Metabolic Bone Disorders Flashcards
(56 cards)
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
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
3
Q
- Woven bone is more __ and __ than lamellar bone
A
cellular and disorganized
4
Q
Function of osteocytes?
A
detect mechanical forces and translate them into biological activity- mechanotransduction
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
6
Q
What do osteoblasts secrete that favor bone formation?
A
- Osteoprotegrin (OPG)
- a decoy receptor for RANKL
7
Q
- Role of GH (growth hormone) on bone?
A
- Acts on resting chondrocytes to induce and maintain proliferation
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
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
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
11
Q
What 4 factors increases RANK-to-OPG ratio (promotes osteoclasts)?
A
- Parathyroid hormone
- IL-1
- Glucocorticoids
- Sclerostin
- produced by osteocytes, inhibits WNT/B catenin pathway
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
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
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
- formation of bone without a pre-existing cartilage matrix
-
Endochondral:
- formation of a cartilage matrix (from chondrocytes) which is then replaced by bone
- how long bones grow
- formation of a cartilage matrix (from chondrocytes) which is then replaced by bone
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
16
Q
- Osteogenesis imperfecta principally affects bone. Can also impact what other tissues?
A
- Rich in type 1 collagen
- joints
- eye
- ears
- skin
- teeth
17
Q
- What is the fundamental abnormality in osteogenesis imperfecta?
A
- Too little bone resulting in extreme skeltal fragility
- impaired type 1 collagen synthesis
18
Q
3 Clinical features of osteogenesis imperfecta?
A
- Mutliple fractures in bone
-
Blue sclera
- thinning of scleral collagen reveals underlying choroidal veins
- Hearing loss
- bones of inner ear easily fracture
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
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-
21
Q
What are the 5 clinical features of osteopetrosis?
A
- Bone fractures
- Anemia, thrombocytopenia and leukopenia with extramedullary hematopoiesis
- due to bony replacement of marrow (myelophthistic)
- Vision and hearing impairement
- due to impingment on cranial nerves
- Hydrocephalus
- Renal tubular acidosis (seen with carbonic anhydrase II mutation)
- lack of carbonic anhydrase result in decrease tubular reabsprotion of HCO3- leading to metabolic acidosis
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
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
* Mucopolysaccharidoses is a group of ___ disease?
* What accumulates in these diseases?
* What do people with these diseases look like?
* 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
* Definition of dysostoses? Arise from?
* Dysplasia?
* 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
* Osteoporosis is defined as?
* Results in what kind of bone?
* Reduction in trabecular **bone mass**
* ****results in **porous** bone with increased risk for fracture
28
* What is risk of osteoperosis based on?
* What factors influence this?
* Based on peak bone mass (attained by 30) and rate of bone loss that follows thereafter
* genetics (Vit. D receptor variants)
* diet
* exercise
29
What are 3 clinical features associated with osteoperosis?
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
* What are some treatment options of osteoperosis?
* What is contraindicated?
1. Exercise, Vitamin D and Ca2+
2. Bisphosphonates
* induce apoptosis of osteoclasts
3. estrogen replacement therapy
4. **Glucocorticoids are contraindicated (worsen osteoporosis)**
31
How does menopause lead to osteoporosis? (MOA?)
* Decreased serum estrogen leads to:
* increased IL-1, IL-6, TNF
* increased expression of RANK, RANKL
* increased osteoblast activity
32
* Paget's disease of bone is a disorder from?
* What age is it usually seen in?
* Does it affect the entire skeleton?
* 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
* What are the three phases of Paget Disease?
* What is the end result?
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
* What is the hallmark of Paget Disease?
* What does biopsy show?
* 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
What are 4 clinical features of Paget's Disease?
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
* Treatment of Paget's Disease?
* Complications?
_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
* Ricketts/Osteomalacia is due to defective?
* Caused by a deficiency in?
* **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
* What 2 sources is Vitamin D derived from?
* Activation requires?
* _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
Vitamin D raises serum Ca2+ and phosphate by acting on which 3 things?
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
Vitamind D deficiency is seen with?
* Decreased sun exposure
* poor diet
* malabsorption
* liver failure
* renal failure
41
* Ricketts is due to?
* Seen in?
* What are clincial presentation/ findings?
* 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
* Osteomalacia is due to?
* Who is it seen in?
* What do lab finding show?
* 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
* Compare lab values for serum calicum, phosphate, ALP and PTH in:
* osteoperosis
* osteopetrosis
* Paget's disease of bone
* Osteomalacia/Rickets
44
* What is osteomyelitis?
* How does it reach the bone?
* who does it typically affect?
* 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
* 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?
* 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
What is usually the cause of osteomyelitis and where does it occur in:
* kids?
* adults?
* _Kids_:
* Transient bacteremia
* Seeds the **metaphysis**
* _Adults_:
* Open wound infection/bacteremia (e.g. diabetic infection of feet)
* Seeds **Epiphysis**
47
* What are the clinical features/ symptoms of osteomyelitis?
* How is it diagnosed?
_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
What are complications of chronic osteomyelitis?
* Pathological fracture
* secondary amyloidosis
* endocarditis
* sepsis
* squamous cell carcinoma
* in draining sinus tracts
* sarcoma
* in infected bone
49
* Lyme disease is caused by?
* How is it transmitted?
* Where is it most common?
* ***Borrelia burgdorferi***
* Transmitted by *Ixodes* deer tick
* natural resevoir is the mouse
* Common in **northeastern** U.S.
50
What are the 3 stages of Lyme disease?
| (A key Lyme pie to the FACE)
* 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
* How is Lyme disease identified in the lab?
* What is the treatment?
* Detection of antibody
* ELISA
* Immunoblot
* Treatment:
* **Doxycycline** (adults)
* Amoxicillin (children)
52
* What causes Rocky Mountain spotted fever?
* What is the vector?
* Where does it most occur?
* *Ricketssia rickettsii*
* Tick
* Occurs primarily in South Atlantic state
* especially **North Carolina**
53
* What are the classic triad of symptoms in Rocky Mountain spotted fever?
* Where does rash typically start and then spread to?
* Classic triad= **headache, fever, rash**
* Rash typically starts at wrists and ankles
* spreads to trunk, palms and soles
54
What is the mechanism of action of *Rickettsia rickettsii*? (RMSF)
* 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
How would you identify RMSF (Ricketssia rickettsii) in the lab?
* Serology
* Enzyme immunoassay
* Aggluntination test
56
* What kind of a cell envelope do Rickettsia rickettsii have?
* Requirement for?
* Treat with?
* Gram (-) cell envelope
* requirement for:
* conezyme A
* NAD
* ATP
* Obligate intracellular
* Treat with doxycycline
