Transcript Bone Health in Adulthood

Workshop:
Osteogenesis Imperfecta in Adults
Malachi J McKenna & Susan van der Kamp
DXA Unit & Department of Endocrinology
St. Vincent’s University Hospital
Dublin, Ireland
Disclosures
• No disclosures or conflicts of interest
Learning Objectives
•Overview of osteogenesis imperfecta in adults
–Classification of OI
–Bone health in adulthood
•Investigation of OI
–Role of DXA
–Role of bone turnover markers
•Medication options
•Case Studies
Learning Objectives
• Overview of osteogenesis imperfecta in
adults
– Classification of OI
– Bone health in adulthood
• Investigation of OI
– Role of DXA
– Role of bone turnover markers
• Medication options
• Case Studies
OI Phenotypes
Nosology of Osteogenesis Imperfecta
Type
Classical Sillence types
I: Mild
II: Perinatal lethal
III: Severely deforming
Affected gene
Mode of
inheritance
COL1A1
AD
COL1A1 or
COL1A2
COL1A1 or
COL1A2
AD
IV: Moderately deforming COL1A1 or
COL1A2
AD
AD
Phenotype
Normal stature, few fractures, blue sclera, hearing
loss in 50%
Severe, multiple fractures, blue or grey sclerae, soft
cranium
Severe, short stature, scoliosis with vertebral
fractures, triangular face, multiple fractures, blue or
grey sclera, frequent hearing loss, platybasia,
dentinogenesis imperfecta
Moderately short stature, mild to moderate scoliosis,
white or grey sclerae
Distinctive histology
V: Moderately deforming
IFITM5
AD
Mild to moderate short stature, dislocation of radial
head, hyperplastic callus, white sclerae
Mineralisation defect
VI: Severe
SERPINF1
AR
Moderately short, scoliosis, fish-scale pattern of
bone lamellation, white sclera
3-hydroxylation defects
VII: Severe
CRTAP
AR
VIII: Severe
LEPRE1
AR
Rhizomelia, short stature, white sclera,
undertubulated long bones
Rhizomelia, white sclera, undertubulated long bones,
seen in Irish Travellers
IX: Severe
PPIB
AR
Similar to type VII & VIII but no rhizomelia
Modified from Forlino A, Cabral WA, Barnes AM, Marini JC. New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol 2011;7:540-57
Critical steps in collagen type I biosynthesis and indication of
genes known to be involved in OI. Type I collagen is the major
structural protein in bone, tendon, ligament, skin & cornea
Mechanism of disease in OI type I
Mechanism of disease in OI type III & IV
Abnormal folding of collagen molecule
Approach to Genetic Testing
Bone Health in Adulthood
• OI type I
– Low or low-normal BMD
– Stable BMD
– Normal or high-normal bone turnover
– Fragility fractures
• Variable prevalence
• Less frequent than childhood
Bone Health in Adulthood
• OI type III & IV
– Low BMD
– Stable BMD
– High-normal or high bone turnover
– Fractures
• Fragility fractures are common but variable prevalence
• Stress fractures may occur easily
– Problems related to bone deformity
• Wheelchair-bound
• Platybasia
Learning Objectives
• Overview of osteogenesis imperfecta in adults
– Classification of OI
– Bone health in adulthood
• Investigation of OI
– Role of DXA
– Role of bone turnover markers
• Medication options
• Case Studies
Challenges of DXA in OI Type I
Challenges of DXA in OI Type III
Panel of Bone Turnover Markers
Resorption
Formation
sCTX
Procollagen I
aminopropeptide
urNTX
Bone specific alkaline
phosphatase
sTRAP5b
Osteocalcin
Collagen-based Markers of Bone
Remodelling
Origin of Collagen Cross Links
N-TELOPEPTIDE
REGION
HELICAL REGION
C-TELOPEPTIDE
REGION
CTx
NTx
Pyr
Dpd
Watts, N. B. Clin Chem 1999 45:1359-68, with permission.
Learning Objectives
• Overview of osteogenesis imperfecta in adults
– Classification of OI
– Bone health in adulthood
• Investigation of OI
– Role of DXA
– Role of bone turnover markers
• Medication options
• Case Studies
Medications for OI
(off-label use of medications)
• Bisphosphonates
– Alendronate
– Risedronate
– Ibandronate
– Zoledronate
• Parathyroid hormone
– rhPTH1-34
• RANKL inhibitor
– Denosumab
Cochrane Review on Bisphosphonates in OI
Dwan K, Phillipi CA, Steiner RD, Basel D. The Cochrane Library 2014, Issue 7
• Current evidence demonstrates that oral or intravenous bisphosphonates
increase bone mineral density in children and adults
• These were not shown to be different in their ability to increase bone
mineral density.
• It is unclear whether treatment consistently decreases fractures, though
multiple studies report this independently and no studies report an
increased fracture rate.
• The studies did not show bisphosphonates conclusively improve clinical
status (reduce pain; improve growth and functional mobility) in people
with osteogenesis imperfecta.
• Given their current widespread and expected continued use, the optimal
method, duration of therapy and long-term safety of bisphosphonate
therapy require further investigation.
• In addition, attention should be given to long-term fracture reduction and
improvement in quality of life indicators.
Study of Teriparatide in Adults with OI
• Evaluation of teriparatide treatment in adults with
osteogenesis imperfecta. Eric S. Orwoll, Jay Shapiro, Sandra
Veith, Ying Wang, Jodi Lapidus, Chaim Vanek, Jan L. Reeder,
Tony M. Keaveny, David C. Lee, Mary A. Mullins, Sandesh
C.S. Nagamani, and Brendan Lee
• Oregon Health and Science University, Portland, Oregon,
USA. Kennedy Krieger Institute, Baltimore, Maryland, USA.
ON Diagnostics, Berkeley, California, USA. Departments of
Mechanical Engineering and Bioengineering, UC Berkeley,
Berkeley, California, USA. Baylor College of Medicine,
Houston, Texas, USA. Howard Hughes Medical Institute,
Houston, Texas, USA.
• J Clin Invest. 2014;124(2):491–498. doi:10.1172/JCI71101
Study of Teriparatide in Adults with OI
BMD Response to Teriparatide
BTM Response to Teriparatide
Bone Strength Response to Teriparatide
Learning Objectives
• Overview of osteogenesis imperfecta in adults
– Classification of OI
– Bone health in adulthood
• Investigation of OI
– Role of DXA
– Role of bone turnover markers
• Medication options
• Case Studies