OI

Question 1

What treatments are there to inhibit bone resorption
(anti-catabolic)

Answer 1

Bisphosphonates
Denosumab

Question 2

What treatments are there to increase bone formation
(anabolic)

Answer 2

Teriparatide
Romosozumab
Setrusumab

Question 3

What does normal sclerostin do?

Answer 3

Decrease bone formation and increases bone resorption
-Inhibits osteoblasts and osteoprogenitor cells

Question 4

How is bone structure different in OI

Answer 4

-Low bone mass: collagen fibers are more widely spaced = more salt crystals deposited (more mineralization)
-increased remodeling: increased bone resorption, inadequate bone formation
-increasd bone porosity (increased channels for vasculature)
-fewer and thinner trabeculae
-narrower bones

Question 5

What gene mutation causes most OI cases

Answer 5

COL1A1 and COL1A2
-80-95% of cases
-autosomal dominant

Question 6

Incidence of OI

Answer 6

1:10,000-20,000
equal male and female prevalence

Question 7

Occurrence of dentinogenesis imperfecta

Answer 7

50% of patients with OI
-collagen is major protein the forms dentin

Question 7

Occurrence of dentinogenesis imperfecta

Answer 7

50% of patients with OI
-collagen is major protein the forms dentin

Question 8

Prevalence of hearing loss in OI

Answer 8

-5% of children
-50% of adults by age 50
-more prevalent in type I OI

Question 9

Non bony complications of OI

Answer 9

-heart structural/valve issues
-vascular issues
-blue sclera
-hearing loss
-respiratory issues (due to chest wall structure and lung connective tissue problems)
-joint hypermobility

Question 10

Which form of OI is lethal in perinatal period

Answer 10

II
-20% are stillbirths
-90% die by 4 weeks old

Question 11

Which form of OI is the most progressively deforming

Answer 11

III

Question 12

Most common form of OI

Answer 12

Type I

Question 13

OI Type I

Answer 13

-most common form
-about half the normal amount of collagen is formed but is normal
-fracture frequency of 1 every 2 years
-neonatal fractures are rare
-sometimes have blue sclera

Question 14

Mutation that causes OI type 5

Answer 14

Mutation in IFITM5 gene that codes for BRIL protein
-increased bone mineralization
-10% of all OI cases
-no dental issues or blue sclera
-issues with interosseous membrane = difficulties with supination/pronation, frequent radial head dislocations
-hypertrophic callus formation

Question 15

How do bisphosphonates work?

Answer 15

-inhibit bone resorption by inhibiting osteoclasts and induce osteoclasts apoptosis
-data shows increased bone mass but no proven decreased in fracture

Question 16

Types of bisphosphonates and their administration

Answer 16

-pamidronate and zoledronic acid: IV every 3-6 months
-alendronate and risedronate: orally every week

Question 17

What is Denosumab

Answer 17

monoclonal antibody which targets RANKL which mediates osteoclast production and survival
-currently in pediatric clinical trial

Question 18

What is Teriparatide

Answer 18

parathyroid hormone analog
-increases bone density
-can only be given for 2 years due to concern of osteosarcoma

Question 19

What is Romosozumab (Evenity)

Answer 19

Sclerostin inhibitor
-sclerostin typically inhibits bone formation by inhibiting osteoblast signaling pathways
-can only be given for 12 months when it loses its effect
-currently in phase 1 study for OI in kids/adults

Question 20

What is Fresolimumab

Answer 20

Anti TGF-beta antibody (transforming growth factor)
-silences protein that is important for bone formation
-in phase I study currently

Question 21

What are the treatments that inhibit bone resorption

Answer 21

-bisphosphonates
-denosumab

Question 22

What are the treatments used to increase bone formation

Answer 22

-denosumab
-setrusumab
-romosuzumab
-TGF beta inhibitory antibody (fresolimumab)
-teriparitide

Question 23

How often is setrusamab given

Answer 23

IV infusion once a month

Question 24

What is age eligibility of Orbit

Answer 24

age 5-25

Question 25

Genetic eligibility of Orbit trial

Answer 25

OI type I, III, or IV confirmed by genetic mutation of COL1A1 or COL1A2

Question 26

Orbit Inclusion criteria

Answer 26

-age 5 to <26 years old
-confirmed OI type I, III, IV with mutation in COL1A1 or COL1A2
-at least 1 fracture in past year or at least 2 fractures in last 2 years, or one major long bone fracture in last 2 years
-willing to not receive bisphosphonates during study

Question 27

What chromosome is COL1A1 on

Answer 27

17

Question 28

What chromosome is COL1A2 on

Answer 28

7

Question 29

Bone formation marker that can be measured

Answer 29

P1NP
(procollagen type 1 N-telopeptide)

Question 30

Bone resorption marker that can be measured

Answer 30

CTX
(type 1 collagen c-telopeptide)

Question 31

What does RANKL do?

Answer 31

-produced by osteoblasts
-stimulates differentiation of osteoclasts

Question 32

What cells produce sclerostin?

Answer 32

Osteocytes

Question 33

What actions does sclerostin have?

Answer 33

-inhibits surface cells from being differentiated into osteoblasts
-inhibits LPR5 (protein that increases bond density during loading activities?)
-Increases RANK production

Question 34

What two disorders are caused by lack of sclerostin?

Answer 34

-sclerosteosis (more severe)
-Van Buchem disease

Question 35

Outcomes of Romosozumab in osteoporosis studies?

Answer 35

-FRAME: decreased vertebral compression fx compared to placebo
-ARCH: better protection from fracture when taken and then transitioned to bisphosphonate, compared to taking bisphos alone
-STRUCTURE: better BMD compared to teriparitide

Question 36

Number of patients enrolling in Phase III of Orbit

Answer 36

Setrusomab = 130
Placebo = 65