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Netter s orthopaedics 1st


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Preface
Netter’s Orthopaedics is an essential text on the pathophysiology, diagnosis, and treatment of
musculoskeletal disorders. The need for such a book results from the commonality of these disorders, which are second only to respiratory illnesses as a reason that patients seek medical care,
and their diversity, in that they comprise everything from injuries and infections to metabolic and
neoplastic diseases.
Patients with conditions affecting the musculoskeletal system present in many settings, requiring that virtually all health care providers be familiar with the diagnosis and treatment of
these disorders. This book, therefore, is intended for use by the many clinicians who will see
these patients—students in medicine, physical therapy, and osteopathy, and residents in primary
care, orthopaedics, family practice, and emergency medicine.
The first 12 chapters of Netter’s Orthopaedics are concerned with topics related to the entire
musculoskeletal system, and provide principles that can be applied to the management of many
disorders. The final 7 chapters are organized by region, and offer techniques of diagnosis and

treatment specific to each region. Given the widely different backgrounds of the anticipated
readers of this book, we have tried throughout to make the text as accessible as possible, presenting practical information in a clear and straightforward manner.
Although the multiplicity and variety of musculoskeletal disorders may make learning this subject seem daunting, an understanding of the anatomy and basic science pertaining to the musculoskeletal system, combined with fundamental principles of evaluation and treatment, can
guide most diagnostic and therapeutic interventions. Therefore, each chapter of this text begins
with relevant basic science to lay the foundation for understanding the pathophysiology, diagnosis, and treatment of the clinical conditions. Because knowledge of anatomy is crucial to the
evaluation and treatment of musculoskeletal conditions, this component of basic science has received particular emphasis.
All of the authors owe a great debt to Frank H. Netter, MD, the medical illustrator who created the majority of the illustrations in this book. Dr. Netter’s legacy, and his importance in medical education, cannot be overstated. Through his art, Dr. Netter has been a mentor to thousands
of physicians and allied health professionals. His precise and beautifully rendered depictions of
the human body in health and illness communicate, as no writer can, the essential concepts of
basic science and applied medicine that every student must learn. It was Dr. Netter’s belief that
a medical illustration is of little value if it does not provide the student with an essential point that
has application in the practice of medicine. Examination of any of Dr. Netter’s works in this book
will demonstrate his dedication to that principle.
Although much of Dr. Netter’s work is just as relevant today as it was when he created it, new
techniques and procedures developed since his death in 1991 have caused us to call upon the
talents of his successors, particularly John A. Craig, MD, and Carlos A. G. Machado, MD. As will
be seen from their work, these artists, trained in the Netter tradition, faithfully uphold the high
standards that Dr. Netter set.
The authors and illustrators hope that Netter’s Orthopaedics will be a valuable resource for
the many individuals who care for patients with these often complex and challenging conditions.
Walter B. Greene, MD

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Acknowledgments
I would like to acknowledge the staff at Saunders who worked on this book and, in particular,
Paul Kelly and Greg Otis who coordinated the development of this project, Jennifer Surich who
managed the editorial process, Jonathan Dimes who directed the art program, and Marybeth
Thiel for providing assistance and support throughout all stages of the project. I would also like
to thank Mary Berry, development editor. Their extraordinary patience and skills were pivotal in
this publication.

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List of Contributing Authors
Walter B. Greene, MD
OrthoCarolina
Charlotte, NC

Derrick J. Fluhme, MD
Associate Partner
South Hills Orthopaedic Surgical Associates
St. Clair Hospital
Pittsburgh, PA

Roy K. Aaron, MD
Professor
Department of Orthopaedics
Brown University School of Medicine
Providence, RI

Freddie H. Fu, MD
David Silver Professor and Chairman
Department of Orthopaedic Surgery
University of Pittsburgh School of Medicine
Pittsburgh, PA

Jeffrey O. Anglen, MD, FACS
Professor and Chairman
Department of Orthopaedics
Indiana University
Indianapolis, IN

Barry J. Gainor, MD
Professor
Department of Orthopaedic Surgery
University of Missouri Hospital and Clinics
Columbia, MO

Judith F. Baumhauer, MD
Professor of Orthopaedics, Chief of Division
of Foot and Ankle Surgery
Department of Orthopaedics
University of Rochester School of Medicine
and Dentistry
Rochester, NY

Lawrence C. Hurst, MD
Professor and Chairman
Department of Orthopaedic Surgery
Stony Brook University
Stony Brook, NY

Philip M. Bernini, MD
Professor of Orthopaedic Surgery
Department of Orthopaedics
Dartmouth-Hitchcock Medical Center
Lebanon, NH

Lee D. Kaplan, MD
Assistant Professor
Department of Orthopaedics
University of Wisconsin
Madison, WI

Eric M. Bluman, MD, PhD
Assistant Clinical Instructor
Department of Orthopaedic Surgery
Brown University School of Medicine
Providence, RI

Keith Kenter, MD
Assistant Professor and Director of Resident
Education
Department of Orthopaedic Surgery
University of Cincinnati
Cincinnati, OH

Susan V. Bukata, MD
Orthopaedic Research Fellow
Department of Orthopaedics
University of Rochester Medical School
Rochester, NY

John D. Lubahn, MD
Department Chair
Program Director
Department of Orthopaedics
Hamot Medical Center
Erie, PA

