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Non-neoplastic bone pathology Osvaldo Rubinstein, MD


Non-neoplastic bone pathology Osvaldo Rubinstein, MD Necrotic bone tissue shows empty lacunae with no evidence of osteocytes. The cortex is usually not affected due ... – PowerPoint PPT presentation

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Title: Non-neoplastic bone pathology Osvaldo Rubinstein, MD

Non-neoplastic bone pathology
  • Osvaldo Rubinstein, MD

  • Bone tissue has a very complex
    hystoarchitecture. In order to understand the
    pathogenesis of bone disorders it is important to
    review the bone histology and the function of
    their cells.

  • Another important consideration is the close
    vicinity between bone tissue and the bone marrow.
    Pathologic processes involving the bone marrow
    (for ex. Leukemia), affect the bone tissue and

Woven and lamellar bone
  • Bone tissue presents in two main forms
    woven bone and lamellar bone. Woven bone is
    inmature and consists of randomly arranged
    collagen fibers within osteoid tissue. It is
    produced when there is a rapid deposition of
    osteoid as it occurs in fetal bone formation.

  • In adults woven bone is deposited when there
    is new bone formation like during the healing of
    fractures or in Pagets disease. The rapidly
    formed woven bone is eventually remodeled into
    lamellar bone which is physically stronger and
    more resilient. Virtually all bone tissue in the
    healthy adult is of the lamellar type.

  • Bone tissue presents in two main patterns
    namely cancellous or compact cortical bone.
  • Cancellous bone consists of a network of
    fine irregular bony plates called trabeculi,
    separated by intercommunicating spaces occupied
    by the bone marrow which is the site of active

Cancellous bone
  • In adults active hematopoiesis takes place in
    the cancellous bone of the spinal column,
    sternum, ribs, skull, pelvis and proximal end of
    the femur. The active marrow is dark red. In the
    marrow of the long bones the bone marrow is
    inactive and shows a yellow color due to the
    predominance of fat tissue and the active marrow
    is located in the thin layer of cancellous bone
    lining the medullary cavity.

  • Compact bone is seen mainly in the long bones.
    It is made up of bony columns parallel to the
    bones long axis. Each column is composed of
    concentric bone layers called lamellae disposed
    around central channels named canals of Havers.
    These canals contain blood vessels and nerves. At
    the periphery of compact bone the Haversian
    systems are replaced by concentrical layers of
    dense cortical bone.


H Haversian Canal O Osteocytes L Lacunae C
Cement Lines P Periosteum
Compact bone
Functional histology
  • Bone is composed of cells and a predominant
    collagenous extracellular matrix( type 1
    collagen) called osteoid, which becomes
    mineralized by the deposition of hydroxyapatite
    providing the bone with rigidity and strengh.
    Bone tissue displays three types of cells.

  • Osteoblasts synthesize and laid down osteoid
    and mediate its mineralization. They are found
    in the cancellous bone lining the bone trabeculi.
    They derive from primitive mesenchymal cell
    called osteoprogenitors. Osteoid becomes
    calcified immediately after deposition. In
    situations where calcium and phosphate ions are
    not available there is an abnormal accumulation
    of osteoid tissu (for ex. Rickets and chronic
    renal failure).

Process of mineralization
Osteoblasts and osteoid.
Osteoblasts Osteoid Compact Bone
  • Osteocytes maintain the integrity of the
    mineralized matrix and mediate the short term
    release or deposition of calcium in order to keep
    calcium homeostasis in the body. The osteocyte
    activity is directly regulated by plasma calcium
    levels and indirectly by parathormone and
    calcitonin secreted by the thyroid gland.

  • Osteocytes represent inactive osteoblasts
    trapped within the newly formed bone lamellae in
    spaces called lacunae. Between adjacent lacunae
    and the central Haversian canal are numerous
    canaliculi (Volkmanns canals), which contain
    fine cytoplasmic extensions of osteocytes. These
    cytoplasmic extensions connect with each other
    and with the periosteum and endostium.

