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MSK Formative 1 > Metabolic Bone Disorders > Flashcards

Metabolic Bone Disorders Flashcards

1
Q
  • Bone matrix is the extracellular component of bone. It is composed of organic component known as osteoid and mineral component (hydroxyapatite)
  • What is osteoid made up of primarily?
A

Type 1 collagen

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2
Q
  • Osteopontin (also called osteocalcin) is produced by which cells?
  • What is the function?
  • The measure of osteopontin in serum serves as marker for?
A
  • Produced by osteoblasts (unique to bone)
  • Plays a role in bone formation and mineralization
    • Ca 2+ homeostasis
  • Serves as sensitive and specific marker for osteoblast activity
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3
Q
  • Woven bone is more __ and __ than lamellar bone
A

cellular and disorganized

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4
Q

Function of osteocytes?

A

detect mechanical forces and translate them into biological activity- mechanotransduction

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5
Q

On which cells in the bone are PTH receptors located?

A
  • Osteoblasts
    • ​when stimulated by PTH release RANKL which binds onto pre-osteoclast RANK to intiate osteoclastogenesis
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6
Q

What do osteoblasts secrete that favor bone formation?

A
  • Osteoprotegrin (OPG)
    • a decoy receptor for RANKL
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7
Q
  • Role of GH (growth hormone) on bone?
A
  • Acts on resting chondrocytes to induce and maintain proliferation
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8
Q
  • WNT is family of secreted factors that are expressed at highest levels in proliferating zone.
  • They promote?
A

Proliferation and maturation of chondrocytes

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9
Q
  • Bone morphogenic proteins (BMPs) are members of TGF- beta family.
  • Expressed at various stages of chondrocyte development in growth plate
  • have diverse effects on?
A

chondrocyte proliferation and hypertrophy

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10
Q

What factors decrease RANK to OPG ratio/ block osteoclast differentiation or activity by favoring OPG expression?

A
  • Growth factors like bone morphogenic proteins (BMP)
  • Sex hormones
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11
Q

What 4 factors increases RANK-to-OPG ratio (promotes osteoclasts)?

A
  1. Parathyroid hormone
  2. IL-1
  3. Glucocorticoids
  4. Sclerostin
    • produced by osteocytes, inhibits WNT/B catenin pathway
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12
Q
  • Achondroplasia is what kind of inherited disorder?
  • Due to impaired?
  • What mutation causes the disorder? (Gain or loss of function?)
A
  • Autosomal dominant
    • related to paternal allele
  • Caused by gain of function mutation in FGFR3
    • ​normally activation of FGFR3 inhibits endochondral growth
    • constitutive activation exaggerates this, suppressing growth
  • Impaired cartilage proliferation in the growth plate
    • common cause of dwarfism
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13
Q

What are the clinical features of achondroplasia?

A
  • Short extremities with normal sized head and neck
    • due to poor endochondral bone formation
    • intramembranous bone formation is not affected
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14
Q
  • Intramembranous bone formation is characterized by?
  • Endochondral bone formation is characterized by?
A
  • Itramembranous:
    • formation of bone without a pre-existing cartilage matrix
      • mechanism by which flat bones (e.g skull, rib cage) develop
  • Endochondral:
    • formation of a cartilage matrix (from chondrocytes) which is then replaced by bone
      • how long bones grow
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15
Q
  • Osteogenesis imperfecta is caused by?
A
  • Deficiency in synthesis of Type 1 collagen
    • autosomal dominant
  • congenital defect that leads to formation of structurally weak bone
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16
Q
  • Osteogenesis imperfecta principally affects bone. Can also impact what other tissues?
A
  • Rich in type 1 collagen
    • joints
    • eye
    • ears
    • skin
    • teeth
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17
Q
  • What is the fundamental abnormality in osteogenesis imperfecta?
A
  • Too little bone resulting in extreme skeltal fragility
    • impaired type 1 collagen synthesis
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18
Q

3 Clinical features of osteogenesis imperfecta?

A
  1. Mutliple fractures in bone
  2. Blue sclera
    • thinning of scleral collagen reveals underlying choroidal veins
  3. Hearing loss
    • bones of inner ear easily fracture
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19
Q
  • Osteopetrosis is an inherited defect of?
  • Results in/ due to?
A
  • Inherited defect of bone resorption due to poor osteoclast function
    • result in abnormally thick and heavy bone that fractures easily
    • like piece of chalk/stone
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20
Q

While multiple genetic variants of osteopetrosis exist, what mutation is often seen?

