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MHD2 > Block 9 - L13, 15 > Flashcards

Block 9 - L13, 15 Flashcards

1
Q

Bone is a ___ tissue that normally mineralizes. List its components.

A

Connective

Inorganic (65%) - calcium hydroxyapetite

Organic (35%) - cells, protein (especially type 1 collagen)

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2
Q

What is unmineralized bone called?

A

Osteoid

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3
Q

What are the roles of osteoblasts?

A
  1. Synthesis, transport, and arrangement of proteins of bone matrix
  2. Initiate mineralization
  3. Cell surface receptors that bind numerous hormones (PTH, Vitamin D, estrogen)
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4
Q

What are osteoblasts that have been surrounded by a matrix?

A

Osteocytes

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5
Q

Which cells are responsible for bone resorption (breakdown)?

A

Osteoclasts

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6
Q

Distinguish osteoblasts, osteocytes, and osteoclasts on histology.

A

Osteoblast: uninuclear, outside of bone
Osteocytes: surrounded by matrix
Osteoclasts: multinuclear

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7
Q

List and define the components of long bone.

A
  1. Epiphysis (cap)
  2. Diaphysis (shaft)
  3. Metaphysis (between cap and shaft)
  4. Compact bone (outer)
  5. Medullary/spongy bone (inner)
  6. Endosteum (surface lining of the inner bone)
  7. Periosteum (surface lining of the outer bone)
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8
Q

Most bones are formed by ___ bone formation, which is the mechanism for ___ bone growth.

A

Enchondral; long

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9
Q

Discuss the process of enchondral bone formation.

A

Formation of cartilage matrix replaced by bone

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10
Q

Discuss the process of intramembranous bone formation.

A

formation of bone without pre-existing cartilage matrix; occurs within membrane-like mesenchymal condensations

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11
Q

What bones are formed through intramembranous bone formation?

A

Flat bones of the skull, mandible, rib cage

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12
Q

What is a callus?

A

Key component of healing bone

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13
Q

Discuss the healing process of a fracture.

A
  1. Fracture
  2. Hematoma formation
  3. Coagulation cascade forms a clot
  4. Granulation tissue forms (2-12 days)
  5. Callus forms
  6. Cartilage forms
  7. Callus calcifies
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14
Q

Fractures can be traumatic or non-traumatic (pathologic). List some causes of a pathologic fracture.

A
  1. Osteoporosis
  2. Vitamin D deficiency
  3. Hyperparathyroidism
  4. Osteogenesis imperfecta
  5. Paget disease
  6. Neoplasm
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15
Q

What is the most common bone disease in humans?

A

Osteoporosis

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16
Q

Define osteoporosis.

A

Decreased bone mass (thinned trabeculae) leading to an increased risk of fracture

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17
Q

Distinguish between osteoporosis and osteopenia.

A

Both have decreased bone mass, but the risk of fracture in osteopenia is NOT markedly increased

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18
Q

What are the two types of generalized osteoporosis and what bones are affected?

A
  1. Primary
  2. Secondary

Most bones can be affected; some preference for ribs, hips, vertebral bones, wrists

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19
Q

Who frequently gets primary osteoporosis?

A

Women (post-menopausal especially), older people

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20
Q

What causes localized osteoporosis?

A

Disuse

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21
Q

When do we reach our peak bone mass?

A

20s and 30s

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22
Q

What are the two major cytokines associated with bone remodeling?

A

RANK and OPG

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23
Q

What contributes to peak bone mass?

A
  1. Physical activity (weight bearing)
  2. Genetic factors
  3. Nutrition
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24
Q

What is bone remodeling?

A

Replacement of old bone with newly formed bone; this enables bone to adapt to mechanical stress, maintain strength, and regulate calcium homeostasis.

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25
Q

What % of bone is remodeled annually?

A

10-18%

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26
Q

Discuss the tightly regulated process of bone remodeling.

A
  1. Quiescent phase
  2. Resorptive phase (osteoclasts, triggered by cytokines)
  3. Reversal phase
  4. Formative phase (osteoblasts)
  5. Completed osteon
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27
Q

What is NF-kappa-B?