  • Osteoclasts are multinucleated giant cells
    that are usually seen in depressions created by
    the reabsortion of bone and called Howships
    lacunae. The cell membrane shows fine microvilli
    forming a ruffled border which secretes several
    organic acids which disolves the mineral
    component of the lamellae while lysosomal
    proteolytic enzymes destroy the organic matrix.
  • Osteoclastic reabsortion participates in
  • a) bone remodeling in response to growth or
    changing mechanical stresses on the skeleton.
  • b) it participates in the long term maintenance
    of blood calcium levels. When a patient presents
    with hypocalcemia the parathyroid gland increases
    the secretion of parathyroid hormone which
    stimulates osteoclastic bone reabsortion and the
    release of calcium ions from bone and respond to
    calcitonin which inhibits osteoclastic activity.

Mature Periostium
  • The outer surfaces of most bones show a layer
    of condensed fibrous tissue called periosteum
    which contains numerous osteoprogenitor cells
    that look like fibroblasts. During bone growth or
    repair, osteoprogenitor cells differentiate into
    osteoblasts which lay lamellae of cortical bone
    by appositional growth.

  • The periostium is bound to underlying bone
  • by Sharpeys fibers which penetrate the
    whole thickness of the cortical bone. The latter
    is not lining articular surfaces and the sites of
    insertion of tendons and ligaments. The
    periostium plays an important role in the repair
    of bone fractures.

Anatomy of long bone
  • Hereditary conditions involving bones can be
    divided into two groups, namely dysostoses and
    dysplasias. These may affect a single bone or the
    entire skeleton.
  • Dysostoses are caused by developmental
    anomalies affecting the migration of mesenchymal
    cells due the mutations of specific genes. They
    are usually limited to defined embryologic
    structures. Some of the most common lesions
  • 1) aplasia (congenital absence of a digit or
  • 2) the formation of extra bones (supernumerary
  • 3) abnormal fusion of bones (premature
    closure of cranial sutures).

Displasias are the result of mutations
that interfere with bone or cartilage growth
and/or maintenance of normal matrix components.
There are many types of bone dysplasia. We are
going to discussonly osteogenesis imperfecta,
achondroplasia, and osteopetrosis
Osteogenesis imperfecta
  • Osteogenesis imperfecta (OI) also known as
    brittle bone disease is a group of hereditary
    disorders caused by a deflective synthesis of
    type I collagen. Since this type I collagen is a
    component of extracellular matrix in other parts
    of the body, there are also numerous
    extraskeletal findings affecting skin, joints,
    and eyes. OI is an autosomal dominant disorder.
    The molecular pathology of OI involves a gene
    mutation coding for type I collagen resulting in
    a premature degradation of the protein.

  • There is great variation in the penetration
    of these mutations with some of them coding for a
    a quality normal collagen and resulting in a
    milder conditon. The main abnormality of OI is
    the formation of little bone resulting in extreme
    skeletal fragility.
  • There are four major presentations of this
  • The type II variant is fatal due to multiple
    postpartum fractures that occur in utero or
    during delivery.
  • Type I OI variant carries a normal lifespan
    with increased tendency to fractures during
    childhood. The classic blue sclerae seen in these
    patients is due to decreased collagen content
    allowing the choroid ocular membrane to be seen.
    There may also be hearing loss due to conduction
    defects in the middle and inner ear.

This X-ray shows bilateral femoral bowing in a
l4-year-old with osteogenesis imperfecta.
Many patients with osteogenesis imperfecta
survive into childhood or even reach adult life.
Because of the innumerable fractures and the very
weak bones, dwarfing and deformity are
Osteogenesis imperfecta showing a fetus with
multiple fractures.
Osteogenesis imperfecta. Note the relative
increased number of osteocytes.
  • Achondroplasia is a major cause of dwarfism.
    The underlying etiology is a point mutation
    leading to the activation of fibroblast growth
    factor receptor 3. Activated FGFR3 inhibits
    chondrocyte proliferation and as a result growth
    plate expansion is suppressed and long bone
    growth is severely stunted. This disorder is
    typically autosomal dominant.

