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I.
INTRODUCTION
The
emphasis of this lecture will be on pathology of the bones and
joints; disease of muscles will be touched on only briefly.
Bone
serves a supportive function. Bones can be classified as either
long (also called tubular) or short and flat.
Long bones have a central shaft, called the diaphysis.
At each end of long bones is the epiphysis. The portion
between the diaphysis and the epiphysis is called the metaphysis.
In immature individuals, a cartilaginous growth plate is
located between the metaphysis and epiphysis. Growth of the long
bones takes place by formation of cartilage, which is then mineralized
in a process called endochondral ossification.The outer
part of the shaft of long bones is composed of tubular canals
arranged in layers like the trunk of a tree. This very strong
type of bone, which is necessary for the long bones to fulfill
their weight-bearing functions, is called cortical or compact
bone. Inside the long bones is a buttressing type of
bone called trabecular, cancellous, or spongious bone,
as well as a cavity containing the bone marrow. Flat
bones are generally bones that don’t bear much weight, such
as the skull. Most flat bones do not form from cartilage,
but instead develop by a process called intramembranous ossification.
Bone first forms as woven bone, which is characterized by
fibers that run “helter-skelter” in random directions.
Woven bone is easier and faster for the body to build than compact
bone, so it is the first type of bone laid down after a fracture.
After fracture of a weight-bearing long bone, the woven bone is
then replaced with stronger compact bone.
Bones
serve a variety of important functions. These include hematopoiesis
(production of blood cells), acting as a reservoir for minerals,
providing structural protection, and providing support and leverage
to enable locomotion.
Ligaments
hold articulating bones together; muscles are attached to bones
by tendons.
Bone
is made of matrix, which is composed of type I collagen
and other substances, and mineral, which is largely calcium
in the form of hydroxyapatite. For proper mineralization, calcium
and associated vitamins (e.g., Vitamin D) are needed, as well
as certain hormones (e.g., parathyroid hormone). Mineral adheres
to the matrix in an orderly fashion if all elements for formation
of bone are in proper working order. Disease can result
from abnormalities in either the matrix or mineral components
of bone.
Throughout
life, bone is constantly turning over, being formed and being
degraded. Two major types of cells are responsible for formation
of bone. Osteoblasts are responsible for making the
matrix of growing bone. Mature osteoblasts residing in mature
bone are referred to as osteocytes. When an osteoblast
is placed under mechanical stress, it responds by producing bone.
Osteoclasts are macrophages that are adapted to living
in bone. Osteoclasts break down and remove bone and are therefore
essential for remodeling. Osteoclasts remove minerals by
secreting acid, and they remove matrix by secreting degradative
enzymes. The growth of any bone requires that matrix and
mineral be added and subtracted in an organized way. The balance
between osteoblasts and osteoclasts needs to be positive up until
a person’s late 20’s, while the skeleton is still being
laid down. Bone loss can occur if osteoclasts get the upper hand.
Bone
is unlike many other structures in the body, in that it undergoes
remodeling as it grows. Remodeling takes place according to Wolff’s
Law, which states that bone is laid down according to the
force that is exerted on it. Use strengthens a bone; disuse
causes it to weaken. One example of Wolff’s Law in
action is formation of a bunion, which is an outgrowth of bone
at the base of the large toe. Due to hereditary factors
or trauma, the tendon that normally runs down the center of the
toe slips to one side in some people. This causes the toe
to curve inward. As a result, the ligaments pull abnormally on
the bones. The force of this pull causes the bone to grow
inappropriately, forming the bunion. The bunion causes pain by
pressing on the skin and joint capsule. Wolff’s Law
also operates during the healing of fractures: it is important
to keep weight on the bone to encourage faster regrowth of bone.
If bones are not subjected to force, they will weaken, e.g., in
patients who are immobilized or in astronauts who are at zero
gravity for long periods of time.
II.
CONGENITAL, HEREDITARY, AND DEVELOPMENTAL DISEASES OF BONE
The
development of bones is a complex process that is regulated by
many different genes. Disease can result from defects in formation
of matrix or from its improper mineralization.
A.
