makes up the remaining 60% of the
ing bone surface), and the cytoplasm of the cell between dry weight of bone and is composed primarily of calcium
the nuclei and the ruffled border is rich in carbonic anhy- hydroxyapatite Ca10 (PO4 )6 (OH)2 . At an ultrastructural level,
drase and in tartrate-resistant alkaline phosphatase (TRAP) bone is once again organized to maximally resist mechan-
[12]. By electron microscopy, there is an abundance of mito- ical forces. Calcium hydroxyapatite crystals are arranged
chondria, lysozomes, and free ribosomes in the cytoplasm. parallel to collagen fibers [27]. The orientation maximizes
Activated osteoclasts show an infolding of the plasma mem- the collagen’s resistance to tensile (stretch) forces and the
brane (ruffled border). At the point where the cell membrane calcium hydroxyapatite’s resistance to compressive forces.
1 Bone Structure and Function 7

Table 1.1 Components of bone matrix Urinary excretion of hydroxyproline (found exclusively in
Bone proteins collagen) and other products of collagen degradation (cross-
Collagens linked products such as pyridinoline and deoxypyridinoline)
Type I collagen – woven and lamellar bone act as markers for collagen breakdown. These measurements
Type II collagen – cartilage
reflect the amounts of bone turnover.
Type III collagen found in certain pathologic conditions
Non-collagenous proteins (synthesized mainly from osteoblasts)
Calcium binding – osteonectin, bone sialoprotein
Enzymes
Adhesion proteins – osteopontin, fibronectin, thrombospondin
Mineralization proteins – osteocalcin
Enzymes – collagenase, alkaline phosphatase, metalloproteinases Alkaline Phosphatase
Cytokines – PG, IL-1, and 6
Growth factors – IGF-1, TGF-β, PDGF Although not generally thought of as a matrix component,
The hydrated (muco)polysaccharide gels
alkaline phosphatase is an osteoblast product (such as osteo-
calcin and osteonectin). There are three related isozymes
that are tissue related and are associated with three sepa-
Diseases which result in abnormal collagen disrupt the rate genes. These are the placental, intestinal, and tissue-
normal mechanical function of bone. Osteogenesis imper- nonspecific forms. The last is seen in high levels in a vari-
fecta, which is caused by abnormal collagen, results in an ety of tissues such as bone, liver, kidney and skin. The
abnormal collagen–calcium hydroxyapatite structure and a role on alkaline phosphatase in biomineralization is still
weak bone matrix. speculative. It has been found in matrix vesicles, but its
exact role is unclear. Serum alkaline phosphatase activity is
increased in growing children, pregnancy, healing fractures,
Paget disease, rickets, osteomalacia, hyperparathyroidism,
Classification of Collagens bone-forming tumors, and certain skeletal metastases. It is
reduced in hypophosphatasia.
Connective tissues contain varying amounts of collagen,
elastin (a related fibrous protein), glycosaminoglycans, and The Hydrated (Muco)Polysaccharide Gels
proteoglycans. Of these, collagen is the most abundant.
Several different types of fibrillar, basement membrane, The functional units of bone extracellular matrix “gels” are
and short chain collagens are recognized. These are the types the glycosaminoglycans (GAGs). Of the several GAGs, four
I–XIII collagens. Each of these differs from each other in main groups are present. Hyaluronic acid, chondroitin and
their biochemical structure. Of the fibrillar collagens, type dermatan sulfates, heparan sulfate and heparin, and keratan
I collagen is found in bone, skin, meniscus, tendon, liga- sulfate. The majority are aggregated to a protein core to form
ment, annulus fibrosis, and joint capsules. About 90% of a proteoglycan. Prior to release from the synthesizing cell,
bone matrix is composed of type I collagen. Bone is also GAGs (except hyaluronic acid) are sulfated. This step allows
the primary organ in which type I collagen is located. There a net negative charge on these molecules. In turn, this charge
are several subtypes of type I collagens. Hydroxylation and serves two functions. First, it keeps the molecules extended,
glycosylation are post-translational modifications of collagen increasing the volume to weight ratio. Second, by attract-
and are specific to bone. These differences or modifications ing osmotically charged cations, it attracts water. This mech-
explain why mineralization only occurs in bone and not in anism creates a gel with very high swelling pressures and
other sites [28]. Type II collagen is located mainly in hyaline tremendous resistance to compression.
cartilage, the vitreous humor of the eye, and the nucleus pul- Highly viscous hyaluronic acid is a major constituent of
posus of the intervertebral disk. The other fibrillar collagens synovial fluid, where it helps in lubrication and reduces fric-
are the “minor” collagens, type III occurs in association with tion. Additionally, it may impede bacteria by its physical
type I and also in tissue undergoing repair. Types V and XI and chemical properties. Its synthesis is thought to be by a
occur in association with types I and II, respectively. Type pathway located in the cell membrane. The remainder of the
IV collagen is the prototype and major component of the GAGs mentioned are biosynthesized within Golgi apparatus
basement membrane. Type VII forms the anchoring filament within the cell cytoplasm.
in epithelial basement membranes, while type VIII is local-
ized to endothelial basement membranes. The least under-
stood class of collagens is the short chain collagens and are Mineralization
comprised of the types VI, IX, and X. Short chain collagens
may function in association with other collagens and have a Calcium hydroxyapatite is the main form of mineral in the
role in cartilage physiology. human. Calcification in the body occurs in several different
8 F.F. Safadi and J.S. Khurana

situations. First, there is the physiologic process of carti- minum intoxication, fluoride intoxication (osteofluorosis),
lage and osteoid mineralization. Second, there is the patho- and phosphate deficiency. The mechanisms of action of alu-
logic extracellular or intracellular “dystrophic” calcification, minum and fluoride are as yet unclear. Mineralization is thus
which occurs in association with inflammation and tissue more than just a straightforward physicochemical process.
damage. Third, there is a “metastatic” calcification, which
occurs in association with altered serum levels of calcium
and phosphate, and finally, calcium can be deposited as a Mineral Deposits
component of crystal forming molecules within the joints in
certain disease states. Pathologic mineralization can be of several different types
Most cases of calcium deposition within the soft tissues (dystrophic, metastatic, or crystal deposition). Calcifica-
are caused by local inflammation, trauma, fat necro- tion deposited in metastatic calcification (associated with
sis, scleroderma, hyperparathryroidism, familial hyperphos- increased serum calcium) is often intracellular. There are sev-
phatemia, sarcoidosis, myeloma, metastases, etc. These eral factors that are important in mineralization (Table 1.2).
encompass both dystrophic and metastatic calcifications and
are typically calcium hydroxyapatite.
Punctate or linear calcification seen radiographically, seen
Remodeling of Bone
along menisci, articular cartilage, or intervertebral disks, is
generally due to calcium pyrophosphate deposition (CPPD
disease). This deposition can very rarely be massive and sim- Bone undergoes “remodeling” throughout life. This involves
ulate tophaceous deposits. In such cases the term tophaceous the coupling of “old bone” resorption and “new” bone for-
pseudogout may be appropriate [29]. mation. Thus all skeletal bone is “renewed” on a continuous
Calcification of osteoid (bone mineralization) differs from basis. This mechanism is important, because of the cyclical
soft tissue calcification in being an orderly process. It is dis- loading and torsional stresses that the skeleton undergoes. In
tributed within the hole zones of collagen molecules. This the absence of renewal, the skeletal bone would fatigue from
method does not disrupt the spatial organization of collagen. repetitive loads within a short period of time.
The process is tightly regulated, but poorly understood. The Bone turnover or remodeling is thought to occur in
mineral is initially deposited as amorphous calcium phos- discrete foci or packets scattered throughout the skeleton.
phate. The initial solid phase is formed at neutral pH. This Each packet takes 3–4 months to complete. Such foci have
phase is randomly and poorly oriented. Subsequently a series been termed bone remodeling units or BRUs by Frost, who
of solid phase transformations occur that lead to poorly crys- described the process in 1964.
talline hydroxyapatite as the final stable solid phase. The About 25% of the metabolically active trabecular and
initiation of mineralization is probably caused by heteroge- about 3% of the cortical bone completely renews itself each
neous nucleation, the active binding of calcium, phosphate, year [15, 30]. The amount of bone added in each remodel-
and calcium phosphate complexes at the nucleation site in the ing cycle, however, reduces slightly with age. This is prob-
matrix rather than by simple precipitation. In mature bone, ably due to a decreased number of osteoblasts and has been
it is possible that poorly crystalline calcium carbonate con- suggested as a possible mechanism for age related (but not
taining hydroxyapatite is deposited rather than an amorphous post-menopausal) osteoporosis.
calcium phosphate or hydroxyapatite. In the adult remodeling takes place by three mechanisms:

• Apposition and resorption at the endosteal surface

The Process of Mineralization • Apposition and resorption at the periosteal surface
• Activation, resorption, and formation at the Haversian
The process of mineralization is complicated and has not system
been satisfactorily elucidated. It is probably under genetic
control, and since the physiologic state of extracellular flu- As can be visualized, the first two processes would result
ids is supersaturated with respect to octacalcium phosphate, in alterations in the thickness and width of tubular bones.
there are probably crystal inhibitors present. These include Conditions such as acromegaly (increased apposition),
substances such as pyrophosphate and serum proteins. osteopetrosis, and hypothyroidism (decreased resorption) as
Matrix vesicles within bone and cartilage cells are thought well as hyperthyroidism (increased resorption) are particu-
to be helpful in this process. larly prone to alter the bones by these mechanisms.
It must be emphasized that mineralization is also under Bone formation during the remodeling process requires
hormonal control. Vitamin D plays an important role. Other prior resorption. Resorption takes approximately 10–15
exogenous factors that affect mineralization include alu- days. The resorption is carried out by a “cutting cone”
1 Bone Structure and Function 9

Table 1.2 Factors important in mineralization basophilic line – the “cement” or the “reversal” line. This
Collagen Collagen provides oriented support for the newly area is poor in collagen and mineral and has a high content
formed crystals. The post-translational of sulfur.
changes in collagen type I make it possible for
Bone formation is carried out by osteoblasts. The pro-
diffusion of large hydrated ions such as
calcium phosphate into the fibril cess takes approximately 3 months. Osteocytes in small areas
Calcium- Phosphoproteins and sialoproteins in the bone of bone that get cut off by newly forming osteons remain
binding matrix may bind calcium to promote crystal as “interstitial” lamellae. Osteoblastogenesis has identifiable
proteins deposition and growth, thus acting as processes of chemotaxis, proliferation, and differentiation of
nucleators. Crystal growth could then depend
on the conformational change in these proteins osteoblasts. This is then followed by mineralization and the
after deposition. The initiation of cessation of osteoblast activity.
mineralization is coincident with the Mediators of osteoblastic activity and bone formation
depolymerization of proteoglycan molecules. include transforming growth factor-beta (TGF-β), bone GLA
Proteoglycans may inhibit calcification by a
number of mechanisms including shielding of
protein fragments, platelet-derived growth factors A and B
collagen, chemical interaction with collagen (PDGF A and B) all of which are chemotactic for osteoblasts.
side chains, sequestering calcium or phosphate Proliferation of osteoblasts is thought to be mediated by
ions or occupying critical space in the TGF-β, PDGF, IGF I and II, and fibroblast growth factors
molecule. Different phosphoproteins have
varying importance in mineralization
(FGFs). Cytokines that may play a role in the differentia-
Pyrophosphate This is a naturally occurring inhibitor of tion of osteoblasts and the production of alkaline phosphatase
calcification. It has a short half-life due to its activity within these cells include IGF-I and bone morpho-
rapid degradation by pyrophosphatases. genetic protein-2 (BMP-2).
Pyrophosphates are present in body fluids and
“Coupling” or bone formation and bone resorption is
increase the stability of the solution phase of
calcium phosphate. Diphosphonates are unexplained. There is emerging evidence that suggests that
pyrophosphate analogs and are powerful “osteoclastogenic” cytokines such as IL-6, IL-1, and IL-11
inhibitors of calcification in large doses as well as “osteoblastogenic” cytokines such as leukemia
Bone Gla Osteocalcin is a highly conserved protein which inhibitory factor may be stimulated together by the same sig-
proteins is abundant in bone matrix. Because of its Gla
residues, it is able to bind calcium, but its role nal transduction pathway. Glycoprotein 130 is a molecule
in mineralization is controversial present in this pathway and is involved in the transduc-
Lipids and Within bone there are acid phospholipids that tion of the signal delivered by each of these cytokines. Sex
proteolipids form complexes with calcium phosphate and steroids inhibit, whereas parathyroid hormone and vitamin
could, thereby, influence mineralization. These
D3 increase glycoprotein 130 in experimental models [15,
substances have the capacity to bind to
calcium 30]. This model, if validated further, would conveniently
Alkaline This is an ectoenzyme produced by osteoblasts explain bone formation–resorption coupling as well as coin-
phosphatase and is likely to be involved with the cide with the various acknowledged facts about the role of
mineralization process. Patients with these hormones in bone turnover.
decreased amounts of enzyme
(hypophosphatasia) have impaired Another mechanism that may explain “coupling,” is the
mineralization (see osteomalacic syndromes in release of osteoblast-stimulating factors such as IGF I and
metabolic bone disease). Alkaline phosphatase II and TGF-β during the osteoclastic process. Coupling is
may be involved in the degradation of the rationale for the counterintuitive, but clinically vali-
inorganic pyrophosphate, thus providing a
sufficient level of organic phosphate for dated method of treating osteoporosis by giving parathyroid
mineralization to proceed hormone.
Several diseases of bone are superimposed on this nor-
mal cellular remodeling sequence. In diseases, such as
of osteoclasts. The trigger for resorption includes the primary hyperparathyroidism, hyperthyroidism, and Paget
stimulatory cytokines IL-1 and IL-6 produced by osteoblasts, disease, there is osteoclast activation. There is also a com-
as well as perhaps, the integrin–RGD sequence interaction pensatory and relatively balanced increase in bone formation,
as well as multiple factors such as transcription factors and because of coupling.
membrane proteins. Other conditions are due to abnormal coupling. Decreased
The osseous defect created by osteoclastic resorption is bone formation after resorption is seen in the osteolytic
filled in by fibrovascular tissue. The fibrovascular core con- lesions of myeloma, where there may be a defect in
tains pericytes, loose connective tissue, macrophages, mes- osteoblast maturation. In solid tumors and in elderly patients
enchymal stem cells, and undifferentiated osteoprogenitor with age-related osteoporosis there may be similar mecha-
cells. The outer edge of the osteon (where resorption ends nisms at work. Osteoblastic activity in the absence of prior
and bone formation first starts) is marked by an intensely osteoclastic activation is thought to occur in some special
10 F.F. Safadi and J.S. Khurana

situations such as osteoblastic metastases, e.g., prostate example, IL-1, IL-6, and E-series prostaglandins. The net
carcinoma metastases, and in bones’ response to fluoride result of exposure to PTH is osteoclast activation and the ini-
therapy. tiation of bone resorption leading to calcium release from
bone.
Additionally, there is evidence to suggest, that in certain
The Regulation of Bone and Cartilage situations PTH stimulates bone formation. When adminis-
tered continuously, it increases osteoclastic resorption and
Endocrine suppresses bone formation. When administered in low doses,
intermittently, it stimulates bone formation without resorp-
• Parathyroid hormone (PTH) and PTHrP tion. This bone-forming effect of PTH has been termed the
• Calcitonin anabolic effect. This anabolic effect too (like the resorptive
• Vitamin D effect) is probably indirect and mediated via substances such
• Vitamin A as IGF-1, TGF-β. Although the anabolic effect of PTH is
• Estrogens dependent on intermittent administration, when serum level
• Androgens of PTH is maintained high even for a few hours it initiates
• Growth hormone (GH) processes leading to new osteoclast formation, and the con-
sequent bone resorption that overrides the effects of acti-
vating genes that direct bone formation. Identification of
Paracrine/Autocrine
PTH-related protein (PTHrP) expression by cells early in the
osteoblast progenitor cells, and its action through the PTH-
• Proteoglycans
1 receptor (PTH1R) upon mature osteoblastic cells, together
• Glyco- and phosphoproteins
with the observation that PTHrP+/– mice are osteoporotic,
• Gamma-carboxyglutamic acid proteins
raise the possibility that PTHrP is a crucial paracrine regula-
• Proteolipids
tor of bone formation.
• Growth factors
• Transforming growth factor-beta (TGF-β)
• Bone morphogenetic protein (BMP) Calcitonin
• Insulin-like growth factors (IGF I and II)
• Epithelial growth factor Calcitonin is a peptide hormone produced by the thyroid
• Fibroblast growth factor parafollicular C cells. Its synthesis and secretion is under the
• Platelet-derived growth factor (PDGF A and B) influence of extracellular calcium levels and certain gastroin-
testinal hormones such as gastrin. It is encoded by a complex
• Other cytokines (interleukins IL)
gene that undergoes alternate splicing. This gene is respon-
sible for several other peptides such as a calcitonin gene-
Parathyroid Hormone related peptide.
Calcitonin causes a short lived fall in plasma calcium.
Parathyroid hormone (PTH) is an 84-amino acid, single- It acts via a receptor to stop the resorption of bone. These
chain polypeptide (called PTH 1-84). It is synthesized in the receptors are present on osteoclasts, preosteoclasts, mono-
parathyroid gland from a biosynthetic precursor pro-PTH. cytes, and certain tumor cells. The major effect on block-
PTH acts on bone, intestine, and kidney. In the latter two, ing of bone resorption, however, is probably via the mature
it enhances calcium resorption. It is also involved in the osteoclast. The mechanism of action is via enhancement of
metabolism of phosphate, bicarbonate, ammonium, magne- adenylate cyclase and stimulating cAMP accumulation. In
sium and in the regulation of acid–base homeostasis in the addition, calcitonin may have mitogenic effect on bone cells.
body. The actions of PTH are influenced by several factors Calcitonin also promotes renal calcium excretion. Its effects
such as 1,25-dihydroxyvitamin D3 , IL-1, TGF-α, EGF. The on calcium homeostasis are lost after 24–48 h. This loss of
production of several of these substances is in turn under the effectiveness can be reduced by simultaneous administra-
control of PTH in a complicated interrelated web. tion of corticosteroids. A possible role of calcitonin in cal-
The best known effect of PTH is osteoclast activation and cium homeostasis is to maintain normocalcemia after a large
subsequent bone resorption. Receptors for PTH are found calcium-containing meal.
on pre-osteoblasts, osteoblasts, and chondrocytes. They are The absence of significant changes in bone mineral den-
not, however, present on osteoclasts. This supports the sity caused by decline or overproduction of calcitonin in
notion, that the action of PTH on the latter is dependent humans has raised the question, whether the pharmacolog-
on the osteoblasts for the production of other cytokines, for ical action of calcitonin as an inhibitor of bone resorption is
1 Bone Structure and Function 11

also of physiological relevance. New data suggest that calci- effect. Several years ago, it was discovered that an imbal-
tonin has a dual action as an inhibitor of bone remodeling, ance of vitamin A during embryonic development has dra-
which may explain, at least in part, why alterations of calci- matic teratogenic effects. These effects have since been
tonin serum levels in humans do not result in major changes attributed to vitamin A’s most active metabolite, retinoic acid
of bone mineral density [31]. (RA), which itself profoundly influences the development
Calcitonin has a role in the therapy of hypercalcemia of of multiple organs including the skeleton. Retinoid signal-
malignancy, in Paget disease, and in osteoporosis. In this ing involves several components, including the skeletogenic
context, it should be mentioned that there is evidence to sug- master regulatory factors, Sox9, and Cbfa1.
gest that the osteoclasts of Paget patients are hyperresponsive
to calcitonin, and remain so for longer periods of time than
Estrogens
do control cells. The molecular mechanisms for this hyperre-
sponsivity is unknown [32].
In experimental situations, reduced estrogen leads to bone
loss. This may be a direct effect on osteoblasts and possi-
Vitamin D bly osteoclasts, although it could be mediated via PTH and
calcitonin.
Ergosterol and 7-dehydrocholesterol are the precursors for
this hormone/vitamin. These compounds are stored in the
Androgens
skin, transported in the body via an alpha-globulin-binding
protein or vitamin D-binding protein (DBP) and become acti-
These act to maintain bone mass through action via receptors
vated by ultraviolet light with a wavelength of 315 nm. This
on osteoblasts. There is an inhibition of the action of PTH
activation generates calciferol and cholecalciferol, respec-
and calcitonin.
tively. These substances are hydroxylated in the liver in the
presence of magnesium to yield 25-hydroxyvitamin D and
then converted further in the proximal tubule of the kid- Growth Hormone
ney to its active form: 1,25-dihydroxyvitamin D. This hor-
mone/vitamin is one of the prime controllers of calcium The effect of growth hormone on bone is mostly mediated
metabolism in the gut, proximal tubule, and bone. Reduced via insulin-like growth hormone (IGF). There may, how-
calcium and increased PTH are the kidneys to increase 1,25- ever, be a direct effect through growth hormone receptors on
dihydroxyvitamin D production. osteoblasts and chondrocytes.
The actions of 1,25-dihydroxyvitamin D include stim-
ulation of calcium-binding proteins, increased osteocal- Proteolipids
cin production, increased osteoclastic activation and bone
resorption, monocytic maturation, myelocytic differentia- These are membrane proteins complexed with acidic phos-
tion, skin growth, and insulin secretion. Lack of vitamin D pholipids. They cause hydroxyapatite deposition. They have
results in impaired mineralization of newly formed bone – a high concentration in the matrix vesicles, where they are
the clinical disease resulting from this is known as rick- thought to have a role in the export of protons and the import
ets in children, and osteomalacia in adults. In both of these of calcium and phosphate across the cell membrane.
conditions, osteoid, the proteinaceous bone matrix, accumu-
lates, but does not mineralize. Excessive vitamin D leads to
increases in bone resorption and hypercalcemia. Growth Factors
Vitamin D works through specific vitamin D receptors.
Receptor sites for 1,25-dihydroxyvitamin D have been iden- Transforming Growth Factor-Beta: TGF-β
tified on several cells. Gene errors in several forms of rick-
ets have been found to occur within these nuclear receptors. TGF-β was initially isolated from “transformed” neoplastic
There is also a suggestion that post-menopausal osteoporo- cells in tissue culture studies. Two “factors” were isolated
sis may be genetically predetermined by the polymorphisms and named TGF-α and -β. TGF-α is not found in bone and is
present in the vitamin D receptor gene [33]. now called epidermal growth factor. There are three human
isoforms of TGF-β. The largest store of TGF-β in the body
is the bone matrix. The current hypothesis is that TGF-β
Vitamin A induces bone formation during remodeling. The action of
TGF-β in bone induction, however, may be only in conjunc-
Retinoids, in excess, decrease the formation of bone and car- tion with other factors such as the bone morphogenetic pro-
tilage matrix. A deficiency of vitamin A has the opposite teins (BMPs).
12 F.F. Safadi and J.S. Khurana

