Osteoporosis: the final frontier 9 January 2015 Adrian Moore.

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

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

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

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

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

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

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!

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.

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.

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

Thanks!