Achondroplasia (dwarfism): is a fairly
rare condition.Achondroplastic dwarfs have relatively normal
torsos and heads, but short arms and legs. The peripheral and
axial skeletons are formed by different mechanisms. Only the peripheral
skeleton is affected in this condition. Likewise,
the drug thalidomide preferentially affected the peripheral skeletons
of developing fetuses, resulting in birth of babies with relatively
normal torsos and heads but, often, gross abnormalities of the
arms and legs. Some arthritic diseases also preferentially affect
either the axial or peripheral skeletons.
B.
Osteopetrosis: arises from a deficiency
in osteoclasts, so that remodeling does not occur properly, and
excess bone is not removed. The bone looks like marble or
rock, which is how the disease gets its name. Despite its rock-like
appearance, the bone is relatively weak, since it lacks the proper
buttressing structure. Patients often have enlarged skulls and
jaws. They also do not have the normal amounts of bone marrow,
so they suffer from anemia, due to lack of production of red blood
cells, and infections, since they are not making sufficient numbers
of white blood cells, either. Infections tend to be a bigger problem
for these patients than anemia. This is also a relatively
rare disease.
C.
Osteogenesis imperfecta: is also called
“brittle-bone disease” and results from mutations in
the gene for a type of collagen. As a result, bones, skin,
teeth, etc. are weaker than normal. Sometimes parents of children
with this condition may be falsely accused of child abuse, since
the children are very prone to fractures.
III.
METABOLIC DISEASES OF BONE
A.
Osteomalacia: is a condition where bone
is soft due to a lack of mineralization. The bone is inadequately
calcified. Osteomalacia is usually caused by inadequate Vitamin
D, which is necessary for uptake of calcium from the diet and
thus for maintenance of proper levels of calcium in the blood.
When levels of calcium in the plasma fall, there is an increase
in release of parathyroid hormone, which, in turn, causes osteoclasts
to break down bone to replenish calcium in the blood. The kidney
also responds by decreasing excretion of calcium and increasing
that of phosphate. Vitamin D is synthesized in the skin in response
to ultraviolet light and is also derived from the diet, especially
from meat and dairy products.
Lack
of Vitamin D in the diet is commonly seen only in underdeveloped
countries. In the US, inability to absorb Vitamin D from the diet
(e.g., due to inflammatory bowel disease or surgical removal of
part of the intestine) is a more usual problem. Vitamin D, whether
ingested or made in the skin, must be converted into an active
form by having one hydroxyl group added in the liver and another
in the kidney. Patients with chronic kidney disease are
therefore prone to developing osteomalacia, since they often cannot
synthesize the active form of Vitamin D. This condition
is called renal osteodystrophy and is more complex than
simple osteomalacia. Patients with renal osteodystrophy
can be treated by giving them the already modified, dihydroxy
form of Vitamin D, as well as by managing their levels of calcium,
phosphorus, and pH (remember the importance of the kidney in the
regulation of these).
The
primary manifestation of the disease in adults is an increased
risk of fractures, and the patient may complain of bone pain.
X-rays of the spine often reveal a loss of mineralization in the
centers of the vertebrae. Approximately 5 to 10% of bone is turned
over each year. If there is inadequate calcium for mineralization,
whatever the cause, the newly formed bone will be weaker than
normal. Bone needs to be maintained.
Osteomalacia
of childhood is called rickets. Symptoms can be severe,
including bowing of the bones.
B.
Osteoporosis: differs from osteomalacia
in that both mineral and matrix are diminished. This
disease results from a disturbance of the normal balance between
osteoblasts and osteoclasts and is an inevitable consequence of
aging. Bone increases up to about age 30, but is lost at about
0.5% per year thereafter. Loss in women may be 3 to 5 times more
than in men. This is probably the most common skeletal disease,
certainly in this country, and is a major cause of hospitalization
in the elderly.
Primary
or senile osteoporosis affects men and women with equal
frequency and is most often seen at age 75 or greater. It
appears that in these patients, the osteoblasts simply “run
out of gas” and stop making adequate amounts of matrix.
Osteoclasts then gain the edge, and bone is lost faster than it
is made. Secondary osteoporosis has several causes. It
commonly occurs in women as a result of changes in the levels
of estrogen after menopause. (It is not the total amount
of estrogen that is critical; otherwise, all men would get osteoporosis).
