Chapter 26: Developmental and Acquired Disorders of Bone Flashcards
1
Q
Which osteoblast-derived protein is unique to bone and can serve as a sensitive and specific marker for osteoblast activity when measured in the serum?
A
Osteopontin (aka osteocalcin)
2
Q
What is the function of osteopontin (aka osteocalcin) produced by osteoblasts?
A
Bone formation, mineralization, and calcium homeostasis
3
Q
What are the roles of the inorganic moiety, hydroxyapatite, in the bone matrix?
A
- Responsible for the hardness of bones
- Repository for 99% of body’s calcium and 85% of phosphorus
4
Q
Which 3 cytokines and 3 GF’s are produced by osteoblasts?
A
- Cytokines = IL-1 + IL-6 + RANKL
- GF’s = IGF-1 + TGF-β + PDGF
5
Q
Differentiate the 2 histologic forms of bone matrix (woven vs. lamelllar) in terms of production, stability, and components
A
- Woven: produced rapidly; fetal period / fracture repair; haphazard collagen arrangement = less structural integrity; always abnormal finding in adults
- Lamellar: SLOW production: parallel collagen; stronger
6
Q
What are 2 functions of osteocytes?
A
- Help to control calcium and phosphate levels
- Detect mechanical forces and translate them into biologic activity (mechanotransduction)
7
Q
What type of cell are osteoclasts?
A
Specialized multinucleated macrophages
8
Q
Osteoclasts attach to bone how; secrete what for bone resorption?
A
- Utilize cell surface integrins for attachment to bone matrix
- Secrete matrix metalloproteases (MMPs) which dissolves inorganic and organic components of bone
9
Q
Differentiate endochondral ossification from intramembranous ossification?
A
- Endochondral: development of the long bones: new bone deposited at bottom of growth plates –> longitudinal growth
- Intramembranous: development of flat bones: new bone deposited on pre-existing surface –> appositional growth
10
Q
When is peak bone mass achieved and when does the steady decline in skeletal mass begin?
A
- Achieved in early adulthood after cessation of skeletal growth
- 4th decade: resorption > formation –> ↓ skeletal mass
11
Q
Briefly discuss the role of RANK, RANKL, and osteoprotegrin (OPG) in bone remodeling and homeostasis, including which cells are associated with each?
A
- RANKL expressed on osteoblasts stimulates RANK on osteoclasts –> activates NF-kB, essential for the generation and survival of osteoclasts; promotes breakdown
- OPG is a secreted “decoy” receptor made by osteoblasts; binds RANKL and prevents interaction w/ RANK; promotes building
12
Q
How do WNT proteins and sclerostin play a role in bone homeostasis and remodeling?
A
- WNT proteins (prod. by osteoprogenitor cells) bind LRP5 and LRP6 receptors on osteoblasts –> activate β-catenin and prod. of OPG
- Sclerostin (prod. by osteocytes) inhibits the WNT/β-catenin pathway
13
Q
How does M-CSF play a role in bone homeostasis and remodeling?
A
- Prod. by osteoblasts and binds M-CSF receptor on osteoclasts
- Stimulates a tyrosine kinase cascade crucial for generation of osteoclasts
14
Q
Describe the paracrine crosstalk btw osteoblasts and osteoclasts in bone homeostasis and remodeling?
A
Breakdown of matrix by osteoclasts liberates and activates matrix proteins, GF’s, cytokines and enzymes; some of which stimulate osteoblasts
15
Q
Brachydactyly types D and E are due to mutations of what gene; what is seen with this disorder?
A
- Mutations in homeobox HOXD13 gene
- Shortening of the terminal phalanges of thumb and big toe
16
Q
Loss-of-function mutations in the RUNX2 gene result in what autosomal dominant disorder?
A
Cleidocranial dysplasia
17
Q
What are the clinical manifestations of Cleidocranial Dysplasia?
A
- Patent fontanelles + Short height + Primitive clavicles
- Delayed closure of cranial sutures
- Wormian bones**: extra bones within cranial sutures
- Delayed eruption of 2’ teeth
*Dustin from Stranger Things*
18
Q
Achondroplasia, the most common skeletal dysplasia has which type of inheritance pattern and is due to what mutation?
A
Autosomal dominant; gain-of-function in FGFR3
19
Q
What are the clinical features of Achondroplasia?