A

TF key for osteoclast generation and survival

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28
Q

Discuss the process of signaling via RANK.

A

When RANK ligand (found on surface of stromal cell/osteoblast) binds to a RANK receptor (found on osteoclasts/precursors), NF-kappa-B is activated (present in osteoclast precursors). This stimulates bone resorption.

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29
Q

Discuss the role of OPG in signaling via RANK.

A

OPG is present on osteoblasts and stromal cells. It can also link with RANK receptor. It prevents binding of RANK ligand.

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30
Q

What two factors contribute to osteoporosis?

A
  1. Menopause

2. Aging

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31
Q

How does menopause contribute to osteoporosis?

A
  1. Decreased serum estrogen
  2. Increased IL-1, IL-6, TNF
  3. Increased expression of RANK, RANKL
  4. Increased osteoclast activity
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32
Q

How does aging contribute to osteoporosis?

A
  1. Decreased replicative activity of osteoprogenitor cells
  2. Decreased synthetic activity of osteoblasts
  3. Decreased biologic activity of matrix-bound growth factors
  4. Reduced physical activity
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33
Q

When does bone resorption become greater than formation?

A

4th decade of life

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34
Q

A VonKossa stain stains mineralized bone ___.

A

Black

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35
Q

How does osteoporosis present?

A
  1. Fractures (minimal associated trauma)
  2. Vertebral fractures (loss of height, kyphoscoliosis, Dowager’s hump)
  3. Pain
  4. Associated complications (PE, pneumonia - due to hospitalization)
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36
Q

When is osteoporosis detectable on x-ray?

A

When 30-40% of bone mass is lost

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37
Q

How is osteoporosis screened for and diagnosed?

A

Bone densitometry (DXA scans)

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38
Q

How is osteoporosis prevented and treated?

A
  1. Exercise
  2. Ca2+ and vitamin D
  3. Bisphosphonates
  4. Estrogen replacement
  5. Recombinant PTH
  6. RANK ligand inhibitor (Denosumab)
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39
Q

List causes of secondary osteoporosis.

A
  1. Hyperthyroidism
  2. Hypogonadism
  3. Hyperparathyroidism
  4. Corticosteroids
  5. Alcohol
  6. Malabsorption
  7. Multiple myeloma
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40
Q

How does hyperthyroidism cause secondary osteoporosis?

A

Increased osteoclastic activity, accelerated bone turnover

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41
Q

How does hyperparathyroidism cause secondary osteoporosis?

A

Increased PTH is sensed by osteoblast receptors. Mediators of osteoclastogenesis are released. Osteoclast activity is increased and bone is resorbed.

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42
Q

How do corticosteroids cause secondary osteoporosis?

A

Inhibit osteoblastic activity

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43
Q

How does alcohol cause secondary osteoporosis?

A

Direct inhibitor of osteoblasts, may inhibit calcium absorption

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44
Q

How does multiple myeloma cause secondary osteoporosis?

A

Secretion of osteoclast activating factor

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45
Q

What causes rickets?

A

Vitamin D deficiency (kids)

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46
Q

What causes osteomalacia?

A

Vitamin D deficiency (adults)

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47
Q

What happens due to vitamin D deficiency?

A

Decreased vitamin D -> decreased Ca2+ and Ph absorption -> decreased serum Ca2+ and Ph -> Increased PTH -> PTH stimulates osteoclasts (release Ca2+ from bone breakdown)

Bone mineralization defect (decreases) leads to accumulation of osteoid (unmineralized bone); ultimately causes decreased bone density

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48
Q

How does osteomalacia present?

A
  1. Loss of skeletal mass (density) = osteopenia
  2. Fractures and microfractures (especially vertebral bodies, femoral neck)
  3. Bone pain
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49
Q

What type of bone is affected in rickets?

A

Growing bones -> growth plate is not adequately mineralized, osteoclasts do not resorb the growth plate cartilage -> the growth plate becomes irregular, thickened, and lobulated

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50
Q

How does rickets appear on histology?

A

Loss of normal architecture, palisading of cartilage, unmineralized bone

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51
Q

How does unmineralized bone appear on H&E?

A

Light pink

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52
Q

What is the rachitic rosary?