Bone Morphogenetic Proteins (BMP) Mechanosensory Systems and Stretch Studies

(Wolff Law)
A bone-inducing substance was first postulated in 1952 by
Marshall Urist et al. [34]. Since then, at least 10 proteins
with this property have been extracted from demineralized Wolff law – Every change in form and function of bones is
bone and named bone morphogenetic proteins 1–10. Their followed by changes in the internal architecture and external
amino acid sequences have been characterized and synthe- conformation, in strict accordance with mathematical laws
sized using recombinant DNA technology [35–40]. Purified (Julius Wolff, 1882).
BMPs have been used to promote bone repair. Several trials Wolff law has been confirmed by experimental stud-
have shown their efficacy in experimental models [41–43]. ies, but only recently there have been studies to investi-
gate the basis of the law at a molecular level. It is clear
that mechanical forces have definite effects on the skeleton.
Insulin-Like Growth Factors: IGF (I and II) For example, individuals who lift weights tend not only to
develop bigger and stronger muscles but also bones. On the
Insulin-like growth factors are produced by many kinds of other hand, weightlessness associated with decreased grav-
cells including osteoblasts and chondrocytes. They act via ity causes rapid decrease in bone mass reflecting the need
receptors to promote proliferation, differentiation, and matrix for constant force in maintaining skeletal bone. Further, an
production of bone and cartilage. The action of growth hor- inability to use a limb causes it to undergo “disuse” osteo-
mone is closely linked with the IGFs. porosis. Children with malunited limb fractures frequently
remodel into almost normal bones. If, on the other hand, they
are unable to bear weight, or use the limb owing to a disease
Other Growth Factors such as poliomyelitis, then the fractures stay malunited. Para-
plegics or quadriplegics with a spastic form of paresis have
These include epithelial growth factor, acid and basic fibrob- exuberant callus; if, however, they have a flaccid paresis they
last growth factors, and platelet-derived growth factors (A fail to develop such an exaggerated response.
and B). They are thought to be particularly important in These examples illustrate the close linkage of mechanical
bone remodeling. PDGFs are heterodimers of A and B chains forces with skeletal response and bone formation. What is
and function via specific receptors. Mutations in the fibrob- poorly understood, however, is how forces get translated into
last growth factors have been thought to play a role in cer- cellular events. It is likely that signaling mechanisms such as
tain kinds of skeletal deformities, including achondroplasia, electrical or chemical messengers, such as certain cytokines,
Apert syndrome, Cruzon syndrome, Pfeiffer syndrome, and mediate these responses. Investigations into the mechanisms
Jackson–Weiss syndrome. have suggested the presence of stretch-sensitive ion chan-
nels and stretch-dependent DNA synthesis in certain cells.
Cytokines: Prostaglandins and Interleukins In addition, when fluid flows through bone matrix carrying
along a species of ion, it creates a stream-generated poten-
Prostaglandins: Prostaglandins have been shown to have tial. Currents are also generated by a “piezoelectric” effect as
multiple effects on bone cells and sometimes contradictory a result of compression of the hydroxyapatite crystal. These
effects in different species. They are powerful bone resor- are various methods by which Wolff law might operate to
bers in certain culture studies (especially true of the E series). control osseous homeostasis.
Prostaglandins are produced by monocytes under appropriate
stimuli. It is possible that some of the effects of interleukins
are mediated by prostaglandins.
IL-6: This is produced by osteoblasts and bone mar-
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Chapter 2

Systematic Approach to Metabolic Diseases of Bone

Akbar Bonakdarpour

Abstract This chapter begins with a brief introduction to diseases can be considered metabolic in nature. Narrower
bone metabolism. The main focus is discussing generalized definitions of the so-called “metabolic diseases of bone” are
diminished bone density (GDBD), but examples of general- almost as numerous as the number of authors who write
ized increased bone density are also briefly presented. Since about them. Endocrine dysfunctions, Paget disease, various
various causes of GDBD are not considered in the WHO nutritional problems, some hereditary diseases of bone, and
definitions, a radiologic classification based on pathophysi- even other categories of disorders have been included under
ology of GDBD will follow, complementing the WHO def- this heading. In this chapter we will limit discussion to dis-
initions and distinguishing osteoporosis from osteomalacia, eases that cause generalized reduction in bone mineral and
osteolysis, and marrow proliferative disorders. The primary regional osteoporosis.
and secondary osteoporoses are discussed. Diagnostic imag- Metabolic causes of increased bone density such as hyper-
ing of osteoporosis by radiography, dual X-ray absorptiom- vitaminosis D and fluorosis will be very briefly mentioned as
etry (DXA), quantitative CT analysis, microcomputerized prototypes.
tomography, quantitative ultrasonography, and MRI is briefly An attempt will be made to correlate the 1994 World
reported. The major risk of advanced osteoporosis is fracture Health Organization (WHO) definitions of osteoporosis
of the spine, hip, and less frequently other bones. A summa- with radiopathophysiological classification of “generalized
rized treatment of osteoporosis is followed by discussion of diminished bone density” (GDBD). The main purpose is to
osteomalacia, rickets, hypervitaminoses D and A, as well as make the two systems complementary. The WHO “defini-
fluorosis. tions” are basically concerned with various stages of osteo-
porosis. Admittedly most, but not all cases of “generalized
Keywords Metabolic bone disease • Osteoporosis • Osteo- diminished bone density” (GDBD) are due to osteoporosis.
malacia • Rickets • Marrow packing disorders • WHO defi- Our approach will give a road map to distinguish osteo-
nitions of osteoporosis • Dual X-ray absorptiometry • Quan- porotic cases from nonosteoporotic entities, such as vari-
titative CT analysis • MRI BMD measurement • Scurvy • ous forms of osteomalacia, hyperparathyroidism, multiple
Reflex sympathetic dystrophy • Osteogenesis imperfecta • myeloma, Gaucher disease, and other forms of GDBD.
Homocystinuria • Osteomalacia • Rickets • Hypophosphata-
sia • Hypervitaminosis D • Hypervitaminosis A • Fluorosis

Bone Metabolism
Introduction
A brief discussion of metabolism of calcium, phosphorus,
Metabolic diseases of bone, strictly defined, are those dis- parathyroid hormone (PTH), and vitamin D will help to bet-
orders of the skeletal system related to abnormalities of all ter understand metabolic bone disease, its diagnosis, and
synthetic (anabolic) and degradative (catabolic) biochemi- treatment.
cal reactions in the body. With this definition, most skeletal

Calcium Metabolism
Akbar Bonakdarpour ()
Department of Radiology, Temple University School of Medicine,
Philadelphia, PA 19140, USA There are between 1,000 and 2,000 g of calcium in the aver-
e-mail: [email protected] age adult human body, 98% of which is in the skeleton. In

A. Bonakdarpour et al. (eds.), Diagnostic Imaging of Musculoskeletal Diseases: A Systematic Approach, 15

DOI 10.1007/978-1-59745-355-4_2, © Springer Science+Business Media, LLC 2010
16 A. Bonakdarpour

adults, 80% of calcium is in cortical bone and 20% in tra- PTH promotes calcium resorption from bone.
becular bone. Calcium exists in three forms in plasma: as In the kidneys, PTH inhibits reabsorption of sodium, cal-
ions, bound to proteins, and as diffusible complexes. The cium, phosphate, and bicarbonate ions in the proximal tubule
normal range of calcium in serum is between 9 and 11 mg of the nephron. It stimulates calcium reabsorption in the dis-
per 100 cm3 (US Food and Drug Administration, Investiga- tal tubule. PTH also stimulates renal synthesis of 1,25(OH)2
tors Manual 2001). At homeostasis, urinary excretion of cal- D3 (1,25-dihydroxycholecalciferol) from hepatically formed
cium typically equals net dietary intake. Serum calcium is 25 hydroxycholecalciferol.
increased by PTH and vitamin D and is decreased by acute PTH also maintains serum magnesium level. (The normal
hypercalcemia and calcitonin. range of magnesium in the blood is 1.8–3.6 mg per 100 cm3
Three organ systems have roles in calcium (Ca2+ ) (US Food and Drug Administration, Investigators Manual
metabolism: 2001).) Magnesium influences secretion of PTH but is much
less active than calcium.
1. GI tract: calcium is absorbed primarily in the proximal
small bowel (both vitamin D and PTH influence calcium
absorption).
2. Kidneys: control calcium excretion by glomerular filtra- Vitamin D Metabolism
tion and tubular reabsorption. PTH and vitamin D con-
trol the latter process. The most active form of vitamin D Vitamin D leads to an increase in serum calcium and phos-
is [1,25(OH)2 cholecalciferol]. Cholecalciferol is vitamin phate, and can be derived from two main sources. Vita-
D3. Its first hydroxylation occurs in the liver and the sec- min D3 is produced as a result of ultraviolet light exposure
ond one occurs in the kidney to produce the most active to the skin, whereas vitamin D2 is obtained from dietary
form of vitamin D. sources.
3. Bones: PTH and vitamin D cause resorption of calcium The primary active form of vitamin D is [1,25(OH)2
from mineralized matrix. Calcitonin is produced by the cholecalciferol or dihydroxycholecalciferol], made in the
parafollicular cells of the thyroid glands and opposes the kidneys. Cholecalciferol is vitamin D3, which in the liver
actions of PTH, thus decreasing the resorption of cal- modifies to 25-hydroxycholecalciferol and in the kidney
cium from bone. Calcitonin is secreted in response to an transforms to the most active form. This form of vitamin D
increase in serum calcium but does not play an important elevates plasma calcium and phosphate levels through sev-
role in normal calcium homeostasis. eral actions.

1. Promotes calcium absorption by the intestines.

Phosphorus Metabolism 2. Promotes phosphorus absorption by the intestines.
3. Potentiates bone resorption induced by PTH.
4. Possibly has a direct effect on bone mineralization.
There are about 1,000 g of phosphorus in the average human
5. Promotes calcium reabsorption by the kidney.
adult body, 85% of which is in the skeleton. The normal
6. Promotes phosphorus reabsorption by the kidney.
range of phosphorus in the serum is 3–4.5 mg per 100 cm3 ,
according to the US Food and Drug Administration, Inves-
tigators Manual 2001. Phosphorus is filtered through the
glomerulus and largely reabsorbed in the proximal tubule. Biochemical Markers of Bone Turnover
Hypophosphatemia increases tubular reabsorption of phos-
phorus. Hyperphosphatemia decreases tubular reabsorption
Biochemical markers of bone turnover provide an indirect
of phosphorus. Parathyroid hormone inhibits tubular reab-
method of evaluating bone metabolism. These markers fall
sorption of phosphorus.
into two groups, those signaling bone formation and those
signaling bone resorption. The former are proteins that are
secreted by active osteoblasts and include osteocalcin, bone
Parathyroid Hormone alkaline phosphatase, procollagen type I N-propeptide and
C-propeptide. Biochemical markers of bone resorption are
Parathyroid hormone works at multiple levels. Its effects on mainly products of catabolism from resorbed type I colla-
the intestinal tract, bones, and kidneys maintain serum cal- gen: C-terminal and N-terminal cross-linking telopeptides of
cium levels: type I collagen, cross-linking molecule deoxypyridinoline,
In the presence of vitamin D, PTH stimulates intestinal and certain amino acids such as hydroxyproline or galacto-
calcium absorption. syl hydroxylysine. Some of these are measured easily and
2 Systematic Approach to Metabolic Diseases of Bone 17

thus routinely used in the clinical evaluation of patients. In over their lifetime. Peak BMD is higher and bone loss
particular, they may be useful for monitoring osteoporosis is of smaller magnitude (20–30%) in men. The rate at
therapy. which this occurs is under the influence of several factors,
including activity, diet, tobacco use, and the presence of
estrogen.
Postmenopausal women tend to lose bone mineral more
Bone Density rapidly than do the premenopausal women. The accelerated
postmenopausal bone loss may cause an additional 2–3%
Maintenance of bone mineral depends upon a balance decline in bone mineral content per year. It occurs initially
between bone synthesis by osteoblasts and bone resorption in the trabecular and then in the cortical compartment. This
by osteoclasts. Normal bone density is related to a balance phase of rapid bone loss eventually decreases and gradually
among the elaboration of osteoid, the mineralization of the reaches a plateau after 8–10 years. In post-oophorectomy
osteoid, and the physiologic bone lysis. These functions cases, bone loss has been reported to be as high as 12% over
are controlled directly or indirectly by hormonal and bio- a 2-year period.
chemical factors beyond and within the bone. A change in In men and women, the process of protracted bone loss
the rate of any of these functions, without a corresponding (involutional osteoporosis) accelerates after the age of 70
adjustment in the rate of the others, causes an imbalance years. Hormonal imbalances have different effects on the
that either increases or decreases bone density. Clinically, development of osteoporosis in men. Testicular secretory
decreased bone density is more important, because it is function declines slowly. Even in very old men, the aver-
much more common than increased bone density. age level of total testosterone is only 20% lower than
The healthy human accumulates bone mass from birth in young men. In contrast, concentrations of bioavailable
until young adulthood. Peak bone mass and consequently testosterone are 50–60% lower than those found in young
peak bone density are achieved around the age of 30 years. men. This leads to bone mineral loss, higher levels of bio-
This peak is influenced by a number of factors, including chemical markers of bone turnover, and higher prevalence
diet, sun exposure, race, and sex. In general, blacks attain of fractures.
higher bone mass than do Caucasians and Asians. Peak bone At the tissue level, increased bone resorption results in
density is higher in men. the perforation and disappearance of trabeculae (Fig. 2.1).
Normally, once peak bone mass is achieved, there is When the trabeculae disappear, the metabolically active sur-
almost a decade of stability where bone density remains face available for osteoclasts decreases and bone loss tends
unchanged. During this stable period, there is normal bone to slow down.
turn over (remodeling or coupling), which means bone There are three distinct types of generalized diminished
resorption and bone production are balanced. Bone remodel- bone density: osteoporosis, osteomalacia, and osteolysis.
ing continues during the entire life and it occurs in compact Each entity has different causes and will be described in more
or cortical bone as well as trabecular or medullary bone. At detail in this chapter. Here we introduce them briefly and they
maturity, 80% of bone is cortical and 20% is trabecular. Nor- will be discussed in more detail later.
mal bone remodeling (coupling) affects 2–3% of the whole In osteoporosis and some cases of generalized osteolysis,
skeletal mass per year. such as primary hyperparathyroidism, there is diffuse bone
loss, but there is no chemical abnormality in the composi-
tion of bone. In other words, one gram of normal bone has an
identical chemical composition to one gram of osteoporotic
Generalized Diminished Bone Density or bone from a patient with hyperparathyroidism. On the
other hand, in osteomalacia, where there is diminished min-
In young adults, bone resorption and bone formation are in eralization of the osteoid, the chemical composition of bone
equilibrium and bone density remains stable. When bone is abnormal.
loss outweighs bone gain, bone density decreases. In both Osteoporosis is defined as a nonfocal reduction of bone
genders, around 40 years of age the process of involutional mass per unit volume (cubic centimeter) without change
osteoporosis (bone loss) starts and bone density begins to in chemical composition of bone. Osteoporosis can also
gradually decrease. Involutional osteoporosis has an ini- be defined as a chronic, progressive disease characterized
tial rate of 0.3–0.5% of bone loss per year. This pro- by low bone mass, microarchitectural bone deterioration
cess continues throughout life and accelerates with age. (Fig. 2.1), and decreased bone strength leading to bone
Women experience a superimposed, transient period of fragility and increased fracture risk.
postmenopausal, accelerated bone loss. Women lose about Regional osteoporosis occurs in cases of disuse osteoporo-
35% of their cortical and 50% of their trabecular bone sis (such as immobilization), reflex sympathetic dystrophy,
18 A. Bonakdarpour