When estrogen levels decline, osteoclasts may become excessively
active and degrade bone inappropriately. It can also occur in
other settings. Immobilization can contribute, so it is important
to ensure that bedridden patients receive appropriate physical
therapy. Some tumors can activate osteoclasts and lead to
areas of bone destruction called lytic lesions. Endocrine
disorders (e.g., removal of ovaries, diabetes, thyroid disease)
can also be contributing factors, as can certain drugs (such as
steroids). Proper diet is also essential for preventing
osteoporosis. Risk factors include genetic background (e.g., Caucasians
are at greater risk), a light build, and a sedentary lifestyle.
Prevention
is very important, i.e., by making sure conditions for building
and maintaining bone are optimal. It is essential to maintain
adequate intake of calcium, Vitamin D, and protein. Teenagers
often have diets that don’t favor formation of strong bone.
Exercise is also important in maintaining good bone (according
to Wolff’s Law). Osteoporosis may become less of a
problem in the future, as women today recognize the benefits of
pursuing a less sedentary lifestyle. In terms of treatment,
estrogen replacement therapy is used for the postmenopausal form.
Drugs (bisphosphonates) to inhibit osteoclasts are available.
On
X-ray, the vertebrae in a patient with osteoporosis may become
concave and collapse inward due to compression fractures,
which may lead to loss of height. There is usually a loss of structure
across the entire width of the vertebrae. (Contrast this to the
situation seen in osteomalacia). Fractures of the hip are very
common and not infrequently lead to death.
Important
note: In osteogenesis imperfecta, only the matrix
is faulty. In osteomalacia, it is the mineral that is deficient.
In osteoporosis, both components are diminished. A failure in
any of the components of bone therefore leads
to mechanical weakness.
C.
Paget’s disease: is a common disorder,
affecting some 2-4% of the population, but it is usually not too
disabling. It is thought to result from uncoordinated functioning
of osteoblasts and osteoclasts, such that too little bone is deposited
in some places and too much in others. It tends to be localized,
involving the axial skeleton. Involvement of the skull may
lead to a change in hat size; involvement of bones in the ear
may lead to hearing loss. Bone pain may be another symptom. The
underlying cause is not known; some have proposed that a viral
infection may be responsible. Patients with Paget’s
disease are at increased risk for developing osteosarcoma, a malignancy
that is usually seen only in the young.
IV.
VASCULAR DISEASE OF THE BONE
Like
any organ, the bone suffers from deprivation of its blood supply.
An infarct in the bone is called avascular necrosis (also
called osteonecrosis). If the pressure in the bone is increased,
the circulation of blood may be impaired. Prolonged administration
of corticosteroids may lead to increased pressure in the enclosed
spaces of the bone and, consequently, avascular necrosis. Another
cause is sickle cell anemia, in which the abnormal red blood cells
may occlude vessels in the bone. In children, the epiphysis is
very vascular. If it slips, which is not an uncommon event,
the vessels may become occluded. Avascular necrosis is not
reversible and leads to weakness of bone and predisposition to
fracture.
V.
INFECTIONS OF BONE (OSTEOMYELITIS)
Bacteria,
usually staphylococci or streptococci, can spread to bone directly
or through the blood. Such infections can lead to tremendous destruction
of bone. Children are particularly vulnerable to hematogenous
spread, since their bones are more highly vascularized than those
of adults. Trauma or orthopedic procedures may introduce bacteria
into bones; orthopedic surgeons must be particularly vigilant
about maintaining sterile operating conditions. Osteomyelitis
can be very difficult to treat. Infections tend to be resistant
to antibiotics, since it is hard to get the drugs into the bone
once damage has occurred. In addition, it is difficult for
phagocytes to enter bone so that they can carry out their roles
in host defense. Mickey Mantle suffered from osteomyelitis for
years. Osteomyelitis can occur in the vertebral column, for example,
in the setting of tuberculosis (called Pott’s disease).
The TB bacilli can invade disks, destroy cartilage, and cause
compression of the spinal cord, leading to hunchback deformity.
This used to be quite a common condition, and it is still seen
today. Osteomyelitis may be very painful and disabling, but, fortunately,
it is relatively uncommon.