A
- Retarded cartilage growth –> shortened prox. extremities + normal trunk length + enlarged head w/ bulging forehead
- NO change in longevity, intelligence or repro. status
20
Q
What is the most common lethal form of dwarfism?
A
Thanatophoric dysplasia
21
Q
Which mutation is associated with Thanatophoric Dysplasia; what is a frequent cause of death for these pt’s?
A
- Gain-of-function in FGFR3
- Pt’s have small chest cavity –> respiratory insufficiency
22
Q
What is the most common inherited disorder of connective tissue?
A
Osteogenesis Imperfecta aka brittle bone disease (Type I Collagen)
23
Q
What is the inheritance pattern and collagen defect associated with Type I Osteogenesis Imperfecta?
A
- Autosomal dominant***
- ↓ synthesis of pro-α1(1) chain of type I collagen
- Abnormal pro-α1(1) or pro-α2(1) chains of type I collagen
24
Q
What are the clinical features of Type I Osteogenesis Imperfecta; life-span and stature of these pt’s?
A
- Most fractures occur before puberty (↓ frequency w/ ↑ age)
- _Normal lifespa_n and normal or near-normal stature
- Blue sclerae
- Loose joints + low muscle tone BUT absent or minimal bone deformity
- Brittle teeth and hearing loss = possible, w/ hearing loss usually manifesting in early 20s or 30s
25
What is the collagen defect seen with type II osteogenesis imperfecta; majority inherited how?
- **Abnormally short pro-α1(1)** chain
- **Unstable _triple helix_**
- Majority are inherited **autosomal _recessive_**
26
What are the clinical featues of Type II Osteogenesis Imperfecta?
- **Death** in **utero** or **within days** of **birth**
- **Numerous fractures** and **severe bone deformity**
- Small stature w/ **underdeveloped lungs** --\> **_respiratory problems_**
27
What is the defect in collagen which causes Type I Osteogenesis Imperfecta?
Collagen **structure** is **_normal_**, but the amount is **less than normal**
28
Osteopetrosis is also known as what?
**Marble bone disease** and **Albers-Schonberg disease**
29
Most of the mutations underlying osteopetrosis interfere with what process?
**Acidification** of the osteo**clast** resorption **pit**, required for the dissoluation of the **Ca2+ hydroxyapatite** within the matrix
30
Describe the defect caused by the mutations in ***CA2*** and ***CLCN7*** associated with osteopetrosis?
- ***CA2***: required to generate **protons** from **CO2** and **H2O** --\> **absence** prevents _osteo**clasts**_ from **acidifying** the **resporption** **pit** and **solubilizing hydroxyapatide**, and also **blocks** the **acidification** of **urine** by **_renal tubular cells_**
- ***CLCN7***, encodes a **proton pump** located on the surface of osteo**clasts**
31
Due to deficient osteo**clast** activity what is seen morphologically in the bones of osteopetrosis?
- Bones involved **_lack_** a **medullary canal**; instead contain **primary spongiosa** (which is normally removed during growth)
- Ends of **long bones** are **bulbous** (**Erlenmeyer flask deformity**)
- **Neural foramina** are **small** and **_compress_** exiting nerves
32
What is the inheritance pattern of the severe infantile form of osteopetrosis and what are the clinical features?
- Autosomal **_recessive_**
- Usually evident **in utero** or **soon after birth**
- **Fracture, anemia**, and **hydrocephaly** --\> **post-partum mortality**
- Those who survive have **CN defects**: optic atrophy, deafness, and facial paralysis
33
What is the inheritance pattern of the mild form of osteopetrosis and what are the clinical features?
- Autosomal **_dominant_**
- Dx in **adolescence** or **adulthood** --\> **repeated fractures**
- **_Mild_** CN defecits and anemia
34
How are osteopenia and osteoporosis defined radiographically?
- Osteo**penia** = bone mass **1.0-2.5 SD's** _below_ the **mean**
- Osteo**porosis** = bone mass _at least_ **2.5 SD's** below **mean** peak bone mass in young adults
35
Other than the decrease in peak bone mass at least 2.5 SD's below the mean, the presence of what other findings signifies osteoporosis?
Presence of an **atraumatic** or **vertebral compression fracture**
36
What is the underlying pathophysiology of age-related changes leading to senile osteoporosis?