A

Enlargement of the costochondral junction seen in rickets

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53
Q

How does rickets present?

A
  1. Enlarged joints, weak joints
  2. Enlarged costochondral junction
  3. Bowing of legs
  4. Soft skull bones = occipital flattening, parietal buckling
  5. Frontal bossing (squared appearance)
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54
Q

Treatment of rickets and osteomalacia?

A

Vitamin D

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55
Q

How does hyperparathyroidism appear on H&E?

A

Osteoclasts bore into the center of bone trabecula (known as dissecting osteitis = railroad tracks)

Microfractures

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56
Q

What is a brown tumor?

A

Bone expansion due to PTH excess - occurs because of hemorrhage from bone microfractures -> influx of macrophages -> extensive repair with ingrowth of fibrous tissue

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57
Q

___ from macrophages is a fibroblast activator.

A

TGF-beta

58
Q

What may happen in severe hyperparathyroidism?

A

Osteitis fibrosa cystica

59
Q

How does hyperparathyroidism present?

A

Decreased bone mass, pain, fractures

60
Q

What is Paget disease of bone?

A

Disease caused by osteoclast dysfunction

Excessive bone resorption followed by disorganized, excessive bone formation

61
Q

What are some theories regarding the etiology of Paget Disease?

A
  1. Slow virus infection (paramyxovirus)
  2. Imbalance of RANK/OPG
  3. Genetic mutations leading to RANK mediated osteoclast stimulation
62
Q

What are the three stages of Paget disease?

A
  1. Osteolytic
  2. Osteolytic-osteoblastic
  3. Osteosclerotic
63
Q

What happens in the osteolytic phase of Paget?

A

Activated osteoclasts break down bone outside of the normal checks and balances (can see bone destruction, more lucid area on x-ray)

64
Q

What happens in the osteolytic-osteoblastic phase?

A

Both (less lucid on x-ray)

65
Q

What happens in the osteosclerotic phase?

A

Osteoblasts continue to work, but the bone has an abnormal mosaic formation

66
Q

How does Paget disease appear on histology?

A

Mosaic pattern of bone with prominent cement lines

67
Q

When does Paget disease begin?

A

Mid-adulthood

68
Q

Paget disease can affect any bone, but what bones are involved in up to 80% of patients?

A
  1. Axial skeleton

2. Proximal femur

69
Q

How does Paget disease present?

A
  1. Incidental finding
  2. Pain in affected bones due to microfractures and bone overgrowth compressing nerves (deafness, for example)
  3. Platybasia
  4. Leontiasis ossea
  5. Secondary arthritis
  6. Bowing of tibia
70
Q

What is platybasia?

A

Flattening of the skull base impinging on foramen magnum

71
Q

What is leontiasis ossea?

A

Protuberant frontal bone

72
Q

How does the skull appear grossly in Paget disease?

A

Marked thickening of the skull

73
Q

Why is Pagetic bone sometimes hypervascular?

A

As osteoblast are activated, vascularity increases. Can even be seen grossly.

74
Q

What can hypervascularized Pagetic bone tissue cause?

A

High output heart failure

75
Q

What is high output heart failure?

A

High CO; elevated resting cardiac index beyond normal range (2.5 to 4 L/min/m2) with normal systolic function

76
Q

What are causes of high output heart failure?

A
  1. Anemia
  2. AV fistulas
  3. Hyperthyroidism
  4. Thiamine deficiency (beri-beri)
  5. Paget’s (detours blood, leading to compensatory increase in CO)
77
Q

5-10% of patients with Paget disease develop ___.

A

Sarcoma (osteosarcoma and fibrosarcoma)

78
Q

How is Paget disease diagnosed?

A
  1. Radiographs
  2. Bone scan (increased osteoblast activity)
  3. Chalk-stick type fracture (clean break)
79
Q

What is elevated in the serum in Paget disease?

A

Alkaline phosphatase (Ca2+, phosphorous normal)

80
Q

How is Paget disease treated?

A

Pain - acetaminophen, NSAIDs

Inhibitors of osteoclast function (bisphosphanates, calcitonin)

81
Q

What are two genetic bone diseases?