Michael G. Ehrlich, MD
Vincent Zecchino Professor and Chairman
Department of Orthopaedics
Brown University School of Medicine
Providence, RI

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List of Contributing Authors
Vincent D. Pellegrini Jr., MD
James L. Kernan Professor and Chair
Department of Orthopaedics
University of Maryland School of Medicine
Baltimore, MD

Peter G. Trafton, MD, FACS
Professor and Vice Chairman
Department of Orthopaedic Surgery
Brown University School of Medicine
Providence, RI

Michael S. Pinzur, MD
Professor of Orthopaedic Surgery and
Rehabilitation
Department of Orthopaedic Surgery and
Rehabilitation
Loyola University Medical Center
Maywood, IL

Edward D. Wang, MD
Assistant Professor
Department of Orthopaedic Surgery
Stony Brook University Hospital and Health
Sciences Center
Stony Brook, NY
D. Patrick Williams, DO
Clinical Professor
Orthopaedic Residency Program
Hamot Medical Center
Erie, PA

David T. Rispler, MD
Assistant Professor
River Valley Orthopaedics
Michigan State University
Grand Rapids, MI

David J. Zaleske, MD
Surgical Director, Orthopaedics
Department of Orthopaedics
Children’s Hospitals and Clinics
Minneapolis and St. Paul, MN

Randy N. Rosier, MD, PhD
Wehle Professor and Chair
Department of Orthopaedics
University of Rochester Medical School
Rochester, NY

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one
Embryology
and Formation
of Bone
David J. Zaleske, MD


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Chapter 1

A

n understanding of embryology facilitates the study of postnatal anatomy
and the treatment of patients with congenital malformations. Furthermore,
as research elucidates the fascinating but complex embryologic process, it
has become clear that many genes and transcription factors involved in
movement from the genome to a three-dimensional organism are phylogenetically conserved. This complex and highly interactive process includes normal cytodifferentiation and morphogenesis, and it is recapitulated, at least in part, in the healing of
injuries. (Note: Bone is the only tissue that regenerates completely after injury [fracture].)
A better understanding of development should allow more precise treatment of many illnesses and, ultimately, tissue engineering with regeneration of specific organs.
disc (gastrula). Mesoderm develops from two
thickenings of ectoderm. The primitive knot
(node) forms a midline cord of mesoderm,
known as the notochord. This primitive
streak gives rise to the rest of the mesoderm,
including the cardiogenic mesoderm, which
separates and is located in front of the
oropharyngeal membrane. Gastrulation is
complete when the mesoderm condenses
into three, initially connected columns that
flank the notochord: the paraxial columns (future somites), the intermediate mesoderm,
and the lateral plates (Figure 1-2). Mesoderm
that surrounds the columns becomes mesenchyme, the loose embryonic connective
tissue that surrounds structures.
Shaping of the embryo involves bending of
the amnion around and under the gastrula
(Figure 1-3). Concurrently, folding of the ectoderm initiates development of the nervous
system, and somites in the paraxial mesoderm
initiate development of the axial skeleton.
The gut is formed from a tube of endoderm. The lateral plate extends and splits to
form the lining of the coelomic cavities. The
superior portion of the lateral plate joins with
the surface ectoderm to form the ventrolateral body wall somatopleure, which ultimately develops into the skin, connective tissue, striated muscle, and bone in the limbs
and some parts of the body wall. The inferior
portion of the lateral plate joins with the endoderm to form the splanchnopleure, which
forms the walls of visceral organs and their
suspending mesenteries.
The mesodermal notochord and the paraxial columns induce ectodermal tissue to form
the neural plate, thus beginning the process of

CELL DIVISION AND THE MAIN
EMBRYONIC PERIOD
The 9 months of prenatal human development can be divided into a period of cell
division (weeks 1 and 2), a main embryonic
period (weeks 3 to 8), and a fetal period (encompassing the last 7 months). Approximately 60 hours after fertilization, the zygote
has progressed to a morula (“little mulberry”),
a ball of cells that continues cell division as it
travels through the uterine tube to the uterine
cavity; it transitions to the fluid-filled blastocyst at approximately day 5. The blastocyst
develops an inner cell mass (embryoblast)
and an outer trophoblast as it adheres and
then is implanted within the posterior wall of
the endometrium of the uterus. By the end of
week 2, the embryo is a two-layered cell disc
of endoderm and ectoderm (Figure 1-1).
The embryonic period progresses from gastrulation to folding of the embryonic disc and
eventual formation of the primordia of all organ systems. It is a very dynamic period of development and morphogenesis, in which
masses of cells coalesce, migrate, and remodel (programmed cell death is included).
Because this is the most active phase of differentiation, abnormalities of development
that occur in the embryonic period usually result in major birth defects. The cardiovascular
system is the first organ system to function at
day 21/22. At that time, the embryo is too
large for diffusion to satisfy the nutritional
needs of the embryo.
Gastrulation is the production of mesoderm during the third week that changes the
bilaminar embryonic disc into a trilaminar

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Embryology and Formation of Bone
Figure 1-1: Cell Division: The First Two Weeks
Myometrium

Four-cell stage
(approx. 40 hr)

Early morula
(approx. 80 hr)

Two-cell stage
(approx. 30 hr)

Endometrium
Advanced morula
(4 days)