- Osteo**blasts** from older pt's have ↓ **proliferative** and **biosynthetic potential**
- **Cellular response** to **GF's** bound to **extracellular matrix** becomes **attenuated** as well
- This form is aka ***low-turnover variant***
37
Who is most at risk for calcium-deficiency leading to future osteoporosis and why?
- **Adolescent** **girls** tend to have **insufficient Ca2+** intake in the diet
- Typically occurs during a period of **rapid bone growth**, _restricting_ the peak bone mass ultimately achieved
38
Why is post-menopausal osteoporosis categorized as a high-turnover variant of osteoporosis; which hormones play the greatest role?
- ↓ **estrogen** = **major role** --\> leads to ↑ in **bone resorption** and **formation**; but **formation \< resorption**
- ↓ **estrogen** --\> ↑ **inflammatory cytokines** which stimulate osteo**clast** recruitment and ↑ **RANKL**, ↓ **OPG** --\> ↓ osteo**clast** proliferation and apoptosis
39
What are 3 cytokines which have been implicated in post-menopausal osteoporosis?
**IL-6**, **TNF-α**, and **IL-1**
40
What is the histologic hallmark of osteoporosis?
**Normal bone** that is **decreased** in **quantity**
41
Which bones are most often affected by the ↑ osteoclasts activity in post-menopausal osteoporosis and what is seen morphologically?
- Bones w/ ↑ **SA** (cancellous bones of **vertebral bodies**)
- **Trabeculae**: perforated, thinned and lose interconnections which ---\> **microfractures** and **vertebral collapse**
42
What is seen morphologically with senile osteoporosis?
**Cortex** _thinned_ by **_subperiosteal**_ and _**endosteal resorption_**, Haversian system widened (may mimic cancellous bone)
43
Vertebral fractures are common in osteoporosis and lead to what?
**Loss** of **height** and **deformities**, such as **lumbar lordosis** and **kyphoscoliosis**
44
Which labs can be used for diagnosis of osteoporosis?
- Labs are **NOT** diagnostic; main purpose of blood tests is to check for **2' causes**
- Dx requires **DEXA-scan**
45
What are 2 frequent complications associated with fractures of the femoral neck, pelvis, or spine seen with osteoporosis?
**Pulmonary embolism** and **Pneumonia**
46
Up to 50% of familial paget disease and 5-10% of sporadic cases harbor which mutation?
Mutations of ***SQSTM1*** ---\> ↑ NF-kB --\> ↑ osteoclast activity
47
What is the hallmark histologic pattern seen with Paget Disease of bone?
- **Mosaic pattern** of **lamellar bone**, seen in the **_sclerotic phase_** (**late stage**)
- **Jigsaw-like** appearance w/ **prominent cement lines** = haphazardly oriented units of lamellar bone
48
What is seen morphologically in the 3 phases of Paget Disease of bone?
1) **Lytic phase**: large **osteo**_clasts_**** w/ **100 nuclei**
2) **Mixed phase**: clasts persist, but lots of **blasts also**; primarily osteo**blastic** at end of stage
3) **Final**: burned-out quiescent **osteosclerotic stage**
49
Which bones are involved in 80% of cases of Paget Disease?
**Axial skeleton** and **proximal femur**
50
What are some of the common presentations and complication of Paget Disease of bone?
- **Chalk-stick type fractures**: long bones of legs
- **Anterior bowing** of femur and tibia, distorts fibular head --\> 2' osteoarthritis
- **Enlargement** of **craniofacial skeleton** --\> **"lion facies****"**
- **Hypervascularity of Pagetic bone** --\> **warms overlying skin**
51
Which complication may arise from the hypervascularity of Pagetic Bone?
↑ blood flow acting as **AV shunt** leading to **high-output heart failure**
52
What are the levels of serum calcium, phosphorus and ALP like in Paget Disease?
- ↑ **ALP** w/ **_normal_** calcium and phosphorus
- **_MOST COMMON_** cause of **isolated** ↑ **ALP** in **adult**
53
What is the most dreaded complication of Paget Disease of bone?
Development of **Sarcoma**; typically **Osteosarcoma** or **Fibrosarcoma**
54
Paget disease of bone is relatively common in whom?
**Whites** in **England**, **France**, **Austria**, regions of **Germany**, **Austrailia**, **New Zealand** and the **U.S.**
55
PTH is responsible for activating which cells in bone?
Osteo**clast** activation --\> ↑ bone resorption and Ca2+ mobilization; effect mediated **_indirectly_** through ↑ **RANKL** expression on osteo**blasts**
56
Symptomatic, untreated primary hyperparathyroidism manifests as what 3 interrelated skeletal abnormalities?
