Osteoporosis: the final frontier 9 January 2015 Adrian Moore.
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Transcript of Osteoporosis: the final frontier 9 January 2015 Adrian Moore.
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Osteoporosis: the final frontier
9 January 2015
Adrian Moore
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The science creative quarterly http://www.scq.ubc.ca/?p=400
The skeleton
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Bone cells
Osteoclasts: multinucleated giant cells that break down bone
Osteoblasts: cells that lay down bone
Osteocytes: cells within the bone matrix
5-10% of our bone structure is replaced each year. This is a normal process that allows repair of tiny cracks and structural weaknesses
Osteoclast
Osteoblasts
Osteocytes
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Bone quantity is the net effect of bone formation and bone resorption
Normal Osteoporosis
Animation courtesy of Dr Susan Ott, University of Washington
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Osteoporosis is a serious and growing problem
Human cost: One year after hip fracture, of the patients that survive: 40% of patients are unable to walk independently, 60% have difficulty with at least one essential activity of daily living, and 80% are restricted in activities, such as driving and grocery shopping
C. Cooper The crippling consequences of fractures and their impact on quality of life Am J Med. 1997
Healthcare cost: In the US the estimated direct expenditure in hospitals and nursing homes for osteoporosis-associated fractures was $18 billion in 2002.
National Osteoporosis Foundation
Future projection: The World Health Organisation estimates that the number of fractures worldwide due to osteoporosis will rise from 1.7 million in 1990 to 6.3 million in 2050
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Medications for osteoporosis
Most available osteoporosis drugs are anti-resorptives
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Sclerosteosis – An inherited high bone mass disorder7
Bone deposited in a normal manner and is very strong
No reported traumatic fractures in sclerosteosis patients
Brunkow et al 2001* reported a point mutation leading to loss of function
Gene termed SOST and its protein product sclerostin
The genetics of sclerosteosis suggests that targeting the protein sclerostin could result in bone growth
Normal
Sclerosteosis
*Brunkow, M.E. et al., Am. J. Hum. Genet. 2001
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What is sclerostin?
Sclerostin is a 190 amino acid glycoprotein
It contains a cystine knot motif from which 3 loops emanate
The protein was cloned (and patented) by scientists at Celltech R&D
An antibody project, targeting sclerostin, was instigated with the main indication being post menopausal osteoporosis
An agreement was signed between Amgen and the former Celltech organisation in 2002 to cover the development and commercialisation of sclerostin antibodies
Veverka et al JBC 2009
NMR structure of sclerostin
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Where is it found?9
Sclerostin is produced by the osteocyte and negatively regulates bone formation by limiting the anabolic output of the osteoblast lineage
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What does it do?
Modified from http://www.wormbook.org/chapters/www_wntsignaling/wntfig1.jpg
No bone formation No bone formationBone formation
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Wild type Transgenic
More in formation on SOST transgenics: Winkler et al Embo J. 2003;22:6267–6276
Phenotype of sclerostin KO and transgenic mice
Sclerostin KO Wild type
Li et al JBMR 2008
KO: dense strong bones Transgenic: weak brittle bones
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Sclerostin antibody reverses bone loss in a rat model of post menopausal osteoporosis
OVX + Scl-AbSham OVX
L4-L5 Vertebra
SHAM OVX050
100150200250300350
*p<0.05
Scl-Ab
*
*M
axim
um
Lo
ad [
N]
Ominsky et al JBMR 2006; 21(1): S44.
BM
D
( g
/cm
2 )
0 7 14 21 28 350.25
0.26
0.27
0.28
0.29
0.30
0.31
0.32
0.33
0.34
0.35
Days
Tibia-Femur
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P1NP sCTx
Adapted from Padhi D, et al. J Bone Miner Res. 2010; DOI 10.1002/jbmr.173.
120
Time (Day)
0 8 15 22 29 36 43 50 57 64 71 78 85
Mea
n P
erc
ent
Ch
ang
e F
rom
Bas
elin
e
-40
0
40
80
200
160
20
Time (Day)
0 8 15 22 29 36 43 50 57 64 71 78 85-80
-40
-20
0
60
40
-60
10 mg/kg
3 mg/kg
Placebo SC (n = 14)
0.1 mg/kg SC (n = 6)
0.3 mg/kg SC (n = 6)
1 mg/kg SC (n = 9)3 mg/kg SC (n = 6)
5 mg/kg SC (n = 9)
10 mg/kg SC (n = 6)
5 mg/kg
Romosozumab increased a marker of bone formation and decreased a marker of bone resorption
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Bone mineral density – Year 1
0 3 6 9 12
Month
0
5
10
15
18 24
Per
cen
t C
han
ge
fro
m B
asel
ine
0 3 6 9 12 18 24
Month
0
2
4
6
-2
Lumbar Spine Total Hip
Romosozumab 210 mg QM ALN TPTD Placebo
McClung et al. NEJM 2014;370:5.
Data are means and 95% CIs
11.3% 4.1%
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Space, the final frontier
July 20, 1969, Neil Armstrong became the first man on the moon
…and in 45 years we’ve gone no further afield…
Images courtesy of NASA History Office and the NASA JSC Media Services Center.
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Challenges of spaceflight are more biological than engineering
Increased radiation levels
Redistribution of fluid to the upper body
Increased intracranial pressure and disrupted vision
Back and abdominal pain
Disturbed circadian rhythm, sleep loss and fatigue
Raw and painfully sensitive skin
Loss of muscle mass
Loss of bone mass
Percent change in BMD per month of spaceflight
LeBlanc JMNI 2000
-1.56%
-1.06%
-0.04%
…and if that leaves you wanting to cry - don’t!
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Effects of sclerostin antibody on bone loss in space
Experimental design
Female, C57Bl/6N mice
9 weeks old at launch
4 groups:
Ground + vehicle (n=15)
Ground + sclerostin antibody (n=15)
Flight + vehicle (n=15)
Flight + sclerostin antibody (n=15)
Mission
Flight: on STS-135 for 13 days
Bouxsein et al, ASBMR Annual Meeting 2012.
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Trabecular bone microarchitecture improved by Scl-Ab
BV/TV (%)
TbTh (µm)
TbN (mm-1)
# p <0.05 Gr-Veh vs FL-Veh
Ground FlightVeh
Veh
0
4
8
12
16
20
#
0
20
40
60
80
0
1
2
3
4
#
SclAb
SclAb
FL-Veh
GR-SclAb FL-SclAb
GR-Veh
Bouxsein et al, ASBMR Annual Meeting 2012.
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0
40
80
120
Sti
ffn
ess
(N/m
m)
Ground FlightVeh
VehSclAb
SclAb
#
0
4
8
12
16
Max
imu
m L
oad
(N
)
Ground FlightVeh
VehSclAb
SclAb
#
0
4
8
12
16
En
erg
y to
Fai
lure
(m
J)
Ground FlightVeh
VehSclAb
SclAb
#
Femoral biomechanical properties by 3 point bending
Bouxsein et al, ASBMR Annual Meeting 2012.
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Acknowledgments
Martyn Robinson, UCB
Romosozumab project teams at UCB and Amgen
STS-135 Musculoskeletal Research Team
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Thanks!