Ovary

Blastocyst
(approx. 5 days)
Early implantation
(approx. 61/2 days)

Fertilization
(12 to 24 hr)
Developing
follicles

Embryoblast
(inner cell mass)

Mature
follicle

Discharged
ovum
Extraembryonic
mesoderm
Yolk sac
Endoderm

Exocoelomic cyst

Ectoderm
Amniotic cavity
Connecting stalk
Cytotrophoblast
Syncytiotrophoblast

Extraembryonic
coelom

Endometrium
Approximately 15th day

neural tube and notochord into the somatopleure. Bone development of the axial skeleton begins with mesenchymal condensations
in the sclerotome. Cells from the mesenchymal primordia differentiate into chondroblasts, which become the cartilaginous precursors of the axial skeleton and bones at the
base of the cranium (Figure 1-4). Enchondral
ossification converts these cartilage templates into various bones. Most bones of the
skull and part of the clavicle develop through
intramembranous (mesenchymal) ossification
with direct formation of bone in mesenchyme
derived from the neural crest.
At each level, the somites migrate ventrally
to incorporate the notochord and dorsally to

neurulation; this plate then folds and invaginates to form the neural tube. Closure of the
neural tube advances cranially and caudally.
As the neural tube invaginates, ectodermal
neural crest cells from each side are joined together. Later, some neural crest cells migrate
to form other tissues (Tables 1-1 and 1-2).

HUMAN AXIAL SKELETAL
EMBRYOLOGY
The axial skeleton includes the vertebrae,
ribs, and sternum. Its development is initiated
by paired condensations in the paraxial mesoderm—the somites. Each somite differentiates
into a sclerotome and a dermomyotome. The
sclerotomes separate and migrate around the

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Chapter 1
Figure 1-2: Gastrulation
Formation of Intraembryonic Mesoderm from the Primitive Streak and Node (Knot)
Ectoderm

Oropharyngeal
membrane

Amniotic cavity
Notochord
Primitive knot
(node)
Primitive
streak
Extraembryonic
mesoderm
Endoderm
Migration of cells
from the
primitive streak
to form the
intraembryonic
mesoderm

Yolk sac
cavity
Cupola of
yolk sac

Oropharyngeal
membrane
Spreading of
intraembryonic
mesoderm

Notochord
Paraxial column

Cloacal
membrane

Intermediate column

Appearance of the
neural plate

Lateral plate

cover the neural tube. The precursors of the
axial skeleton have formed by the fourth embryonic week. Somites undergo rearrangement by division into superior and inferior
halves; then, adjacent superior and inferior
halves join together to form single vertebral
bones (Figure 1-5). Thus, the vertebral arteries are relocated to the middle of the vertebral body.
Vertebral bodies, the posterior bony arch,
and vertebral processes have a similar pattern
of formation with various dimensions and nuances (refer to Figures 13-2 and 13-4 in Chapter 13). Development of C1 (atlas) differs
from that of C2 (axis) in that the body (cen-

trum) of the atlas fuses to the C2 body and becomes the odontoid process (dens). Parts of
the somites may fail to segment, migrate, or
rejoin appropriately. This failure is the basis
for congenital scoliosis, which may be associated with rib fusion at single or multiple levels
(see Chapter 13).

Skeletal Muscle and Peripheral Nerve
Embryology
Similar to the somites, myotomes are
paired and segmented. Each segmental myotome is innervated by a spinal nerve. The
dermatomes divide into an epimere—the
small dorsal segment—and a hypomere—

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Embryology and Formation of Bone
Figure 1-3: Folding of the Gastrula and Early Development of the Nervous
System
Midsagittal section of folding gastrula
Notochord
in gastrula

Cross section of folding gastrula

Amnion
Amnion
Connecting
stalk
Extraembryonic
mesoderm
Allantois

Oropharyngeal
membrane
Cardiogenic
mesoderm

Cloacal
membrane

Yolk sac

Neural crest
Neural plate
forming
neural tube
Somite
Intermediate
mesoderm
Intraembryonic
coelom
Notochord

Yolk sac

Vertebrate Body Plan after 4 Weeks
Intermediate mesoderm:
Embryonic endoderm
Nephrogenic ridge
forming gastrointestinal
Nephrogenic cord
(gut) tube
Genital ridge
Splanchnopleure
Somatic mesoderm (endoderm plus
of lateral plate
lateral plate
mesoderm)
Somatopleure
(ectoderm plus
Amnion tucking
lateral plate
around the sides
mesoderm)
of the folding
Gut tube
embryo
Yolk sac (stalk
just out of the
plane of section)

Splanchnic
mesoderm
of lateral plate
Hepatic
diverticulum
Septum
transversum

Yolk sac stalk
and allantois
within the
umbilical
cord

Dermomyotome
of somite

Dorsal Views
Somites
appear
(day 20)

Neural
groove

Notochord
Somite sclerotome
surrounds the neural
tube and notochord to
form vertebral column
Spinal nerve
Dermomyotome
Aorta
Dorsal
mesentery
Ventral
mesentery
Umbilical
cord
Amnion against
chorion
Amniotic cavity
Neural tube
above notochord

Intermediate
mesoderm
Embryonic
gut tube
Yolk sac stalk
compressed into
umbilical cord

cord
Neural
plate

Intraembryonic
mesoderm

Sclerotome
of somite

Intraembryonic
coelom
Amnion surrounded by
surrounding lateral plate
the umbilical mesoderm