A
  1. Osteogenesis imperfecta

2. Achondroplasia

82
Q

Why can primary biliary cirrhosis cause osteopenia?

A

Fat absorption is impaired in this disease. Vitamin D is a fat-soluble vitamin and is not being absorbed.

83
Q

What is another name for osteogenesis imperfecta?

A

Brittle bone disease

84
Q

What causes osteogenesis imperfecta?

A

Defect in type 1 collagen (bone, joints, ears, eyes, skin, teeth)

85
Q

How does osteogenesis imperfecta present?

A
  1. Multiple fractures of multiple bone
  2. Accordion-like shortening of limbs
  3. Bowing under pressure
  4. Blue sclera (see directly into choroid)
  5. Small, mis-shapen, blue-yellow teeth
86
Q

What are the goals of treatment of osteogenesis imperfecta?

A
  1. Maximize mobility/function
  2. Minimize fracture risk
  3. Pain control
  4. Psychosocial
87
Q

What causes achondroplasia?

A

Defect in signal transduction system of FGF receptor 3

88
Q

Achondroplasia is also known as “___,” and is the most common disease of the ___.

A

Dwarfism; growth plate

89
Q

Discuss the mutation of achondroplasia.

A

FGFR3 normally inhibits cartilage proliferation.

The activating mutation leads to constant inhibition of cartilage differentiation and proliferation. This retards growth plate development.

90
Q

How is achondroplasia inherited?

A

AD (but also see new mutations)

91
Q

How does achondroplasia present?

A
  1. Trunk of relatively normal length
  2. Shortened proximal extremities
  3. Enlarged head
  4. Bulging forehead
  5. Depression of root of nose
92
Q

What happens in thanatophoric dwarfism?

A

Lethal form of dwarfism leading to perinatal death

Underdeveloped thorax causes respiratory insufficiency

Also craniofacial abnormalities

93
Q

What is osteonecrosis?

A

Bone death due to infarction

94
Q

Discuss the pathogenesis of osteonecrosis.

A

Ischemia (mechanical, thrombosis/embolism, vessel injury, vascular compression)

95
Q

What are possible causes of osteonecrosis?

A
  1. Trauma
  2. Corticosteroids
  3. Infection
  4. Dysbarism
  5. Radiation therapy
  6. Connective tissue disorders
  7. Vasculitis
  8. Sickle cell anemia (common)
  9. Tumors
  10. Gaucher disease
96
Q

How does osteonecrosis appear microscopically?

A

Homogenous pink bone, empty lacunae, no cells

97
Q

How does osteonecrosis due to subchondral infarcts present?

A

Pain, collapse, secondary arthritis

98
Q

How does osteonecrosis due to medullary infarcts present?

A

Clinically silent

99
Q

Compare the frequency of primary bone neoplasms in kids vs. adults.

A

Children and adolescents > adults

100
Q

What are the three most common primary bone neoplasms?

A
  1. Hematopoietic (40%)
  2. Chondrogenic (22%)
  3. Osteogenic (19%)
101
Q

What is an osteoid osteoma?

A

Benign osseous tissue tumor nidus surrounded by a halo of reactive bone formation

102
Q

How does an osteoid osteoma appear on H&E?

A

Haphazard bone and osteoid rimmed by prominent osteoblasts

Loose connective tissue, very vascular

103
Q

Where do osteoid osteomas arise?

A

Cortex of femur and tibia

104
Q

Osteoid osteomas are ___ (size).

A

<2cm

105
Q

What population is osteoid osteoma common in?

A

Men <25 years old (5-25)

106
Q

Why do osteoid osteomas present with a lot of pain, when does it happen, and how is it treated?

A

Tumor secretes prostaglandin E2; common at night; aspirin

107
Q

How are osteoid osteomas treated?

A

Radiofrequency abalation, surgery

108
Q

What is the most common primary malignant bone tumor?

A

Osteosarcoma (osteogenic sarcoma)

109
Q

Where are osteosarcomas common?

A

Medullary cavity, metaphysis, long bones

Knee (50%)
Hip (15%)
Shoulder (10%)
Jaw (8%)

110
Q

How does osteosarcoma appear grossly?