VI.
TRAUMA AND FRACTURES OF THE BONE
Fractures
can be classified as natural, in which the force applied
is appropriate to break bone, or pathologic, which result
from forces that would be insufficient to break normal bone. The
most common causes of pathologic fractures in the US are osteoporosis
and cancer.
Classifications
of fractures include:
-
Simple: the broken bone remains
approximately in its original location.
- Displaced:
the fractured bone is depressed (e.g., in the skull) or
out of alignment.
- Comminuted:
refers to a situation when the bone is shattered into fragments.
- Compound:
the broken bone protrudes through the skin.
- Spiral:
the fracture encircles the bone, winding its way down in
a spiral fashion.
- Greenstick,
bowing, torus, stress: are terms that refer to fractures
that do not extend through the entire thickness of the bone.
After
a long bone is fractured, a cartilaginous collar called callus
forms at the broken ends. Next, woven bone is laid down; eventually,
this is converted to compact bone. In young people, bones tend
to heal relatively quickly and get remodeled to their original
form. In fact, the healing bones of children sometimes become
too long, since their growth is accelerated. Proper healing of
fractures is a much bigger problem in the elderly.
Failure
to immobilize a fracture in a long bone properly can result in
a lack of fusion (non-union) and formation of a
pseudoarthrosis (false joint). Sometimes fat is released
from the marrow of broken bones. This fat can cause emboli, which
may result in infarcts in distant organs, such as the lung. Infection
is another possible complication. Fractures that do not heal and
some cases of avascular necrosis need to be treated by replacing
the affected bone with a prosthetic one (e.g., for fractured hip).
VII.
TUMORS OF BONE
By
far the most common tumors of bone are metastatic in origin, meaning
that they come from another organ. Cancers of the breast, lung,
prostate, thyroid, and kidney all tend to spread to bone. Breast
cancer cells in bone tend to activate osteoclasts and thus be
osteolytic (dissolving bone), thereby increasing the risk
of fracture. Prostate cancers in bone also increase the risk of
fracture but tend to activate osteoblasts, causing sclerotic
lesions. In these lesions, the bone is thicker but weaker than
normal, since it lacks the proper buttressing structure.
Primary
tumors of bone include osteosarcoma, which usually develops
at the ends of long bones. This cancer occurs most commonly in
children, especially at puberty. In adults, osteosarcoma sometimes
develops in association with Paget’s disease.Multiple
myeloma is a tumor of plasma (antibody-producing) cells that
causes lytic lesions in bone and bone marrow. This disease is
usually seen in older individuals and is increasing in incidence.
Multiple myeloma is usually very painful and difficult to treat.
VIII.
DISEASES OF JOINTS
What
looks like a space in an x-ray of a joint is actually mostly cartilage.
There is only a small space, which is filled with synovial fluid.
The synovium is the lining of the joint space. The bursae
are fluid-filled outpouchings of synovium that lie between the
tendon and joint and serve to lubricate and cushion. Joints composed
of two or more articulating surfaces are called diarthroses.
These may be hinged, sliding, spherical, etc. Ligaments
are wrapped around joints, which are also stabilized by the joint
capsule, muscles, and tendons. Cartilage has no blood supply,
so the cartilage in a joint gets its nourishment from the synovial
fluid.
A.
Osteoarthritis
Osteoarthritis
(OA) is a disease of wear and tear that results from repeated
use of a joint. It is a common disease, the incidence of which
increases with age. It is not an inflammatory condition (in contrast
with rheumatoid arthritis, which is discussed next). It is primarily
a disease of cartilage, whereas RA is a disease of the synovial
lining of the joint. It is exaggerated by any condition that affects
normal articulation of the joint, including injury, congenital
dislocation, or overuse and abuse. It can affect both small and
large joints; its tendency to involve specific joints is to some
degree hereditary. For example, in women, a tendency to develop
OA of the distal finger joints is maternally transmitted. Common
sites for OA to develop include the hips, knees, hands, and spine.
OA
may develop secondary to a variety of conditions. These include
metabolic conditions (for example, acromegaly or hemophilia),
anatomic problems (such as congenital dislocations), repeated
trauma (including sports or occupational stresses), or neuropathies
(as in diabetes), which prevent the patient from feeling whether
he or she is placing undue stress on a joint.