  • Affected individuals are heterozygotes. Since
    homozygosity lead to abnormal chest development,
    it may trigger death from respiratory failure.
    The most severe abnormalities of this condition
    includes marked disproportionate shortening of
    the proximal extremities, bowing of the legs, and
    a lordotic posture. The cartilage growth plates
    are disorganized and hypoplastic.

  • Osteopetrosis is a rare genetic disorder
    characterized by reduced osteoclast bone
    reabsortion resulting in diffuse, symmetric
    skeletal sclerosis.
  • The name osteopetrosis refers to the
    stone-like quality of the bone, however, the
    bones are fragile and prone to fractures.
  • Four types of osteopetrosis have been
    identified, namely1) infantile malignant
    osteopetrosis, 2) type II carbonic anhydrase
    deficiency and 3) autosomal dominant types I and
  • Carbonic anhydrase is required by osteoclasts
    to release hydrogen ions in order to acidify and
    solubidize the hydroxyapatite crystals so that
    they can be digested. Therefore, the lack of this
    enzyme inhibits bone reabsortion.
  • Lack of bone reabsortion leads to the
    obliteration of the medullary cavity of long
    bones by lamellar bone and the epiphysis become

  • Infantile malignant osteopetrosis is autosomal
    recessive and ends up in postpartum mortality due
    to 1) fractures taking place inside the uterus,2)
    anemia, and 3) hydrocephaly. If the baby
    survives, they may develop optic atrophy,
    deafness, and facial paralysis. Due to lack of
    marrow spaces there is suppression of
    hematopoiesis resulting in fatal infections due
    to absence of white cells.

  • The autosomal dominant benign form may not be
    detected until adolescence or adulthood by x-rays
    performed to establish the cause of repeated
    fractures. They also may develop milder cranial
    nerve deficiencies and anemias. Since osteoclasts
    derive from marrow monocytes precursors, bone
    marrow transplants provide affected patients with
    osteoprogenitor cells able to produce normally
    functioning osteoclasts. Patients who underwent
    this procedure showed reversal of many of the
    skeletal abnormalities.

This spinal radiograph shows dense calcification
of the vertebrae, the pathognomonic radiographic
feature that gives this illness its alternative
nameof chalk bone disease or marble bone
This clinical photograph depicts an infant with
autosomal recessive osteopetrosis congenita, the
lethal form of the disease.
Although they are hard to discern,, the sclerae
are blue, a physical sign of value in the
diagnosis of this disease in patients beyond
early infancy. As the markings on the anterior
abdominal wall show, this patient has massive
hepatosplenomegaly as a consequence of
extramedullary hematopoiesis.
  • I. Osteoporosis
  • It is a disease characterized by increased
    porocity of the skeleton due to reduced bone
    mass. It is associated with increased bone
    fragility and the potential to develop fractures.
    The disorder may affect a single bone or a region
    such as diffuse osteoporosis of a limb. It may
    also affect the entire skeleton when it is the
    result of a metabolic bone disorder. Generalized
    osteoporosis may be primary or secondary to many
    pathologic conditions.
  • Primary osteoporosis includes two types senile
    and postmenopausal.

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  • Microscopically there is thinning of bone
    trabeculi and widening of Haversian canals.
    Osteoclastic activity is present but not
    increased. The mineral content of the remaining
    bone is normal. With increasing age, the capacity
    to synthesize bone decreases while osteoclastic
    activity remains intact.
  • In menopausal females, decreased estrogen
    levels accounts for an annual loss of 2 of
    cortical bone and 9 of cancellous bone. 50 of
    menopausal women suffer osteoporotic fractures in
    comparison to 3 of men the same age.