- **Osteoporosis**
- **Brown tumors**
- **Osteitis fibrosa cysticab**
57
Combination of ↑ bone cell activity, peritrabecular fibrosis, and cystic brown tumors is the hallmark of?
Severe **hyper**parathyroidism and is known as **generalized osteitis fibrosa cystica (von Recklinghausen disease of bone)**
58
The osteoporosis seen with hyperparathyroidism is most severe in which bones and the ↑ osteoclast activity is most prominent where?
- _Most_ **severe** in the **phalanges, vertebrae** and **prox. femur**
- ↑ **osteoclast** activity is **most prominent** in **cortical bone** (**subperiosteal** and **endosteal surfaces**), but **medullary** bone is also affected
59
In hyperparathyroidism the osteoclasts may tunnel into and dissect centrally along the length of trabeculae, producing what?
**Dissecting osteitis**; looks like **"railroad track****"**
60
Kidney disease causes skeletal abnormalities (renal osteodystrophy) through what 3 mechanisms?
- **Tubular dysfunction**: renal tubular acidosis --\> ↓ pH dissolves hydroxyappatite
- **Generalize renal failure**: ↓ phosphate excretion, chronic **hyperphosphatemia**, hypocalcemia, and **2' hyperparathyroidism**
- ↓ **prod.** of **secreted factors**: kidney converts Vit D to active form (1,25-D3) and secretes proteins **BMP-7** and **Klotho**
61
What is the fundamental defect in osteomalacia (adults) and rickets (children)?
**Impairment** of **mineralization** and resultant accumulation of **unmineralized matrix**
62
What is a simple vs. compound vs. comminuted fracture?
- **Simple** = overlying **skin intact**
- **Compound** = bone _communicates_ w/ the skin surface
- **Comminuted** = bone is **fragmented**
63
What is definition of a displaced fracture?
**Ends** of the bone at fracture site are _not_ aligned
64
What is a "Greenstick" fracture?
Extending only _partially_ through the bone, common in **infants** when bones are _soft_
65
What is a pathologic fracture?
Involving bone weakened by an _underlying_ disease process, such as tumor
66
What occurs immediately post bone fracture?
- **Rupture** of **blood vessels** results in a **_hematoma_** which fills the fracture gap and surrounds area of bone injury
- **_Clotted blood_** ---\> **fibrin mesh** seals site and creates framework for influx of inflammatory cells and ingrowth of fibroblasts + new capillaries
67
As the hematoma forms immediately post-fracture what is released from degranulated platelets and migrating inflammatory cells; causes what?
- Release **PDGF**, **TGF-**β, and **FGF**
- **Activate** osteoprogenitor cells in periosteum, medullary cavity and surrounding soft tissues; stimulates osteo**clastic** and osteo**blastic** activity
68
What are the major changes seen at the end of the first week following a bone fracture?
- **Organization** of the **hemaoma** + **matrix prod.** in **adjacent tissues** + **remodeling** of the **fractured ends** of the **bone**
- **Fusiform** and predominantly **uncalcified tissue** aka ***soft tissue callus*** or ***procallus***
- Provides some **_anchorage_** between the ends of fracture bone but **NOT** structural rigidity
69
After 2 weeks of fracture repair what occurs?
- Soft tissue callus is transformed into **bony callus**
- Activated osteoprogenitor cells _deposit_ subperiosteal trabeculae of **woven bone**
- **Bony callus** reaches _maximum girth_ at end of **2nd** to **3rd week** and helps _stabilize_ the fracture site
70
Healing of a bone fracture is complete with restoration of what?
The **medullary cavity**
71
Most cases of osteonecrosis (avascular necrosis) are due to what 2 etiologies?
- **Fractures** or **corticosteroid tx**
- May also be seen w/ **bisphosphonate tx** (especially **jaw!**)
72
Regardless of etiology, medullary infarcts (osteonecrosis) are geographic and involve which parts of bone?
**Trabecular** bone & **marrow**
73
Why is the cortex not typically affected in medullary infarcts (osteonecrosis)?
Due to its **collateral blood flow**
74
What is the characteristic morphology seen with with subchondral infarcts of osteonecrosis?
**_Triangular_** or **_wedge-shaped_** segment of tissue that has the subchondral bone plate as its base undergoes necrosis
75
What does dead bone look like microscopically?