Amnion pressed
against the chorion

Neural plate

Cranial
neuropore

Early
closure
of neural
tube
(day 21)

Late
closure
of neural
tube
(day 22)

1.8 mm

2.0–2.1 mm

Week 3 (late)

Week 4 (early)

5

Caudal
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Chapter 1
Table 1-1

Table 1-2

Ectodermal Derivatives

Mesodermal Derivatives

Primordia

Derivatives

Primordia

Derivatives

Surface ectoderm

Skin epidermis
Sweat, sebaceous, and
mammary glands
Nails and hair
Tooth enamel
Lacrimal glands
Conjunctiva
External auditory meatus
Oral and nasal epithelium
Anterior pituitary
Inner ear
Lens of eye

Notochord

Induction of neurulation
Intervetebral disc nucleus
pulposus

Neural tube

Neural crest

Amnion

Paraxial column
Somites
Myotome
Dermatome

Central nervous system,
including cranial nerves
Retina/optic nerves
Posterior pituitary
Spinal cord, including
lower motor neurons
and presynaptic
autonomic neurons
with associated axons
Ganglia and sensory
neurons associated with
spinal dorsal root and
cranial nerves
Adrenal medulla cells
Melanocytes
Bone, muscle, and
connective tissue in the
head and neck

Bone and cartilage
Skeletal muscle
Dermis of the skin

Intermediate
mesoderm

Gonads
Kidneys and ureters
Uterus and uterine tubes
Upper vagina
Ductus deferens, epididymis,
and related tubules
Seminal vesicles and
ejaculatory ducts

Lateral plate
mesoderm

Dermis (ventral)
Superficial fascia and
related tissues (ventral)
Bones and connective
tissues of limbs
Pleura and mesoderm
GI connective tissue
stroma

Cardiogenic
mesoderm

Heart and pericardium

trunk wall muscles, as well as to muscles of
the limbs. Myotomes fuse to form individual
muscles; therefore, most muscles are innervated by more than one spinal nerve root.
Back and abdominal muscles are innervated
by multiple spinal nerves, whereas the
brachial and lumbosacral plexuses combine
multiple spinal nerves into single peripheral
nerves that innervate the limb muscles. Limb
muscles are divided into (1) ventral extensor
compartment muscle groups innervated by
anterior division branches of the ventral rami
in the brachial and lumbosacral plexus, and
(2) dorsal flexor compartment muscle groups
innervated by posterior division branches of
the ventral rami (Figure 1-6).

Protective bag (with
chorion) around the
fetus

the larger ventral segment. The epimere is innervated by the dorsal ramus of a spinal
nerve, and the hypomere is innervated by the
ventral ramus.
The epimere is the site of origin of the intrinsic back muscles (ie, splenius group, erector spinae, transversospinalis group). The hypomere gives rise to the lateral and ventral

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Embryology and Formation of Bone

Figure 1-4: Myotomes, Dermatomes, and Sclerotomes
Differentiation of somites into myotomes, sclerotomes, and dermatomes
Cross section of human embryos
A. At 19 days
Neural groove

Ectoderm of embryonic disc

Somite

Cut edge of amnion

Mesoderm

Intraembryonic coelom
Endoderm (roof of yolk sac)

Notochord

B. At 22 days

Ectoderm

Neural tube

Dorsal aortas

Dermomyotome

Intraembryonic coelom

Sclerotome

Cut edge of amnion

Notochord

Endoderm of gut

Mesoderm
C. At 27 days
Ectoderm
Dermomyotome

Sclerotome
contributions

Spinal cord

to neural arch
to vertebral body
(centrum)
to costal process

Dorsal aortas
Posterior cardinal vein
Mesoderm

Notochord

D. At 30 days

Coelom

Note: Sections A, B, and C are
at level of future vertebral body,
but section D is at level between
developing bodies

Spinal cord
Dorsal root ganglion
Ventral root of spinal nerve
Mesenchymal contribution
to intervertebral disc

Ectoderm (future epidermis)
Dermatome (future dermis)

Aorta

Myotome

Posterior cardinal vein
Coelom

Notochord (future nucleus pulposus)
Mesoderm
Mesonephric kidney

Dorsal mesentery

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Chapter 1
Figure 1-5: Muscle and Vertebral Column Segmentation
Progressive stages in formation of vertebral column, dermatomes, and myotomes
Ectoderm

Ectoderm

Dermomyotome

Somite

Sclerotome

Myocoele
Sclerotome

Primordium of
vertebral body

Notochord

Notochord

Intersegmental
artery

Intersegmental
artery
Ectoderm
Vertebral body
Dermatome
Intervertebral fissure
Myotome
Intersegmental artery
Nucleus pulposus
forming from
notochord

Segmental nerve
Nucleus pulposus

Ectoderm (future
epidermis)

Annulus fibrosus of
intervertebral disc

Dermatome of
subcutaneous
tissue (dermis)

Vestige of notochord

Myotome
Vertebral body
(centrum)
Costal process

Intersegmental artery
Segmental nerve

Appendicular Skeletal Embryology

continues to progress slightly ahead of lower
limb development. Blood vessels develop in
the limb buds early and before the development of bone or nerves. During the sixth
week of gestation, the distal portion of the
limb bud becomes paddle-like, with indentations and rays that ultimately develop into the
digits of the hands and feet.
Mesenchymal condensations are initially
continuous in the extremities. Interzonal re-