A B

Fig. 2.1 Osteoporosis. a – Low power microscopic section of normal images is a reflection of these histological aberrations. a and b are cour-
bone in an iliac crest biopsy. b – Microscopic section of osteoporotic tesy of Dr. Peter Bullough, Hospital for Special Surgery, New York and
bone in an iliac crest biopsy. Note thinning and discontinuity of bone Dr. Vincent Vigorita, State University of New York, Health Sciences
trabeculae. Coarsening of the trabecular pattern on radiographs and CT Center, Brooklyn, NY

regional migratory osteoporosis, and several other entities DXA, QCT, and quantitative ultrasonography (Table 2.1).
that will be discussed later in the appropriate sections of this Most but not all cases of diminished bone density result from
chapter. osteoporosis.
Osteomalacia arises when there is diminished mineraliza- In the following radiological classification (Table 2.1), we
tion of osteoid. There may be normal or excessive produc- consider other causes of diminished bone density in addition
tion of osteoid. The result is an alteration in the chemical to osteoporosis. This classification is complementary and not
composition of the bone with greater elasticity but lower ten- contradictory to WHO definitions of diminished bone den-
sile strength. Osteomalacia is diagnosed histologically by the sity, introduced in 1994.
presence of enlarged osteoid seams observed in decalcified Admittedly, this radiological classification is an
sections of the bone. oversimplification of a very complicated problem. For
Osteolysis is generally considered to be a focal loss of
bone in direct response to a pathologic process such as infec-
tion, neoplasm, other focal processes such as post-traumatic Table 2.1 Radiological classification of generalized diminished bone
clavicular osteolysis, a local manifestation of a systemic density (osteopenia)∗
disease such as distal clavicular osteolysis that occurs in Osteopenia
hyperparathyroidism and rheumatoid arthritis, or acrooste- Osteopenia is generalized diminished bone density (GDBD) of any
olysis of the digital tufts as observed in polyvinyl chloride cause or if the etiology is unknown. Osteopenia includes
osteoporosis, osteomalacia, and osteolysis
workers, scleroderma, epidermolysis bullosa, hyperparathy- Osteoporosis
roidism, frostbite, and thermal injury. The various forms of Osteoporosis is defined as a reduction of bone mass per unit
regional or focal osteolysis are covered in the appropriate volume (cubic centimeter). The chemical composition of bone is
chapters of this book. Here we confine our discussion to com- normal. Histologically, it is diminished osteoid∗∗ formation
paring osteoporosis with generalized osteolysis. This may be Osteomalacia
Osteomalacia is inadequate osteoid mineralization and chemical
caused by an osteoclast-activating hormone (OAH) (such as
composition of bone is changed
parathormone) or osteoclast-activating factors (OAFs) such Osteolysis
as the OAFs excreted by myeloma cells or in other types of Osteolysis is increased rate of bone resorption by osteoclasts or it
cancer cells. Generalized osteolysis may also be seen in mar- is caused by marrow proliferative and/or marrow packing
row packing disorders such as Gaucher disease. In this group disorders. The chemical composition of bone may or may not be
changed. This cause of diminished bone density may be
of patients, generalized diminished bone density (GDBD) is generalized or focal. In this classification we are interested in
neither due to osteoporosis nor due to osteomalacia. generalized form of this third group
We will use the general term of osteopenia to include the ∗ This classification takes into consideration pathophysiology of dimin-

three distinct forms of generalized diminished bone density ished bone density.
∗∗ Osteoid is bone matrix before calcification.
(GDBD), which are radiologically documented accurately by
2 Systematic Approach to Metabolic Diseases of Bone 19

example, aging osteoporotic patients also tend to have fracture than those who do not. Thus, prediction of
increased levels of plasma PTH. Age-related secondary osteoporotic fractures cannot been easily and accurately
hyperparathyroidism is a significant cause of diminished estimated.
bone density in elderly men and women due to calcium • The role of genetic factors in the pathogenesis of osteo-
and vitamin D deficiency. Intestinal absorption of calcium porosis is confirmed by epidemiological studies.
decreases with age. Synthesis of endogenous vitamin • Lifestyle risk factors for osteoporosis include alcohol
D decreases from aging of the skin and lower sunlight abuse, smoking, low calcium intake, and lack of physical
exposure. Furthermore, synthesis of [1,25(OH)2 D3] is also activity.
diminished from age-related reduction in the activity of • Chronic conditions such as Cushing disease, hemochro-
renal enzyme (1 α-hydroxylase). Consequently, calcium matosis, hypogonadism, gastrointestinal abnormalities
and vitamin D deficiency causes secondary age-related such as Crohn disease, and chronic pancreatitis predispose
hyperparathyroidism. the patients to osteoporosis.
On the other hand, patients with hyperparathyroidism, • Some drugs such as corticosteroids, thyroid hormone,
myeloma, or osteomalacia may also have secondary disuse antiandrogen treatment, and to a lesser extent heparin and
osteoporosis. Therefore, the distinction among these three loop diuretics cause osteoporosis.
types of GDBD is not always clear-cut. Nonetheless, this • The risk of developing fractures increases in condi-
classification provides a practical systematic approach to dif- tions that increase the possibility of fall such as neu-
ferentiate the main causes of generalized diminished bone rologic disorders, heart conditions leading to orthostatic
density GDBD and every type of generalized decreased bone hypotension, and in patients who are treated with neu-
density will not be considered osteoporosis as it is done in roleptics, antidepressants, and antihypertensive medica-
WHO definitions. tions.
These three processes may appear similar on radiographs
and DXA. Hence, the general term osteopenia is used when Much research has gone into measuring bone mineral
the etiology of GDBD is not known. It is important to content in order to determine on average when an indi-
remember that definition of osteopenia in this classification vidual is at risk for fracture. While many of these tests
is quite different from its definition in WHO definitions of give local measurements of BMD, no clinically practical
diminished bone density. available test gives information regarding the microarchi-
tecture of the bone. The architecture of bone is likely
to be as important in predicting fractures as is the abso-
lute amount of bone since the organization of the mate-
Osteoporosis rial will affect its overall strength. Recently, microcomputed
tomography and high-resolution MRI using SNR-efficient
Osteoporosis is the most common bone disease in humans sequences, high magnetic field (3 Tesla), and phased array
and affects both sexes. By definition, osteoporosis is nonfo- coils have been used for the in vivo study of the trabecular
cal diminished bone mass per unit volume of bone (cubic microarchitecture of bone, but these techniques at present
centimeter). are not clinically available. Others have used susceptibil-
Normal adults lose bone mass beyond the age of 40 ity effects to evaluate the overall directional components of
years by the process of involutional osteoporosis, which was bone.
described previously. This loss of bone begs the question Osteoporosis may be divided into primary or secondary
as to when the loss is pathologic and when it is physio- forms. Primary osteoporosis is age related and can be seen
logical. The practical answer to this question is that osteo- in both men and women. In secondary form of osteoporo-
porosis becomes pathologic when the patient is at risk for sis, bone loss is precipitated by a variety of chronic medical
fracture without major trauma. This risk will depend not conditions, medications, nutritional deficiencies, and other
only on the bone mass of the individual and the microar- causes.
chitecture of the bone but also upon several other factors There are multiple pathophysiological mechanisms that
as follows: lead to secondary osteoporosis. For example, certain amino
acids and vitamin C are necessary for osteoid synthesis. A
• Women at greatest risk for osteoporosis are Caucasian deficiency in these causes dietary osteoporosis. If the nec-
ectomorphs with low calcium intake, sedentary lifestyles, essary amino acids are depleted in the synthesis of sug-
little sun exposure, and early menopause. On the other ars (glycogenesis), as probably occurs in diabetes melli-
hand, those individuals who are more active or who tus and Cushing disease, or if the catabolic destruction
take more physical risks are clearly at greater risk for is greater than the supply, as in thyrotoxicosis, we might
20 A. Bonakdarpour

Table 2.2 Etiological classification of osteoporosis WHO Definitions of Osteoporosis

Osteoporosis may be primary or secondary. About 40% of cases
are secondary osteoporosis
A. Primary osteoporosis In 1994, the WHO established definitions for diagnosis of
Primary osteoporosis has 2 types: osteoporosis based on the results of quantitative BMD mea-
1. Type 1 – Postmenopausal osteoporosis surements using dual-energy X-ray absorptiometry (DXA).
2. Type 2 – Age-related (senile) osteoporosis The results of DXA are commonly expressed in terms of
B. Secondary osteoporosis T scores (standard deviations from young gender-associated
1. Dietary deficiency:
normal peak bone mass) or Z scores (standard deviations
a. Scurvy – vitamin C
b. Copper from mean sex and age-matched control bone mass): These
c. Protein malnutrition definitions divide BMD measurements into four groups
d. Calcium malnutrition (Table 2.3).
2. Endocrine:
a. Hypogonadism – Primary or secondary Table 2.3 WHO definitions of bone density
b. Ovarian agenesis (Turner syndrome) and testicular
• Normal: T score not more than one standard deviation below the
dysgenesis (Klinefelter syndrome)
young adult female reference mean
c. Adrenal cortex:
• Osteopenia (low bone mass): T score between 1 and 2.5 standard
i. Cushing syndrome – adrenal neoplasm deviations below the young adult female reference mean peak
ii. Addison disease bone mass
d. Pituitary: • Osteoporosis: T score more than 2.5 standard deviations below
i. Cushing disease – pituitary adenoma with cortical the young female reference mean
hyperplasia • Severe osteoporosis (established osteoporosis): T score more than
ii. Acromegaly 2.5 standard deviations below the young adult female mean in the
e. Hyperthyroidism presence of one or more osteoporosis fragility fractures
f. Diabetes mellitus (pancreas)
g. Nonendocrine tumors that secrete ACTH-like polypeptides
(such as small cell carcinoma of the lungs) The young adult female reference mean is determined
3. Disuse atrophy or stress shielding – osteoporosis due to lack of with the use of the mean hip BMD from the National Health
stress stimulus, prolonged immobilization, weightlessness in
and Nutrition Examination Survey reference database of
space flights, advanced arthritides, and paralysis∗
4. Chronic liver disease and alcoholism women aged 20–29 years.
5. Idiopathic juvenile osteoporosis If DXA measurements at different sites are considerably
6. Iatrogenic (excessive steroids, heparin, and vitamin A) disparate, most clinicians use the lowest BMD measurement.
7. Congenital/Genetic: The lowest T score of the distal third of the nondominant
a. Osteogenesis imperfecta radius may also be used. This approach has been recom-
b. Homocystinuria mended by most experts including the International Society
c. Neuromuscular disease and dystrophies
for Clinical Dosimetry. The results are reported as a density
d. Trisomy 18
e. Trisomy 13–15
measurement in gram per square centimeter in addition to T
f. Progeria and Z scores.
g. Ehlers-Danlos syndrome The WHO definitions tell the truth but not the whole truth.
h. Menke syndrome (the congenital copper deficiency) There are several problems with these definitions:
∗ See discussion of Wolff law in the discussion of fracture healing in

Chapter 5 trauma and in Chapter 1.

• It makes no distinction between various causes of
decreased bone density (DBD). Certainly, not all patients
designate the resulting osteoporosis as endocrine. Cells may with decreased bone density are osteoporotic. Neverthe-
inherit genes that code for a deficient or defective set of less, since the majority of cases with diminished bone
enzymes, resulting in a congenital inability to differenti- density, in older age, are due to osteoporosis, the WHO
ate into osteoblasts, a condition we recognize as osteoge- classifications are the best practical approach currently
nesis imperfecta. Thus we may set up a classification of available.
osteoporosis in two primary and seven secondary groups • It is neither a sensitive nor a specific predictor of fracture.
(Table 2.2). This is because it is based on a relatively inaccurate test
Two forms of osteoporosis are recognized: high turnover of projectional BMD determination.
osteoporosis where the bone can be shown to be actively • It makes no attempt to adjust the measurement for bone
remodeling using double labeling with tetracycline and low microarchitecture.
turnover osteoporosis where the bone shows little or no • The definition makes no adjustment for individual
remodeling activity with tetracycline labeling. lifestyle.
2 Systematic Approach to Metabolic Diseases of Bone 21

• In the WHO system, T scores are based on standard devi-

ations from young female normal peak bone mass. Peak
bone mass is different in male and female.

Diagnostic Imaging of Osteoporosis

Radiographic evaluation

Radiographs show generalized and uniform decreased den-

sity of the skeleton, with coarse trabeculae, and thinning of
the cortices. Trabecular coarsening (Figs. 2.1, 2.2, and 2.3)
occurs because initial trabecular loss occurs in the secondary
trabeculae. These trabeculae are oriented perpendicular to the
loading force on the bone. Their loss effectively increases
the length of the primary trabeculae that are oriented along
lines of the loading force. As these trabeculae become
longer, they have to increase their diameters substantially
to mitigate the effects of the increased length and bear the
same load.
In the spine, prominent trabeculae sometimes show verti-
cal striations, mimicking the corduroy pattern seen in heman-
giomas (Fig. 2.3). Confusing these two entities is unlikely,
however, since osteoporosis is a systemic disease with
systemic changes while hemangiomas are typically focal
lesions. In severe osteoporosis, there is increased lucency of Fig. 2.3 Osteoporosis of the lumbar spine. Lateral radiograph showing
diminished bone density, thinning, and accentuation of cortical density
the medullary portion of vertebral bodies and accentuation as
compared with the medullary portion of vertebrae, giving the impres-
well as thinning of cortices, producing an appearance similar sion of an “empty box.” There are various degrees of biconcave defor-
mity of several vertebral bodies related to microscopic insufficiency
fractures (see Fig. 2.4c). Note significant coarsening of trabecular mark-
ings in the form of vertical striations due to osteoporotic loss of sec-
ondary trabeculae (arrows). This appearance should not be confused
with hemangiomas

to an “empty box” (Fig. 2.3). This appearance has been said

to be particularly prominent in steroid-induced osteoporosis.
Fractures of vertebral bodies are the most common insuffi-
ciency fractures in osteoporosis. Sometimes the osteoporotic
vertebral body “microfractures” cause biconcave deformi-
ties that simulate “fish vertebrae” (Figs. 2.3, 2.4, and 2.5).
The vertebral bodies may collapse anteriorly, causing wedge
deformity (Figs. 2.5 and 2.6) and kyphosis. These patterns
of vertebral body deformity also may be seen in other
types of osteopenic states (osteolysis and osteomalacia). At
times, severe osteoporotic fractures cause significant defor-
mity causing a “crush appearance” (Figs. 2.5 and 2.12).
Insufficiency fractures of the skeleton usually can be diag-
nosed on radiographs, but sometimes they may be subtle and
bone scan or preferably MRI is required to make the diagno-
sis (Figs. 2.7 and 2.8).
Fig. 2.2 Osteoporosis. There is diminished bone density, coarsening of
trabecular pattern (short arrows), cortical thinning, and pelvic fractures Multiple myeloma may present with an appearance
(long arrows) that is identical to age-related osteoporosis. About 25%
22 A. Bonakdarpour

Fig. 2.4 Osteoporosis. a is gross

specimen of an osteoporotic
spine with compression fracture
and b is a radiograph of an
osteoporotic spine, with severe
fracture and “fish vertebrae” in a
different patient. c is a low power
magnification revealing a healing
microfracture with callus
formation in the spine. These
microfractures create gross
radiological vertebral body
deformities. a and c are courtesy
of Dr. Peter Bullough, Hospital
for Special Surgery, New York,
and Dr. Vincent Vigorita, State
University of New York, Health
Sciences Center, Brooklyn, NY

A B C

of patients with multiple myeloma have marked diffuse (such as Gaucher disease), hyperthyroidism, chronic immo-
and uniform diminished bone density without focal oste- bilization, hepatic insufficiency, diabetes mellitus, drug-
olytic lesions. This is related both to excretion of an induced osteoporosis from corticosteroids and heparin, drug-
osteoclastic-activating factor by myeloma cells and to mar- induced osteomalacia caused by anticonvulsant therapy,
row proliferation and packing by the tumor cells (Figs. 2.9 Cushing disease/syndrome, and rheumatoid arthritis also
and 2.10). Metastatic disease, osteomalacia, primary and cause decreased bone density and are in the differential diag-
secondary hyperparathyroidism, marrow packing disorders nosis of osteoporosis.

Fig. 2.5 Genants semiquantitative method for reading osteoporotic spine. From left to right: Wedge, biconcave, and crush deformities are
vertebral fractures. Vertebral body fractures are graded from 0 to 3 in demonstrated in normal and Grades 1–3 fractures
the assessment of osteoporotic fractures in lateral radiographs of the
2 Systematic Approach to Metabolic Diseases of Bone 23

Fig. 2.6 Progress of

osteoporotic fracture in lateral
spine radiographs. a shows
compression fracture of the
superior vertebral body and
anterior decreased height of L1
on July 28, 1988 (Grade 2
fracture). b shows increased
compression (wedge deformity)
after 4 months. Therefore,
fracture grading has increased
from Grade 2 to 3 in this interval
according to Genants
semiquantitative criteria

A-7-28-88 B-11-21-88

Bone density must diminish by 30–40% before it is recog- accurate than both radiographs and DXA, but it is more dif-
nizable radiographically. For this reason, radiographs are not ficult to perform, less precise, and give the patient more radi-
sensitive to early loss of bone density. Radiographic appear- ation than DXA (Fig. 2.17).
ance of congenital forms of osteoporosis such as osteoge- The precision error of DXA (1–2%) is relatively high
nesis imperfecta (Fig. 2.11) are more or less similar to the compared with patients’ annual rate of bone loss or gain.
acquired forms. This entity is discussed in more detail in Thus, a 2-year interval between measurements is necessary
Chapter 13. for meaningful monitoring using this technique, in mon-
Dual X-ray absorptiometry (DXA), quantitative CT anal- itoring therapeutic efficacy. In the interval, follow-up of
ysis (QCT) and quantitative ultrasonography, though imper- osteoporotic patients may be done using standardized visual
fect, detect diminished bone density at a much earlier stage (or semiquantitative) assessments of vertebral deformities. In
of development than do radiographs. At present, DXA is the standardized assessment radiographs of the spine, numerical
most commonly used procedure for early detection of osteo- scores are assigned to vertebral deformities, and distinct
porosis (Figs. 2.13, 2.14, 2.15, and 2.16), primarily because categories are assigned to the shape or the type or the
its results are easily reproducible from one examination to severity of vertebral fractures in a definable and reproducible
another. manner. No measurements of vertebral dimensions are
Even so, radiographs still have a major role in the manage- made. This semiquantitative radiographic approach not only
ment of osteoporotic fractures and in the differential diagno- helps the clinical research of osteoporosis but also provides
sis of causes of decreased bone density. QCT is also more more practical accurate follow-up during treatment of this

a b

Fig. 2.7 Insufficiency fractures in a 78-year osteoporotic female. a is b is a T2-weighted axial MR image of the pelvis showing the same
a T1-weighted axial MR image of the pelvis showing an insufficiency fracture with increased signal intensity consistent with acuity (arrow).
fracture with decreased signal intensity of the left pubic bone (Arrow). Courtesy of Dr. Murali Sundaram, Cleveland Clinic, Cleveland, Ohio
24 A. Bonakdarpour

borderline cases that reveal minimal changes but cannot be

called Grade 1 fracture. This system has faults but is practical
and reproducible among institutions if used by experienced
readers.