In
OA, pain tends to worsen as the affected joint is used. Therefore,
patients usually feel best in the morning (contrast this with
symptoms of RA below).
In
OA, the cartilage of the joint is worn away. Early in the
disease, the cartilage may become frayed (fibrillation).
The underlying bone becomes sclerosed and looks like
polished ivory, a condition called eburnation. Spurs
of new bone called osteophytes may form, limiting the mobility
of the joint. These spurs form according to Wolff’s law:
because the normal articulation of the joint is lost, tendons
may pull abnormally and cause stresses that favor the formation
of the osteophytes. The joint may squeak due to the presence of
loose pieces of cartilage and bone (“joint mice”). Large
osteophytes may form in the joints of the hands (called Heberden’s
nodes or Bouchard’s nodes depending on
their location). These may be very painful. Osteophytes in the
spine may compress nerves, leading to sciatica. Bone degeneration,
due to misalignment of the joint, may also result in formation
of cysts.
B.
Rheumatoid arthritis
Osteoarthritis
and rheumatoid arthritis (RA) are both very common diseases, although
the incidence of OA is much higher - almost everyone will develop
some degree of OA if he or she lives long enough. RA affects 1
to 2% of the population and is more common in temperate climates
than in tropical areas. Genetic factors appear to play a
role in RA, since it is more common in people with certain forms
of MHC (HLA) genes. Patients with RA usually feel the most stiffness
in their joints when they first awaken; the symptoms tend to improve
as the joints are used (contrast this with OA above). OA tends
to affect weight-bearing joints and the distal joints of the hands
and feet. RA often starts in the wrists and peripheral joints
of the hands, but may involve any and virtually every joint in
the body. In sharp contrast to OA, RA may also have systemic
manifestations.
RA
is an inflammatory, autoimmune disorder of uncertain cause.
A blood test for so-called rheumatoid factor can aid in diagnosis.
In RA, pannus forms in the joint. Pannus is abnormally
proliferating synovial tissue that is filled with inflammatory
cells. The pannus, which has a cauliflower-like appearance,
can destroy the surface of the joint. RA can involve the
ligaments, tendons and their sheaths, leading to contractures
of the hands, etc. The inflammatory process can actually eat through
tendons, causing them to snap, so that the patient can no longer
extend or flex. In this way, RA can cause serious disability even
without destroying the joints themselves. Affected joints may
fuse and become immobile (ankylose); the only effective
treatment for this condition is replacement of the joint with
a prosthesis. Ankylosis is not typically seen in OA.
Children
can also be afflicted with RA. In juvenile RA, the disease sometimes
affects proper development of the bones in the face, resulting
in an abnormally small chin. A particular form of RA, called Still’s
disease, is sometimes associated with development of a salmon-colored
rash.
C.
Miscellaneous problems with joints
Lyme
disease is an illness caused by spiral-shaped bacteria, called
spirochetes, that are spread through the bites of ticks. It may
cause arthritis. In some patients, the early stages of the disease
are marked by the presence of a spreading rash called erythema
migrans.
In
the spinal column, a herniated intervertebral disk may press on
the nerve roots. Often, the patient leans in the direction
opposite to the herniation to relieve the pressure. Repeated bleeding
into the joints (e.g., due to hemophilia or sickle cell disease)
may be a source of damage. A dislocation refers to a situation
where bones in a joint do not contact one another. In a subluxation,
there is partial contact. Dislocations and subluxations
can be congenital. A clubfoot may arise due to intrauterine
conditions that cause improper development of the foot. Binding
of feet, once widely practiced on women in China, can lead to
gross deformity.
Gout
is a disease that results from abnormal accumulation of uric acid
crystals. These tend to precipitate in the coolest parts
of the body, such as the ears, big toes, and elbows. Visible collections
of crystals are called tophi and may cause granulomatous
inflammation. The uric acid crystals may also be microscopic.
When neutrophils try to clear away these tiny crystals by ingesting
them, the neutrophils are damaged and injurious substances leak
out, causing tissue damage (see the lecture on inflammation).