Limb development begins as outpouchings
(paddle-like extensions) from the somatopleure ventrolateral body wall that appear
during the early part of the fifth embryonic
week. The limb somatopleure mesenchyme is
capped by the apical ectodermal ridge. Upper limb bud mesenchymal condensations
appear 1 to 2 days before the lower limb buds
appear, and morphogenesis of the upper limb

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Embryology and Formation of Bone
Figure 1-6: Development of Epimere and Hypomere Muscle Groups and
Their Nerve Innervation
Somatic development

Ventral root

Dorsal root

Epaxial muscles
Dorsal ramus

Posterior cutaneous nerve

Ventral ramus
Posterior division
Anterior division

Epaxial muscles
Dorsal ramus

Hypaxial
muscles
(extensors
of limb)

Ventral ramus

Hypaxial muscles
in thoracic and
abdominal wall
Hypaxial muscles
(flexors of limb)

Lateral cutaneous nerve

Hypaxial muscles
(flexors of arm
and shoulder)

Anterior cutaneous nerve

genesis and cytodifferentiation. Specific portions of the limb bud direct this process. The
zone of polarizing activity (ZPA), an area of
mesenchymal cells located at the caudal aspect of each limb bud, directs patterning
along the anteroposterior axis (anterior refers
to the thumb side and posterior is the little finger) by a gradient of the gene Sonic hedgehog
(Shh). Transcription molecules Wnt7a and
Lmx-1 are necessary for dorsoventral patterning. Proteins such as syndecan-3, tenascin,
and versican mediate the formation of the
mesenchymal condensations and their transformation to cartilage. Core binding factor 1
(Cbfa1) and Indian hedgehog (Ihh) are involved in the cartilage maturation process
leading to endochondral ossification.

gions form between these condensations.
These interzonal regions cavitate to form
joints (Figure 1-7). Articular cartilage and intraarticular structures such as ligaments and
menisci are formed from interzonal tissue.
The upper and lower limb buds rotate in
opposite directions during development (Figure 1-8). Therefore, segmental dermatomes
within the limbs also rotate and are not organized in the proximal-to-distal linear arrangement found along the trunk.
Descriptive embryology at the tissue level
is increasingly elucidated at the molecular
level (see Figure 1-9). Interaction of transcription factors, growth and inductive factors, and
adhesion molecules establishes the information blueprint for bone and joint morpho-

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Chapter 1
Figure 1-7: Joint Development
Development of three types of synovial joints

Cartilage
(rudiment of bone)
Perichondrium

Precartilage
condensation
of mesenchyme

Joint capsule
Circular cleft
(joint cavity)

Site of future
joint cavity
(mesenchyme
becomes
rarefied)

Periosteum

Perichondrium
Cartilage

Articular menisci

Articular disc

Epiphyseal cartilage
growth plate
Epiphyseal bone
Joint capsule
Synovial
membrane
Joint cavity
Articular cartilages

Joint cavities

Joint cavity

Epiphyseal bone
Interphalangeal
joint

Knee joint

Bone Formation

Sternoclavicular
joint

Endothelial cells invade the condensation to
form a blood supply; then, osteoblasts form
new bone—a process that is followed by remodeling (Figure 1-10). Most bones of the
calvaria, the facial bones, and, in part, the
clavicle and mandible are formed through intramembranous ossification.
All other bones (ie, base of the skull, axial
skeleton, appendicular skeleton with the exception of the clavicle) develop in the
cartilage condensations derived from mesenchymal aggregates. Chondrocytes hyper-

The term bone has two common meanings:
(1) it may refer to osseous, or bone, tissue; or
(2) it may denote an organ, such as the
femoral bone.
At the end of the embryonic period and the
beginning of the fetal period, the mesenchymal precursors of the skeleton begin to form
osseous tissue through two methods. With intramembranous formation, the mesenchymal
connective tissue of the neural crest condenses under the influence of specific signals.

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Embryology and Formation of Bone
Figure 1-8: Limb Rotation and Dermatomes
Preaxial border
C7
C8

Upper limb

C6
T1

C3
C4
C5

T2

Postaxial border
Preaxial border

L2
L3
L4

Lower limb

L5
S1

S2

Postaxial border
At 6 weeks
At 6 weeks. Limbs bend anteriorly, so elbows and knees
point laterally, palms and soles face trunk

At 8 weeks. Torsion of lower limbs results in twisted or “barber
pole” arrangement of their cutaneous innervation

Dorsal surface
Postaxial border
S1

L5

L4

L3

L2
S2

Preaxial border
At 8 weeks

Big toe

11

S3

S3


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Chapter 1

Figure 1-9: Growth Factors
Limb buds in 6-week embryo
Growth factors that influence limb morphology:
Fibroblast growth factor-8 (FGF-8)—limb bud initiation
Retinoic acid—limb bud initiation
FGF-2, 4, and 8—outgrowth of the limbs
Bone morphogenetic proteins—apoptosis of cells between digits
Sonic hedgehog—establishment of craniocaudal limb axes
Wnt-7a—dorsal patterning of the limbs
En-1—ventral patterning of the limbs