Quantitative Evaluation of Osteoporosis

Dual-Energy X-ray Absorptiometry (DXA)

Dual X-ray absorptiometry (DXA) employs an X-ray source

that emits two beams of different energy. BMD is calcu-
lated based on measuring the differential tissue absorption of
Fig. 2.8 Insufficiency fracture. Same patient. Coronal T1-weighted energy from these two X-ray beams. DXA measures the pro-
MR image of the pelvis showing a longitudinal decreased signal inten- jectional or area BMD expressed in gram per square centime-
sity in the right sacral wing (arrow) consistent with right sacral wing
insufficiency fracture. Courtesy of Dr. Murali Sundaram, Cleveland
ter, which depends on both the volumetric BMD (vBMD,
Clinic, Cleveland, Ohio expressed in g/cm3 ) and bones dimensions, specifically the
thickness of the bone measured. Thus, area BMD does not
condition. Several such methods have been introduced by distinguish higher BMD recordings of a larger amount of
Smith et al., Meunier, Kleerekoper et al., and Genant. bone mineral from bones that are merely bigger. Even so,
The semiquantitative visual grading introduced by Genant fracture risk is determined by both the degree of bone min-
has proven to be most practical and has been widely applied eralization and the bone size, and so area BMD is a good
in epidemiological studies and clinical trials (Fig. 2.5). In predictor of fracture risk. The accuracy and the precision of
this approach, the T4 to L4 vertebral bodies are evaluated DXA are better than those of older, single-energy densito-
on lateral radiographs of the spine. Each of these verte- metric methods.
brae is given a grade related to severity of fracture and Clinically, DXA (Figs. 2.13, 2.14, 2.15, and 2.16) is used
averaged to create a “spinal fracture index” (SFI: Grade 0, to measure the bone mineral density (BMD) of the lumbar
normal; Grade 1, mild fracture; Grade 2, moderate frac- spine, the hip, the distal forarrm [142], the calcaneus, and the
ture; and Grade 3, severe fracture). In each grade, wedge, whole body. DXA is reliable in diagnosing osteoporosis and
biconcave, and crush deformities are evaluated (Fig. 2.5). to some extent for evaluating fracture risk. Quantitative com-
In Genants method the authors give a “Grade 0.5” also for puterized tomography is superior to DXA, but neither test is

Fig. 2.9 Multiple myeloma. a –

Myeloma in a 40-year-old man
revealing only diminished bone
density (osteopenia) without
osteolytic lesions in skeletal
survey. Note cortical thinning of
the sternum and the spine with
Grade 1 wedging of the vertebral
bodies. b – Close-up view of the
spine reveals the spinal changes
more clearly. The vertebral
bodies have the so-called “empty
box” appearance, demonstrating
changes similar to osteoporosis,
best seen in the lower thoracic
segments. Courtesy of Dr. Murali
Sundaram, Cleveland Clinic,
Cleveland, Ohio A B
2 Systematic Approach to Metabolic Diseases of Bone 25

Fig. 2.10 Myeloma. This is a

54-year-old female with
myeloma. The skeletal survey
reveals no discrete lesions. There
is mild osteoporosis. a – Lateral
thoracic spine shows thinning and
disproportionate density of the
cortex compared to the trabecular
bone, giving an empty box
appearance to vertebral bodies.
There is Grade 1 biconcave
deformity of the lower thoracic
segments. b – AP view of the
pelvis shows cortical thinning
and minimal coarsening of the
trabecular markings of the hips.
Courtesy of Dr. Michael
Bromberg, Temple University
Hospital, Philadelphia, PA
A B

Fig. 2.11 Osteogenesis

imperfecta. Lateral and AP
lumbar spine radiographs
showing progression of
osteoporosis in a case of Type 1
osteogenesis imperfecta over a
10-year period. This woman was
11 years old in 1955. The
biconcave deformities improve
between the two studies, the
radiographic findings are more or
less similar to the acquired forms
of osteoporosis

1955 1965 1955 1965

a good predictor of fracture. There is a fair correlation among Quantitative Computerized

BMD measured at different sites in an individual, but the best Tomography (QCT)
predictor of risk of fracture at a given site in an individual is
BMD measured at that site.
The lumbar spine is a common site for bone densito- The advantage of quantitative computerized tomography is
metry. However, the presence of osteophytes causes spuri- that it allows selective measurements of the trabecular bone
ously high BMD measurements in patients with spondylo- without cortical bone. This is valuable because trabecular
sis, especially in men. The most reliable sites of BMD mea- bone has 8–10 times the surface area of cortical bone and
surement using DXA are the femoral neck and the total hip. is therefore more affected by osteoclastic activity than is cor-
Both predict fracture risk equally, but the total hip measure- tical bone. QCT is most practical when applied to the spine.
ment is more suitable for monitoring treatment as it con- It is not as widely used as DXA because of limited avail-
tains a larger volume of bone comprising both cortical and ability, relatively high radiation, and a higher precision error
trabecular bone. (Fig. 2.17).
26 A. Bonakdarpour

A B C

Fig. 2.12 Osteoporosis. MR a and b and CT c sagittal images in a 93- suggests a nonacute fracture. Sagittal reconstructed CT c performed at a
year-old osteoporotic man with compression fracture of the L3 vertebral later date showing diminished bone density, coarse vertical trabeculae,
body. Sagittal T1 MRI a shows deformity and decreased signal inten- severe progressive crush deformity, decreased height of central verte-
sity of the body of L3. Note enlarged spinous processes and decreased bral body, and a retropulsed fragment (arrow) into the spinal canal due
intraspinous distances of Baastrup phenomena, which contributed in to the progression of the Grade 3 fracture. Courtesy of Jeffrey P Kochan
part to the patients pain. T2 sagittal MRI b lack of T2 signal abnormality MD, Temple University Hospital, Philadelphia, PA

Microcomputerized Tomography value of QUS for osteoporotic fractures is slightly lower

than DXA. Despite several advantages of QUS (noninva-
sive, free of ionizing radiation, small and inexpensive equip-
Microcomputerized tomography has been developed during
ment), QUS has not yet acquired a place in clinical practice.
the last few years. This technique provides high-resolution
The long-term stability of these devices is poor. Values of
images of trabecular architecture. It may be used for spec-
QUS parameters measured in vivo depend on temperature of
imen evaluation. Its applications have been extended to in
water bath and skin, positioning of foot, concentration and
vivo animal and human imaging. This technique is still an
type of detergent in the water bath, as well as thickness of
investigative tool and at present, it is not widely used.
soft tissues. Few studies have examined the potential util-
ity for evaluation of bone loss and monitoring of treatment.
Currently, there are no diagnostic thresholds of osteoporosis
Quantitative Ultrasonography for QUS.

Quantitative ultrasonography (QUS) measures bone density

using changes in two parameters of ultrasound transmission:
speed of sound (SOS) and broadband ultrasound attenuation Magnetic Resonance Imaging (MRI)
(BUA). The highest BUA and SOS values are observed in
young people with high bone mass; these values decrease MRI, though currently impractical as a clinical test, shows
with age. QUS can be applied where a bone is close to the some remarkable promise as a more accurate predictor of
skin surface, at the calcaneus, phalanges of the fingers, the osteoporotic fracture. Two methods of MRI BMD measure-
patella, and the tibia. ment have been developed: one that uses ultrahigh-resolution
The calcaneus is sensitive to disturbances of bone turnover MRI to evaluate trabecular mass and another that uses sus-
because it contains 90% trabecular bone that is metaboli- ceptibility effects to determine mineral content. The for-
cally active. QUS claims to reflect not only bone quantity mer, though accurate, samples too small a portion of the
but also its trabecular microarchitecture, elasticity, and stiff- skeleton to be representative. The second method is based
ness, an advantage over DXA and QCT, but this claim is upon the observation that susceptibility effects are directly
weak. Correlation between QUS and BMD measured at dif- related to trabecular bone mass. Not only is this the case, but
ferent sites is modest. Furthermore, the clinical predictive the measurements show anisotropy with respect to the main
2 Systematic Approach to Metabolic Diseases of Bone 27

Fig. 2.13 Normal DXA followed for 6.5 years. A 75-year-old woman –0.1, –0.4, and –0.8, all within normal limits according to WHO def-
in 2007, normal follow-up DXA over 6.5 years. The patient had three initions. Courtesy of Dr. Alan Maurer, Temple University Hospital,
studies on 6/27/2000, 3/15/2005, and 11/20/2007. Lowest T scores: Philadelphia, PA

magnetic field, suggesting that MR measurements using this porosis. It is estimated that osteoporosis currently “affects
technique might also provide some information about bone 200 million women worldwide”. This makes osteoporosis
microarchitecture. Unfortunately, this technique is currently one of the most common diseases of the elderly. In 1988,
impractical for a number of reasons, including the size of the direct cost of osteoporotic fractures was estimated at 35
the scanner bore, the time it takes to complete the study, the billion dollars in the United States. In Europe the current
availability of the equipment, and the cost of MRI compared total direct cost is estimated to be over 31 billion Euros and
with DXA. may rise to a yearly cost of about 76 billion Euros by the
year 2050.
Low BMD, due to osteoporosis, is mainly age associ-
Osteoporosis Is a Major Public Health ated, but other factors such as low BMI, weight loss after
Problem the age of 25 years, lack of physical activity, poor nutri-
tion, tobacco smoking, chronic alcoholism, gastrectomy, cer-
The prevalence of osteoporosis increases with age. One out tain drugs (mainly corticosteroids, loop diuretics, thyroid
of three women between ages of 60 and 70 is osteoporotic. hormones) also contribute to declining bone mass. Post-
Two out of three women at age 80 are osteoporotic. In menopausal osteoporosis develops prematurely in young
1995, 9.4 million American women suffered from osteo- individuals who undergo oophorectomy (Fig. 2.18). Patients
28 A. Bonakdarpour

Fig. 2.14 Osteopenia DXA hip. Woman 48, lowest T score –2.1 consistent with osteopenia. Courtesy of Dr. Alan Maurer, Temple University
Hospital, Philadelphia, PA

may show as much as 12% bone loss in the 2 years following common type of osteoporotic fractures [1] (Figs. 2.3, 2.4, 2.5,
oophorectomy. 2.6, and 2.7).
About 1.5 million fractures in the United States are Hip fracture (Fig. 2.19a) is the most disastrous conse-
attributed to osteoporosis annually. They occur primarily in quence of osteoporosis. Its incidence increases exponentially
the spine, the hip, and the distal forearm. Approximately with age in both men and women. The risk of hip fracture
50% are vertebral, 20% in the hip, 20% in the wrist. At is increased in people with other common osteoporotic
age 60, women suffer osteoporosis-related fractures at a rate fractures, mainly vertebral and distal radius fractures. There
that is six times that of age-matched men. By 70 years are two main determinants of the risk of hip fracture: low
of age, osteoporosis is present in both genders, and the BMD and falls. Unfortunately, balance worsens as people
ratio of osteoporosis-related fractures declines to 2:1. The age and so falls become more likely.
estimated lifetime risk of sustaining an osteoporotic frac- Fracture of the distal radius (Fig. 2.19b) is the third most
ture is 40% for women and 13% for men at age 50 years. frequent osteoporotic fracture in women at age 80. It is also
The risk for hip fracture is 17.5% for women and 6% often one of the earliest manifestations of osteoporosis. In
for men. men over 65 years of age, the incidence of distal radius
The most common complaint from osteoporosis is back fracture is four times lower compared with women of the
pain. The onset may be insidious or sudden following same age.
injury. There is a definite relationship between osteoporosis Fracture of the proximal third of the humerus, particularly
and spinal compression fractures that occur spontaneously its surgical neck, is another common fracture in osteoporotic
or with minimal trauma. Vertebral fractures are the most patients.
2 Systematic Approach to Metabolic Diseases of Bone 29

Fig. 2.15 Osteoporosis DXA. Black woman 57, osteoporotic spine, the lowest spinal T score –3.5 and Z score –2.1. Courtesy of Dr. Alan Maurer,
Temple University Hospital, Philadelphia, PA

Prevention and Treatment of Osteoporosis treatment of osteoporosis. Most of these agents are in the
bisphosphonate class of drugs and act by decreasing bone
Prevention turnover.
Bisphosphonates (BP) – Bisphosphonates (BP) are potent
inhibitors of bone resorption that inhibit the activity of osteo-
Prevention of osteoporosis is based on nutritional factors and
clasts. These are commonly used in the treatment of post-
exercise. Dietary calcium should be about 800 mg per day
menopausal osteoporosis.
for adults and 1,500 mg per day for adolescents. Recom-
Hormone replacement therapy (HRT) – Hormone replace-
mended calcium intake for postmenopausal women is 1,000–
ment therapy (HRT), either estrogen alone or in combination
1,500 mg per day.
with progesterone, increases BMD at all skeletal sites in early
and late postmenopausal women. It is associated, however,
with an increased incidence of endometrial cancer (about
Treatment 1% per year) and other complications such as deep venous
thrombosis (DVT), pulmonary embolism, hypertension, and
Currently, prevention of bone loss is much more effec- gallstones. Therefore, it is indicated only in high-risk patients
tive than treatment of established osteoporosis. Nonethe- with evidence of rapid bone loss.
less, if detected at an early stage, osteoporosis is a poten- Selective estrogen receptor modulators (SERM) – Selec-
tially treatable disease. During recent years, several effec- tive estrogen receptor modulators (SERM) are synthetic
tive new drugs have been approved for the prevention and molecules that have the ability to bind to estrogen
30 A. Bonakdarpour

Fig. 2.16 Treated osteoporosis showing improvement. The patient was age of 66 to –1.1 in 2007 at the age of 73. Four DXA studies were
a white woman, treated with Fosamax (alendronate sodium) from July performed. Courtesy of Dr. Alan Maurer, Temple University Hospital,
2001 to November 2007. T score increased from –1.5 in 2001 at the Philadelphia, PA

Fig. 2.17 Normal single-energy

QCT. a is axial CT image of L4
of a 59-year-old female. b reveals
that the study is normal and BMD
is 0.2 SD above mean A B
2 Systematic Approach to Metabolic Diseases of Bone 31

Vertebroplasty and Kyphoplasty

Vertebroplasty, discussed in more detail in Chapter 14, is

an injection of methyl methacrylate into a compressed ver-
tebral body. This technique yields excellent relief of spinal
pain. It is an outpatient procedure performed under local
anesthesia and sedation and consequently has become very
popular (Fig. 2.20).
Kyphoplasty, similar to vertebroplasty, is the injection of
cement into a compressed vertebral body with the intent of
reducing the kyphotic deformity. First, a high-pressure bal-
loon is inserted into the vertebral body in an attempt to ele-
vate the depressed endplate and to create a cavity. The bal-
loon is withdrawn and a high-viscosity preparation of acrylic
cement is injected to fill the cavity. Unlike vertebroplasty,
this is a surgical procedure that typically requires a hospital
Fig. 2.18 Post-oophorectomy osteoporosis. There are healing fractures admission and general anesthesia.
of the left superior and inferior pubic rami in a 31-year-old female, after
oophorectomy (arrows)

Scurvy
receptors throughout the body and act as estrogen ago-
nists or antagonists depending upon the target organ. Ralox- Scurvy is caused by a deficiency in vitamin C (ascorbic acid)
ifene is the only SERM currently on the market for and is rarely encountered in the western hemisphere. Vitamin
osteoporosis. C deficiency results in an inability on the part of the finer
Calcium and vitamin D – Calcium and vitamin D are indi- ramifications of the vascular tree to contain blood, resulting
cated mainly for the prevention of bone loss in the elderly in a bleeding diathesis. Vitamin C is also essential in the
and are a useful adjunct therapy in osteoporosis. production of adequate normal intercellular collagen and
Teriparatide rhPTH – The first effective stimulator of organic bone matrix. Thus, its absence leads to osteoporosis.
bone formation, the recombinant 1–34 fragment of human The radiographic manifestations of infantile scurvy
parathyroid hormone [rhPTH(1–34)], has recently been (Figs. 2.21 and 2.22) reflect osteoporosis and hemorrhage.
approved. Alterations are first apparent and are most marked in areas in

Fig. 2.19 AP right hip

radiograph. a shows a femoral
neck fracture and lateral wrist
radiograph. b shows a radial
fracture, which are the second
and the third most common
osteoporotic insufficiency
fractures, respectively. Vertebral
body fractures are the most
common osteoporotic fractures A B
32 A. Bonakdarpour

Fig. 2.20 Vertebroplasty in a

93-year-old osteoporotic man.
The patient was bedridden for 8 2
months due to severe pain
secondary to compression
fractures of L2 and L3 vertebral 3
bodies (arrows). A remarkable
recovery was noted immediately
following vertebroplasty
reconstruction of the L3 vertebral
body and after subsequent
vertebroplasty of the L2 vertebral
compression fracture several
months later. The patient was able
to ambulate within days of each
procedure. Courtesy of Jeffrey P
Kochan MD, Temple University
Hospital, Philadelphia, PA

Fig. 2.21 Scurvy. a shows

diminished bone density, thinning
of cortices, ring epiphyses of
distal femurs (arrows), and
subperiosteal calcifying
hematomas (short arrows). Note
fracture of the R distal femur
through scorbutic zone, causing
lateral slipped distal femoral
epiphysis (long arrow). b reveals
increased density of the zone of
provisional calcification in distal
tibia and fibula (arrows). c
demonstrates that the fracture has
healed without shortening of the
femur. The epiphysis is centrally
located (arrow). Distal femur is
undergoing remodeling and will
be similar to the left femur after
completion of the remodeling
process
A B C

which the enchondral growth of bone is most rapid, e.g., the centers becomes thicker than normal and, combined with the
wrists, knees, and costochondral junctions. thin, sparse trabeculae of the center, results in a radiographic
The zone of provisional calcification in the physeal plate appearance described as “ring epiphysis” or Wimberger ring
forms normally, but it shows increased density (Fig. 2.21b). (Fig. 2.21a).
This is known as the white line of Frankel. There is a radi- The bone cortex becomes thin as a consequence of bone
olucent band adjacent to the zone of provisional calcification, resorption and deficient periosteal new bone production. The
the so-called Trummerfeld zone or the “scorbutic zone.” This trabeculae become small as a result of continued resorption
band may be evident first at the periphery of the metaphysis of bone combined with defective formation of new bone.
and present as a notch at the metaphyseal margin, the cor- Many of the finer trabeculae completely disappear.
ner sign. Fractures through this zone superficially suggest In untreated scurvy, subperiosteal hemorrhage appears on
epiphyseal separations but are really subepiphyseal; hence, radiographs only as a vague, irregular shadow of soft tissue
healing occurs without disturbing the bone growth. These density adjacent to the cortex of the bone. Once the scurvy
fractures are responsible for lateral spurring at the end of the is treated and healing begins, the subperiosteal hematomas
shaft, the so-called Pelkin spur (Fig. 2.21a). calcify peripherally and appear as large juxtacortical densi-
Epiphyseal centers are affected in the same way as is the ties. This is probably one of the earlier radiographic signs of
metaphysis. The zone of provisional calcification around the healing.
2 Systematic Approach to Metabolic Diseases of Bone 33

Fig. 2.22 Scurvy. a shows

enlargement of several of the left
costochondral junctions (arrows),
the so-called scorbutic rosary.
Note the lucency, the scorbutic
zone, adjacent and proximal to
dense epiphyseal zone of
calcification of the right upper
humerus (short arrow). b shows
extensive calcified subperiosteal
hematoma that should not be
mistaken for periosteal reaction
or myositis ossificans. Given the
required time calcified hematoma
will be absorbed

A B

Prognosis temperature regulation with hypothermia, nodular twisted

hair, tortuous vessels, and osseous alterations. The last are
characterized by metaphyseal spurs, flaring of the anterior
Scurvy is a preventable disease and one that is readily
end of the ribs, periosteal new bone and in the skull, Wormian
amenable to dietary adjustment. Moreover, massive doses of
bones (sutural bones). Within months of birth, osteoporo-
vitamin C do not produce toxicity. Unless scurvy has been
sis becomes apparent. Patients frequently die early in life
present for a long time, all signs of its presence are reversed
because of sepsis.
by adequate therapy.
Nutritional copper deficiency may be encountered in
malnourished infants who have been rehabilitated on a
high-calorie, low-copper diet (milk). These patients develop
osseous alterations similar to those found in Menke syn-
Copper Deficiency drome. Similar alterations in bones can also be seen in small
infants receiving total parenteral alimentation (Fig. 2.23). In
Although rare, both congenital and acquired deficiencies of infants with chronic intestinal malabsorption and in prema-
copper have been described. The congenital form is Menke ture infants, anemia and neutropenia develop in addition to
kinky hair syndrome, and the acquired type results from
nutritional deficiency of copper. The radiological manifesta-
tions of copper deficiency resemble those of scurvy because
in both, collagen is deficient and improperly constituted
causing poor bone formation and osteoporosis. As opposed
to scurvy where ascorbic acid itself is lacking, in acquired
copper deficiency the pathology relates to copper require-
ments of ascorbic acid oxidase.
When copper is deficient, many systems are affected: red
blood cells, leukocytes, hair, bones, and blood vessels – from
impaired formation of collagen and elastin; and in the brain,
copper deficiency results in a failure of myelinization.
Menke syndrome is a sex-linked recessive disorder that
results in a defect in the intestinal absorption of copper.
Parenteral administration of copper may be therapeutic. In
patients with this disease, levels of serum copper and ceru- Fig. 2.23 Copper deficiency. The patient is a premature hyperali-
loplasmin are low. Infants with this disease are susceptible mented infant. Note periosteal reaction in both femurs (arrows) and the
to infection, have convulsions, mental retardation, unstable presence of osteopenia
34 A. Bonakdarpour

osseous abnormalities. Osteoporosis is noted early and is tor control induced by the inciting event leads to osteo-
associated with retardation of bone development, resulting in porosis. Precipitating factors are numerous and include soft
a retarded bone age. Periosteal new bone may also develop. tissue injury, arthritides, infection, fractures, sprains, dislo-
cations, and operative procedures. RSD has been reported
in association with central nervous lesions such as brain
Endocrine Osteoporosis tumors and severe head injury as well as myocardial infarc-
tion, cervical osteoarthritis, and other causes. These changes
Estrogen, androgens, or a combination of the two is usually affect an entire extremity or the distal portion of
necessary for normal osteoblastic activity. Hypogonadism an extremity such as hand or foot. It may occur along
related to ovarian agenesis (Turner syndrome) and testicular the distribution of a single nerve involving a portion of a
dysgenesis (Klinefelter syndrome) may be associated with hand.
osteoporosis. Radiological Findings: Early on radiographs of patients
Excess cortisol (the major adrenocorticoid) producing with RSD show only soft tissue swelling that corresponds
Cushing syndrome/disease may also lead to osteoporosis. to the clinical findings of swelling, vasomotor tissue discol-
Iatrogenic Cushing syndrome is caused by long-standing use oration, and hyperesthesia. Later the swelling decreases and
of corticosteroids in systemic diseases such as systemic lupus patients’ radiographs appear normal, or they show osteope-
erythematosus or rheumatoid arthritis. Besides osteoporosis, nia. Eventually, if not treated, the musculature of the affected
steroids may also cause ischemic necrosis of the bones, espe- part atrophies and patients develop osteoporosis.
cially femoral heads, humeral heads, and femoral condyles.
The osteoporosis that results from thyrotoxicosis is
believed to be caused by the high rate of catabolism of pro-
teins that it induces and hence a lack of substrate to form Osteogenesis Imperfecta
osteoid. Osteoporosis in diabetes mellitus occurs from diver-
sion of substrate proteins into much needed glycogen.
Osteogenesis imperfecta is discussed in Chapter 13. Please
see also (Fig. 2.11 )of this chapter.