**Empty lacunae** surrounded by necrotic _adipocytes_ which frequently rupture
76
What is seen with the trabeculae that remains in subchondral infarcts (osteonecrosis)?
- Acts as **_scaffolding_** for the deposition of _new bone_ in process known as **"creeping substitution"**
- Pace is **_too slow_** to be effective, so there is **collapse** of the necrotic bone and distortion, fracture and even **sloughing** of the **articular cartilage**
77
Medullary infarcts are usually small and clinically silent except when they occur in the which 3 settings?
- **Gaucher disease**
- **Dysbarism** (i.e., the **"bends"**)
- **Sickle cell anemia**
78
What is the origin of most osteomyelitis in both healthy children and adults?
- **Children**: _hematogenous_ spread from **trivial mucosal injuries** i.e., defecation or vigorous chewing of hard foods or from minor infections of skin
- **Adults**: more often arise as complication of **_open_ fractures**, **surgical procedures**, and **_diabetic_ infections** of the **feet**
79
Which 3 organisms are commonly cultured in osteomyelitis seen in pt's with UTI's are who are IV drug users?
***E. coli*** + ***Pseudomonas*** + ***Klebsiella***
80
Pt's with C5, 6, 7, 8, and 9 deficiency have increased susceptibility to which organism causing osteomyelitis?
***Neisseria***
81
What is the seen in the acute phase of osteomyelitis?
Bacteria proliferate and induce **neutrophilic** inflammatory rxn; **necrosis** of bone cells and marrow ensues within first **48 hours**
82
In children the periosteum is loosely attached to the cortex, so what is often seen in the acute phase of osteomyelitis?
**Sizable subperiosteal _abscesses_** may form, which **dissect** for **long distances** along the bony surface
83
What does the term sequestrum refer to in terms of osteomyelitis; what is seen with rupture of the periosteum?
- **_Dead bone_** following **subperiosteal abscess**
- **Rupture** of periosteum ---\> soft tissue **abscess** which can channel to become a **draining sinus**
84
What is seen commonly with epiphyseal infection (osteomyelitis) in infants?
Spread thru the **articular surface** or **along capsular** and **tendoligamentous insertions** into joints ---\> **septic** or **suppurative arthritis**
85
What is seen in the chronic phase (after first week) of osteomyelitis; what does the term involucrum refer to?
- **Chronic** inflammatory cells release **cytokines** that stimulate **osteoclastic** resorption, ingrowth of fibrous tissue and deposition of reactive bone at the periphery
- **Newly deposited bone** can form a **shell** of **living tissue**, known as _**involucum**,_ around the segment of devitalized infected bone
86
Describe the morphological variants of osteomyelitis known as Brodie abscess and Sclerosis osteomyelitis of Garre?
- **_Brodie abscess_**: small **interosseous** abscess frequently involves cortex & is **walled off by reactive bone**
- **_Sclerosing osteomyelitis of Garre_**: in **_jaw_** and assoc. w/ extensive new bone formation that obscures much of the underlying osseous structure
87
Diagnosis of osteomyelitis is strongly suggested by what characteristic radiographic findings?
**Lytic focus** of **bone destruction** surrounded by **zone of sclerosis**
88
Unexplained fever vs. localized pain are more common findings of osteomyelitis in which age group (adults or children)?
- **Unexplained fever** = **children**
- **Localized pain** = **adults**
89
In mycobacterial osteomyelitis the organisms usually originate from where?
_**Blood** borne_, originating from a focus of active visceral disease during initial stages of primary infection; can be direct extension
90
What are some of the complications which may arise in the setting of tuberculous spondylitis (Pott disease)?
- **Permanent compression fractures** --\> **scoliosis** or **kyphosis** & neurological deficits 2' to spinal cord and nerve compression
- **Other:** tuberculous arthritis, sinus tract formation, psoas abscess & amyloidosis
91
How and when does skeletal syphillis present when congenital?
- Appear about **5th** month **gestation** and _fully developed_ at birth
- **Saber shin**: massive reactive periosteal bone deposition on **medial** and **anterior** surfaces of the tibia
92
In acquired syphillis when do the bone lesions typically present and how?
- May begin in early _**tertiary** stage_, **2-5 years** after initial diagnosis
- **Saddle nose**, palate and extremities (esp. **long tubular bones** like **tibia**)
