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)
2
Q
What is unmineralized bone called?
A
Osteoid
3
Q
What are the roles of osteoblasts?
A
- Synthesis, transport, and arrangement of proteins of bone matrix
- Initiate mineralization
- Cell surface receptors that bind numerous hormones (PTH, Vitamin D, estrogen)
4
Q
What are osteoblasts that have been surrounded by a matrix?
A
Osteocytes
5
Q
Which cells are responsible for bone resorption (breakdown)?
A
Osteoclasts
6
Q
Distinguish osteoblasts, osteocytes, and osteoclasts on histology.
A
Osteoblast: uninuclear, outside of bone
Osteocytes: surrounded by matrix
Osteoclasts: multinuclear
7
Q
List and define the components of long bone.
A
- Epiphysis (cap)
- Diaphysis (shaft)
- Metaphysis (between cap and shaft)
- Compact bone (outer)
- Medullary/spongy bone (inner)
- Endosteum (surface lining of the inner bone)
- Periosteum (surface lining of the outer bone)
8
Q
Most bones are formed by ___ bone formation, which is the mechanism for ___ bone growth.
A
Enchondral; long
9
Q
Discuss the process of enchondral bone formation.
A
Formation of cartilage matrix replaced by bone
10
Q
Discuss the process of intramembranous bone formation.
A
formation of bone without pre-existing cartilage matrix; occurs within membrane-like mesenchymal condensations
11
Q
What bones are formed through intramembranous bone formation?
A
Flat bones of the skull, mandible, rib cage
12
Q
What is a callus?
A
Key component of healing bone
13
Q
Discuss the healing process of a fracture.
A
- Fracture
- Hematoma formation
- Coagulation cascade forms a clot
- Granulation tissue forms (2-12 days)
- Callus forms
- Cartilage forms
- Callus calcifies
14
Q
Fractures can be traumatic or non-traumatic (pathologic). List some causes of a pathologic fracture.
A
- Osteoporosis
- Vitamin D deficiency
- Hyperparathyroidism
- Osteogenesis imperfecta
- Paget disease
- Neoplasm
15
Q
What is the most common bone disease in humans?
A
Osteoporosis
16
Q
Define osteoporosis.
A
Decreased bone mass (thinned trabeculae) leading to an increased risk of fracture
17
Q
Distinguish between osteoporosis and osteopenia.
A
Both have decreased bone mass, but the risk of fracture in osteopenia is NOT markedly increased
18
Q
What are the two types of generalized osteoporosis and what bones are affected?
A
- Primary
- Secondary
Most bones can be affected; some preference for ribs, hips, vertebral bones, wrists
19
Q
Who frequently gets primary osteoporosis?
A
Women (post-menopausal especially), older people
20
Q
What causes localized osteoporosis?
A
Disuse
21
Q
When do we reach our peak bone mass?
A
20s and 30s
22
Q
What are the two major cytokines associated with bone remodeling?
A
RANK and OPG
23
Q
What contributes to peak bone mass?
A
- Physical activity (weight bearing)
- Genetic factors
- Nutrition
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.
25
What % of bone is remodeled annually?
10-18%
26
Discuss the tightly regulated process of bone remodeling.
1. Quiescent phase
2. Resorptive phase (osteoclasts, triggered by cytokines)
3. Reversal phase
4. Formative phase (osteoblasts)
5. Completed osteon
27
What is NF-kappa-B?
TF key for osteoclast generation and survival
28
Discuss the process of signaling via RANK.
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.
29
Discuss the role of OPG in signaling via RANK.
OPG is present on osteoblasts and stromal cells. It can also link with RANK receptor. It prevents binding of RANK ligand.
30
What two factors contribute to osteoporosis?
1. Menopause
| 2. Aging
31
How does menopause contribute to osteoporosis?
1. Decreased serum estrogen
2. Increased IL-1, IL-6, TNF
3. Increased expression of RANK, RANKL
4. Increased osteoclast activity
32
How does aging contribute to osteoporosis?
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
33
When does bone resorption become greater than formation?
4th decade of life
34
A VonKossa stain stains mineralized bone ___.
