1. The Negative BMU Balance Mean wall thickness (µm)
Women 20 40 60 80
Age (yr)
Ac. F /yr) 4 2 3 1
Remodeling rate
Vedi et al 1982
Erickson et al 1999
The Negative BMU Balance 10 50 90
Formation by BMU
Resorption by BMU
Lips et al 1979
Mean wall thickness (µm)
Three abnormalities compromise bone material and structure

2. Cort Trab 90% 45% 55% 10% 50-64 65-79 80+ Cort Trab
Perimeter available for remodeling (m)
2.5 2
Cort
1.5 1
Trab
0.5
<50
60-79
80 +
mgHA/yr
Age (yrs) 5
Amount of bone lost from the cortical and trabecular compartments 4
Cort 3 2
Trab
90% 1
45%
55%
10%
Zebaze et al 2010

3. The Four Envelopes of Bone
Periosteal
Intracortical
Endocortical
Trabecular

4. Treat BMD Higher density of a decreasing Bone Volume Untreated
Perturbed
Steady State
Restored, Slower
Higher density of
a decreasing
Bone Volume
BMD
Structure more compromised if a weaker remodeling suppressant used because residual tissue level remodeling with the negative BMU balance in more BMUS despite treatment decays bone
Untreated
Treat
Structural decay

5. Weiss et al Drug Metab Distribut 2006;36:2043
Trabecular Bone High Surface/Volume Configuration
Accessible to remodeling and treatment
C14 Zoledronic Acid Distribution
Tibia
Vertebrae
Skull
days 25 50 75
100 nmol/g
DRUG
Weiss et al Drug Metab Distribut 2006;36:2043

6. Cortical Bone Low Surface/Volume
Endocortical
surface
Less
Access

7. HORIZON-PFT Study 2301 Slide Library
Bone 49 (2011) 128–132
HORIZON-PFT Study 2301 Slide Library
V3 1-May-07
BP on bone surfaces
Weeks
High Affinity ALN 2.4
Low affinity RISED 1.2
-20
-40
-60
-80
L4 trabec BFR % control
Mararachia et al Bone 1996;19:281
Allen et al Bone 2011;49:128
CONFIDENTIAL

8. Penetration into Bone Matrix
High Affinity Compound
Low Affinity Compound
Turek et al Calcif Tissue Int 2012;90:202

10. Mice constitutively activated PTH/PTHrP receptor have high porosity
Cortical porosity (%)
Cortical vBMD
(mg/cm2)
1350
1250
1150 \
1050
OPG
ALN
ZOL
Vehicle
Cortical porosity
(%) 6 4 2
***
OPG
ALN
ZOL
Vehicle
Toughness (MPa)
Cortical porosity (%) 15 10 5
OPG**
ALN
ZOL
Vehicle
OPG** 8 6 4 2
Cortical porosity (%)
Femur energy to failure (Nmm)
**relative to vehicle
ALN
ZOL
Vehicle
Ohishi et al Am J Pathol 2009;174:2160

11. Antiresorptive Therapies and the Surface Extent of Remodeling Reflected in the Mineralizing Surface MS/BS (%) 10
Normal mg
Bone H et al JBMR 2010
Placebo
Odanacatib 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
L-235 % 8 6 4
Ris
Ibn
Zol
Aln
DMab 2
Recker JBMR 1988;31:133
Eriksen Bone 2002;31:620
Chavassieux JCI 1997;100:1475
Recker OI 2004;15:231
Recker JBMR 1008;23:6
Reid JBMR 2010

12. Restored, same number, more shallow
BP = fewer, same depth?
Steady State
Perturbed
Restored, same number, more shallow
BMD
Steady state remodeling restored.
Whether there is bone loss, no loss or gain depends on bone balance.
Structure more compromised if a weaker remodeling suppressant used because residual tissue level remodeling with the negative BMU balance in more BMUS despite treatment decays bone
Untreated
Treat
Structural decay

13. 20 16 12 8 4
Prox Femur Trab Bone
Prox Femur Endocort Surface 75 50 25
0.8
0.4
100 60 20
Veh mg/kg 6 4 2
1.2
0.6 16 8
Veh mg/kg
Fem. Neck Trab Bone
Veh mg/kg
Haversian Canal Surface 25 20 15 10 5
1.5
1.0
0.5
p=0.05
MS/BS (%)
p<0.001
p<0.01
p<0.005
1.0
0.8
0.6
0.4
0.2
p<0.05
MAR (µm/d) 60 30
Explain terms
In the trab cpt at the PF reduction in remodelling intensity in the Rx gp cf vehicle which reached sig in 30mg/kg gp
While for MAR there was a reduction only in the 6mg/kg gp
This leads to reduced BFR in both Rx groups
6mg/kg group due to reduced MAR
30mg/kg group due to reduced remodelling intensity
100 50
p<0.05
BFR (µm3/µm3/yr)
p=0.05
p<0.001
p<0.005
p<0.01
Veh mg/kg
p values refer to difference relative to vehicle 13

14. Vehicle OD 30 mg/kg 0.8 0.4 Periosteal Surface
Proximal Femur Femoral Neck 30 20 10 50 25
Vehicle
MS/BS (%)
0.8
0.4
p<0.05
0.3
0.2
0.1
MAR (µm/d)
OD 30 mg/kg 30 20 10
120 60
p<0.01
p<0.05
BFR (µm3/µm3/yr)
p values refer to difference relative to vehicle 14

15. Ronacalerat – Ca Receptor Antagonist6 8 10 12 4 2
--2
% Change BL M6
M12 BL M6
M12 -4 -2 2 4 6
LS aBMD
Total Hip aBMD
% Change
TERI
TERI
ALN
ALN
PBO
RONA
RONA
PBO
160
120 80
Time (h) 40
200 1 2 3 4 5 6 7 8
Intact PTH (mg/L)
Sept 3rd:
MW Comments: Verifying Data.
RONA
ALN
PBO
Fitzpatrick et al JBMR 2011