Women

20 40 60 80 Age (yr)

Ac. F

/yr

)

4

2

3

1

0

Remodeling rate

Vedi et al 1982

Erickson et al 1999

The Negative BMU Balance

60

20

40

80

10 50 90 Age (yr)0 20 40 60 80

80

60

40

20

0

Formation by BMU

Age (yr)

Resorption by BMU

Lips et al 1979

Mea

n w

all t

hick

ness

(µm

)

Mea

n w

all t

hick

ness

(µm

)

50-64 65-79 80+0

1

2

3

4

5

mgHA/yr

45% 55%

10%

90%Trab

Cort

0

0.5

1

1.5

2

2.5

0 <50 60-79 80 +

Cort

Trab

Age (yrs)

Perimeter available for remodeling (m)

Zebaze et al 2010

Amount of bone lost from the cortical and

trabecular compartments

Periosteal

The Four Envelopes of Bone

Trabecular

Endocortical

Intracortical

Untreated

Structural decay

Treat

BMD

Perturbed Steady State Restored, Slower

Higher density ofa decreasingBone Volume

Trabecular Bone High Surface/Volume Configuration

Accessible to remodeling and treatment

C14 Zoledronic Acid Distribution

Tibia

Vertebrae

Skull

days

--16 16 48 80 112 144 176 208 240

25

50

75

100 nmol/g

0

Weiss et al Drug Metab Distribut 2006;36:2043

DRUG

Endocortical surface

Less Access

Cortical Bone Low Surface/Volume

Bone 49 (2011) 128–132

BP on bone surfaces

Mararachia et al Bone 1996;19:281

1-2 2-3 3-4

Weeks

High Affinity ALN 2.4

Low affinity RISED 1.2

0

-20

-40

-60

-80

L4 tr

abec

BFR

% c

ontr

ol

Allen et al Bone 2011;49:128

Penetration into Bone Matrix

Turek et al Calcif Tissue Int 2012;90:202

High Affinity Compound Low Affinity Compound

0 2 4 6 8

OPG

ALNZOL

Vehicle

Cortical porosity (%)

Cortical vBMD (mg/cm2)

1350

1250

1150\

1050

OPG**

0 2 4 6 8

8

6

4

2

0

Cortical porosity (%)

Femur energy to failure (Nmm)

Vehicle

Toughness (MPa)

0 2 4 6 8Cortical porosity (%)

15

10

5

0

OPG**ALN

ZOL

Vehicle

ZOLALN

Ohishi et al Am J Pathol 2009;174:2160

Mice constitutively activated PTH/PTHrP receptor have high porosity

OPG

ALN

ZOL

Vehicle

Cortical porosity (%)

6 4

2 0

***

**relative to vehicle

Recker JBMR 1988;31:133Eriksen Bone 2002;31:620Chavassieux JCI 1997;100:1475Recker OI 2004;15:231Recker JBMR 1008;23:6Reid JBMR 2010

0

2

4

6

Normal

Ris Ibn Zol Aln DMab

Antiresorptive Therapies and the Surface Extent of Remodeling Reflected in the Mineralizing Surface MS/BS (%)

8%

10

3 10 25 50 mg

Bone H et al JBMR 2010

Placebo

Odanacatib

0

2

4

6

8

%

10

Pennypacker et al JBMR 2011

Ovx+L-235

2 mg/kg

10 mg/kg

Ovx

Ovx+ALN

*Sham

BFR/BS Vertebral Cancellous Bone, rabbits

120

100

80

60

40

20

0

L-235

Untreated

Structural decay

Treat

Steady state remodeling restored. Whether there is bone loss, no loss or gain depends on bone balance.

BMD

Perturbed Restored, same number, more shallow Steady State

BP = fewer, same depth?

Prox Femur Trab Bone

Veh 6 30 mg/kg

MS/

BS (%

)

MAR

(µm

/d)

B

FR (µ

m3 /

µm3 /

yr)

20

16

12

8

4

0

1.0

0.8

0.6

0.4

0.2

0

60

30

0

p values refer to difference relative to vehicle

Prox Femur Endocort Surface75

50

25

0

0.8

0.4

0

100

60

20

0 Veh 6 30 mg/kg

6

4

2

0

1.2

0.6

0

16

8

0Veh 6 30 mg/kg

Fem. Neck Trab Bone

Veh 6 30 mg/kg

Haversian Canal Surface25

20

15

10

5

0

1.5

1.0

0.5

0

100

50

0

p<0.05

p<0.05

p<0.001

p<0.001

p<0.005

p<0.005

p=0.05

p<0.01

p<0.01

p=0.05

p<0.05

30

20

10

0

0.3

0.2

0.1

0

30

20

10

0

50

25

0

0.8

0.4

0

120

60

0

Periosteal Surface Proximal Femur Femoral Neck

Vehicle

OD 30 mg/kg

p<0.05

p<0.01

p values refer to difference relative to vehicle

MS/

BS (%

)

MAR

(µm

/d)

B

FR (µ

m3 /

µm3 /

yr)

LS aBMD

0

6

8

10

12

4

2

--2

% C

hang

e

BL M6 M12 BL M6 M12-4

-2

0

2

4

6Total Hip aBMD

% C

hang

e

0

160

120

80

Time (h)

40

200

0 1 2 3 4 5 6 7 8

Inta

ct P

TH (m

g/L)

TERI

ALN

PBO

PBO

PBO

TERI

ALN

ALN

RONA

RONA

RONA

Fitzpatrick et al JBMR 2011

Ronacalerat – Ca Receptor Antagonist