Black
35
How does osteoporosis present?
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)
36
When is osteoporosis detectable on x-ray?
When 30-40% of bone mass is lost
37
How is osteoporosis screened for and diagnosed?
Bone densitometry (DXA scans)
38
How is osteoporosis prevented and treated?
1. Exercise
2. Ca2+ and vitamin D
3. Bisphosphonates
4. Estrogen replacement
5. Recombinant PTH
6. RANK ligand inhibitor (Denosumab)
39
List causes of secondary osteoporosis.
1. Hyperthyroidism
2. Hypogonadism
3. Hyperparathyroidism
4. Corticosteroids
5. Alcohol
6. Malabsorption
7. Multiple myeloma
40
How does hyperthyroidism cause secondary osteoporosis?
Increased osteoclastic activity, accelerated bone turnover
41
How does hyperparathyroidism cause secondary osteoporosis?
Increased PTH is sensed by osteoblast receptors. Mediators of osteoclastogenesis are released. Osteoclast activity is increased and bone is resorbed.
42
How do corticosteroids cause secondary osteoporosis?
Inhibit osteoblastic activity
43
How does alcohol cause secondary osteoporosis?
Direct inhibitor of osteoblasts, may inhibit calcium absorption
44
How does multiple myeloma cause secondary osteoporosis?
Secretion of osteoclast activating factor
45
What causes rickets?
Vitamin D deficiency (kids)
46
What causes osteomalacia?
Vitamin D deficiency (adults)
47
What happens due to vitamin D deficiency?
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
48
How does osteomalacia present?
1. Loss of skeletal mass (density) = osteopenia
2. Fractures and microfractures (especially vertebral bodies, femoral neck)
3. Bone pain
49
What type of bone is affected in rickets?
Growing bones -> growth plate is not adequately mineralized, osteoclasts do not resorb the growth plate cartilage -> the growth plate becomes irregular, thickened, and lobulated
50
How does rickets appear on histology?
Loss of normal architecture, palisading of cartilage, unmineralized bone
51
How does unmineralized bone appear on H&E?
Light pink
52
What is the rachitic rosary?
Enlargement of the costochondral junction seen in rickets
53
How does rickets present?
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)
54
Treatment of rickets and osteomalacia?
Vitamin D
55
How does hyperparathyroidism appear on H&E?
Osteoclasts bore into the center of bone trabecula (known as dissecting osteitis = railroad tracks)
Microfractures
56
What is a brown tumor?
Bone expansion due to PTH excess - occurs because of hemorrhage from bone microfractures -> influx of macrophages -> extensive repair with ingrowth of fibrous tissue
57
___ from macrophages is a fibroblast activator.
TGF-beta
58
What may happen in severe hyperparathyroidism?
Osteitis fibrosa cystica
59
How does hyperparathyroidism present?
Decreased bone mass, pain, fractures
60
What is Paget disease of bone?
Disease caused by osteoclast dysfunction
Excessive bone resorption followed by disorganized, excessive bone formation
61
What are some theories regarding the etiology of Paget Disease?
1. Slow virus infection (paramyxovirus)
2. Imbalance of RANK/OPG
3. Genetic mutations leading to RANK mediated osteoclast stimulation
62
What are the three stages of Paget disease?
1. Osteolytic
2. Osteolytic-osteoblastic
3. Osteosclerotic
63
What happens in the osteolytic phase of Paget?
Activated osteoclasts break down bone outside of the normal checks and balances (can see bone destruction, more lucid area on x-ray)
64
What happens in the osteolytic-osteoblastic phase?
Both (less lucid on x-ray)
65
What happens in the osteosclerotic phase?
Osteoblasts continue to work, but the bone has an abnormal mosaic formation
66
How does Paget disease appear on histology?
Mosaic pattern of bone with prominent cement lines
67
When does Paget disease begin?
Mid-adulthood
68
Paget disease can affect any bone, but what bones are involved in up to 80% of patients?
1. Axial skeleton
| 2. Proximal femur
69
How does Paget disease present?
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
What is platybasia?