Stress Deficiency Osteoporosis

(Disuse Atrophy)

The physiology of stress remodeling of bone is discussed in

Chapter 5. According to Wolff Law, dynamic loading of a
bone induces remodeling and bone formation; the absence of
load causes bone to reabsorb. Thus, immobilization of a limb
will cause bone reabsorption with consequent osteoporosis.
Signs of disuse osteoporosis may be noted after only a few
weeks of complete bed rest. If a limb is immobilized in plas-
ter, the osteopenia is more dramatic. Space flights likewise
cause osteoporosis due to weightlessness.

Reflex Sympathetic Dystrophy

Reflex sympathetic dystrophy (RSD), also known as causal-

gia, Sudeck atrophy, algoneurodystrophy, and several other
names, is a syndrome of pain, hyperesthesia, vasomotor
disturbances, and dystrophic changes that may improve
with sympathetic denervation. RSD usually develops follow-
ing an injury, even one that is deemed insignificant. Pain
Fig. 2.24 RSD. Coned down radiographs of the first and second digits
swelling and a dramatic patchy decrease in bone substance
of both hands show reflex sympathetic dystrophy (RSD) of the right
develop (Fig. 2.24). Although not proven, it is believed that hand, compared to the normal on the left. There is diminished bone
increased blood flow from a neurogenic loss of vasomo- density of the right hand
2 Systematic Approach to Metabolic Diseases of Bone 35

Idiopathic Juvenile Osteoporosis

Idiopathic juvenile osteoporosis is a rare disease that clin-

ically begins about 2 years before puberty in otherwise
healthy children who complain of back pain or ankle or
knee pain from metaphyseal infractions. Although diaphy-
seal fractures may occur, metaphyseal injuries are typical
of this entity. There is no sex predilection. Serum calcium,
phosphorus, and alkaline phosphatase are normal. The only
consistent finding is a low positive to markedly negative cal-
cium balance, usually correlating with clinical and radiologi-
cal findings. Mild, moderate, and severe forms of the disease
have been described. Idiopathic juvenile osteoporosis is self-
limiting, but if significant trabecular bone is lost, the bone
mass and hence its radiological appearance do not return to
normal.
Radiological Manifestations: Patients have generalized
osteoporosis, vertebral body deformities in the form of fish
vertebrae or compression fractures. They also develop meta-
physeal and occasionally diaphyseal fractures in the long Fig. 2.25 Homocystinuria. Lateral lumbar radiographs showing spinal
bones. changes in a 15-year-old patient with homocystinuria. Radiologic
changes are very similar to those of osteogenesis imperfecta and other
types of childhood osteoporosis. Note severe fish vertebrae and thick-
ening of the vertebral endplates
Homocystinuria
The demineralization is transitory and typically occurs
Homocystinuria is an autosomal recessive disease caused in the lower extremity, particularly the proximal femur.
by an inborn error of methionine metabolism. Clinically, Regional migratory osteoporosis and transient osteoporo-
patients have mental retardation, dislocation of the optic sis may be examples of the same spectrum of disease
lens (typically into the anterior chamber of the globe), with migration being a relatively uncommon manifestation.
thromboembolic disease, and osteoporosis. They may have Rarely, it may be associated with spinal osteoporosis. The
a Marfan-like appearance and seizures. Some cases respond diagnosis is now made accurately on MR imaging of the
to pharmacologic doses of vitamin B6. Homocystine is found
in the urine.
In early life, usually no radiological changes are visible in
the skeleton. In the growing skeleton, patients may develop
accelerated formation of the hamate and capitate in the wrist
and the cuboid and lateral cuneiform in the foot. Arachn-
odactyly may be present, but it is not as marked as in Marfan
syndrome.
Osteoporosis with vertebral flattening, biconcavity
(Fig. 2.25), anterior wedging, kyphosis, and scoliosis may
be seen. Elongation of the long bones, metaphyseal flaring,
and joint deformity may be present. Sometimes prominent
growth arrest lines are observed.

Idiopathic Regional Migratory Osteoporosis

This is a disorder of unknown etiology with multiple

episodes of articular pain and regional osteoporosis. Once Fig. 2.26 Transient osteoporosis. In May 2007, this 34-year-old female
physician presented with right hip pain in immediate postpartum period.
considered a disease state of the third trimester of pregnancy,
AP and frog-leg radiographs of the right hip show mild osteopenia of the
it is now known to be more common in men around the third proximal right femur, more pronounced in the frog-leg view. Courtesy
decade of life. of Dr. Mahvash Rafii, New York
36 A. Bonakdarpour

A B
Fig. 2.27 Transient osteoporosis. Same patient as in Fig. 2.26. a is suppressed MR image showing increased signal intensity consistent
the axial T1-weighted MR image of the hips revealing decreased sig- with bone marrow edema (arrows). Courtesy of Dr. Mahvash Rafii,
nal intensity of the right femoral neck, extending to the femoral head, New York
and sparing the subchondral region. b is the axial T2-weighted, fat-

hip with normal or equivocal findings on radiographs (Figs. available calcium, phosphorus, or both in the fluid that per-
2.26, 2.27, 2.28, and 2.29). For further information, refer to meates osteoid. A number of mechanisms lead to this defi-
Chapter 5. ciency including inadequate dietary intake, defective absorp-
tion through the gut wall, and failure of the kidneys to con-
serve the mineral supply. During pregnancy and during the
Inadequate Osteoid Mineralization periods of accelerated growth, there is increased demand
for mineral and this may outstrip a tenuous level of intake.
A variety of skeletal diseases have normal or near-normal In other diseases such as hypophosphatasia and vitamin D-
osteoid production but mineralization is defective. More than dependent rickets, mineral supply may be normal but the
30 different etiologies cause clinical syndromes related to formed osteoid may not accept it.
disturbances of matrix mineralization. In the majority of The common denominator in all these conditions is a
these diseases, the pathology lies in an inadequate amount of lack of osseous rigidity (increased elasticity) in the immature
skeleton at sites of growth and in mature bones at points of
stress where turnover (physiologic lysis plus replacement) is
most rapid. Defective mineralization becomes apparent first
at sites of rapid growth because of the high rate of bone pro-
duction.
Several approaches have been used to classify the diseases
associated with osteomalacia. An etiologic approach is prob-
ably most practical. In a comprehensive review of the subject,
Mankin classified rickets and osteomalacia on a pathophysi-
ological basis. Table 2.4 represents a modified classification
of the most important of these diseases.
All these conditions are called rickets when they occur in
growing bone and osteomalacia if they involve the mature
skeleton. We discuss nutritional rickets and osteomalacia as
the archetype of most of these diseases, followed by discus-
sion of some of the more important specific diseases (Table
2.4).

Rickets
Fig. 2.28 Transient osteoporosis. The same case as Fig. 2.27. Coronal
STIR MR image also shows increased signal intensity consistent with
bone marrow edema of the right femoral head and neck. Courtesy of Dr. Rickets is a disturbance in the formation of bone in the grow-
Mahvash Rafii, New York ing skeleton caused by a failure of deposition of mineral
2 Systematic Approach to Metabolic Diseases of Bone 37

Fig. 2.29 The same case as Fig.

2.28. Transient osteoporosis
follow-up MRI in October 2007.
a is the T1-weighted coronal
image of the right hip and b is the
coronal STIR image of the pelvis
including both hips. Both images
show resolution of bone marrow
edema and normal signal
intensity of the right proximal
femur. The patient was
asymptomatic at this time.
Courtesy of Dr. Mahvash Rafii,
New York

A B

Table 2.4 Etiological classification of rickets and osteomalacia within the organic matrix of cartilage and bone at the growth
1. Deficiency states plate. The failure may result from a deficiency in the dietary
a. Vitamin D deficiency intake of calcium or phosphorus to a failure of adequate
b. Calcium deficiency absorption through the gut wall or other causes presented in
c. Phosphorus deficiency
Table 2.4.
d. Solar irradiation deficiency
e. Rickets of prematurity
Because active rickets is manifested only in the growing
2. Absorptive skeleton, its expression is seen in the first period of rapid
a. Gastrointestinal abnormalities growth, between 6 months and 3 years, though its effect
b. Hepatobiliary disease may be encountered earlier. Less severe form rickets may not
c. Pancreatic abnormalities manifest themselves until the prepubertal years.
3. Hereditary renal tubular diseases (renal rickets) Economically advanced nations have learned that it is pos-
a. Vitamin D-dependent rickets (VDDR) sible to prevent nutritional rickets even among its less advan-
i. Autosomal recessive
taged citizens. Both calcium and phosphorus are ubiquitous
b. Vitamin D refractory rickets (VDRR)
i. X-linked dominant in milk and other dairy products. Today, an inadequate intake
ii. Autosomal dominant, recessive or sporadic (Rare) of vitamin D in infancy and early childhood is the most com-
c. Vitamin D refractory rickets with glycosuria mon cause of nutritional rickets. In lieu of sun exposure as a
d. Fanconi syndromes means to vitamin D formation, synthetic preparations of vita-
i. Autosomal recessive form min D, also in milk, have all but eliminated this form of rick-
ii. Lowe syndrome ets. Only in underdeveloped nations with low sun exposure,
iii. Wilson disease
populations suffering from famine and cults with dietary
iv. Tyrosinemia
v. Lignac-Fanconi syndrome
eccentricities does advanced rickets occur in numbers.
a. Renal tubular acidosis (distal tubular) Rarely severe fibrocystic disease of the pancreas or more
b. Autosomal dominant with variable penetrance often celiac disease may interfere with calcium absorption
4. Renal osteodystrophy (uremic osteopathy) to an extent that insufficient calcium is absorbed through the
5. Iatrogenic gut. In these diseases, calcium binds to fats and passes in the
a. Anticonvulsant therapy stool.
b. Intravenous hyperalimentation
Rickets has been reported in premature infants of very
c. Nonabsorbable antacids
d. Peritoneal dialysis
low birth weight with increasing frequency. The pathogen-
e. Hemodialysis (amyloidosis – B2 microglobulin – 100% esis is probably metabolic, nutritional, and in some cases
involvement in adults following 15 years of dialysis) iatrogenic.
6. Tumor related
7. Miscellaneous
a. Hypophosphatasia Radiological Manifestations
b. Vitamin D refractory rickets, type II
c. Atypical axial osteomalacia
Radiographic changes of rickets are best illustrated in the
long bones (Fig. 2.30). Although generalized osseous alter-
38 A. Bonakdarpour

Fig. 2.30 Nutritional rickets. AP

radiograph of the knees
demonstrates diminished bone
density, haziness of epiphyseal
contour, paint brush appearance
of metaphysis and decreased
density of the zone of provisional
calcification of the femur and
tibia on both sides

ations occur, the first and most apparent are found at sites
where the growth of bone is most rapid, e.g., the wrist, knees,
and costochondral junctions (Fig. 2.31).
The earliest radiographic sign of rickets is haziness, fol-
lowed by disappearance, of the zone of provisional calci-
fication. Radiographic findings in the metaphysis are more
apparent because bone growth is most rapid in this por-
tion of long bones. Radiographically, the width and depth
of the radiolucent physeal cartilaginous matrix interposed
between the epiphyseal center and the metaphysis increases.
Attempts at ossification of the irregularly deposited osteoid
enhance the irregularity of the metaphyseal region, resulting
in a radiographic appearance that has been compared to the
bristles of a paintbrush. Cupping of the ends of diaphyses
of the bones probably results from mechanical factors acting
upon the soft, unmineralized osteoid at the metaphysis.
The smaller trabeculae may undergo complete resorption
so that the bones have nearly similar radiodensity as the soft
tissue marrow. For the same biomechanical reasons as in
osteoporosis, the trabeculae oriented along the lines of stress Fig. 2.31 Nutritional rickets. This is a different patient. AP radio-
accrue mineral and appear prominent. Defective mineraliza- graph of the chest demonstrating rachitic rosary more obviously on
tion leads to deceptively thick cortices, but they are made up the left
2 Systematic Approach to Metabolic Diseases of Bone 39

of poorly ossified osteoid that may show cortical radiolucent

streaks. In the infant, failure of mineralization at the mar-
gins of the cranial sutures creates an appearance of increased
width of the sutures. In the chest, rachitic rosary may be seen
at the costochondral junctions.
Greenstick fractures are common in patients with rickets.
The soft osteoid predisposes to bowing in weight-bearing
bones. Sharply defined, focal areas of decreased density
(Looser zones) may be seen perpendicular to the cortex
and traversing incompletely the shaft of the long bones.
These are rare in childhood rickets but are common in adult
osteomalacia.
When rickets begins to heal, the zone of the provisional
calcification appears at the site it would normally occupy
if there had been no interference with mineralization and
the bone had grown normally. Later the radiolucent meta-
physis fills in with new bone. At this time, the radiographic
appearance of concavity at the diaphyseal ends of the long
bones may be most marked. The epiphyseal centers reconsti-
tute hemispherically since the base of the center grows at a
slower rate than the periphery. The epiphyseal centers failed
to ossify because rickets reappear falsely, suggesting a rapid
increase in the patients bone age (Fig. 2.32). Bowing of the
Fig. 2.33 This is a case of treated rickets with residual bowing defor-
weight-bearing long bones persist after completion of treat-
mity. The deformity will improve with remodeling during growth of the
ment of nutritional rickets (Fig. 2.33), but they eventually patient. This is in contrast to osteomalacia where deformities do not
will remodel and disappear as normal growth continues. improve but remain as sequelae of the disorder
Regardless of cause, the radiological changes of rick-
ets, whether caused by failure of calcium absorption in bil-
iary atresia (Fig. 2.34) or in nutritional rickets, are similar.
Scurvy and rickets may occur simultaneously, in economi- 1. Haziness and later disappearance of the zone of provi-
cally deprived regions of the world, where starvation is often sional calcification.
rampant (Figs. 2.35 and 2.36). 2. Diminished bone density.
Summary of Radiological Manifestations of Rickets: 3. Widening of the physeal plate.
4. Irregularity of the metaphysis.
5. Concavity of metaphysis and later cupping.
6. Coarsening of the trabecular pattern.
7. Cortex deceptively thick initially and later thin.
8. Greenstick fractures.
9. Deformity (bowing of weight-bearing long bones).
10. Looser zones (rare).
11. Blurring of the contour of epiphyseal centers.
12. Rachitic rosary – physeal enlargement and irregularity at
the anterior ends of the ribs.
13. Delayed growth.
14. False widening of cranial sutures.

Prognosis
Fig. 2.32 Nutritional rickets. AP pelvis of another patient with nutri-
tional rickets after treatment. The proximal femoral epiphyses show
Ordinarily, the assurance of adequate intake of calcium and
remineralization. This phenomenon is not related to the growth of the
epiphyses, but it is demonstrating the result of treatment and partial phosphorus and the addition of vitamin D to the diet are
recalcification of the epiphyseal cartilage all that is required to treat nutritional rickets. If the disease
40 A. Bonakdarpour

Fig. 2.34 Biliary rickets. AP

radiographs of the upper (a) and
lower extremities (b) of a
51/2-month-old girl with biliary
atresia showing mild ricketic
changes. Metaphyseal irregularity
(thin arrow) and loss of cortex of
the distal femoral epiphyses
(arrow) are present

A B

does not respond to dietary measures, then other confound- only from differences in the response of growing and mature
ing causes of the rickets should be sought. bone to a deficiency of calcium, phosphorus, or vitamin
D. Full-blown osteomalacia rarely occurs in the western
hemisphere.
Osteomalacia The causes of the inadequate mineral supplies for skele-
tal maintenance are listed in Table 2.4. Dietary deficiencies
Osteomalacia is a disease of mature remodeling bone. The severe enough to cause osteomalacia are rare in industrial
pathogenesis of osteomalacia is exactly the same as that of countries. Nevertheless, there are reports of osteomalacia
rickets. The differences between the two conditions result among vegetarians and diet faddists. There are also reports of

Fig. 2.35 Combined rickets and

scurvy. AP radiographs of the
upper (a) and lower extremities
(b) of a patient with rickets and
scurvy. Bowing and fraying of
the metaphyses are
manifestations of rickets and ring
epiphyses as well as dense
provisional zone of calcification
are manifestations of scurvy A B
2 Systematic Approach to Metabolic Diseases of Bone 41

As with patients suffering from rickets, patients with

latent or early symptomatic osteomalacia, Milkman syn-
drome, may also develop Looser zones or Milkman pseud-
ofractures. These occur more often in the diaphyses of large
cylindrical bones but flat bones, particularly those of the
pelvis, may also be involved. Looser zones may also be seen
in the femoral necks, inferior pubic rami, and medial borders
of the scapulae. They are usually multiple, often symmetri-
cal. They have the appearance that resembles stress fractures
although usually there is no history of trauma.
Some authors have reported an association between osteo-
malacia and femoral neck fractures. Some have postulated
that osteoporotic patients who develop hip fracture may have
subclinical osteomalacia.
As the skeleton softens, weight bearing causes bowing of
the long bones of the lower extremity. The pelvis becomes
flattened laterally causing the pubic bones to protrude
anteriorly.

Fig. 2.36 Combined rickets and scurvy. AP radiograph of the left ribs
Radiological Manifestations
of the same patient as in Fig. 2.34 with combined rickets and scurvy.
Rosary of the costochondral junctions is a manifestation of both disor-
ders, but it is dense related to scurvy
Early in the course of osteomalacia, a coarse trabecular pat-
tern may be the only evidence of pathology. The coarse tra-
becular pattern is a consequence of inadequate mineraliza-
tion of secondary trabeculae; the larger primary trabeculae
osteomalacia in elderly people who eat poorly, the so-called are well seen in contrast with the unossified osteoid and
“tea and toast” diet. soft tissues of the marrow (Fig. 2.37). The weight-bearing
Dietary deficiencies are more common in economically
underdeveloped countries, among those who live on inad-
equate rations and those denied sunlight. Social practices
such as completely covering clothing in women in some
cultures in India and parts of Asia have been reported to
cause osteomalacia from lack of vitamin D as a result of
actinic rays deprivation.
Fat absorption disturbances that result from chronic dis-
ease of the bowel and pancreas may also result in osteomala-
cia. Chronic steatorrhea, sprue, fibrosing pancreatic disease,
disturbances in the biliary duct system, and long-standing
ulcerative colitis may result in conditions that inhibit the
absorption of fat-soluble vitamin D. Unabsorbed fatty acids
may form insoluble soaps with the available calcium in the
bowel. This in turn stimulates bowel motility, causes diar-
rhea, and moves the intestinal contents through the gut too
fast for efficient absorption. The net result is poor absorption
of vitamin D, calcium, and phosphorus from the bowel lumen
to the blood.
A rare type of osteomalacia, known as puerperal or mul-
tiple pregnancy osteomalacia, occurs in young women who
bear several children in rapid succession and nurse them
Fig. 2.37 Osteomalacia. There is diminished bone density, coarsening
between confinements. This practice depletes the skeletal
of the trabecular pattern of bones, and cortical thinning. In the absence
calcium and phosphorus stores in order to meet the demand of Looser zones and deformity, these findings alone do not establish
of the growing fetus and the nursing infant. diagnosis of osteomalacia
42 A. Bonakdarpour

Fig. 2.38 Osteomalacia. a – AP

radiograph of the hip shows
diminished bone density, cortical
thinning, a Looser zone in the
superior border of the femoral
neck (white arrow), and mild
coxa vara. b – AP radiograph of
the femur shows healing Looser
zone on the convex border of the
femur (long arrow). There is a
broad-base osteochondroma-like
bony protuberance at the site of a
healed fracture and/or a Looser
zone along the medial border of
the body of the femur (arrow
head). The short arrow points at a
previous fracture or Looser zone
(osteoid seam). Note lateral
bowing of the femur. Looser
zones and deformities establish
the diagnosis of osteomalacia
A B

long bones, especially femur deform and bow (Fig. 2.38).

