OI Flashcards
What treatments are there to inhibit bone resorption
(anti-catabolic)
Bisphosphonates
Denosumab
What treatments are there to increase bone formation
(anabolic)
Teriparatide
Romosozumab
Setrusumab
What does normal sclerostin do?
Decrease bone formation and increases bone resorption
-Inhibits osteoblasts and osteoprogenitor cells
How is bone structure different in OI
-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
What gene mutation causes most OI cases
COL1A1 and COL1A2
-80-95% of cases
-autosomal dominant
Incidence of OI
1:10,000-20,000
equal male and female prevalence
Occurrence of dentinogenesis imperfecta
50% of patients with OI
-collagen is major protein the forms dentin
Occurrence of dentinogenesis imperfecta
50% of patients with OI
-collagen is major protein the forms dentin
Prevalence of hearing loss in OI
-5% of children
-50% of adults by age 50
-more prevalent in type I OI
Non bony complications of OI
-heart structural/valve issues
-vascular issues
-blue sclera
-hearing loss
-respiratory issues (due to chest wall structure and lung connective tissue problems)
-joint hypermobility
Which form of OI is lethal in perinatal period
II
-20% are stillbirths
-90% die by 4 weeks old
Which form of OI is the most progressively deforming
III
Most common form of OI
Type I
OI Type I
-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
Mutation that causes OI type 5
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
How do bisphosphonates work?
-inhibit bone resorption by inhibiting osteoclasts and induce osteoclasts apoptosis
-data shows increased bone mass but no proven decreased in fracture
Types of bisphosphonates and their administration
-pamidronate and zoledronic acid: IV every 3-6 months
-alendronate and risedronate: orally every week
What is Denosumab
monoclonal antibody which targets RANKL which mediates osteoclast production and survival
-currently in pediatric clinical trial
What is Teriparatide
parathyroid hormone analog
-increases bone density
-can only be given for 2 years due to concern of osteosarcoma
What is Romosozumab (Evenity)
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
What is Fresolimumab
Anti TGF-beta antibody (transforming growth factor)
-silences protein that is important for bone formation
-in phase I study currently
What are the treatments that inhibit bone resorption
-bisphosphonates
-denosumab
What are the treatments used to increase bone formation
-denosumab
-setrusumab
-romosuzumab
-TGF beta inhibitory antibody (fresolimumab)
-teriparitide
How often is setrusamab given
IV infusion once a month
What is age eligibility of Orbit
age 5-25
Genetic eligibility of Orbit trial
OI type I, III, or IV confirmed by genetic mutation of COL1A1 or COL1A2
Orbit Inclusion criteria
-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
What chromosome is COL1A1 on
17
What chromosome is COL1A2 on
7
Bone formation marker that can be measured
P1NP
(procollagen type 1 N-telopeptide)
Bone resorption marker that can be measured
CTX
(type 1 collagen c-telopeptide)
What does RANKL do?
-produced by osteoblasts
-stimulates differentiation of osteoclasts
What cells produce sclerostin?
Osteocytes
What actions does sclerostin have?
-inhibits surface cells from being differentiated into osteoblasts
-inhibits LPR5 (protein that increases bond density during loading activities?)
-Increases RANK production
What two disorders are caused by lack of sclerostin?
-sclerosteosis (more severe)
-Van Buchem disease
Outcomes of Romosozumab in osteoporosis studies?
-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
Number of patients enrolling in Phase III of Orbit
Setrusomab = 130
Placebo = 65