Osteoporosis. Note the thin trabeculi and
enlarged marrow spaces.
Complications of osteoporosis
  • The outcome of osteoporosis depends on which
    bones are involved.
  • Thoracic and lumbar vertebral fractures are
    common, causing loss of height, and
    kyphoscoliosis that may compromise respiratory
  • Pulmonary embolism and pneumonia may be
    complications of fractures of the femoral neck,
    pelvis, or spine.
  • Levels of calcium, phosphorus and alkaline
    phosphatase are usually within normal limits.
  • The condition is asymptomatic until a fracture
  • X-rays are diagnostic only when 30-40 of bone
    mass has been lost. Today, osteoporosis is
    treated with drugs that act by increasing the
    bone mass.

Pagets Disease
  • This condition is characterized by repetitive
    episodes of regional osteoclastic activity
    leading to bone reabsortion (osteolytic stage),
    followed by bone formation (mixed osteoclastic
    osteoblastic stage) and finally by ceasing all
    cellular activity (osteosclerotic stage).
  • At the end of this pathology process there
    is a gain in bone mass but the newly formed bone
    is disordered and lacks strength. The bone can be
    cut with an ordinary knife without decalcifying
    the tissue.
  • Pagets disease usually occurs in
    mid-adulthood and is more common thereafter. It
    may be monostotic or it may happen in multiple
    sites in the skeleton (polyostotic).

  • In the proliferative phase of the disease
    when it involves the skull, symptoms include
    headaches, visual and auditory disturbances
    caused by compression of cranial nerves.
  • Back pain is common with vertebral lesions,
    as well as disabling fractures of vertebral
    bodies and nerve root compression.
  • Afflicted long bones in the legs are often
    deformed, and brittle long bones are subject to
    chalkstick fractures.
  • Osteogenic sarcoma may develop in 1 of these
    patients. They occur in pagetoid bones.
  • Most patients with Pagets disease have mild
    symptoms that are easily controlled.

  • In the osteolytic phase there are numerous
    osteoclasts associated with large Howships
  • In the mixed phase, osteoclasts persist but
    bone trabeculi are lined by prominent
  • The marrow is replaced by loose connective
    tissue containing osteoprogenitor cells. The
    newly formed bone at the end is remodeled by
    forming markedly distorted lamellar bone.
  • The patognomonic histologic feature of
    Pagets disease is the mosaic pattern of the
    prominent cement lines which surround units of
    the abnormal lamellar bone.

  • A
  • 1) Lytic stage
  • 2) Mixed stage
  • 3) Area of new bone
  • B
  • Bone reabsortion
    replaced by new compact bone
  • C
  • Sclerotic stage

Paget disease. Elbow joint
Pagets disease
  • Pagets disease

  • Current evidence suggests that a
    paramyxovirus is the cause of Paget disease.This
    virus can induce IL1 and MCSF cytokines that
    strongly activate osteoclasts. The axial skeleton
    or femur are invloved in 80 of the cases.
  • Complications of this conditon include
    skeletal neuromuscular and cardiovascular
    abnormalities. In most cases these are mild and
    discovered as incidental radiographic findings.
  • Serum alkaline phosphatase is markedly
  • In patients with extensive polyostotic
    disease hypervascular bone lesions may lead to
    high output congestive cardiac failure.

The four processes of metabolic bone disease
  • excessive synthesis of osteoid
  • inadequate synthesis of osteoid
  • inadequate mineralization of osteoid
  • excessive resorption of mineral and osteoid

  • Genetic factors may inhibit vitamin D
    absortion and they can influence calcium uptake
    or PTH synthesis.
  • Prolonged glucocorticoid therapy increases
    bone reabsortion and reduces bone synthesis.
  • Mechanical activities stimulate bone
    remodeling. Therefore reduced physical activity
    increases bone loss (for ex, immobilized limbs or
    systemic effects on astronauts which are unloaded
    in a gravity free environment).