In anteroposterior projection the angle between the femoral
neck and the shaft may become more acute, causing coxa
vara deformity (Figs. 2.38 and 2.39). The pelvis and the
spine deform as the result of bone softening (Fig. 2.40).
In the final stages, disuse osteoporosis complicates the pic-
ture so that the bones show severe and marked trabec-

Fig. 2.40 Osteomalacia. There is diminished bone density demon-

strated by cortical thinning, bilateral coxa vara, Looser zones of the
left femoral neck, and body of the left femur (arrows), as well as lev-
oscoliosis of the lower lumbar spine. Note deformity of the pelvis and
lateral bowing of both femurs. Looser zones and deformities establish
the diagnosis of osteomalacia. There is bilateral coxa vara

ular loss and cortical thinning. Looser zones are more

commonly seen.
As already mentioned, Looser zones or pseudofractures
are transverse lucencies traversing the diameter of bone
incompletely. They are radiolucent by virtue of their com-
position of osteoid and fibrous tissue (Figs. 2.38, 2.39,
and 2.40). Pseudofractures may be seen in other conditions
such as Paget disease and fibrous dysplasia. When they
Fig. 2.39 Osteomalacia. There is diminished bone density shown by
occur in bones that otherwise have a normal appearance,
thinning of the cortices (arrow). A healing Looser zones (osteoid seam)
is present in the left femoral neck (long arrow). Note the presence of Looser zones strongly suggest the presence of osteomala-
moderate coxa vara cia. Looser zones are more commonly seen in the pubic
Other documents randomly have
different content
devait ouvrir le feu en tirailleur, M. Guizot faire tête au ministre, et
M. Thiers achever la déroute. Du reste,—était-ce par égard pour les
scrupules du chef des doctrinaires?—on ne devait pas proposer le
rejet du crédit, ni chercher à renverser le cabinet de vive force; on
croyait arriver au même résultat, en l'affaiblissant, en le
déconsidérant, «en l'aplatissant»—c'est le mot dont on se servait—
par une discussion qui mettrait au grand jour son impossibilité de
vivre.

Le débat s'engage, le 12 mars 1838. Tout marche d'abord suivant

le plan arrêté. À la fin du premier jour, M. Jaubert prononce un
discours très-vif, très-mordant; il conclut au vote des crédits, mais
les accorde au gouvernement du Roi, non au ministère; et, usant
d'une formule empruntée aux polémiques de 1830, il déclare les
voter quoique demandés par M. Molé et non parce que[318]. Il
n'épargne aucun sarcasme au cabinet, l'accuse de donner «le
spectacle de l'impuissance, du discrédit», et de pratiquer la maxime
diviser pour régner: tactique imprudente, ajoute l'orateur, qui
pourrait bien avoir pour résultat inattendu de réunir tout le monde
contre lui. Le soir, les coalisés, rassemblés chez la duchesse de
Massa, sont tout entrain de leur début; ils croient tenir la victoire; M.
Guizot et M. Thiers rient ensemble et se communiquent leurs projets
de discours.

La séance du 13 est occupée par des orateurs secondaires. Le 14,

M. Molé prend la parole. Il ne cherche pas sans doute à définir sa
politique beaucoup plus amplement et plus nettement que dans les
discussions précédentes; mais il porte la tête plus haut, le ton est
plus ferme, plus hardi, plus fier, tout en gardant la distinction froide
et d'apparence sereine qui est comme la marque de cet orateur. «Ce
que nous venons vous demander, dit-il tout de suite, ce n'est pas de
l'argent, c'est votre confiance.» Prenant l'offensive, il met en
demeure les doctrinaires de déclarer si M. Jaubert a parlé en leur
nom: «Ce n'est pas nous, dit-il, qui avions demandé à l'honorable
orateur l'alliance; ce n'est pas nous qui l'avons rompue; mais, qu'il le
sache, nous refusons tout vote et tout appui motivés comme les
siens.» Il raille son contradicteur de ne pas oser repousser les fonds
secrets, par crainte de se trouver détaché de la majorité qui soutient
le cabinet. Vient ensuite une sortie contre ces hommes possédés de
«l'esprit de domination», qui «se placent à côté du pouvoir pour le
morigéner», et qui, ayant proclamé le ministère «mort-né», ne lui
pardonnent pas «sa durée et son succès». Enfin, se retournant vers
les masses conservatrices de la Chambre: «Messieurs, c'est à vous
maintenant à porter votre arrêt. Vous arrivez de tous les points de la
France, vous savez quel mandat vous avez reçu. S'il nous est
contraire, si l'on vous a dit:—Hâtez-vous, allez renverser les
dépositaires du pouvoir; si l'on vous a dit:—Le ministère qui a fait
l'amnistie n'a pas notre confiance, remplissez votre mandat,
Messieurs; nous saurons y obéir. Mais si, au contraire, on vous a dit:
—Secondez ce ministère, donnez-lui l'appui dont il aura besoin pour
lutter contre les passions de plus d'une nature coalisées contre lui,
alors, entourez-le de votre confiance et donnez-nous enfin le moyen
de faire le bien.» Cet appel habile et digne paraît favorablement
accueilli. Rien cependant n'est décidé: les grands orateurs ne sont
pas encore entrés en ligne.

Voici M. Guizot à la tribune. Au début, on peut croire qu'il va

s'engager à fond: il s'associe à ce qu'a dit M. Jaubert. Mais aussitôt,
comme effrayé de se trouver séparé du centre, il proteste qu'il ne
veut pas prendre une attitude d'opposition, ni «presser le
renversement du ministère». Ce n'est pas qu'il soit satisfait. «Notre
situation n'est pas bonne, dit-il; au lieu de se fortifier, le pouvoir
s'affaiblit; au lieu de s'élever, il s'abaisse; au lieu de s'organiser, la
société tâtonne et se disperse.» Il dénonce, dans la Chambre,
«l'esprit d'opposition»; dans le gouvernement, «l'esprit d'hésitation»,
mais sans sortir des généralités vagues, des dissertations froides.
L'auditoire est étonné, déçu. Si réservée que soit la critique de
l'orateur, elle est assez visible pour déplaire au centre, mais trop
embarrassée pour lui en imposer. Quant au centre gauche, il est
irrité de voir sa campagne ainsi compromise, et murmure les mots
de défection et de trahison. De là, une malveillance croissante de
l'auditoire qui réagit sur l'orateur, et rend plus gênée encore sa
parole d'ordinaire décidée et superbe. Quand il descend de la
tribune, l'Assemblée demeure morne et glaciale. Quel contraste avec
les ovations qui lui avaient été faites, en 1836 et en 1837, dans ces
mêmes discussions sur les fonds secrets! On en vient à se demander,
les uns avec mélancolie, les autres avec une satisfaction jalouse, si
l'orateur n'est pas «fini». «M. Guizot, écrit, le surlendemain, de Paris,
M. de Barante, a fait, pour la première fois, un fiasco complet: la
désolation est dans son camp. Moi-même, son vieil ami, le cœur m'a
saigné de sa mésaventure, tout en blâmant sa fausse
manœuvre[319].»

Fort démontés par cet insuccès, les coalisés n'ont plus d'espoir
qu'en M. Thiers. Mais celui-ci, considérant la partie comme perdue et
préférant se réserver pour une meilleure occasion, demeure
immobile et silencieux. À sa place, on entend M. Passy dénoncer la
politique «décolorée et vacillante» du cabinet. M. Molé était sauvé.
Quelques mots de réplique lui suffisent pour clore le débat. Un
amendement de M. Boudet, tendant à réduire de 300,000 francs le
chiffre du crédit, est repoussé par 233 voix contre 184, et l'ensemble
de la loi est voté par 249 voix contre 133.

Peu après, le 6 avril, ces crédits étaient également votés par la

Chambre des pairs, non sans que le ministère eût à subir les
épigrammes de M. Villemain et de M. Cousin, et à entendre les
graves réserves du duc de Broglie[320]. Celui-ci aurait préféré garder
le silence, mais le ministère, exalté par son succès dans l'autre
Chambre, n'avait pu se retenir de provoquer la contradiction. Un des
amis de M. Molé, M. de Brigode, avait prononcé un discours
sarcastique contre ceux qui, tout en désapprouvant la politique du
cabinet, n'osaient pas cependant conclure au rejet des crédits,
raillant «cette opinion entortillée qui consiste à distribuer le blâme en
même temps que l'argent». Sans doute, il faisait allusion, en termes
respectueusement élogieux, à la réserve désintéressée du duc de
Broglie, mais c'était pour mieux accabler les doctrinaires de l'autre
Chambre, ces «candidats ministres qui ne peuvent plus vivre sans
portefeuille». Si désireux qu'il fût de demeurer à l'écart, le duc se
crut obligé de défendre ses amis. Après avoir protesté sévèrement
contre cette façon d'attaquer les membres d'une autre Chambre, il
contesta qu'il n'y eût pas de milieu entre le rejet des crédits et
l'approbation complète du ministère. Quant à lui, il déclarait accorder
les fonds secrets, parce que la sûreté du Roi et la tranquillité du pays
étaient en jeu; «mais si l'on veut, ajoutait-il, dénaturer mon vote;
mais si l'on veut, à toute force, le transformer en acte d'adhésion
pure et simple à la politique du cabinet... je proteste hautement... Si
je pensais, comme je le pense en effet dans une certaine mesure,
que la situation présente des affaires n'est rien moins que
satisfaisante; si je pensais que c'est une situation triste, fâcheuse et
précaire; si je pensais que l'ordre, rétabli à la vérité dans les rues,
sur la place publique, n'est pas le progrès, tant s'en faut, dans les
idées, dans les intelligences; si je disais enfin que le gouvernement
n'exerce pas, sur la Chambre et sur le pays, l'ascendant que je
voudrais lui voir exercer, et que la politique du cabinet, celle qui lui
est propre, spéciale, favorise plus qu'elle ne combat cet
affaiblissement du ressort de l'autorité,—je ne dirais, Messieurs, que
ce que j'ai le droit de dire en votant les fonds secrets, et je suis
certain qu'on n'aurait aucun droit de m'accuser, pour cela, ni de
duplicité, ni d'ambition déguisée.»

III

La coalition avait débuté par un gros échec. Elle n'en fut pas
dissoute; les alliés continuèrent à se concerter pour la formation des
commissions, pour la nomination des présidents de bureaux, mais
sans entrain, à mi-voix, la tête basse, comprenant que, pour le
moment, toute attaque de front était impossible. Du côté du cabinet,
au contraire, on triomphait. La presse officieuse, devenue
nombreuse, grâce aux subventions libéralement distribuées par M.
Molé[321], semblait vouloir précipiter la déroute par ses sarcasmes et
ses invectives. La Presse dénonçait ces «dix à douze ambitions
insurgées, non pas contre ce que fait le gouvernement, mais contre
l'idée de voir faire par d'autres mains ce que les leurs n'ont pas su
exécuter», ces «amours-propres qui ne peuvent s'accoutumer à
croire qu'on gouverne sans eux». Le Journal des Débats flétrissait ce
qu'il appelait «cette espèce d'émeute d'ambitions impatientes», et il
ajoutait, un autre jour: «Les coalisés s'évertuent à nous dire qu'il n'y
a pas de coalition; nous le savons bien! Nous l'avons déjà dit: ce
n'est qu'une émeute où se sont donné rendez-vous toutes les
prétentions, toutes les rivalités, toutes les jalousies.»

Les doctrinaires étaient ceux qui souffraient le plus de ces

attaques. La presse, qui les maltraitait ainsi, s'adressait à leur
monde, à celui dont l'estime et la reconnaissance les avaient jusqu'ici
consolés de leur impopularité auprès des partis de gauche. Aussi M.
Guizot eût-il vivement désiré prévenir cette hostilité du Journal des
Débats: il avait tâché d'amener à la coalition M. Bertin de Vaux; mais
celui-ci, qui se souvenait d'avoir ouvert son journal à M. de
Chateaubriand, pour y appuyer la coalition contre M. de Villèle,
répondit à son éloquent tentateur: «J'ai pour vous, à coup sûr,
autant d'amitié que j'en ai jamais eu pour Chateaubriand; mais je ne
vous suivrai pas dans l'opposition. Je ne recommencerai pas à saper
le gouvernement que je veux fonder: c'est assez d'une fois.» Les
doctrinaires étaient bien obligés de reconnaître que les sévérités de
la presse conservatrice à leur égard trouvaient écho dans l'opinion.
Leur conduite n'eût pu s'expliquer, sinon se justifier, que par le
succès; avec l'échec, ils apparaissaient non-seulement coupables,
mais maladroits et, par suite, un peu ridicules. «La coalition, écrivait
un observateur, fait beaucoup de tort à M. Guizot et à ses amis, dans
l'opinion de la masse des conservateurs, de tout ce qui tient à la
cour, de tout ce qui, étranger aux passions et aux doctrines de
partis, ne désire que le repos et s'inquiète trop du bruit des luttes
parlementaires pour ne pas condamner, de prime abord, quiconque
les provoque. Beaucoup de personnes qui, jusqu'à présent, voyaient
dans M. Guizot le chef le plus vigoureux des défenseurs de l'ordre
monarchique, ne parlent plus de lui que comme d'un ambitieux
vulgaire[322].»
 Pour se défendre, les doctrinaires n'avaient plus que le Journal
général, de médiocre publicité. En étaient-ils donc réduits à faire
plaider leur cause par les feuilles du centre gauche? Mais celles-ci,
qui, pendant tant d'années, n'avaient vécu que d'attaques contre ces
mêmes doctrinaires, étaient peu disposées à devenir leurs
apologistes; elles eussent plus volontiers récriminé contre la
faiblesse de M. Guizot dans la dernière bataille parlementaire. Aussi
se bornaient-elles le plus souvent à prendre acte et, en quelque
sorte, possession de la nouvelle alliance, ne se gênant pas pour le
faire en des termes fort compromettants pour leurs alliés. «Le
résultat peut-être le plus grave de cette discussion, disait le
Constitutionnel, au lendemain du débat sur les fonds secrets, c'est
que voici les doctrinaires, naguère les défenseurs les plus ardents de
la prérogative royale, engagés dans les voies de l'opposition et
prenant leur part de cette lutte dont chacun comprendra la portée.
Or, le premier pas, dans toute carrière nouvelle, est toujours le plus
difficile à faire, et, celui-là franchi, les doctrinaires, habitués, par la
nature de leur esprit, à pousser toute situation à l'extrême,
laisseront bientôt de côté un reste de scrupule, comme un bagage
gênant pour le combat. En attendant, la majorité du 13 mars, dont
ils étaient les derniers et les plus fidèles champions, est maintenant,
grâce à leur défection, complétement dissoute[323].» Ces
commentaires devaient paraître à M. Guizot et à ses amis plus
pénibles encore que les duretés de la presse conservatrice.

Malgré sa réserve habituelle, M. Molé ne contenait pas la joie que

lui causaient la défaite de ses ennemis et surtout l'humiliation des
doctrinaires. Devait-il donc lui-même se trouver bien à l'aise? Au
début de son administration, il avait cru nécessaire d'avoir toujours
avec lui l'un des grands orateurs, soit M. Guizot, soit M. Thiers. Du
dernier débat, il sortait mortellement brouillé avec tous deux à la
fois. Néanmoins, le plaisir de n'être plus protégé le faisait passer
par-dessus le péril de cette double rupture. D'ailleurs, et surtout
depuis les nouvelles élections, sa tactique, à l'égard du centre
gauche comme du centre droit, était de gagner les soldats en
écartant les chefs. Il ne rêvait pas un déplacement en masse,
déterminé par de grandes idées, par l'autorité d'un programme, par
le prestige d'un drapeau. Il procédait par conquêtes individuelles,
variant ses moyens selon les personnes, selon leurs convictions ou
leurs faiblesses; montrant tour à tour les diverses faces de son
programme; parlant aux uns de résistance, aux autres de
conciliation, à tous de leur intérêt personnel. C'était devenu l'une de
ses principales occupations. Il fallait voir ce grand seigneur prendre
par le bras le plus bourgeois des députés, l'attirer dans l'embrasure
d'une fenêtre, lui faire mille grâces, le traiter d'un air de prédilection
et avec une familiarité caressante. Pour un tel travail, M. Molé avait
des aptitudes particulières; peu d'hommes ont poussé plus loin l'art
de la séduction.

Les adversaires criaient à la corruption; ce n'était pas toujours

sans motif. Non que le ministre acquît à prix d'argent les députés
comme les journaux; mais les faveurs de l'administration, les places
tendaient, de plus en plus, à devenir la monnaie courante avec
laquelle on payait les votes. Sur 459 députés, on ne comptait pas
moins de 191 fonctionnaires: ceux qui ne l'étaient pas eux-mêmes
avaient à caser ou à faire avancer des parents, des amis, des clients.
Ce mal n'était pas né avec M. Molé; il datait du jour où avait été
dissous le cabinet du 11 octobre, où les partis s'étaient trouvés
déclassés, morcelés, mêlés, désorientés, et où les compétitions de
personnes avaient remplacé, au Parlement, les luttes de principes. Ni
M. Thiers, pendant le ministère du 22 février, ni M. Guizot, pendant
celui du 6 septembre, n'avaient été innocents de la faute que, depuis
le 15 avril, leurs amis reprochaient si fort à M. Molé. Tout au plus
celui-ci y était-il tombé un peu plus avant, parce qu'il n'avait, par lui-
même, ni parti préalablement constitué, ni doctrine bien fixe. Il
corrigeait d'ailleurs, ou du moins voilait, par son excellente tenue et
la parfaite dignité de ses manières, ce que la besogne avait parfois
d'un peu suspect. Et puis, ne l'oublions pas: si grave que ce mal
parût alors à une pudeur publique encore facile à effaroucher, il était
limité, et laissait intacte la plus grande partie de l'administration;
depuis, on a fait mieux, et nous avons vu, sous d'autres régimes,
cette administration devenir, sans vergogne aucune, à tous ses
degrés et dans tous ses rouages, une immense entreprise
d'exploitation électorale au bénéfice du parti régnant.

