biology and biomechanics of normal & osteoporotic bone · biology and biomechanics of normal...
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BIOLOGY and BIOMECHANICS OF NORMAL & OSTEOPOROTIC BONE
Andreas Panagopoulos, MD, PhDAssistant Professor in Orthopaedics
University Hospital of Patras, Orthopaedic Clinic
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Objectives
• Bone structure and physiology
• Remodeling and bone metabolism
• Factors affecting bone strength and quality
• Biomechanics and damage in osteoporosis
• Future research- conclusions
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2 important Mechanical Functions of Bone
- rigid skeletal framework that supports and protects other body tissues
- forms a system of rigid levers that can be moved by forces from the attaching muscles
- mineral storage
Outline
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Hierarchical structure
Seeman & Delmas
N Engl J Med 2006; 354:2250-61
Macrostructure
Microstructure
Matrix Properties
Cellular Composition and Activity
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Properties at the cellular, matrix,microarchitectural, and macroarchitectural levelsmay all impact bone mechanical properties
These factors are interrelated and co-acting
Therefore, one cannot expect that changes in asingle property will be solely predictive ofchanges in bone mechanical behavior
Bone function
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Lower strength and stiffness of osteoporotic bone
Mineral content slightly higher than that of normal bone
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When no changes in bonequality occur at 5 mm level,probably there are nochanges in lower scales also
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• collagen fibrils
• mineral plates
• non-fibrillar protein-based
organic matrix
Atomic Force Microscope
Bone “glue”
Bone building blocks
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Important cells
Bone Structural Units (BSU)
Basic Multicellular Units (BMU)
Bone remodeling
Basic regulator: osteocyte?
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Bone Structural Units (BSU)
BSU (osteons) is the structural end result of a focused bone renewal
Cortical bone: concentric rings (lamellae)
Cancellous bone: flat and stacked in saucer shaped depressions
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Basic Multicellular Units (BMU)
Under normal steady state conditions, the amountof bone removed is precisely replaced and there is no netchange in bone mass.Only bone architecture is changed
Cancellous BMU Cortical BMU
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OsteoclastsMonocytes
Pre-osteoblasts
Osteoblasts
Osteocytes
Bone remodeling cycle
FormationResorption
GM-CSFIL-1IL-6
RANKLPGE2
TNF-
Formation
OPGTGF-Estrogen
Resorption
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Osteocytes sensing and integrating mechanical andchemical signals from their environment to regulateboth bone formation and resorption.
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RANK Ligand is a Central Mediator in the Activation phase of bone remodeling
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Wnt-signal pathway in osteoblasts
Luck of Wnt pathway reducesthe amount of β-catenin in thecytoplasm due to highdegradation. As a result importantcontrol of protein transcription inosteoblasts is lost.
Wnt
LRP co-receptor
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Wnt pathway antagonists
• SFRP1
• WIF-1
• DKK-1
• Sclerostin
All act as inhibitors of LRP5/6
Reduction of osteoblastogenesis
OSTEOPOROSIS
Over-expression
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Osteocyte-driven bone resorption & formation
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Why Bone Remodels?
• Allows bone to respond to loads (stress)
• Maintain materials properties
• Allows repair of microdamage
• Participates in serum Ca2+ regulation
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This increase in RANKL signaling iscaused by the osteocyte apoptosis,not the bone microdamage itself
Osteoclasts are then recruited toresorb damaged and apoptoticosteocytes during the microdamagerepair process
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NO response of osteocytes in a mechanically loaded mouse fibula
Mechanically loadControl
deformation of load-bearingbone matrix and interstitialfluid flow around osteocytes
Osteocyte apoptosis (X) is caused by lack of fluid flow at the tip of the cutting cone,osteoclasts are attracted by apoptotic and RANKL producing osteocytes, and as a result,the cutting cone follows the loading direction.
