Module 6: Bone: Pagets, Achondroplasia, Osteogenesis Imperfecta

Question 1

Moving on to Paget’s Disease, what are the causes?

Answer 1

• -Associated with Paramyxoviruses (measles, RSV and mumps) in childhood
• -common in older French and British men
• -genetic predisposition with p62 mutation – increased RANK-RANKL mutation — increased osteoclasts

Question 2

What is the pathogenesis for Paget’s Disease?

Answer 2

Virus stimulates IL-6 — IL-6 and M-CSF activate osteoclasts — osteoclasts hyper responsive to RANKL and Vit D — abnormal bone remolding
(Excessive osteoclastic activity with compensatory osteoblastic activity)

Question 3

What bones are affected in Paget’s disease?

Answer 3

Mainly axial skeleton and long bones

• –femur (most common), humerus, tibia, ulnar, radius, skull and spine
• -affects multiple bones (polyostotic)

Question 4

What are the three phases of Paget’s Disease?

Answer 4

Osteolytic phase: excess osteoclast activity
Mixed phase: both osteolytic and osteoblastic activity (more osteoblastic) and angiogenesis
Osteosclerotic phase: burn out stage so just osteoblasts (increased bone mass)
–all three co-exist - temporal heterogeneity

Question 5

What is the presentation for patients with Paget’s Disease?

Answer 5

Asymptomatic but can have pathological fractures in femur

–can also have bowing in tibia

Question 6

CHF is the most common cause of death in patients with Paget’s Disease, what is the mechanism for the heart failure?

Answer 6

In order for osteoblasts to lay down bone they need angiogenesis and its so much that it leads to increased AV shunting which leads to more blood flow to the heart and this leads to CHF (Called high output CHF)

Question 7

Explain the bone biopsy in 5b for patients with Paget’s disease?

Answer 7

Mosaic Pattern of lamellar bone with cement lines and resorption pits (Howships lacunae) due to haphazard laying of bone osteoid

• -cement lines
• -pink is osteoid (half hazard)
• -resorption pits (Howship’s Lacunae)

Question 8

Explain the skull bone in 5b for patients with Paget’s diesase

Answer 8

Gross: thick and hypervascular (b.c of angiogenesis) —phase II and III
Also see holes at the front indicates osteolytic activity – phase I
–example of temporal heterogeneity

Question 9

Explain the x-ray seen in 5a for patients with Paget’s disease?

Answer 9

Features the radius

• -black arrow: osteosclerotic: phase II and III (radiopaque)
• -white arrow: osteolytic: phase I (radiolucent)

Question 10

What is seen in blood and urine in patient with Paget’s Disease?

Answer 10

Normal Ca, PO4 and PTH 
High ALP (marker of osteoblastic activity) 
Elevated hydroxyproline in urine (marker of osteoclastic activity) -- product of collagen breakdown

Question 11

Finally what are the complications in patients with Paget’s Disease?

Answer 11

1. Pathological fractures — DVTs — PE
2. Secondary osteoarthritis of hip and knee
3. High output congestive cardiac failure (again excess osteoblastic activity in mixed phase and the increased need for angiogenesis)
4. Bowing of the tibia — pathological chalk stick fractures
5. Thick bones – press on cranial nerves in skull (CN VIII — hearing loss) or spinal nerves in the spine (paralysis)

Question 12

Paget’s disease can have malignant transformation, explain

Answer 12

Secondary osteosarcoma of the  femur
--osteosarcoma in old person think Pagets
--more common than osteoclastoma 
Osteoclastoma
--giant cell tumor of bone

Question 13

Moving on to Achondroplasia, what is the etiology?

Answer 13

FGFR3: gain of function AD mutation which inhibits chondrocyte proliferation at growth plate (normally FGFR3 is inhibited because it does down regulate cartilage proliferation)

• -majority are new, sporadic mutations
• -thanatotropic type: homozygous form is not compatible with life b.c chest cavity is too small

Question 14

What bones are affected in Achondroplasia?

Answer 14

Affects bones formed from endochondrial ossification (From cartilage)

• long bones: femur and humerus
• -does not affect bones formed from intramembranous ossification (No cartilage)

Question 15

What is the presentation for patients with Achondroplasia?

Answer 15

Disproportionate short stature : short femur and humerus
–GH deficiency (dwarfism) is proportionate
Normal Intelligence
Normal Head Circumference
Normal life expectancy
(cretinism: short life expectancy and mental retardation due to iron deficiency and therefore hypothyroidism)

Question 16

What would a biopsy of the growth plate show for a patient with achondroplasia?

Answer 16

Hypoplastic

• -no chondrocyte proliferation (Shorter)
• -more bone formers than should be so your growth plate closes with lack of cartilage proliferation

Question 17

Moving on to the next topic of Osteogenesis Imperfecta (Brittle bone disease). What is the etiology for type I and type II?