Chez les soldats qu'il cherchait ainsi à détacher de leurs anciens

chefs, M. Molé rencontrait des sentiments, les uns bons, les autres
mauvais, qui facilitaient sa tâche. C'était, dans beaucoup d'esprits
honnêtes, tranquilles, timides si l'on veut, la fatigue des agitations
malfaisantes ou seulement stériles, le scandale produit par des
impatiences et des coalitions ambitieuses qui se laissaient voir trop à
nu; c'était aussi cette réflexion de bon sens que le pouvoir n'était
pas tellement fort qu'on pût impunément le secouer, ni le régime
parlementaire si populaire qu'il fût sans péril de multiplier à ce point
les crises ministérielles. Ceux mêmes qui ne se dissimulaient pas la
faiblesse ou les torts du cabinet, disaient, avec le Journal des
Débats: «Mieux vaut un ministère faible qui vit, que des ministères
forts que leur force n'empêche pas de mourir avec une effrayante
rapidité[324].» On rappelait, en outre, que ce cabinet n'avait en
réalité pris la place de personne, que les grands chefs
parlementaires, invités à refaire le 11 octobre, n'avaient pu
s'entendre, et l'on était fondé à dire avec le même journal: «Eh, mon
Dieu! le ministère a-t-il donc recueilli un héritage de concorde et
d'union? a-t-il dissipe des trésors de paix et de force?» C'étaient là
les bons sentiments. En voici qui l'étaient moins. Plus d'une fois,
depuis 1830, nous avons dû noter, dans la Chambre, ce prétendu
esprit d'indépendance qui n'était qu'une impatience démocratique de
toute discipline, de toute hiérarchie, et surtout une révolte des
médiocrités jalouses contre les supériorités intellectuelles et sociales.
Contenu, pendant plusieurs années, par un autre sentiment, d'un
ordre aussi peu relevé, mais au moins plus raisonnable, par la peur,
il s'était épanoui librement, dès que le danger avait diminué. De là,
ces instincts tracassiers et envieux, ces amours-propres sans cesse
offusqués, qui trouvaient toute subordination intolérable; de là, cette
tendance à se détacher par degrés des chefs naturels pour en
chercher d'autres moins imposants, à dissoudre les grands partis
pour former de petits groupes, par cette seule raison qu'il est plus
facile d'être important dans un petit groupe que dans un grand parti.
Déjà Casimir Périer avait eu à combattre ces mauvais sentiments, et
le ministère du 11 octobre, après avoir continué la lutte, avait fini
par y succomber. Pour les députés atteints de ce mal, n'était-ce pas
une nouveauté agréable que de se voir invités par le gouvernement
lui-même à secouer le joug des hommes en renom, à rompre le peu
qui restait des liens de parti? «La manie d'indépendance, disait un
contemporain, est flattée de la pensée qu'au moment où les chefs
des diverses fractions de la Chambre se réunissent dans une
combinaison, il dépend de leurs obscurs adhérents de la faire
manquer en se séparant d'eux. Ce sentiment, qui tient à l'état
général des esprits, est ménagé avec assez d'adresse par M. Molé et
par les journaux qui dépendent de lui. La Revue de Paris ne disait-
elle pas, ces jours derniers, qu'il ne fallait pas faire du gouvernement
représentatif le despotisme des talents supérieurs[325]?» Plus on
répétait à ces députés que M. Molé était inférieur en éloquence et en
prestige à ses rivaux, plus leur amour-propre se trouvait à l'aise avec
lui. «Mon cher monsieur Guizot, disait le Roi au chef des
doctrinaires, vous voulez former dans la Chambre un parti; vous
voulez la gouverner comme on gouverne un parti. Cela ne se peut
pas avec nos petites gens, avec notre démocratie envieuse. Pourquoi
est-ce qu'on vous en veut, à vous? Parce que vous voulez vous
placer haut et vous y tenir ferme. On aime mieux M. Molé, parce
qu'il a moins de prétention et de fermeté[326].» Une faveur ainsi
fondée n'était-elle pas bien fragile et même dangereuse? Quand il
caressait, excitait, exploitait ces médiocrités vaniteuses et jalouses,
le président du conseil ne faisait-il pas un peu comme ceux qui, pour
s'emparer du pouvoir, fomenteraient l'indiscipline dans l'armée, et
qui, une fois arrivés, ne sauraient où trouver des soldats soumis et
fidèles?

M. Molé parvenait en effet assez facilement à détacher de M.

Thiers, et surtout de M. Guizot, plusieurs des députés qui les avaient
suivis jusqu'alors. Mais voulait-il, de ces mêmes éléments, se faire
une majorité, il se heurtait à cette indépendance qui avait pris goût
à ne subir aucun lien, à n'accepter aucune prééminence. En fin de
compte, il n'avait fait qu'augmenter la désagrégation des partis,
l'émiettement de l'Assemblée. Au lendemain de cette discussion des
fonds secrets, où il avait cru mettre définitivement la coalition en
minorité, le triomphe des opposants dans l'organisation des
bureaux[327], ou le rejet de quelqu'un de ses projets, lui faisait sentir
son peu d'influence sur la Chambre. Dès le 7 février, M. de Barante,
favorable cependant à M. Molé, écrivait: «Cette Chambre est dans
un état d'éparpillement dont on peut s'affliger et s'inquiéter. Aucune
opinion ne la rallie, aucun nom propre n'agit sur elle, hormis en
méfiance. Chacun vote et parle à sa fantaisie, sans nulle déférence
pour qui que ce soit, ni quoi que ce soit. La manie démocratique a
fait de grands progrès. Le repoussement de toute hiérarchie, la
répugnance pour toute discipline est le trait marquant du public et
de la Chambre. Le ministère n'est point directement menacé par
cette situation fâcheuse sous le rapport moral, alarmante pour
l'avenir, mais encore sans action sur la politique, encore sans péril
pour le présent. On ne veut ni de M. Thiers, ni de M. Guizot; M.
Dupin est devenu odieux à presque tous; il n'est pas question de M.
Barrot; mais M. Molé, quoiqu'il convienne autant qu'il est possible,
n'aura, sur chaque question, qu'une majorité nécessaire, sans
dévouement, sans tenue. Sa vie ministérielle sera désagréable,
même quand elle ne sera pas difficile. Il sera contraint de se
préoccuper des embarras de la journée, de veiller, à chaque
moment, sur les tours qu'on voudra jouer, non point à lui, mais au
pouvoir qu'on ne cherche ni à honorer ni à affermir, bien au
contraire[328].»

IV

Dans de telles conditions, l'œuvre législative ne pouvait avancer

que péniblement: la session ne fut pas cependant stérile. Grâce
surtout au concours de la Chambre des pairs, à la fois plus
compétente que celle des députés, et moins absorbée par les
intrigues parlementaires, les ministres parvinrent à faire voter
plusieurs lois d'un grand intérêt pratique, sur l'extension de la
juridiction des juges de paix[329], sur le régime des aliénés[330], sur
les faillites[331], sur les attributions des conseils généraux[332]:
encore ne parlons-nous que des lois qui furent alors complétement
terminées, et négligeons-nous les projets secondaires. Seulement, le
gouvernement eût voulu davantage. Combien de ses propositions
échouaient ou se trouvaient dénaturées par les caprices de la
Chambre! «Ceux mêmes des députés qui ne voudraient pas voir
tomber le ministère, écrivait alors un observateur, s'habituent à ne
tenir aucun compte de sa volonté, à écarter ou à bouleverser
impitoyablement tous ses projets, à lui rendre en un mot la vie aussi
dure que possible. Voilà ce que beaucoup de niais appellent
l'indépendance. En vérité, on se croirait revenu aux illusions puériles
de 1789, sur la séparation absolue du pouvoir législatif et du pouvoir
exécutif[333].»

Parmi les projets ainsi maltraités, on peut citer celui qui élevait à
dix mille francs la pension de la veuve du général Damrémont,
commandant en chef de l'armée d'Afrique, qui venait de succomber
héroïquement, en pleine victoire, sous les murs de Constantine:
circonstances exceptionnelles qui justifiaient le chiffre élevé de la
pension. M. Molé fut appuyé, cette fois, par M. Guizot et M. Thiers.
«Ne faisons pas dire, s'écria ce dernier, que le résultat d'un
gouvernement de discussion est de tout amoindrir, de tout
dessécher. Montrons au contraire qu'une grande nation peut discuter
ses affaires, sans devenir petite, sans refuser aux braves qui
meurent pour elle, la récompense qui leur est due... Si vous étiez
exposés à voir les finances de l'État compromises par des faits
semblables, à la bonne heure! mais quant à les voir compromises
par des actes héroïques, je suis rassuré: il n'y en aura jamais assez
pour que vos finances puissent périr.» Vainement toutes les autorités
gouvernementales et parlementaires, d'ordinaire divisées, se
réunissaient-elles dans un même effort, on put juger par le vote
combien peu elles pesaient devant l'«indépendance» des députés et
aussi devant leurs préventions mesquines. La majorité repoussa le
chiffre du gouvernement et ne vota qu'une pension de 6,000
francs[334].
 Peu de questions étaient alors aussi importantes et urgentes que
celle des chemins de fer. La France se trouvait en retard sur plus
d'un pays voisin. Déjà, en 1837, le ministère Molé avait, sans succès,
présenté à la Chambre un premier projet d'ensemble. Il en présenta
un nouveau en 1838[335]. Le plan n'était pas sans hardiesse: il
comprenait neuf lignes principales, dont sept, partant de Paris,
aboutissaient à la frontière belge, au Havre, à Nantes, à Bayonne, à
Toulouse, à Marseille, à Strasbourg; les deux autres allaient de
Bordeaux à Marseille, et de Marseille à Bâle: soit onze cents lieues
de voies ferrées et une dépense d'un milliard. Pour le moment, on
n'en devait entreprendre que trois cent soixante-douze lieues. La
construction de ce réseau était réservée à l'État. La commission de
la Chambre fit mauvais accueil à ce projet[336]. Elle ne se contenta
pas de critiquer la construction par l'État, de manifester ses
préférences pour l'industrie particulière: sur ce point elle pouvait
avoir en partie raison; le rapporteur, M. Arago, blâma en outre
l'exécution d'ensemble: à son avis, l'art des chemins de fer était
encore dans l'enfance, et il y avait avantage à attendre, pour profiter
des découvertes que feraient les nations plus pressées que nous. La
discussion dura plusieurs jours[337]. Le président du conseil, le
ministre des finances et celui des travaux publics y prirent part. Le
résultat de leurs efforts fut le rejet complet du projet, à l'énorme
majorité de 196 voix contre 69[338].

Non-seulement la Chambre ne votait pas ce que lui demandait le

gouvernement, mais elle votait ce dont il ne voulait pas. La question
de la conversion des rentes n'avait pas fait un pas depuis qu'elle
avait amené la chute du cabinet du 11 octobre. Le 15 février 1838,
M. Gouin déposa de nouveau une proposition de conversion, qui fut
aussitôt favorablement accueillie par la commission chargée de
l'examiner. Nul n'ignorait que le ministère la voyait avec déplaisir, et
que le Roi personnellement y était fort hostile. Quand vint cependant
la discussion, discussion passionnée, approfondie, qui en deux fois
ne dura pas moins de six jours[339], les ministres se bornèrent à
indiquer quelques brèves objections d'opportunité, sans s'engager à
fond. Dans cette matière où rien n'eût dû se faire en dehors de
l'initiative du gouvernement, celui-ci laissait tout débattre et décider
sans lui, malgré lui, gardant une attitude effacée, incertaine, comme
s'il n'avait pas d'opinion, ou plutôt comme s'il se sentait impuissant à
la faire prévaloir. Aussi une immense majorité, 251 voix contre 145,
vota-t-elle sans se gêner la conversion que le ministère eût voulu
écarter. Comme pour mieux marquer le rôle subalterne où elle
prétendait réduire le cabinet, la Chambre lui enjoignit, par une
disposition spéciale, de rendre compte de l'exécution de la mesure,
dans un délai de deux mois à compter de l'ouverture de la session
suivante. Il est vrai que la Chambre des pairs, sur laquelle le Roi usa
personnellement de son influence, repoussa le projet à la presque
unanimité[340]. Ce vote débarrassa le ministère de la question, mais
ne lui rendit pas son autorité sur la Chambre des députés.

Les journaux opposants se gardaient de laisser dans l'ombre tous

ces échecs. Ce n'était dans leurs colonnes que sarcasmes contre les
ministres mis en minorité, sommation de quitter la place. M. Molé et
ses collègues faisaient la sourde oreille, ou bien répondaient, non
sans quelque raison, que ces votes n'impliquaient pas volonté de les
renverser, encore moins désignation de leurs successeurs. Quant à la
mortification subie, ils tâchaient de s'en consoler, en déclarant que
«le temps des majorités systématiques était décidément passé[341]».
«Nous avons un étrange ministère», disait de son côté, avec plus de
malice que d'exacte vérité, un doctrinaire, M. Vitet; «on le met tous
les jours à la porte de la Chambre, honteux et battu; le lendemain,
on râtisse les allées, et il n'y paraît plus[342].»

À regarder le seul Parlement, la session finissait donc mal pour le

ministère. Mais après tout, il restait debout. À la confusion des
prophètes qui lui avaient prédit, dès sa naissance, une mort si
prompte, malgré l'hostilité chaque jour plus acharnée de tous les
grands noms et de tous les grands talents de la Chambre[343],
contre l'attente de tous les spectateurs, il avait duré. Cette durée
pouvait exciter les colères, mais ne permettait plus le dédain.
Personnellement, M. Molé avait grandi: ses adversaires eux-mêmes
étaient obligés de le reconnaître. On ne pouvait nier son habileté et
son bonheur. Il n'était pas jusqu'à son talent oratoire qui n'eût gagné
en aplomb, en ampleur, en énergie, sans rien perdre de sa politesse
simple et sobre. Même après M. Guizot et M. Thiers, et sans pouvoir
leur être comparé, il avait eu des succès de tribune. L'effacement de
ses collègues contribuait à le mettre plus encore en lumière. C'est
bien lui qui recevait et portait tous les coups. Il s'en vantait et s'en
plaignait[344], tout entier à cette lutte, passionnément sensible à
l'amertume des échecs comme à la joie des succès, et trouvant dans
cette sorte d'excitation nerveuse une vigueur physique qui étonnait
ses amis et ses adversaires[345].

M. Molé se sentait fort de l'appui de la Couronne. Jamais Louis-

Philippe n'avait eu un président du conseil autant selon ses goûts.
Avec Casimir Périer et le duc de Broglie, il avait connu des ministres
sûrs, mais incommodes; avec Thiers, un ministre commode, mais
peu sûr. Cette fois, il avait un ministre commode et sûr. M. Molé, tout
en gardant la dignité, même un peu susceptible, de son attitude, ne
cherchait ni à limiter, ni à masquer l'action personnelle du Roi. Sa
première éducation politique sous Napoléon lui avait appris, non à
vouloir régenter ou éclipser son souverain, mais à le servir avec
docilité et intelligence. D'ailleurs actif, passionné même dans ce que
M. Bertin appelait la «grande intrigue politique», le président du
conseil se montrait plutôt de disposition un peu indolente pour les
affaires et n'était pas jaloux de s'en réserver exclusivement la
charge. Louis-Philippe, très-laborieux, au contraire, ne demandait
qu'à la prendre. C'était vraiment lui, maintenant, qui dirigeait notre
diplomatie et traitait avec les ambassadeurs étrangers. Par M. de
Montalivet, il était maître du ministère de l'Intérieur. Au ministère de
la Guerre, le général Bernard acceptait facilement l'intervention
chaque jour plus active, et du reste fort intelligente et fort
patriotique, du duc d'Orléans; presque quotidiennement, lui ou ses
chefs de division allaient travailler avec le prince[346]. La faiblesse
même du cabinet, les mortifications que lui infligeait la Chambre,
tout ce qu'il y avait alors de dérangé et de faussé dans la machine
parlementaire augmentaient et en même temps rendaient plus
visible cette action royale, souvent utile et bienfaisante au fond, mais
qu'il était dangereux, en l'état des esprits, de trop afficher.

M. de Barante, quoique très-prononcé contre la coalition, se

préoccupait alors de ce danger; après avoir indiqué que Louis-
Philippe «se jetait bien avant» dans toutes les affaires, il ajoutait:
«Le Roi a besoin de toute sa prudence pour gouverner une situation
qui n'est pas prudente; il lui faut manœuvrer bien juste et dans les
limites étroites de la Charte, puisqu'il y a évidemment autocratie
dans toutes les questions[347].» Mais ce prince, nous avons déjà eu
plusieurs fois occasion de le remarquer, n'aimait pas seulement à
agir; il aimait à faire voir qu'il agissait: justement confiant dans sa
sagesse et son habileté, il était bien aise que le public fût à même
de lui en savoir gré. La reconnaissance qu'il croyait ainsi obtenir, lui
faisait négliger les préventions qu'il irritait. Aussi, loin de sentir le
besoin de se contenir et de se dissimuler, jouissait-il pleinement
d'avoir grandi le rôle réel et apparent de la Couronne, et, se
rappelant à quels effacements il avait dû se soumettre en d'autres
temps, il se félicitait de l'heureuse habileté avec laquelle, en
quelques années, il avait amené un changement si complet. Dans
cet état d'esprit, il était peu disposé à écouter les observations qui
lui étaient faites sur ce sujet. Un jour, au cours de la session de
1838, M. Dupin crut devoir l'avertir que son intervention «faisait
grief» dans une partie de la Chambre. Louis-Philippe répondit
aussitôt en revendiquant son droit de «diriger ses ministres» et de
les «congédier quand ils lui résistaient». M. Dupin insista; sans nier
que l'action royale ne pût être très-considérable et très-efficace dans
le gouvernement constitutionnel, il soutenait qu'il valait mieux n'en
pas faire montre, qu'elle devait rester une affaire d'intérieur entre les
ministres et le souverain, que celui-ci ne pouvait pas avoir «d'amour-
propre d'auteur», et il ajoutait: «Puisqu'il est de règle que les
ministres sont responsables, pourquoi ne pas leur laisser toute la
responsabilité? N'est-il pas essentiellement avantageux à la
Couronne de se couvrir de l'axiome anglais: Le Roi ne peut mal
faire?—Ah! s'écria vivement le prince, c'est parce qu'il ne fait rien. En
France, un pareil roi serait considéré comme un porc à
l'engrais[348]!» Quelques jours après, causant avec M. Guizot, Louis-
Philippe lui disait: «Je sais que vous ne voulez pas annuler le Roi, me
mettre hors de mes affaires. Je ne le souffrirai jamais. Mais il y a des
hommes qui le veulent; il y en a parmi vos amis[349].»

Le Roi soutenait donc résolûment des ministres qui lui plaisaient,

et ne se gênait pas pour le faire savoir. Les députés conservateurs
étaient informés qu'ils lui seraient agréables en appuyant le cabinet.
Lui-même prenait à part certains d'entre eux, dans les réceptions
des Tuileries, et, avec une grande abondance de conversation,
souvent avec beaucoup d'esprit et d'éloquence, il tâchait de les
amener à voter comme il le désirait: c'est ce qu'il appelait «chambrer
les députés». Il s'employait, en même temps, à rendre plus difficile
l'alliance de M. Thiers et de M. Guizot. Son moyen était de donner à
entendre à chacun d'eux qu'il pourrait prochainement recueillir seul
la succession de M. Molé, et que par suite il ne devrait pas
contracter d'alliance inutile et compromettante. Un jour, par
exemple, en mai 1838, M. Guizot était venu présenter aux Tuileries
une députation d'industriels; Louis-Philippe le retint et causa avec lui
de la situation: «Cela ne peut pas aller, dit-il; cela n'ira pas! Je
n'abandonnerai pas mes ministres. Je soutiens toujours mon cabinet.
Mais si M. Molé m'apportait sa démission, je serais bien
embarrassé...»—M. Guizot: «Le gouvernement représentatif ne
guérit les maux qu'à la dernière extrémité.»—Le Roi: «Cela n'est pas
gai; c'est moi qui suis le malade. Quand vous m'avez proposé, l'an
dernier, un cabinet de vos amis, je n'ai pas osé, j'en conviens.
Depuis, nous n'avons pas gagné de terrain. Je ne sais ce qui
arrivera. J'aurai besoin d'un plan de campagne. Pensez-y. Je vous
demande d'y penser[350].» En même temps, il s'arrangeait pour
qu'on fît entrevoir à M. Thiers une perspective analogue[351]. Le
chef du centre gauche et celui des doctrinaires affectaient de n'être
pas dupes des coquetteries royales; ils en riaient même parfois
ensemble. Mais, au fond, l'idée d'un pouvoir non partagé ne laissait
pas que de chatouiller agréablement l'ambition et le ressentiment de
chacun d'eux. En tout cas, ce langage du Roi n'était pas fait pour
diminuer l'hésitation et la froideur que M. Guizot venait de montrer
dans la première campagne de la coalition.