Gout can be treated with drugs that enhance the excretion or decrease
the production of uric acid. Gout commonly affects the great toe
(podagra), often causing a great deal of pain. Patients
may also develop kidney stones, since they excrete too much uric
acid.
People
with a particular form of the MHC molecule called B27 are at increased
risk of developing a type of “reactive” arthritis that
fuses the spine, called ankylosing spondylitis (“poker
spine”). This fusion occurs because the ligaments
overlying the posterior of the spine calcify. The spine
becomes a rod-like structure that cannot bend properly.
Patients may exhibit a stooped posture. Other types of spondylitis
are associated with psoriasis and Reiter’s syndrome.
Reiter’s syndrome may follow infections of the GI and GU
tracts, including venereal infection, particularly in men with
the B27 allele. It may involve conjunctivitis, iritis, ulcerations
of the penis, and “sausage” swelling of the toes.
The
meniscus is a structure in the knee joint that keeps the
tibia in alignment with the femur. The meniscus can tear,
but it can be repaired with arthroscopic surgery. The terms strain
and sprain refer to tears in the tendons/muscles or
ligaments, respectively. Ligaments can take a long a time
to heal, so sprains can be serious. In bursitis, bursae
get filled with fluid.Epicondylitis is due to damage of
tendons in the elbow area. Sports are a common cause, as reflected
in the common names of “tennis elbow” for lateral epicondylitis
and “golf elbow” for medial epicondylitis.
IX.
MORE AUTOIMMUNE DISORDERS
A.
Scleroderma
In
scleroderma (meaning "hard skin"),
the skin becomes thickened and inflexible, which can lead to deformities
such as “claw hand” (sclerodactyly). Scleroderma
is often associated with Raynaud’s syndrome, which is characterized
by the fingers turning white in the cold and blue when rewarmed.
In the setting of scleroderma, it is thought that Raynaud's syndrome
is due to an autoimmune disorder in which T cells make cytokines
that cause blood vessels to respond in an exaggerated way.
Thus, vessels constrict and expand too much in response to cold
and heat. In scleroderma, the deep vessels may be affected,
leading to ischemia and necrosis in the kidneys. It should
be noted that not all people with Raynaud’s syndrome develop
scleroderma; in fact, most do not. A severe form of scleroderma
is called systemic sclerosis.
B.
Systemic lupus erythematosus (SLE)
SLE
is an autoimmune disorder associated with production of antibodies
directed against the patient’s own DNA and other components
in the cell nucleus. It most commonly occurs in women of reproductive
age. Episodes can be triggered by exposure to the sun. The
disease can be quite variable. It can be confined to the
skin (discoid lupus), or it can affect almost any organ
system in the body, which is where this disease gets the “systemic”
part of its name. Often, a “wolf-like” rash is seen
on the face: hence the “lupus erythematosus” part
of the name. Patients may also have arthritis, although this arthritis
is not usually deforming. SLE can be treated medically with variable
success.
X.
MUSCLE DISEASES
As
you might guess from its name, dermatomyositis is a disease
that affects the muscles and skin. It is seen in both children
and adults. A characteristic sign of the disease is a heliotrope
(lilac-colored) rash on the eyelids. The disease may affect other
parts of the body, particularly in children. A scaly, purplish
rash may develop over the joints, and patients may suffer from
muscle weakness and pain. Polymyositis is a disease
of unknown cause characterized by inflammation of the muscles.
Duchenne’s
muscular dystrophy is marked by muscular weakness and is the
disease for which Jerry Lewis holds a telethon each year.
This is an inherited disease. The specific gene that is
mutated in patients who inherit the disorder has been identified
and encodes a protein called dystrophin, but there is no
cure as yet. Death often results from respiratory failure.
Fortunately, this condition is relatively uncommon.
A
rare condition is selective muscle atrophy, which affects
very specific muscles, e.g., in the neck or the lower part of
the face. The cause is unknown.
Myasthenia
gravis is an autoimmune disease where the body makes antibodies
against acetylcholine receptors on muscle cells. See the
immunology lecture for more details.
Trichinosis
is a parasitic infection of muscle that is contracted
by eating undercooked, infected pork. It is rare in the
US.
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