A
  • Carbonic anhydrase II mutation
    • leads to loss of acidic microenvironment needed for bone resorption

Enzyme that converts water and carbon dioxide into bicarbonate which dissociates into H+ and HCO3-

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21
Q

What are the 5 clinical features of osteopetrosis?

A
  1. Bone fractures
  2. Anemia, thrombocytopenia and leukopenia with extramedullary hematopoiesis
    • due to bony replacement of marrow (myelophthistic)
  3. Vision and hearing impairement
    • due to impingment on cranial nerves
  4. Hydrocephalus
  5. Renal tubular acidosis (seen with carbonic anhydrase II mutation)
    1. lack of carbonic anhydrase result in decrease tubular reabsprotion of HCO3- leading to metabolic acidosis
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22
Q
  • Osteopetrosis can be a mutation in carbonic anhydrase II.
    • What does mutation in this cause?
    • What is another mutation is osteopetrosis?
A
  • CA2 is required by osteoclasts and renal tubular cells
    • to generate protons from carbon dioxide and water
  • Absence of CA2 prevents osteoclasts from acidifying the resporption pit and solubilizing hydroxyapatite
    • also blocks acidification of urine by renal tubular cells

Other mutation: CLCN7

  • encode proton pump located on surface of osteoclasts
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23
Q

What is the morphology of bone in osteopetrosis?

A

Due to deficient osteoclast activity:

  • lack of medullary canal
  • ends of long bones are mishapen
  • deposited bone is not remodeled and tends to be woven
24
Q

Treatment of osteopetrosis?

A

Bone marrow transplant

  • osteoclasts are derived from monocytes
    • monocytes from hematopoeisis in bone marrow
25
Q
  • Mucopolysaccharidoses is a group of ___ disease?
  • What accumulates in these diseases?
  • What do people with these diseases look like?
A
  • Group of lysosomal storage diseases
  • Mucopolysaccharides accumulate inside chondrocytes
    • cause apoptotic death of cells
    • result in structural defect of articular cartilage (hyaline cartilage)
  • Affected individuals frequently have:
    • short stature,
    • chest wall deformities
    • malformed bones
26
Q
  • Definition of dysostoses? Arise from?
  • Dysplasia?
A
  • Dysostoses:
    • abnormalities in single bone or localized group of bone
      • arise from defects in migration and condensation of mesenchyme
  • Dysplasia:
    • global disorganization of bone and/or cartilage
27
Q
  • Osteoporosis is defined as?
  • Results in what kind of bone?
A
  • Reduction in trabecular bone mass
    • ​results in porous bone with increased risk for fracture
28
Q
  • What is risk of osteoperosis based on?
  • What factors influence this?
A
  • Based on peak bone mass (attained by 30) and rate of bone loss that follows thereafter
    • genetics (Vit. D receptor variants)
    • diet
    • exercise
29
Q

What are 3 clinical features associated with osteoperosis?

A
  1. Bone pain and fractures in weight bearing areas such as:
    • vertebrae (leads to loss of height and kyphosis)
    • hip
    • distal radius
  2. Decreased Bone density
    • measured with DEXA scan
  3. Serum Ca2+, Phosphate, PTH and alkaline phosphate are normal
    • ​​help to exclude osteomalacia (present similarly)
30
Q
  • What are some treatment options of osteoperosis?
  • What is contraindicated?
A
  1. Exercise, Vitamin D and Ca2+
  2. Bisphosphonates
    • induce apoptosis of osteoclasts
  3. estrogen replacement therapy
  4. Glucocorticoids are contraindicated (worsen osteoporosis)
31
Q

How does menopause lead to osteoporosis? (MOA?)