Apical ectodermal
ridge

Zone of polarizing
activity
Mesenchymal
bone precursor

Growth factors that promote tissue development:
Bone morphogenetic protein family—bone
development
Indian hedgehog—bone development
Growth/differentiation factor 5—joint formation
Transforming growth factor-␤ family—myoblast
proliferation
Nerve growth factor—sensory and sympathetic
neurons
Insulin-like growth factor-1 (IGF-1)—general
proliferation of limb mesoderm
Scatter factor (hepatic growth factor)—myotome cell
migration in the limbs

Extensor
muscle

Flexor
muscle
Preaxial compartment

Postaxial compartment
Ant. division
nerve
Post. division
nerve

Ventral compartment
Flexor muscles
Anterior division nerves

12

Dorsal compartment
Extensor muscles
Posterior division nerves


0691 ch 01.qxd 6/3/07 11:20 AM Page 13

Embryology and Formation of Bone

Figure 1-10: Intramembranous (mesenchymal) Bone Formation
Initial bone formation in mesenchyme
Mesenchymal cells
Reticular fibers in extracellular
fluid of mesenchyme
Osteoblasts (from mesenchymal
cells) sending out extensions
Bundles of collagen fibers laid
down as organic osteoid matrix

Lacuna
Mineralized bone matrix
(organic osteoid and collagen
fibers impregnated with
hydroxyapatite crystals)
Osteocytes (from
osteoblasts)

Extensions of osteocytes
filling canaliculi

Early stages of intramembranous bone formation
Capillaries in
narrow spaces

Periosteum of
condensed mesenchyme
Trabeculae of cancellous (woven)
bone lined with osteoblasts
forming in mesenchyme

Dense peripheral layer of subperiosteal
bone surrounding primary cancellous bone.
Both initially consist of woven bone

Bone trabeculae lined with osteoblasts
Capillary
Nerve fiber

Marrow spaces
(primary osteons)

13


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Chapter 1
trophy within the cartilage anlage. Capillaries
invade the central region of the anlage. Enchondral ossification ensues, and the primary
ossification center is formed (see Figure 111). Primary centers of ossification most often develop at various prenatal times that are

unique to each bone. Most long-bone primary centers of ossification are present by
the eighth week of gestation (Figure 1-12).
Some small bones (eg, patella, wrist, midfoot) do not initiate ossification until early
childhood.

Figure 1-11: Endochondral Ossification in a Long Bone
Growth and ossification of long bones (humerus, midfrontal sections)

Perichondrium
Periosteum

At 8 weeks

Proliferating small-cell
hyaline cartilage
Hypertrophic calcifying
cartilage
Thin collar of cancellous
bone from periosteum
around diaphysis

Epiphyseal capillaries

Calcified
cartilage

Canals, containing
capillaries, periosteal
mesenchymal cells,
and osteoblasts,
passing through
periosteal bone into
calcified cartilage
(primary ossification
center)
At 9 weeks

Epiphyseal (secondary)
ossification center for head

Cancellous endochondral
bone laid down on spicules
of calcified cartilage

Outer part of periosteal bone beginning
to transform into compact bone

Primordial marrow cavities

Central marrow (medullary) cavity
Epiphyseal capillary

At 10 weeks

At birth

Greater tubercle

Proximal
physis

Epiphyseal
ossification
centers of
lateral epicondyle,
medial epicondyle,
trochlea, and
capitulum
Calcified cartilage

Articular cartilage of head

Anatomical neck

Epiphyseal
ossification
centers for
head and
greater tubercle

Sites of
growth
in length
of bone
Distal
physis

Proliferating
growth cartilage

Bone of proximal epiphysis

Hypertrophic
calcifying cartilage

Proximal metaphysis

Enchondral bone
laid down on spicules
of degenerating
calcified cartilage
Enchondral bone
laid down on spicules
of degenerating
calcified cartilage
Hypertrophic
calcifying cartilage

At 10 years

14

Distal metaphysis
Bone of distal epiphysis

Articular cartilage
of condyles

Proliferating
growth cartilage

At 5 years

Diaphysis; growth in width
occurs by periosteal bone
formation


0691 ch 01.qxd 6/3/07 11:20 AM Page 15

Embryology and Formation of Bone

Figure 1-12: Ossification Present in the Newborn
Skeleton of full-term newborn
Time of appearance of ossification centers (primary unless otherwise indicated)
Anterior fonticulus (fontanelle)

Parietal bone (12th week)

Coronal suture

Sphenoid fonticulus (fontanelle)

Frontal bone (9th week)

Squamosal suture

Nasal bone (9th week)

Temporal bone (9th week)

Lacrimal bone (12th week)

Mastoid fonticulus (fontanelle)

Ethmoid bone (12th week)

Occipital bone (9th week)
Styloid process

Sphenoid bone (12th week)
Maxilla (9th week)

Clavicle (7th–8th weeks)

Zygomatic bone (9th week)

Secondary proximal epiphyseal
center of humeral head
(8th fetal–1st month postnatal)

Mandible (9th week)
Center for hyoid bone
(36th week)

Ribs (8th to 9th week)
Scapula (8th week)

Intervertebral disc

Humerus (6th–8th weeks)
Sternum (8th – 9th week)
Vertebral body

Radius (6th–8th weeks)

Triradiate cartilage

Ulna (6th–8th weeks)
Carpal cartilages

Large femoral head articulating
with shallow acetabulum (2nd–
6th month postnatal)