Flattening of the skull base impinging on foramen magnum
71
What is leontiasis ossea?
Protuberant frontal bone
72
How does the skull appear grossly in Paget disease?
Marked thickening of the skull
73
Why is Pagetic bone sometimes hypervascular?
As osteoblast are activated, vascularity increases. Can even be seen grossly.
74
What can hypervascularized Pagetic bone tissue cause?
High output heart failure
75
What is high output heart failure?
High CO; elevated resting cardiac index beyond normal range (2.5 to 4 L/min/m2) with normal systolic function
76
What are causes of high output heart failure?
1. Anemia
2. AV fistulas
3. Hyperthyroidism
4. Thiamine deficiency (beri-beri)
5. Paget's (detours blood, leading to compensatory increase in CO)
77
5-10% of patients with Paget disease develop ___.
Sarcoma (osteosarcoma and fibrosarcoma)
78
How is Paget disease diagnosed?
1. Radiographs
2. Bone scan (increased osteoblast activity)
3. Chalk-stick type fracture (clean break)
79
What is elevated in the serum in Paget disease?
Alkaline phosphatase (Ca2+, phosphorous normal)
80
How is Paget disease treated?
Pain - acetaminophen, NSAIDs
| Inhibitors of osteoclast function (bisphosphanates, calcitonin)
81
What are two genetic bone diseases?
1. Osteogenesis imperfecta
| 2. Achondroplasia
82
Why can primary biliary cirrhosis cause osteopenia?
Fat absorption is impaired in this disease. Vitamin D is a fat-soluble vitamin and is not being absorbed.
83
What is another name for osteogenesis imperfecta?
Brittle bone disease
84
What causes osteogenesis imperfecta?
Defect in type 1 collagen (bone, joints, ears, eyes, skin, teeth)
85
How does osteogenesis imperfecta present?
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
What are the goals of treatment of osteogenesis imperfecta?
1. Maximize mobility/function
2. Minimize fracture risk
3. Pain control
4. Psychosocial
87
What causes achondroplasia?
Defect in signal transduction system of FGF receptor 3
88
Achondroplasia is also known as "___," and is the most common disease of the ___.
Dwarfism; growth plate
89
Discuss the mutation of achondroplasia.
FGFR3 normally inhibits cartilage proliferation.
The activating mutation leads to constant inhibition of cartilage differentiation and proliferation. This retards growth plate development.
90
How is achondroplasia inherited?
AD (but also see new mutations)
91
How does achondroplasia present?
1. Trunk of relatively normal length
2. Shortened proximal extremities
3. Enlarged head
4. Bulging forehead
5. Depression of root of nose
92
What happens in thanatophoric dwarfism?
Lethal form of dwarfism leading to perinatal death
Underdeveloped thorax causes respiratory insufficiency
Also craniofacial abnormalities
93
What is osteonecrosis?
Bone death due to infarction
94
Discuss the pathogenesis of osteonecrosis.
Ischemia (mechanical, thrombosis/embolism, vessel injury, vascular compression)
95
What are possible causes of osteonecrosis?
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
How does osteonecrosis appear microscopically?
Homogenous pink bone, empty lacunae, no cells
97
How does osteonecrosis due to subchondral infarcts present?
Pain, collapse, secondary arthritis
98
How does osteonecrosis due to medullary infarcts present?
Clinically silent
99
Compare the frequency of primary bone neoplasms in kids vs. adults.
Children and adolescents > adults
100
What are the three most common primary bone neoplasms?
1. Hematopoietic (40%)
2. Chondrogenic (22%)
3. Osteogenic (19%)
101
What is an osteoid osteoma?
Benign osseous tissue tumor nidus surrounded by a halo of reactive bone formation
102
How does an osteoid osteoma appear on H&E?
Haphazard bone and osteoid rimmed by prominent osteoblasts
Loose connective tissue, very vascular
103
Where do osteoid osteomas arise?
Cortex of femur and tibia
104
Osteoid osteomas are ___ (size).
<2cm
105
What population is osteoid osteoma common in?
Men <25 years old (5-25)
106
Why do osteoid osteomas present with a lot of pain, when does it happen, and how is it treated?