A
  • Decreased serum estrogen leads to:
    • increased IL-1, IL-6, TNF
    • increased expression of RANK, RANKL
    • increased osteoblast activity
32
Q
  • Paget’s disease of bone is a disorder from?
  • What age is it usually seen in?
  • Does it affect the entire skeleton?
A
  • Increased but disordered and structurally unsound bone mass
    • imbalance between osteoclast and osteoblast function
  • Usually seen in late adulthood (> 60)

Localized process involving one or more bones; doesn’t involve entire skeleton

  • uknown etiology
33
Q
  • What are the three phases of Paget Disease?
  • What is the end result?
A
  1. Initial osteoclastic phase
  2. mixed osteoclastic-osteoblastic stage with predominance in osteoblastic activity
  3. evolves in a final burned out stage with osteoblastic

End result is thick, sclerotic bone that fractures easily

34
Q
  • What is the hallmark of Paget Disease?
  • What does biopsy show?
A
  • biopsy reveals a mosaic pattern of lamellar bone
    • jigsaw puzzle like appearence is produced by unusually prominent cement lines which join haphazardly oriented units of lamellar bone
35
Q

What are 4 clinical features of Paget’s Disease?

A
  1. Bone pain
    • due to microfractures
  2. Increase hat size
    • skull is commonly affected
  3. Hearing loss
  4. Lion like facies
    1. involvement of craniofacial nerves
  5. Isolated eleveated alkaline phosphotase test
    • most common cause of isolated eleveated alkaline phosphotase in patients > 40
36
Q
  • Treatment of Paget’s Disease?
  • Complications?
A

Treatment:

  • Calcitionin
    • inhibit osteoclast function
  • Bisphosphonates
    • induces apoptosis of osteoclasts

Complications:

  • High output cardiac failure
    • due to formation of AV shunts in bone
  • Osteosarcoma
    • possible if osteoblasts get mutated
37
Q
  • Ricketts/Osteomalacia is due to defective?
  • Caused by a deficiency in?
A
  • Defective mineralization of osteoid
    • Osteoblasts normally produce osteoid which is then mineralized with calcium and phosphate to form bone
  • Due to low levels of vitamin D
    • which results in low serum calcium and phosphate
38
Q
  • What 2 sources is Vitamin D derived from?
  • Activation requires?
A
  • Normally derived from
    1. Skin upon exposure to sunlight (85%)
    2. Diet
  • Activation requires:
    • 25-hydroxylation by the liver
    • followed by 1-alpha-hydroxylation by proximal tubule cells of kidney
39
Q

Vitamin D raises serum Ca2+ and phosphate by acting on which 3 things?

A
  1. Intestine:
    • increase absorption of calcium and phosphate
  2. Kidney:
    • increase reabsorption of calcium and phosphate
  3. Bone:
    • increase resorption of calcium and phosphate
40
Q

Vitamind D deficiency is seen with?

A
  • Decreased sun exposure
  • poor diet
  • malabsorption
  • liver failure
  • renal failure
41
Q
  • Ricketts is due to?
  • Seen in?
  • What are clincial presentation/ findings?
A
  • Low Vitamin D in children (< 1 year), resulting in abnormal bone mineralization
  • Present with:
    1. Pigeon breast deformity
      • inward bending of ribs with anterior protusion of sternum
    2. Frontal bossing (enlarged forehead)
      • due to osteoid deposition on skull
    3. Rachitic rosary
      • due to osteoid deposition at the costochondral junction
    4. Bowing of legs
      • may be seen in ambulating children
42
Q
  • Osteomalacia is due to?
  • Who is it seen in?
  • What do lab finding show?
A
  • Due to low Vitamin D in adults
    • inadequate mineralization results in weak bone with increased risk of fracture
  • Lab findings include:
    • Decreased serum Ca2+
    • Decreased serum phosphate
    • Increased PTH
      • trying to increase serum Ca2+
    • increased alkaline phosphotase
      • basic environment needed to lay down bone
43
Q
  • Compare lab values for serum calicum, phosphate, ALP and PTH in:
    • osteoperosis
    • osteopetrosis
    • Paget’s disease of bone
    • Osteomalacia/Rickets
44
Q
  • What is osteomyelitis?
    • How does it reach the bone?
  • who does it typically affect?
A
  • Infection (inflammation) of bone marrow and bone
    • organisms may reach the bone by:
      • hematogenous spread
      • extension from contiguous site
      • direct implantation
  • usually occurs in children
45
Q
  • All types of organisms can cause osteomyelitis, but which is the most common?
  • What are 6 causes of osteomyelitis and who is more at risk for each one?
A
  • Most commonly bacterial

