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80. 60. 40. 20. Resorption by BMU. Formation by BMU. 80 60 40 20 0. Mean wall thickness (µm). Mean wall thickness (µm). Age (yr). 0. 10. 50. 90. Age (yr). 20 40 60 80. Erickson et al 1999. Lips et al 1979. 4. Remodeling rate.

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80

60

40

20

Resorption by BMU

Formation by BMU

80

60

40

20

0

Mean wall thickness (µm)

Mean wall thickness (µm)

Age (yr)

0

10

50

90

Age (yr)

20 40 60 80

Erickson et al 1999

Lips et al 1979

4

Remodeling rate

The Negative BMU Balance

Women

3

Ac. F /yr)

2

1

0

Vedi et al 1982

Age (yr)

20

40

60

80


Perimeter available for remodeling (m)

2.5

2

Cort

1.5

1

Trab

0.5

0

0

<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%

45%

55%

1

10%

0

50-64 65-79 80+

Zebaze et al 2010


The Four Envelopes of Bone

Periosteal

Intracortical

Endocortical

Trabecular


Restored, Slower

Steady State

Perturbed

Higher density of

a decreasing

Bone Volume

BMD

Untreated

Treat

Structural decay


Trabecular Bone High Surface/Volume Configuration

100 nmol/g

Accessible to remodeling and treatment

C14Zoledronic Acid Distribution

75

Vertebrae

50

Tibia

DRUG

25

Skull

0

--16 16 48 80 112 144 176 208 240

days

Weiss et al Drug MetabDistribut 2006;36:2043


Cortical Bone Low Surface/Volume

Endocortical

surface

Less

Access


Bone 49 (2011) 128–132

BP on bone surfaces

0

-20

-40

-60

-80

High Affinity ALN 2.4

L4 trabec BFR % control

Low affinity RISED 1.2

1-2 2-3 3-4

Weeks

Mararachia et al Bone 1996;19:281

Allen et al Bone 2011;49:128


Penetration into Bone Matrix

High Affinity Compound

Low Affinity Compound

Turek et al Calcif Tissue Int 2012;90:202


Mice constitutively activated PTH/PTHrP receptor have high porosity

1350

1250

1150

\

1050

Cortical porosity

(%)

Cortical vBMD

(mg/cm2)

6

4

2

0

OPG

Vehicle

ALN

ZOL

ZOL

Vehicle

ALN

***

OPG

0 2 4 6 8

Cortical porosity (%)

Femur energy to failure (Nmm)

8

6

4

2

0

OPG**

Toughness (MPa)

15

10

5

0

OPG**

**relative to vehicle

ALN

ALN

ZOL

ZOL

Vehicle

Vehicle

0 2 4 6 8

0 2 4 6 8

Cortical porosity (%)

Cortical porosity (%)

Ohishi et al Am J Pathol 2009;174:2160


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

10

Normal

10

L-235

BFR/BS Vertebral Cancellous Bone, rabbits

%

Odanacatib

120

100

80

60

40

20

0

%

8

Ovx+L-235

2 mg/kg

10 mg/kg

8

Ovx

6

6

Ovx+ALN

*Sham

4

4

Ris

Ibn

Zol

Aln

DMab

2

2

0

3 10 25 50 mg

Placebo

0

Pennypacker et al JBMR 2011

Bone H et al JBMR 2010

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


BP = fewer, same depth? porosity

Steady State

Perturbed

Restored, same number, more shallow

Steady state remodeling restored.

Whether there is bone loss, no loss or gain depends on bone balance.

BMD

Untreated

Treat

Structural decay


Prox porosity Femur Endocort Surface

20

16

12

8

4

0

Prox Femur Trab Bone

Haversian Canal Surface

Fem. Neck Trab Bone

6

4

2

0

75

50

25

0

25

20

15

10

5

0

p=0.05

MS/BS (%)

p<0.001

p<0.01

p<0.005

0.8

0.4

0

1.0

0.8

0.6

0.4

0.2

0

1.2

0.6

0

1.5

1.0

0.5

0

p<0.05

MAR (µm/d)

60

30

0

100

60

20

0

16

8

0

100

50

0

p<0.05

BFR (µm3/µm3/yr)

p=0.05

p<0.001

p<0.005

p<0.01

Veh 6 30 mg/kg

Veh 6 30 mg/kg

Veh 6 30 mg/kg

Veh 6 30 mg/kg

p values refer to difference relative to vehicle


30 porosity

20

10

0

Periosteal Surface

Proximal Femur Femoral Neck

50

25

0

Vehicle

MS/BS (%)

0.8

0.4

0

0.3

0.2

0.1

0

p<0.05

MAR (µm/d)

OD 30 mg/kg

30

20

10

0

120

60

0

p<0.01

p<0.05

BFR (µm3/µm3/yr)

p values refer to difference relative to vehicle


Ls abmd

Ronacalerat porosity– Ca Receptor Antagonist

LSaBMD

Total Hip aBMD

% Change

TERI

12

TERI

6

ALN

10

ALN

PBO

4

8

RONA

2

% Change

6

RONA

PBO

4

0

2

-2

0

200

-4

--2

160

BL

M6

M12

BL

M6

M12

RONA

120

Intact PTH (mg/L)

80

ALN

40

PBO

0

0

1

2

3

4

5

6

7

8

Time (h)

Fitzpatrick et al JBMR 2011


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