Non-neoplastic bone pathology Osvaldo Rubinstein, MD

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Non-neoplastic bone pathology

• Osvaldo Rubinstein, MD

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• 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.

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• 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
  viceversa.

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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.

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• 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.

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• 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
  hematopoiesis.

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Cancellous bone
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• 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.

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• 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.

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H Haversian Canal O Osteocytes L Lacunae C
Cement Lines P Periosteum
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Compact bone
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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.

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• 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).

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Process of mineralization
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Osteoblasts and osteoid.
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Osteoblasts Osteoid Compact Bone
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• 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.

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• 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.

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• 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.

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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.

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• 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.

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Anatomy of long bone
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• 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
  include
• 1) aplasia (congenital absence of a digit or
  rib).
• 2) the formation of extra bones (supernumerary
  digits).
• 3) abnormal fusion of bones (premature
  closure of cranial sutures).

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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
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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.

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• 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
  condition
• 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.

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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
inevitable.
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Osteogenesis imperfecta showing a fetus with
multiple fractures.
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Osteogenesis imperfecta. Note the relative
increased number of osteocytes.
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Achondroplasia

• 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.

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• 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.

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Osteopetrosis

• 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
  II.
• 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
  deformed.

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• 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.

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• 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.

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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
disease.
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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.
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ACQUIRED DISEASES OF BONE DEVELOPMENT

• 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.

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Osteoporosis
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Osteoporosis. Note the thin trabeculi and
enlarged marrow spaces.
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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
  function.
• 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
  develops.
• 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.

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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).

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• 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.

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• In the osteolytic phase there are numerous
  osteoclasts associated with large Howships
  lacunae.
• In the mixed phase, osteoclasts persist but
  bone trabeculi are lined by prominent
  osteoblasts.
• 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.

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

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Paget disease. Elbow joint
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Pagets disease
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• Pagets disease

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• 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
  elevated.
• In patients with extensive polyostotic
  disease hypervascular bone lesions may lead to
  high output congestive cardiac failure.

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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

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• 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).

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Hyperparathyroidism

• 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.

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• 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.

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• 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.

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Osteitis fibrosa cystica, early stage.
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Osteitis fibrosa cystica, terminal stage.
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Osteoclasts reabsorbing bone trabeculi
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Fractures

• 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
  aligned.
• If the fracture occurs at the site of a
  previous lesion (for example, bone cyst or a
  malignant tumor) it is called a pathologic
  fracture.
• 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.

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• The repair of a fracture is a highly regulated
  process.
• 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
  callus.
• 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
  bearing.

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• 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
  loads.
• Callus remodeling restores the original size,
  shape and the cancellous architecture of the
  medullary cavity.

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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
  completed.
• 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.

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• 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.

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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.

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• 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
  substitution).

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Osteomyelitis

• 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
  disease.
• It could be acute or chronic and the most
  common etiologic agents are pyogenic bacteria and
  M. tuberculosis

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Acute osteomyelitis
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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.

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• 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.

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• 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.

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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.

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Chronic osteomyelitis
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Chronic osteomyelitis
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Chronic osteomyelitis
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• 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.

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• 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.

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• 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.