Metacarpals (2nd–4th months)
Phalanges (2nd–6th months)

Pubic symphysis
Femur (6th–12th weeks)

Ilium (8th week)
Coxal
bone

Secondary distal epiphyseal
center of femur (36th week)

Ischium (16th week)
Pubis (16th week)

Secondary proximal center
of tibia (8th fetal–1st month postnatal)

Patella (6th year)
Center for talus (4th–8th months)

Tibia (6th–12th weeks)

Metatarsals (2nd–6th months)

Fibula (6th–10th weeks)

Phalanges (2nd–4th months)
Center for calcaneus (4th–7th months)

15


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Chapter 1
The diaphysis is the shaft of a long bone
(see Figure 1-11). Metaphyses are the adjacent flared-out regions. Epiphyses are the
ends of a long bone. The physis or growth
plate, which is located between the metaphysis and the epiphysis of long bones, provides
longitudinal growth until the time of skeletal
maturity. Growth of small bones and of the
epiphysis is promoted by growth cartilage
that surrounds these structures.
Bone tissue forms within the cartilaginous
ends, or chondroepiphyses, of long bones,
which are called secondary centers of ossification. In humans, the only secondary center of
ossification that forms before birth is the one
located at the distal femur, which forms at 36
weeks’ gestation (see Figure 1-12). The appearance of various secondary centers of ossification may be used to determine the biologic or bone age of a given child.

repair, or turnover) is woven bone. At the microscopic level, the osteoid matrix of woven
bone reveals an amorphous or patchwork
pattern of osteoblasts, osteoid matrix, and
randomly oriented collagen fibers. Woven
bone remodels internally to lamellar bone.
This process requires close coupling of bone
formation and bone resorption. Osteoblasts
form bone, osteocytes maintain bone, and osteoclasts (specialized macrophages) resorb
bone. With successive resorption and formation, woven bone is remodeled into concentric lamellar bone, which is made up of collagen fibers, haversian systems, and interstial
lamellae aligned for maximum strength per
volume of bone. The cells that deposit newly
formed bone, the osteoblasts, become surrounded by bone matrix and develop into
mature osteocytes, which form cellular extensions for intercellular transport (Figure 114).

BONE STRUCTURE AND HISTOLOGY
Bone Growth and Remodeling

Bone as an organ consists of trabecular and
cortical bone (Figure 1-13). Both types of
bone contain the same cell and matrix
elements, but structural and functional differences between the two are observed. Cortical bone, sometimes called compact bone, is
denser (80% to 90% of the volume is calcified) and stronger than cancellous bone. The
diaphyses of long bones primarily comprise
cortical bone. Thus, shafts of long bones have
a relatively small cross-sectional area that can
accommodate the bulk of surrounding musculature while continuing to resist lifting and
weight-bearing stresses. Cancellous bone,
sometimes called trabecular bone, is a network of bony trabeculae or struts that are
aligned to counteract stress and support articular cartilage. Only 15% to 25% of the
medullary canal is made up of cancellous
bone; the remaining volume is occupied by
marrow, blood vessels, fibrous tissue, and
fatty tissue. The metaphysis and the epiphysis
primarily comprise cancellous bone covered
by a relatively thin layer of cortical bone.
Growth of the entire human body involves
a net accumulation of bone mass. Newly
formed bone (during development, fracture

Cartilaginous growth regions throughout
the skeleton are programmed to add to the
size of bones as organs. Absolute and relative
changes in the size and shape of bones
throughout the fetal and postnatal periods
cause the changes in body size and proportion that result in growth of the organism. This
occurs in single bones and regions. For example, the calvaria is much larger than the facial
skeleton at birth (the ratio is 8:1 in a newborn
compared with 2:1 in an adult). Similarly, upper limb growth is more rapid during early
gestation, and it is not until birth that the
length of the lower limbs is equal to that of the
upper limbs.
The physis is organized to move cells along
columns in a progression of cytodifferentiation
(Figure 1-15). Cells at similar levels in adjacent
columns resemble one another and constitute
zones. Growth or movement occurs from the
small cell phenotype on the epiphyseal side of
the physis to hypertrophic cells on the metaphyseal side. The blood supply to the reserve
and the proliferating zones is derived from the
epiphyseal artery, whereas the hypertrophic
zone is avascular. Metaphyseal vessels supply

16


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Embryology and Formation of Bone

Figure 1-13: Histology of Bone
Cortical (compact) bone
Subperiosteal outer
circumferential lamellae
Periosteum

Endosteal surface
Trabeculae project
into central
medullary (marrow)
cavity

Interstitial lamellae
Capillaries in haversian canals
Perforating fibers
Periosteal vessels

Inner circumferential
lamellae

Trabecular bone (schematic)
On cut surfaces (as in sections), trabeculae
may appear as discontinuous spicules
Osteoid (hypomineralized matrix)
Active osteoblasts produce osteoid
Inactive osteoblasts (lining cells)
Marrow spaces contain
hematopoietic cells and fat
Osteoclasts (in Howship’s lacunae)
Osteocytes
Trabeculae
Section of trabecula (schematic)
Active osteoblasts
Osteoid (hypomineralized matrix)
Inactive osteoblasts (lining cells)
Osteocytes
Osteoclast (in Howship’s lacuna)