Tumor secretes prostaglandin E2; common at night; aspirin
107
How are osteoid osteomas treated?
Radiofrequency abalation, surgery
108
What is the most common primary malignant bone tumor?
Osteosarcoma (osteogenic sarcoma)
109
Where are osteosarcomas common?
Medullary cavity, metaphysis, long bones
Knee (50%)
Hip (15%)
Shoulder (10%)
Jaw (8%)
110
How does osteosarcoma appear grossly?
White tumor filling the medullary cavity; soft tissue mass (infiltrating through the cortex)
111
How does osteosarcoma appear on H&E?
Anaplastic malignant tumor cells derived from osteoblasts trying to form bone
Neoplastic bone
112
What can be seen on X-ray with osteosarcoma?
Codman triangle
113
What is a Codman triangle?
Triangular shadow between the cortex and raised ends of the periosteum
114
What causes a Codman triangle?
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
70% of osteosarcomas have genetic abnormalities, including nonspecific ploidy changes and chromosomal aberrations. What tumor suppressor gene mutations are associated?
1. RB gene (germline mutations -> 1000x risk)
| 2. P53 (Li-Fraumeni syndrome)
116
Describe the epidemiology of osteosarcoma.
M>F
| Majority <20 y/o (second peak in 60's and 70's)
117
What is a condition that predisposes to osteosarcoma?
Paget's
118
How does osteosarcoma present?
Painful, enlarging mass
119
What is the prognosis of osteosarcoma?
1. Aggressive
| 2. Often metastasizes through the blood stream (to the lung)
120
How is osteosarcoma treated?
Chemotherapy, limb sparing therapy
121
What is an osteochondroma (exostosis)?
Most common benign bone tumor forming a stalk of well-differentiated hyaline cartilage
122
Where do osteochondromas occur?
Bones of endochondral origin (metaphysis near growth plate of long tubular bones)
Most commonly distal femur, proximal tibia, proximal humerus
123
Discuss the epidemiology of osteochondroma.
Presents in late adolescence/early adulthood
M>F (3:1)
124
How does osteochondroma present?
Slow growing mass (pain if stalk fracture or nerve impingement)
125
When does growth of an osteochondroma stop?
Growth plate closes
126
What is multiple hereditary exostosis syndrome?
AD disease in which osteochondromas develop in childhood
127
What causes multiple hereditary exostosis syndrome?
Germline los of function mutations in EXT1 or EXT2 genes - leads to defective enchondral ossification setting stage
128
Multiple hereditary exostosis syndrome may become malignant - what can arise?
Chondrosarcoma or other sarcomas
129
What is a chondrosarcoma and where is it found?
Malignant bone cancer, found in central portion of skeleton (pelvis, shoulder, ribs)
130
How does chondrosarcoma appear grossly?
Jelly-like tumor in the medullary portion of bone; broken into cortex
131
How does chondrosarcoma appear on H&E?
Multiple malignant chondrocytes per lacuna
132
Discuss the epidemiology of chondrosarcoma.
>40 y/o
| M>F
133
How does chondrosarcoma present?
Painful enlarging masses
134
Where does chondrosarcoma metastasize?
Lungs and skeleton
135
The majority of bone neoplasms are caused by ___.
Metastasis from other parts of the body
136
Any cancer can metastasize to any bone. What are common sources in adults and children?
Adults: prostate, breast, kidney, lung
Children: neuroblastoma, Wilm's tumor, rhabdomyosarcoma
137
How does cancer metastasize to the bone?
1. Direct extension
2. Lymphatic/hematogenous spread
3. Intraspinal seeding through venous plexus
138
What is a lytic bone metastases?
Destroys bone (prostaglandins, IL, PTH-related hormones) via osteoclast bone resorption stimulation
139
What is a blastic bone metastases?
Sclerotic response (WNT protein stimulates osteoblastic formation)
140
List the sources of lytic bone metastases.
1. Breast
2. Lung
3. Thyroid
4. Kidney
5. Multiple Myeloma
141
List the sources of blastic bone metastases.
1. Prostate
