women 20406080 age (yr) ac. f /yr) 4 2 3 1 0 remodeling rate vedi et al 1982 erickson et al 1999 the...
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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
)
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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
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Periosteal
The Four Envelopes of Bone
Trabecular
Endocortical
Intracortical
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Untreated
Structural decay
Treat
BMD
Perturbed Steady State Restored, Slower
Higher density ofa decreasingBone Volume
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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
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Endocortical surface
Less Access
Cortical Bone Low Surface/Volume
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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
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Penetration into Bone Matrix
Turek et al Calcif Tissue Int 2012;90:202
High Affinity Compound Low Affinity Compound
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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
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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
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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?
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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
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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)
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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