M. Molé n'avait pas seulement la Couronne pour lui. Dans le pays,

parmi ceux surtout qui n'étaient pas politiquement enrôlés, il s'était
acquis, sinon des concours très-actifs, du moins des sympathies
assez étendues. Depuis le 15 avril 1837, date de la formation du
cabinet, il n'y avait eu ni émeute, ni trouble, ni attentat contre la vie
du Roi[352]. Ce calme, cette sécurité paraissaient fort agréables,
après les secousses et les inquiétudes des années précédentes. On
était disposé à en faire honneur à la politique pacifiante de M. Molé.
Sans doute, à y regarder de près, personne n'eût pu dire le mal
révolutionnaire complétement guéri. Les sociétés secrètes étaient
toujours en travail. La société des Saisons avait remplacé, à la fin de
1836, celle des Familles; sous l'action de l'ouvrier imprimeur qui
l'avait fondée, Martin Bernard, et à la différence des associations
plus bourgeoises qui avaient conduit l'attaque sous la Restauration
et au lendemain de 1830, elle cherchait à se recruter surtout dans
les ateliers. L'amnistie lui procura le concours de Blanqui, de Barbès
et de plusieurs autres anciens condamnés. La propagande en reçut
une impulsion nouvelle. Des feuilles clandestines, publiées à
intervalles irréguliers, de novembre 1837 à septembre 1838, le
Moniteur républicain d'abord, l'Homme libre ensuite, prêchaient
ouvertement le régicide et le pillage[353]. Le 29 septembre 1838, la
police découvrit l'imprimerie secrète d'où sortaient ces factums; peu
après, elle saisit plusieurs dépôts d'armes; il en résulta des procès et
des condamnations. Mais tout cela ne fit pas grand bruit; cette
agitation demeurait souterraine et était d'ailleurs assez
restreinte[354]. Aussi le public n'y prêtait guère attention. Il lui
suffisait que l'ordre ne fût pas troublé à la surface, que la rue fût
tranquille. Ce repos satisfait du pays, n'était-ce pas après tout un
réel succès pour le gouvernement?

À cette quiétude s'ajoutait la jouissance d'une prospérité

matérielle chaque jour croissante. L'année 1838 marque une date
dans l'histoire budgétaire du règne. Alors finit ce qu'on pourrait
appeler la liquidation financière de 1830. Une révolution coûte cher:
elle a toujours ce double effet de diminuer les recettes et
d'augmenter les dépenses. Les revenus des contributions indirectes,
qui, sous la Restauration, avaient constamment progressé et
s'étaient élevés de 397 millions à 583, baissèrent brusquement de
59 millions à la suite des événements de Juillet. Il fallut emprunter,
et le crédit ébranlé ne permettait de le faire qu'à de lourdes
conditions; quelques mois avant la révolution, un emprunt en 4 pour
100 s'était placé à 102 fr. 7 c. ½: en mars 1831, un emprunt en 5
pour 100 se négocia à 84 francs. On se crut en outre politiquement
obligé, dans un intérêt de popularité, à diminuer les droits sur les
boissons, ce qui fit perdre au trésor 30 à 40 millions, diminution
imparfaitement compensée par une élévation des droits de mutation,
ainsi que des contingents de la contribution personnelle et mobilière,
et de celle des portes et fenêtres. En même temps que de causes
d'augmentations de dépenses! armements pour faire face aux
troubles du dedans et aux périls du dehors[355]; ouverture d'ateliers
nationaux pour occuper l'ouvrier sans travail et le distraire de
l'émeute; subsides ou avances à l'industrie en détresse; soldes de
congé à deux mille officiers licenciés pour cause politique, et
pensions de retraite aux fonctionnaires disgraciés; obligation de
remplir les arsenaux vidés pour l'armement de la garde
nationale[356], etc., etc. De là, pendant les premières années de la
monarchie, nécessité de se procurer des ressources extraordinaires,
que l'on demanda à l'emprunt, aux ventes de bois, aux centimes
additionnels, à la dette flottante, et qui ne s'élevèrent pas à moins
de 900 millions[357]. C'est à proprement parler le coût des
événements de Juillet.

Mais, dans les années suivantes, à mesure que le mal

révolutionnaire se guérit, le mal financier diminua également. Les
revenus indirects regagnèrent ce qu'ils avaient perdu et reprirent
une progression rapide. Le crédit se releva; déjà, en 1832, on
empruntait en 5 pour 100 à 98 fr. 50 c., soit 14 francs de plus que
l'année précédente[358]: et, ce qui valut mieux encore, dans les
années suivantes on ne rouvrit plus le grand-livre. Une économie
courageuse ramena presque au niveau antérieur à 1830 le chiffre
des dépenses subitement grossies au lendemain de la
révolution[359]. Des réformes heureuses accomplies dans notre
législation budgétaire et dans notre comptabilité augmentèrent les
garanties d'ordre, de probité et de contrôle[360]. Dès 1836 et 1837,
la situation était redevenue très-satisfaisante. Enfin, en 1838, on
arriva à ce résultat que les 900 millions de charges extraordinaires
supportées par le pays à la suite de la révolution ne laissaient plus
aucune trace, ni dans la fortune de l'État, ni dans celle des
particuliers[361]. Rien n'en restait, soit dans les dépenses, soit dans
les recettes du budget présenté pour l'exercice suivant. Bien qu'on
eût accru notablement les dépenses de l'armée[362], des travaux
publics, de l'instruction publique[363], bien qu'on eût payé les 25
millions de l'indemnité américaine, bien qu'on eût diminué les
recettes de 15 millions par la suppression de la loterie et des jeux, et
de 9 millions par l'abaissement des tarifs de douanes, la balance des
dépenses et des recettes, sans aucun emploi de ressources
extraordinaires, faisait ressortir un excédant réel[364]: toutes charges
ordinaires acquittées, il restait une réserve disponible de 80 millions,
pouvant servir à développer la richesse et la puissance nationales.
Les travaux publics, en effet, reçurent alors une grande impulsion;
des lois diverses engagèrent l'État pour une somme de 341 millions,
chiffre énorme pour l'époque. Ces travaux portaient sur les routes,
les ponts, les rivières, les canaux et les ports; les chemins de fer n'y
étaient comptés que pour 11 millions, représentant les frais d'études
préliminaires. On devait faire face à cette charge sans création de
ressources extraordinaires. Il fut ainsi dépensé 6,834,522 francs en
1837, 36,177,662 francs en 1838, 54,852,427 francs en 1839[365].
Ajoutons, pour mieux montrer à quel point toute conséquence
financière de la révolution avait alors disparu, que le jeu de
l'amortissement avait ramené la dette inscrite à ce qu'elle était avant
1830, c'est-à-dire à 163 millions de rentes[366]. La dette flottante se
trouvait réduite à un chiffre très-prudent. Quant au relèvement du
crédit, on en peut juger par ce fait que le 5 et le 3 pour 100 se
cotaient dans les environs de 119 francs et 86 francs[367]. En même
temps paraissait, le 31 mai 1838, la fameuse ordonnance sur le
règlement de la comptabilité: monument considérable, où étaient
réunies, dans un ordre méthodique, toutes les mesures législatives
ou administratives prises, depuis vingt-cinq ans, pour adapter la
comptabilité publique aux institutions nouvelles de la France. Ce
relèvement si rapide et si complet des finances de l'État est au plus
grand honneur de la monarchie constitutionnelle. Celle-ci ne faisait
d'ailleurs que recommencer l'œuvre qu'elle avait déjà accomplie une
première fois dans ce siècle, après les désastres de 1814 et de 1815.

Le bon état de la fortune publique était la conséquence et le signe

du bon état des fortunes privées. Celles-ci avaient merveilleusement
gagné au rétablissement de la sécurité. Ce progrès se manifestait
par l'accroissement des dépôts aux caisses d'épargne, du rendement
des contributions indirectes, des importations et des
exportations[368], de la navigation commerciale[369]. Partout, un
grand élan d'affaires, d'entreprises de toutes sortes, auxquelles les
capitaux s'offraient abondants, hardis, parfois même trop confiants.
M. Molé encourageait ce mouvement qui lui paraissait un dérivatif
utile à l'agitation politique. Là encore, cependant, tout n'était pas à
louer. À cette activité industrielle, commerciale, financière, se mêlait
forcément une fièvre d'agiotage fort dangereuse pour la santé
morale de la nation. Parmi les innombrables sociétés en commandite
qui se fondaient pour les objets ou sous les prétextes les plus divers,
plusieurs étaient peu sérieuses, quelques-unes malhonnêtes et
dignes de figurer au dossier de Robert Macaire. Les cours des
actions variaient, dans une même bourse, de 50, de 200 et même de
300 francs. Ces scandales furent dénoncés à la tribune de la
Chambre, et l'on demanda la mise à l'ordre du jour d'une loi
spéciale. Une telle atmosphère n'était pas bonne pour l'esprit public,
qui tendait à s'y matérialiser. Mais, malgré ce fâcheux revers, la
médaille était brillante: le pays se sentait en grand progrès de
richesse et de prospérité.

Contraste singulier! D'une part, dans la masse de la nation, une

impression de repos et de sécurité; un bien-être un peu égoïste et
terre à terre, mais réel. D'autre part, dans le Parlement et ses
entours, l'incertitude, le trouble et le malaise[370]. De là, entre ces
deux mondes, une séparation contre nature qui menaçait d'être
chaque jour plus profonde: le pays devenait étranger et indifférent à
la politique; il le devenait d'autant plus que la partie en vue de cette
politique, celle qui se traitait à la tribune, semblait désormais réduite
à des questions de personnes, peu intéressantes et souvent même
inintelligibles pour le public. On conçoit qu'un tel résultat ne fût pas
fait pour plaire aux libéraux, qui, dans les généreuses espérances de
la jeunesse du siècle, avaient rêvé d'un idéal politique plus relevé.
Aussi se laissaient-ils volontiers aller entre eux à des gémissements
que nous retrouvons dans leurs correspondances. M. de Barante,
alors en congé, écrivait de Paris, le 16 mai 1838, à M. Bresson: «Le
calme continue à être complet dans l'opinion des classes inférieures;
elles sont plus contentes qu'elles ne l'ont été depuis cinquante ans.
La prospérité est croissante, le bien-être en progrès rapide. On
n'entrevoit aucun principe de fermentation. Mais dans la région,
maintenant assez restreinte, des opinions politiques, tout est confus,
anarchique, envenimé d'intérêt et d'amour-propre. C'est un spectacle
affligeant. Il serait fait pour détruire l'espèce de sécurité dont nous
jouissons, n'était ce vaste fond d'indifférence où vont s'éteindre
toutes les passions, où se glacent du jour au lendemain toutes les
vivacités.» Il ajoutait, le 27 mai: «Il y a du calme, de la prospérité;
les opinions sont affaissées; mais un manque complet de conviction,
d'affection; nul souci du bien public; aucune émulation littéraire; rien
d'élevé, rien d'animé, rien de prévoyant. C'est un état moral
déplorable. Heureusement, il excite beaucoup de dégoût et d'ennui.»
Le 29 juin, M. de Barante quittait Paris, pour passer en Auvergne;
voici ce qu'il y voyait: «L'indifférence de la province est complète;
chacun s'isole encore plus qu'à Paris. Il n'existe plus aucun lien
d'opinion. Chacun est à ses affaires, sans songer qu'il y a un
gouvernement. Cela a son bon côté. Mais le principe de cette
apparente sécurité n'a rien de très-moralement honorable[371].» M.
Royer-Collard était d'un pessimisme plus sombre, plus absolu, et par
suite plus suspect; toutefois, à côté d'exagérations évidentes, il y
avait une part de vérité dans ce qu'il écrivait à M. Molé, le 23 juillet
1838: «Il me semble que la France n'a plus rien à donner; elle dort
d'un sommeil qui n'a pas même de rêves. Quand je disais à Vitry, il y
a un an: La politique est maintenant dépouillée de sa grandeur, je
ne disais point assez. La vérité d'aujourd'hui, c'est qu'il n'y a pas
même de politique. Y a-t-il encore un gouvernement, un roi, des
ministres, des Chambres? On pourrait l'ignorer; on ne le sait que par
la mémoire. Est-ce un bien? est-ce un mal? Nous l'apprendrons un
jour; en attendant, nous nous en passons sans regret. Est-ce votre
tort ou votre habileté? Ni l'un ni l'autre, je pense; mille causes
connues ou inconnues ont amené ce prodigieux résultat[372].» M.
Royer-Collard avait raison de voir là autre chose que le fait de M.
Molé. En effet, on avait déjà observé les premiers symptômes de ce
mal, à une époque où M. Molé n'avait pas encore eu le temps
d'influer sur la direction de l'esprit public. Dès le 12 novembre 1836,
la duchesse de Broglie écrivait à M. de Barante: «Il me semble que
l'indifférence du public est absolue: c'est une indifférence de fond et
universelle, non pas pour tel gouvernement, mais pour tous; c'est un
désabusement de toutes les formes, de toutes les promesses. Il
semble que le pays sache qu'on ne lui fera jamais ni grand bien ni
grand mal, que les menaces ne s'exécutent pas plus que les
promesses ne se tiennent, et que son premier intérêt est d'être
tranquille, pour que chacun vaque à ses affaires... Le petit monde
politique est tout absorbé dans ses querelles, dont le cercle se
resserre de plus en plus[373].»

Ces plaintes sans doute contenaient beaucoup d'observations

utiles à recueillir et à méditer; toutefois elles témoignaient de la
déception intime de quelques natures d'élite, plutôt qu'elles ne
peuvent être acceptées comme un jugement mesuré et exact de la
situation. En notant l'insuffisance morale de l'esprit public, ces
critiques oubliaient trop les imperfections nécessaires de toute
société humaine, et surtout d'une société travaillée par tant de
révolutions; ils ne tenaient pas non plus assez de compte des
avantages d'un bien-être qui était l'un des buts du gouvernement et
que peu d'époques avaient connu au même degré. Et puis, étaient-
ils bien nombreux, ceux qui sentaient ce que ce bien-être avait
d'incomplet et d'abaissé? Le vulgaire, c'est-à-dire le pays presque
tout entier, ne partageait pas ce souci, et son contentement n'en
était pas troublé. «Les gens habiles et sérieux, écrivait encore M. de
Barante, s'affligent et s'inquiètent de cette atonie. Les coteries
politiques s'en indignent. Les masses de la population n'y songent
guère[374].» Elles étaient tout entières à la jouissance de la paix et
de la prospérité qui succédaient aux agitations et aux souffrances
des premières années du règne.

D'ailleurs, à regarder en dehors du Parlement, tout semblait

sourire, en ce moment, à la royauté nouvelle. À la sécurité du
présent, venait s'ajouter l'espoir de l'avenir. Le 24 août 1838,
madame la duchesse d'Orléans donnait le jour à un fils qui recevait
le titre de comte de Paris. C'était l'épilogue heureux des grandes
fêtes qui, l'année précédente, à l'occasion du mariage du prince
royal, avaient paru célébrer l'établissement définitif de la monarchie
de Juillet. Celle-ci ne trouvait-elle pas dans la naissance du jeune
prince comme un gage nouveau de durée? Le vieux roi, ayant
devant lui son fils et son petit-fils, ne pouvait-il pas croire l'avenir de
sa dynastie assuré? Les événements ont sans doute cruellement
démenti ces prévisions. Quatre ans après, le duc d'Orléans
succombait à un accident vulgaire; encore six autres années, et le
comte de Paris suivait en exil sa mère veuve et son aïeul détrôné.
Mais si les destinées de l'enfant de 1838 ont été tout autres qu'on ne
les entrevoyait alors, il n'est pas dit, grâce à Dieu, que les
espérances fondées sur son berceau seront à jamais trompées. Pour
avoir été retardé, son rôle n'en sera-t-il même pas grandi, et la
France ne se trouvera-t-elle pas recevoir de lui plus encore qu'elle
n'en attendait au jour de sa naissance?

VI

Cet état de l'esprit public n'était pas de nature à encourager les

coalisés. Ils devaient se faire scrupule de persister à agiter un pays
si tranquille et si heureux de sa tranquillité. À défaut de ce scrupule,
ne comprendraient-ils pas qu'il n'était ni de leur intérêt personnel, ni
de celui du régime parlementaire dont ils se disaient les champions,
d'apparaître ainsi en trouble-fête? Aussi bien, dans leurs rangs et
surtout à leur tête, pouvait-on discerner plus d'un symptôme de
lassitude et d'hésitation. À la fin de la session, M. Thiers et M. Guizot
s'étaient plutôt évités que recherchés. Le premier gardait rancune au
second d'avoir mal joué son rôle dans le débat des fonds secrets. Le
chef des doctrinaires s'effrayait du scandale produit au centre par la
coalition et se sentait chaque jour davantage blâmé et abandonné
par ses anciens amis. M. Molé ne faisait-il pas du reste dire à tous
deux qu'il était sur le point de remanier son cabinet, et disposé à
entrer en composition tantôt avec l'un, tantôt avec l'autre? La
session finie, M. Thiers s'enfuyait aux Eaux-Bonnes; de là, il devait
se rendre en Italie, et n'annonçait pas l'intention de revenir avant la
rentrée des Chambres. M. Guizot quittait également Paris et semblait
absorbé par des travaux fort étrangers aux intrigues parlementaires;
il publiait dans la Revue française une série d'études d'une
inspiration très-haute, sur le mouvement religieux qui se manifestait
alors dans les âmes.

Toutefois si les chefs étaient distraits ou dégoûtés, la passion de la

coalition persistait, vivace, dans une partie des deux états-majors.
Ceux-ci, jusqu'à la fin de la session, avaient eu soin de se concerter,
et, après la dispersion du Parlement, ils se montraient résolus à
continuer la bataille dans la presse. Un député se distinguait par son
ardeur: c'était un doctrinaire, M. Duvergier de Hauranne. Chose
singulière, cet homme politique qui va apparaître le plus acharné des
coalisés, en était aussi le plus désintéressé. Beaucoup s'étaient jetés
dans cette campagne par rancune ou ambition personnelles, par
dépit de ne plus être ministre ou impatience de le devenir. Rien de
pareil chez M. Duvergier de Hauranne. Indépendant par situation et
par caractère, il ne rêvait pas de portefeuille, et il devait, jusqu'au 24
février 1848, refuser tous ceux qui lui seront offerts[375]. Mais cet
esprit vigoureux, net, avisé, était aussi un esprit exclusif, absolu,
batailleur, ne voyant guère qu'une idée à la fois, et, qu'elle fût vraie
ou fausse, la poussant sans ménagement jusqu'au bout. Longtemps
après, en 1860, M. Guizot, qui l'avait beaucoup pratiqué, d'abord
comme le plus zélé de ses amis, ensuite comme le plus âpre de ses
adversaires, écrivait finement de lui: «Un boulet de canon va droit
au but, quand il est lancé dans la bonne direction. L'esprit de
Duvergier est de même nature; il n'a jamais qu'une passion... C'est
une nature élevée, désintéressée, sincère, très-honnête. Il est très-
intelligent dans la voie où il marche. Il ne voit rien en dehors. Il a
tout ce qui fait bien penser et bien agir, quand on a bien commencé.
Il lui manque ce qui préserve de se mal engager et d'aller loin dans
l'erreur, sans s'en douter[376].» Entré à la Chambre en 1831, enrôlé
parmi les doctrinaires dont il avait naguère connu plusieurs dans les
bureaux du Globe, M. Duvergier de Hauranne avait été d'abord tout
entier à la «résistance», fort animé contre la gauche, plus rebelle
que personne à toute transaction avec le tiers parti. Mais, le plus
gros du danger révolutionnaire une fois conjuré, il fut saisi d'une
autre idée qui bientôt ne le posséda pas moins entièrement. La
politique, depuis 1830, ne lui parut plus être l'effort de la monarchie
pour se dégager de la révolution dont elle était sortie, mais la lutte
du pouvoir royal contre le pouvoir parlementaire. Remontant du
coup en deçà des journées de Juillet, il se retrouvait dans l'état
d'esprit des 221, et reprochait à Louis-Philippe de vouloir faire par
habileté ce que Charles X avait tenté par violence[377]. Cette
évolution paraît s'être accomplie chez M. Duvergier de Hauranne
vers la fin du ministère du 11 octobre. C'est alors que dans tous les
actes de la Couronne, dans ses démarches les plus innocentes, aussi
bien que dans ses imprudences, il crut découvrir les indices, les
preuves de son dessein d'affaiblir le Parlement, de diviser les chefs
de la majorité et de les exclure du ministère, afin de se rendre plus
maîtresse du gouvernement. Le ministère Molé, où il ne vit que la
création et l'instrument du pouvoir personnel, lui apparut comme le
dénoûment de cette longue conspiration. État d'esprit particulier,
qu'on a quelque peine à concevoir aujourd'hui. On sait en effet
maintenant à quoi s'en tenir sur l'erreur théorique et l'impossibilité
pratique de la trop fameuse maxime: «Le Roi règne et ne gouverne
pas»; on sait que la force des choses la repousse comme l'histoire la
condamne; on sait qu'en Angleterre, sur la terre natale du régime
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