A

White tumor filling the medullary cavity; soft tissue mass (infiltrating through the cortex)

111
Q

How does osteosarcoma appear on H&E?

A

Anaplastic malignant tumor cells derived from osteoblasts trying to form bone

Neoplastic bone

112
Q

What can be seen on X-ray with osteosarcoma?

A

Codman triangle

113
Q

What is a Codman triangle?

A

Triangular shadow between the cortex and raised ends of the periosteum

114
Q

What causes a Codman triangle?

A

The tumor has broken through the cortex and lifted the periosteum, resulting in reactive periosteal bone formation. Only the periosteum at the very margin of the lesion has time to ossify creating a triangular lip of new bone.

115
Q

70% of osteosarcomas have genetic abnormalities, including nonspecific ploidy changes and chromosomal aberrations. What tumor suppressor gene mutations are associated?

A
  1. RB gene (germline mutations -> 1000x risk)

2. P53 (Li-Fraumeni syndrome)

116
Q

Describe the epidemiology of osteosarcoma.

A

M>F

Majority <20 y/o (second peak in 60’s and 70’s)

117
Q

What is a condition that predisposes to osteosarcoma?

A

Paget’s

118
Q

How does osteosarcoma present?

A

Painful, enlarging mass

119
Q

What is the prognosis of osteosarcoma?

A
  1. Aggressive

2. Often metastasizes through the blood stream (to the lung)

120
Q

How is osteosarcoma treated?

A

Chemotherapy, limb sparing therapy

121
Q

What is an osteochondroma (exostosis)?

A

Most common benign bone tumor forming a stalk of well-differentiated hyaline cartilage

122
Q

Where do osteochondromas occur?

A

Bones of endochondral origin (metaphysis near growth plate of long tubular bones)

Most commonly distal femur, proximal tibia, proximal humerus

123
Q

Discuss the epidemiology of osteochondroma.

A

Presents in late adolescence/early adulthood

M>F (3:1)

124
Q

How does osteochondroma present?

A

Slow growing mass (pain if stalk fracture or nerve impingement)

125
Q

When does growth of an osteochondroma stop?

A

Growth plate closes

126
Q

What is multiple hereditary exostosis syndrome?

A

AD disease in which osteochondromas develop in childhood

127
Q

What causes multiple hereditary exostosis syndrome?

A

Germline los of function mutations in EXT1 or EXT2 genes - leads to defective enchondral ossification setting stage

128
Q

Multiple hereditary exostosis syndrome may become malignant - what can arise?

A

Chondrosarcoma or other sarcomas

129
Q

What is a chondrosarcoma and where is it found?

A

Malignant bone cancer, found in central portion of skeleton (pelvis, shoulder, ribs)

130
Q

How does chondrosarcoma appear grossly?

A

Jelly-like tumor in the medullary portion of bone; broken into cortex

131
Q

How does chondrosarcoma appear on H&E?

A

Multiple malignant chondrocytes per lacuna

132
Q

Discuss the epidemiology of chondrosarcoma.

A

> 40 y/o

M>F

133
Q

How does chondrosarcoma present?

A

Painful enlarging masses

134
Q

Where does chondrosarcoma metastasize?

A

Lungs and skeleton

135
Q

The majority of bone neoplasms are caused by ___.

A

Metastasis from other parts of the body

136
Q

Any cancer can metastasize to any bone. What are common sources in adults and children?

A

Adults: prostate, breast, kidney, lung

Children: neuroblastoma, Wilm’s tumor, rhabdomyosarcoma

137
Q

How does cancer metastasize to the bone?

A
  1. Direct extension
  2. Lymphatic/hematogenous spread
  3. Intraspinal seeding through venous plexus
138
Q

What is a lytic bone metastases?

A

Destroys bone (prostaglandins, IL, PTH-related hormones) via osteoclast bone resorption stimulation

139
Q

What is a blastic bone metastases?

A

Sclerotic response (WNT protein stimulates osteoblastic formation)

140
Q

List the sources of lytic bone metastases.

A
  1. Breast
  2. Lung
  3. Thyroid
  4. Kidney
  5. Multiple Myeloma
141
Q

List the sources of blastic bone metastases.

A
  1. Prostate

MHD2 (34 decks)

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