june 2004 bone quality sourced from nih consensus development panel on osteoporosis. jama 285:...
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June 2004
Bone Quality
Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785-95; 2001
ArchitectureTurnover RateDamage AccumulationDegree of MineralizationProperties of the collagen/mineral matrix
June 2004
Bone Remodeling Process
ResorptionCavities
Bone
Osteoclasts
Lining Cells
Osteoblasts
Osteoid
Lining Cells
MineralizedBone
June 2004
High Bone Turnover Leads to Development of Stress Risers and Perforations
Stress Risers
Perforations
Bone
Osteoclasts
Fracture
BoneStrength
MaterialProperties
Remodeling
FallsShape &
Architecture Exercise & Lifestyle
Hormones
NutritionBone Mass
PosturalReflexes
Soft TissuePadding
Reproduced with permission from Heaney RP. Bone 33:457-465, 2003
Factors Leading to Osteoporotic Fracture: Role of Bone Remodeling
June 2004
June 2004
Consequences of an Imbalance in Bone Turnover
Normal BoneNormal Bone Osteoporotic BoneOsteoporotic BoneMechanism of Action Animation of Bone Remodeling Process, 2002, Eli Lilly & Company
Excessive suppression Increased mineralization
Accumulation Increased brittlenessof microcracks
Skeletal fragility
Excessive suppression Increased mineralization
Accumulation Increased brittlenessof microcracks
Skeletal fragility
• There is a complex relationship between bone turnover and bone quality
• A decrease of bone turnover increases mineralization and permits filling of remodeling space
Bone Turnover, Mineralization, and Bone Quality
June 2004
June 2004
Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and/or
Prolonging Mineralization
Antiresorptive Agent
Newly formed bone
Increased MineralizationRemodeling space
June 2004
Rate of Bone Turnover
Bone turnover is an essential physiological mechanism for repairing microdamage and replacing “old” bone by “new” bone.
Healthy bone is a living tissue.
Can excessive reduction in bone turnover be harmful for bone?
How much suppression is too much?
Clinical paradigm:
Clinical question:
June 2004
Changes in Biochemical Markers Predict an Increase in Bone Mineral
Density During Antiresorptive Therapy
• Treatment with antiresorptive agents produce greater proportional changes in bone turnover markers than in BMD
• Measurable changes in bone turnover markers tend to occur before changes in BMD
• There are significant correlations between changes in bone turnover markers and changes in BMD
Sourced from Looker AC et al. Osteoporos Int 11:467-480; 2000
June 2004
Bone Turnover Markers
• Bone turnover markers are components of bone matrix or enzymes that are released from cells or matrix during the process of bone remodeling (resorption and formation).
• Bone turnover markers reflect but do not regulate bone remodeling dynamics.
June 2004
Relationship Between Changes in Bone Resorption Markers and Vertebral Fracture Risk
VERT Study
• A decrease in urinary CTX and NTX at 3-6 months was associated with vertebral fracture risk at 3 years
• A decrease in urinary CTX >60% and of urinary NTX >40% gave little added benefit in fracture reduction
Sourced from Eastell R et al. Osteoporos Int 13:520; 2002
June 2004
Raloxifene and Alendronate Reduce Bone Turnover in Women with Osteoporosis
Sourced from Stepan JJ et al. J Bone Miner Res 17 (Suppl 1):S233; 2002
*p< 0.01 compared to premenopausal levels
Mean Serum CTX Mean Serum PINP
0
100
200
300
400
500
ALNRLX
*
PIN
P (
μg/
L) ±
1 S
D
CT
X (
ng/L
) ±1
SD
0
10
20
30
40
50
ALN RLX
*
Premenopausal†Premenopausal†
†The area between the dotted lines is + 2SD of the mean premenopausal value
June 2004
Effects of Raloxifene and Alendronate on Markers of Bone Resorption
C-Telopeptide/Creatinine Ratio
-100
-80
-60
-40
-20
0
20
40
60
Placebo
Raloxifene 60 mg/d
Alendronate 10 mg/d
Median % changeat 1 Year
*†
*
*†
% of Women Below Lower Limit
of Premenopausal Range (52 µg/mmol) at 1 Year
*p <0.05 vs. PL †p <0.05 vs. RLX
Sourced from Johnell O et al. J Clin Endocrinol Metab 87:985-992, 2002
June 2004
• Very low turnover leads to excessive mineralization and the accumulation of microdamage
• Very high turnover leads to accumulation of perforations and a negative bone balance