Causes include:

  1. Staphylococcus aureus: most common
  2. N. gonorrhoeae: sexually active young adults
  3. Salmonella: sickle cell disease
  4. Pseudomonas: diabetic or IV drug use
  5. Pasteurella- associated with dog/cat scratch or bite
  6. Mycobacterium tuberculosis: usually involve lumbar vertebrae (Pott disease)
46
Q

What is usually the cause of osteomyelitis and where does it occur in:

  • kids?
  • adults?
A
  • Kids:
    • Transient bacteremia
    • Seeds the metaphysis
  • Adults:
    • Open wound infection/bacteremia (e.g. diabetic infection of feet)
    • Seeds Epiphysis
47
Q
  • What are the clinical features/ symptoms of osteomyelitis?
  • How is it diagnosed?
A

Signs/Symptoms:

  1. Bone pain with systemic sign of infection (fever, leukocytosis)
  2. Lytic focus (abscess) surrounded by sclerosis on bone x-ray
    • lytic focus is called sequestrum
    • sclerosis is called involucrum

Diagnosed by blood culture

Image shows Brodie abscess

48
Q

What are complications of chronic osteomyelitis?

A
  • Pathological fracture
  • secondary amyloidosis
  • endocarditis
  • sepsis
  • squamous cell carcinoma
    • in draining sinus tracts
  • sarcoma
    • in infected bone
49
Q
  • Lyme disease is caused by?
  • How is it transmitted?
  • Where is it most common?
A
  • Borrelia burgdorferi
  • Transmitted by Ixodes deer tick
    • natural resevoir is the mouse
  • Common in northeastern U.S.
50
Q

What are the 3 stages of Lyme disease?

(A key Lyme pie to the FACE)

A
  • Stage 1: early localized,
    • erythema migrans, flu like symptoms
  • Stage 2: early disseminated
    • secondary lesions, carditis, AV block, facial nerve (Bell) palsy, transient arthritis
  • Stage 3: late disseminated
    • encephalopathies, chronic arthritis

A Key Lyme pie to the FACE

  • Facial Nerve Palsy
  • Arthritis
  • Cardiac block
  • Erythema migrans
51
Q
  • How is Lyme disease identified in the lab?
  • What is the treatment?
A
  • Detection of antibody
    • ELISA
    • Immunoblot
  • Treatment:
    • Doxycycline (adults)
    • Amoxicillin (children)
52
Q
  • What causes Rocky Mountain spotted fever?
  • What is the vector?
  • Where does it most occur?
A
  • Ricketssia rickettsii
  • Tick
  • Occurs primarily in South Atlantic state
    • especially North Carolina
53
Q
  • What are the classic triad of symptoms in Rocky Mountain spotted fever?
  • Where does rash typically start and then spread to?
A
  • Classic triad= headache, fever, rash
  • Rash typically starts at wrists and ankles
    • spreads to trunk, palms and soles
54
Q

What is the mechanism of action of Rickettsia rickettsii? (RMSF)

A
  • Attachment of tick to host
    • injected into host blood
  • Reactivation from avirulant state to highly pathogenic form
  • Disseminate through lympahtics and blood
    • enter vascular endothelial cells and establish foci of infection
  • spread to contiguous and distant endothelial and smooth muscle cells
    • cause increase vascular permeability
      • leads to tissue edema, hypoproteinemia, and reduced perfusion of organs
55
Q

How would you identify RMSF (Ricketssia rickettsii) in the lab?

A
  • Serology
    • Enzyme immunoassay
    • Aggluntination test
56
Q
  • What kind of a cell envelope do Rickettsia rickettsii have?
    • Requirement for?
  • Treat with?
A
  • Gram (-) cell envelope
    • requirement for:
      • conezyme A
      • NAD
      • ATP
  • Obligate intracellular
  • Treat with doxycycline

MSK Formative 1 (11 decks)

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