17


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Chapter 1
Figure 1-14: Composition of Lamellar Bone
Osteocytes
Originate from
osteoblasts

Osteoblasts
(Matrix-forming cells) Originate
from mesenchyme
Hypomineralized matrix (osteoid)
Mineralized matrix (bone)

Osteoclasts
Originate from bone marrow–derived
macrophage- monocyte line

which lay down bone on the calcified cartilage
armatures. Osteoclasts immediately begin to
remove the first-formed woven bone and cartilaginous septa, and osteoblasts produce
more mature cancellous bone in the secondary spongiosa.
Remodeling is disrupted in osteopetrosis, a
genetic disease characterized by dysfunction
of the osteoclasts. In osteopetrosis, the bones
appear dense or like “marble” on radiographs
because the primary spongiosa with its calcified cartilage cores persists throughout the
bone as an organ. Osteopetrotic bone, however, is markedly weaker than normal bone
because the deficiency in internal remodeling
does not permit the production of stronger
lamellar bone.
The physis directs growth along the longitudinal axis. The total longitudinal growth of a
bone is the height gained by a hypertrophic
chondrocyte multiplied by the aggregate of
all such cellular activity. Different growth
plates contribute different percentages to
overall longitudinal growth. For example, the
distal femoral physis contributes 70% to the
growth of the femur, whereas the proximal
femoral physis contributes 30%.
The circumferential growth of bone occurs
by appositional intramembranous formation.

the area of primary spongiosa but do not enter
the physis.
Cells of the reserve zone participate in the
production of matrix and the storage of
metabolites that are required farther along the
growth plate (see Figure 1-15). Stem cells for
longitudinal growth reside in the upper proliferative zone. Newly formed cells progress
through the proliferative zone to the hypertrophic zone, where chondrocytes enlarge
and the proteoglycan matrix is degraded to
disaggregated, short-chain protein polysaccharides—a process that allows the matrix to
become calcified. In the upper portion of the
hypertrophic zone, chondrocytes switch to
anaerobic glycolysis and store calcium in the
mitochondria. In the lower portion of the hypertrophic zone, the energy is depleted and
calcium is discharged into the matrix, which
permits hydroxyapatite crystal formation and
provisional calcification. Progressive calcification forms longitudinal septa, on which enchondral ossification can occur. Because calcified cartilage matrix has more calcium per
unit volume than does bone, the zone of provisional calcification is seen as a dense band
on radiographs.
In the primary spongiosa region of the metaphysis, blood vessels bring in osteoblasts,

18


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Embryology and Formation of Bone
Figure 1-15: Close-up View of Epiphysis, Physis, and Adjacent Metaphysis
Articular cartilage
Epiphyseal growth plate
(poorly organized)
Secondary (epiphyseal)
ossification center
Reserve zone

Epiphyseal artery

Proliferative zone

Ossification groove
of Ranvier

Maturation zone

Perichondral fibrous
ring of La Croix

Degeneration zone

Hypertrophic
zone

Zone of provisional
calcification

Perichondral artery

Primary spongiosa
Metaphysis

Last intact transverse
cartilage septum

Secondary spongiosa

Metaphyseal artery

Periosteum

Diaphysis
Cartilage
Calcified cartilage
Bone

Nutrient artery
Peripheral fibrocartilaginous element of growth plate
Load

Perichondral fibrous
ring of La Croix
(provides support)
Ossification groove
of Ranvier (provides
cells for growth in
width)
Illustration of how
perichondral fibrous ring
of La Croix acts as limiting
membrane and provides
mechanical support to
cartilaginous growth plate

19


0691 ch 01.qxd 6/3/07 11:20 AM Page 20

Chapter 1
Figure 1-16: Physis (Growth Plate)
Zones
Structures

Histology

Functions

Blood
supply

PO2

Cell (chondrocyte)
health

Cell
respiration

Cell
glycogen

Anaerobic

High
concentration

Aerobic

High
concentration
(less than in
above)

Secondary bony
epiphysis
Epiphyseal
artery
Matrix
production
Reserve zone
Storage

Matrix
production

Poor
(low)

Good, active. Much
endoplasmic reticulum,
vacuoles, mitochondria

Excellent Excellent

Cellular
proliferation
(longitudinal
growth)

Fair

Excellent. Much
endoplasmic reticulum,
ribosomes, mitochondria.
Intact cell membrane

Hypertrophic zone

Degenerative
zone

Zone of
provisional
calcification

Calcification of
matrix

Metaphysis

Primary
spongiosa

Vascular
invasion and
resorption of
transverse
septa
Bone formation

Secondary
spongiosa
Branches of
metaphyseal
and nutrient
arteries

Poor
(very
low)

Closed
capillary
loops

Poor

Good

Good

Remodeling
Internal:
Removal of
cartilage bars, Excellent Excellent
replacement
of fiber bone
with lamellar
bone
External:
Funnelization

20

Progressive
deterioration

Anaerobic
glycolysis

Anaerobic
glycolysis

Cell death

Progressive reversion to aerobic

Nil
Last intact
transverse
septum

Still good
Progressive decrease

Preparation
of matrix for
calcification

Progressive decrease

Maturation
zone

Glycogen consumed until depleted

Poor
(low)

Progressive change to anaerobic

Proliferative
zone

Vessels
pass
through,
do not
supply
this zone

Aerobic

Nil

?

?


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