Bone Turnover Effects Bone Quality
-6
Effects of Raloxifene on Trabecular and Cortical BMD Measured by Spinal vQCT
MORE Trial - 2 Years
-4
-2
0
2
4
6
Mid Mid Total Total Total Mid Integral Cortical LumbarTrabecular Integral Trabecular Integral Integral Central Spine BMD
(g/cm 2)
†* * *
-4
-2
0
2
4
6
-4
-2
0
2
4
6
Mid Mid Total Total Total Mid Integral Cortical LumbarTrabecular Integral Trabecular Integral Integral Central Spine BMD
(g/cm 2)
†
†* * *
% C
hang
e of
BM
D
-4
-2
0
2
4
6
Mid Mid Total Total Total Mid Integral Cortical LumbarTrabecular Integral Trabecular Integral Integral Central Spine BMD
(g/cm 2)
†* * *
-4
-2
0
2
4
6
-4
-2
0
2
4
6
Mid Mid Total Total Total Mid Integral Cortical LumbarTrabecular Integral Trabecular Integral Integral Central Spine BMD
~AP DXA ~LAT DXA ~LAT DXA (g/cm 2)
Placebo Raloxifene (pooled)
*p value <0.05†p value <0.10*p value <0.05†p value <0.10*p value <0.05†p value <0.10*p value <0.05†p value <0.10
†
†* * *
June 2004Genant H et al. J Bone Miner Res 18(Suppl 2); S383, 2003
vQCT Volumetric quantitative computed tomographyDXA Dual x-ray absorptiometry
June 2004
Bone Quality
Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95, 2001
Architecture
Turnover Rate
Damage Accumulation
Degree of Mineralization
Properties of the Collagen/Mineral Matrix
Dogs Treated with High Doses of Bisphosphonates2
Mic
rocr
ack
Sur
face
Den
sity
(m
/mm
2 )M
ean
± S
EM
Placebo
Risedronate
Alendronate
20
15
10
5
0
***
*P<.05 vs placebo**P<.01 vs placebo1Reproduced with permission from Komatsubara S. J Bone Miner Res 18:512-520, 2003
2Reproduced with permission from Mashiba T et al. J Bone Miner Res 15:613-620; 2000
Bisphosphonates Increase Microcracks
Risedronate2
Alendronate2
Incadronate1
Beagle dogs treated 1 year with 6x the clinical dose
Beagle dogs treated 3 years with 2.5 xthe clinical dose
June 2004
June 2004Reproduced with permission from Mashiba T et al. Bone 28:524-531, 2001
Effects of Risedronate and Alendronate on Microcracks
Microcrack in the right femoral neck cortex from a risedronate treated dog
Microcracks in the third lumbar vertebral body from an alendronate treated dog
Risedronate Alendronate
June 2004
Effect of Long-Term Bisphosphonate Treatment - Incadronate
Reproduced with permission from Komatsubara S. J Bone Miner Res 18: 512-520, 2003
June 2004
Effects of Raloxifene on Microcracks in Monkey Vertebrae
Microcrack Surface Density
Sourced from Burr DB. Osteoporo Int 13, Suppl 3, S73-74; 2002
0
10
20
30
40
50
60
70
80
90
Ovx CEE Ralox 1 Ralox 2 Sham
**
*C
rack
Sur
face
Den
sity
(C
r.S
.Dn.
)
* p<0.05
CEE-conjugated equine estrogensRalox 1 – 1 mg/kgRalox 2 – 5 mg/kg
June 2004
Reproduced with permission from Seeman E. Advances in Osteoporotic Fracture Management 2: 2-8, 2002 and Fyhrie DP. Bone 15:105-109, 1994
Microdamage in Human Trabecular and Cortical Bone
June 2004
Bone Quality
Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95, 2001
Architecture
Turnover Rate
Damage Accumulation
Degree of Mineralization
Properties of the Collagen/Mineral Matrix
June 2004
Old bone
New bone~50% mineralized
Bone Mineralization of the Basic Multicellular Unit
Bone Mineralization of the Basic Multicellular Unit
Primary mineralization (3 months3 months)Secondary mineralization (years)
TimeTime
100 -
50 -
0 -De
gre
e o
f Min
era
lizatio
n (
%)
De
gre
e o
f Min
era
lizatio
n (
%)
Ott S. Advances in Osteoporotic Fracture Management 2: 48-54, 2003
Sourced from Ott S. Advances in Osteoporotic Fracture Management 2: 48-54, 2003
Primary mineralization (3 months3 months)
June 2004
-
De
gre
e o
fD
eg
ree
of M
iner
aliz
atio
nM
iner
aliz
atio
n(%
)(%
) -
De
gre
e o
fD
eg
ree
of M
iner
aliz
atio
nM
iner
aliz
atio
n(%
)(%
) 100
50
0Old bone
Ott S. Advances in Osteoporotic Fracture Management 2: 48-54, 2003
Bone Mineralization of the Basic Multicellular Unit
--
Primary mineralization (3 months)
Secondary mineralization (years)
Bone fullymineralized
June 2004
Homogeneous vs. Heterogeneous Mineralization
• “Microdamage progression is prevented by the roughness (or heterogeneity) of mineral densities and differing directions of mineralized collagen present.”