  • In a normal situation the parathyroid gland
    maintains normal calcium levels by activating
    osteoclasts which increase bone reabsortion,
    increase the synthesis of vitamin D and increase
    urine excretion of phosphates.
  • However, excessive levels of PTH resulting
    from autonomous parathyroid secretion (for
    example parathyroid adenoma) or underlying renal
    disease (secondary hyperthyroidism) leads to
    significant skeletal changes due to uncontrolled
    osteoclast activity.

  • The marrow spaces are occupied by
    fibrovascular tissue, hemorrhagic areas
    resulting from fractures of weakened bone and
    large hemosiderin pigment deposits (Brown tumor).
    Cystic changes are common, so this lesion is
    called osteitis fibrosa cystica. Bones are
    increasingly subjected to fractures, deformities,
    and joint pathology.
  • These lesions may regress with the reduction
    of PTH levels.

  • In renal failure, hyperphosphatemia impairs
    vitamin D synthesis which inhibits calcium
    gastrointestinal absortion. The low calcium level
    is followed by increased parathyroid function in
    order to maintain normal calcium levels
    (secondary hyperthyroidism).
  • The effect on bone tissue is the loss of
    cortical and trabecular bone specially in the
    subperiosteal region.
  • Microscopically there is increased number of
    osteoclasts and erosion of bone surfaces.

Osteitis fibrosa cystica, early stage.
Osteitis fibrosa cystica, terminal stage.
Osteoclasts reabsorbing bone trabeculi
  • They are the most common bone lesions.
  • They can be classified as
  • 1) complete or incomplete.
  • 2) closed when the overlying skin is intact.
  • 3) compound when the bone fragments ulcerate the
    overlying skin
  • 4) committed when the bone is splintered and
  • 5) displaced when the fractured bone is not
  • If the fracture occurs at the site of a
    previous lesion (for example, bone cyst or a
    malignant tumor) it is called a pathologic
  • A stress fracture develops slowly over time
    following a group of microfractures associated
    with increased physical activity especially with
    repeated weight on bone like in military boot
    camp or in certain sports.

  • The repair of a fracture is a highly regulated
  • 1) A trauma causing the fracture ruptures blood
    vessels resulting in a large blood clot. The
    fibrin mesh traps inflammatory cells and
    different growth factors that activate bone
    progenitor cells. One week later this tissue is
    primed for matrix synthesis and is called soft
  • The soft tissue callus is able to hold the
    ends of the fractured bone in apposition, but is
    not calcified and not able to support weight

  • 2) Bone progenitors in the medullary cavity
    deposit new foci of woven bone and activated
    mesenchymal cells differentiate into
    chondroblasts. within 2-3 weeks.
  • Following ossification, the fractured bony
    ends are bridged by a bony callus.
  • Excess amount of fibrous tissue, cartilage
    and bone that were produced in the early callus
    is reabsorbed due to pressure by weight-bearing
    joints, from non-stressed sites and the
    fortification of regions supporting greater
  • Callus remodeling restores the original size,
    shape and the cancellous architecture of the
    medullary cavity.

Complications of the healing process of feactures
  • 1) Displaced and comminuted fractures frequently
    result in some deformity. Devitalized fragments
    of splintered bone require reabsortion delaying
    the healing and enlarging the callus requiring a
    long remodeling process that sometimes is never
  • 2) Inadequate immobilization of the affected bone
    results in constant movement of the fracture site
    not allowing the formation of the bony callus.
    Therefore, the latter at the and is composed of
    fibrous tissue and cartilage resulting in a
    delayed union or nonunion and permanent
    instability of the bone.

  • 3) Too much motion along the fracture causes
    cystic degeneration of the central portion of the
    callus which eventually is lined by synovial like
    cells creating a false joint (pseudoarthrosis).
    In this case, like in non-union, surgical
    intervention is needed to remove interposing soft
    tissues so that the fracture site is stabilized.
  • 4) Infection will suppress bone healing which is
    a risk in comminuted or open fractures.
  • 5) Bone repair may be impaired by inadequate
    levels of calcium or phosphorus, vitamin
    deficiencies, systemic infections, diabetes, and
    vascular insufficiency.