Answer 17

For both types: mutation in Type I collagen (organic component)
—type I: AD mutation
–type II: AR mutation (Worse than type I)
Essentially opposite of osteomalacia
(less than 40% of organic bone)

Question 18

What is the presentation for type I Osteogenesis Imperfecta?

Answer 18

Type I AD

• -blue sclera: it is thin so reveals the veins (Choroidal veins)(ehler’s danlos also gives blue sclera)
• -deafness (Conductive)
• -Misshapen teeth
• -pathological fractures in long bones

Question 19

What is the presentation for type II Osteogenesis Imperfecta?

Answer 19

Type II AR (usually die in utero)

• -multiple fractures in utero (defect in type I and II collagen)
• -small thoracic cavity (underdeveloped lungs) – most common COD at birth is respiratory failure
• -Intraparenchymal fractures from multiple skull fractures they are weak

Question 20

Briefly on Ehler-Danlos Syndrome, what is the pathogenesis?

Answer 20

Inappropriate cleavage of collagen fibers

Question 21

What is the presentation for Ehler-Danlos Syndrome?

Answer 21

Hyperextensibility of skin and joints
Easy bruising
Blue Sclera

Question 22

What are the complications in Ehler-Danlos syndrome?

Answer 22

Aortic Dissection

Osteopenic Bone: kyphoscoliosis and spondolisthesis

Question 23

Briefly on Marfan’s syndrome, what is the etiology?

Answer 23

Mutation of fibrillin gene on chromosome 15

Question 24

What is the presentation in patients with Marfan’s syndrome?

Answer 24

Tall with long extremities 
Hyperflexible Joints 
Kyphosis 
Scoliosis 
Pectus Excavatum

Question 25

What is seen in the eyes and CVS in patients with Marfan’s syndrome?

Answer 25

Eyes: subluxation of lens (ectopic lentis) and blue sclera
CVS: MVP, aortic dilatation due to cystic medionecrosis and aortic regurgitation

Question 26

Briefly what is the reason for Scurvy?

Answer 26

Abnormality of collagen synthesis

–decreased vitamin C – failed hydroxylation of proline and lysine – defective cross linking of collagen

Question 27

What is the presentation for patients with scurvy?

Answer 27

Bleed gums
Angulations of the costo-chondral junction
Failure to thrive

Question 28

What are the complications in patients with scurvy?

Answer 28

Fragile capillaries and venules – subperiosteal hemorrhages
Defective osteoid synthesis – microfractures
Bony deformities

Question 29

Last topic of this card deck is Osteopetrosis also called marble bone disease, what is the etiology?

Answer 29

Genetic mutation in carbonic anhydrase II gene, chloride channel gene or RANKL gene
–all these affect the ability of osteoclast to demineralize bone aka making an acidic environment

Question 30

What is the pathogenesis for osteopetrosis aka marble bone disease?

Answer 30

Without acidic environment — osteoclastic activity is impaired – primary spongiosa layer which is normally broken down by osteoclasts is retained – narrowed medullary cavity – no hematopoeisis – pancytopenia
–bone is forming but not breaking down (blast over clast)
–therefore osteoblastic activity is happening so progressive deposition of bone on pre-existing matrix due to the lack of osteoclastic activity
This is opposite from osteoporosis

Question 31

If you have all this increased osteoblastic activity and thick bones, why are bones not stronger in osteopetrosis?

Answer 31

Because you need a balance of osteoblastic and osteoclastic activity

Question 32

Osteopetrosis is common in what population?

Answer 32

Common in children — BM failure – EM hematopoiesis in liver and spleen =
hepatosplenomegaly

Question 33

What is the presentation for patients with osteopetrosis?

Answer 33

1. Pancytopenia with EM hematopoiesis: recurrent infections (most common COD), bleeding and fatigue
2. Erlenmeyer Flask Deformity: thick bones that can bend quickly (seen on x-ray as metaphyseal flaring)
3. Pathological fractures
4. Deafness and facial nerve paralysis: affects skull bones and CN 7 and 8 –called lion bone faces (Seen in leprosy)
5. Carpel tunnel syndrome: affects ulnar and median nerves
6. Compression of spinal nerves

Question 34

What investigations are done for patients with osteopetrosis?

Answer 34

PCR looking for deficiency
X-ray: deformities
–bone is very white and bright (marble appearance) from excess mineralization (radiopaque)
–Erlenmeyer flask deformity: metaphyseal flaring that is more prominent around the kne and hips

Question 35

What is seen on bone marrow biopsy, slide 3, for patients with Osteopetrosis?

Answer 35

Cortex (1)
Suppose to be medullary cavity (2) however the primary spongiosa layer is present because there is no osteoclastic activity so therefore retention of this layer — no hematopoiesis and therefore pancytopenia

Question 36

What is seen in the blood for patients with osteopetrosis?

Answer 36

Low Ca, PO4

High PTH and ALP (Super high)

Question 37

Finally what are complications of osteopetrosis?

Answer 37

COD= recurrent infections
Heart failure
Deafness