• “Cracks require energy to progress through bone, and when the mineral density is high and distribution of the tissue mineral density is homogeneous less energy (derived from deformation) is required for microdamage progression.”
Seeman E. Advances in Osteoporotic Fracture Management 2: 2-8, 2002
June 2004
Homogeneous vs. Heterogeneous Mineralization
Reproduced with permission from Boivin GY et al. Bone 27:687-694; 2000
Heterogeneous Homogeneous
Low mineralization
High Mineralization
June 2004
Heterogeneous Mineral Distribution in Iliac Bone
Reproduced with permission from Boivin GY et al. Bone 27:687-694; 2000
*Stiffness**Toughness
Reproduced with permission from Seeman E. Advances in Osteoporotic Fracture Management 2: 2-8; 2002 and Currey JD. J Biomechanics 12: 459-469; 1979
The Relationship Between Mineralization and Bone Strength is Complex
June 2004
63 65 67 69 71
25
20
15
10
6
Breaking Stress*
Ash Density (%)
kg
/mm
2
8
6
4
2
065 66 67 68
Ash Density (%)
Modulus of Impact**
June 2004
Distributions of Mineralization
Homogeneous Mineralization
Heterogeneous
Mineralization
June 2004
Alendronate Increases Bone Mineralization in Women with OsteoporosisTwo Years Three Years
0
5
10
15
20
Degree Mineralization of cancellous Bone (g. mineral/cm3 bone)
% o
f the
num
ber
of m
easu
rem
ents 15 PLA 2 yrs (N=11872)
9 ALN 2 yrs (N=6220)
Reproduced with permission from Boivin GY et al. Bone 27:687-694; 2000
.50
.60
.70
.80
.90
1.0
1.2
1.3
1.4
1.5
1.6
0
5
10
15
20
Degree Mineralization of cancellous Bone (g. mineral/cm3 bone)
% o
f the
num
ber
of m
easu
rem
ents 13 PLA 3 yrs. (N=12057)
16 ALN 3 yrs. (N=136313)
.50
.60
.70
.80
.90
1.0
1.2
1.3
1.4
1.5
1.6
June 2004
Baseline
Degree of Mineralization (g mineralization/cm3 bone)
Total Iliac Bone - Raloxifene 60 mg/dTotal Iliac Bone - Placebo
EndpointEndpoint
Baseline
% D
istr
ibu
tion
% D
istr
ibu
tion
Raloxifene Treatment Induces a Normal Pattern of Bone Mineralization
Sourced from Boivin G et al. J Clin Endocrinol Metab. 2003;88: 4199-4205.
Two-year treatment with raloxifene results in a heterogeneous mineral distribution with a modest increase in mineralization
Baseline
June 2004
Mineralization Distributions with Osteoporosis Agents: RLX Compared to
Placebo
Homogeneous bone Narrower curvehigher peak
Heterogeneous Bone Wider curve
Baseline MineralizationPlacebo – Ca
VitDraloxifene
Boivin GY et al. J Clin Endocrinol Metab 88:4199-4205, 2003
June 2004
Teriparatide Treatment Forms New Not Fully Mineralized Bone
Misof et al. J Clin Endocrinol Metab 88:1150-6, 2003
June 2004
Calcium Peak in Male and Female Patients Following Treatment with Intermittent PTH
Misof et al. J Clin Endocrinol Metab 88:1150-6, 2003
23.0
22.0
21.0
20.0
5
4
3
2
Ca Peak[wt%]
Ca Width[wt% Ca]
Cortical Cancellous Cortical CancellousBone Bone Bone Bone
Cortical Cancellous Cortical CancellousBone Bone Bone Bone
Male Patients Female Patients
Male Patients Female Patients
Before PTH
After PTD
June 2004
Overlaid Fluorescence Labeling Lines of Calcium Peak Widths Following Treatment
with Intermittent PTH
Misof et al. J Clin Endocrinol Metab 88:1150-6, 2003
Black Arrow–
Ca Peak was 18.19%White Arrow- Interstitial bone Ca Peak was 23.05%