Osteonecrosis (avascular necrosis)
  • Ischemic necrosis resulting in bone
    infarction occurs fairly frequently.
  • It may be caused by
  • 1) vascular compression or rupture after a
    bone fracture.
  • 2) steroid therapy
  • 3) Thromboembolic disease (nitrogen bubbles
    in Caisson disease)
  • 4) Primary vasculitis
  • 5) Steroid therapy or fractures are the most
    common causes.

  • Necrotic bone tissue shows empty lacunae with
    no evidence of osteocytes.
  • The cortex is usually not affected due to
    collateral blood supply.
  • In subchondral infarcts the overlying
    anticular cartilage remains viable because
    synovial fluid provides nutrition.
  • With time, osteoclasts reabsorb necrotic
    trabeculi. Any remaining dead bone fragments act
    as scaffolds of new bone formation (creeping

  • Osteomyelitis represents inflammation of the
    bone and marrow cavity.
  • It could be a complication of a systemic
    infection or may represent an isolated focus of
  • It could be acute or chronic and the most
    common etiologic agents are pyogenic bacteria and
    M. tuberculosis

Acute osteomyelitis
Pyogenic osteomyelitis
  • The microorganisms reach the bone by three
    main routes
  • a) hematogenous spread (most common)
  • b) extension from an infected adjacent joint or
    soft tissue
  • c) traumatic implantation after compound
    fractures or orthopedic procedures.

  • Staphylococcus aureus is the most common
    etiologic agent. Escherichia coli and group B
    streptococci affect mainly neonates while
    salmonella is an especially common pathogen in
    patients with sickle cell disease.
  • In as many as 50 of cases, no microoganisms
    can be isolated.
  • In acute osteomyelitis, causal bacteria may
    proliferate, creating an acute inflammatory
    response, or causing tissue necrosis.
  • Entrapped bone becomes necrotic and is
    called sequestrum.

  • Rupture of the periosteum may form an abcess
    in the surrounding soft tissue and the formation
    of a draining sinus.
  • Sometimes the sequestrum becomes fragmented
    forming foreign bodies that are eliminated
    through the sinus tract.

Chronic osteomyelitis
  • It takes place one week after the onset of
    the infection. During this stage there are
    numerous chronic inflammatory cells. Leukocyte
    cytokines stimulates osteoclastic bone
    reabsortion, fibrous tissue regrowth and bone
    formation at the periphery.
  • Reactive woven or lamellar bone is then
    deposited forming a shell of living tissue around
    a segment of necrotic bone called involucrum.

Chronic osteomyelitis
Chronic osteomyelitis
Chronic osteomyelitis
  • Viable bacteria may remain in the sequestrum
    for many years after the infection.
  • Osteomyelitis usually presents as an acute
    systemic illness with malaise, fever, leukocytes
    and throbbing pain on the affected bone.
  • Diagnosis is suggested by characteristic
    radiologic findings such as a focus of osteolysis
    surrounded by a sclerotic rim.

  • Chronicity may develop when there is delay in
    the diagnosis, extensive bone necrosis,
    inappropriate antibiotic therapy, and/or weakened
    host defenses.
  • A combination of antibiotics and surgical
    drainage is usually curative but 25 of the cases
    do not respond and it is necessary to surgically
    remove the affected bone.

  • Direct spread of the infection is also
    possible (for example, from mediastinal or
    retropentoneal lymph nodes to the vertebrae).
  • The synovium is a common site for the
    initial infection extending to the adjacent
    epiphysis causing extensive caseous necrosis and
    bone destruction.
  • Tuberculosis of the vertebral bodies also
    known as Potts disease is an important form of
    osteomyelitis causing collapse of the vertebral
    bodies followed by neurologic deficits.
  • The caseous exudate destroys adjacent soft
    tissues forming abcesses (cold abcess) that
    eventually will drain on the skin surface by the
    formation of sinus tracts.
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