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Load-carrying behavior of bone
the maximum load thematerial can sustain
the energy required to break the material
stored elastic energy
initial reaction to a load
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Bone is a highly heterogenous material, partially because it hasbeen adapted to resist different, complex and varying stresses
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cannot be measured non-invasively
used in clinical practice
used in clinical research
Determinants of fragility
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5 15 25 35 45 55 65 75 85
Bone throughout the lifespan
Age (Years)
Pubertal
Growth Spurt Menopause
BMD
Resorption
Formation
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Age-related modulation of the skeleton
intrinsic factors
genetics, peak bone mass hormonal changes (FSH, GH), levels of oxidative stress,free radical generationchanges in telomere length
extrinsic factors
nutritional habitslifestyle choiceslack of exercise
Aging
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analogous 3D quantification
loading >> stronger effect on formation thanon resorption of trabecular bone
increase of the formation surface withmechanical stimulation
the resorption thickness is independent of loading in trabecular bone in all age groups.
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Osteoporosis
reduction in bone mass, disruption in bone micro-architecture
“IMBALANCE” in bone remodeling
– Excessive RANKL/RANK signaling
– Inadequate OPG production
– Inadequate Wnt/LRP-5 activity
– “Excessive” inhibition of the pathway
CHANGES in BIOMECHANICAL STRENGTH FRACTURES
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Material Properties
• Mineral -Mineral-to-matrix ratio -Crystal size
• Collagen -Type -Cross-links
• Microdamage/microfracture
Bone Quality Framework
Structural Properties
• Geometry -Size -Shape
• Microarchitecture -Trabecular architecture -Cortical thickness/porosity
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McNamara L M J. R. Soc. Interface 2010;7:353-372
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how bone loss in osteoporosisalters bone mechanical strength?
Bone mass
Cancellous microarchitecture
Cortical microarchitecture
Porosity
Whole bone strength
Bone tissue properties
Sequence of events in the bone loss cascade
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Bone mass during osteoporosis
DEXA (preferred technology for quantifying BMD) quantitative computed tomography (QCT), absorptiometry, quantitative roentgen micro-densitometryquantitative ultrasound (QUS)
BMD do not fully explain susceptibility to bone fracture
(only 10–53% of bone fractures that occur in female post-menopausal patients over the age of 65 can be attributed to a BMD level low enough)
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Cancellous micro-architecture during osteoporosis
Bone histomorphomety - Stereology istypically used to characterize bonemicro-architecture by quantifying:
• cortical porosity,• cortical thickness,• trabecular number,• trabecular thickness• trabecular connectivity
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↑ Cortical Thickness (Ct.Th) ↑ Trabecular Number (Tb.N)
↑ Trabecular Thickness (Tb.Th)
Tb.Th = 1/Tb.S
↓ Trabecular Separation (Tb.Sp)
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trabecular thinning, thickening of remaining trabeculadeeper resorption cavities, micro-fracture loss of trabecular connectivity
fracture risk prediction is improved by approximately 13% as compared with BMD alone
Cancellous micro-architecture during osteoporosis
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Cortical micro-architecture during osteoporosis(41 iliac biopsies, age 19-90)
Age (years)
0
3
6
9
12
15
0 20 40 60 80
r = 0.78 P < 0.001
(%)
Brockstedt et al. Bone 1993; 14:681-91
4-fold increase in
cortical porosity from
age 20 to 80
Increased heterogeneity
with age
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Related changes in geometry
Adaptation to maintain whole bone strength
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Related changes in mechanical properties
-8%
-11%
-34%
Elastic modulus, E
Ultimate strength, S
Toughness
-64%
-68%
-70%
Bouxsein & Jepsen, Atlas of Osteoporosis, 2003
Cortical bone(% loss 30-80 yrs)
Cancellous bone(% loss 30-80 yrs)
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Related changes in bone strength
0
2000
4000
6000
8000
10000
Femoral neck(sideways fall)young
old
Courtney et al. J Bone Joint Surg Am. 1995; 77:387-95
Mosekilde. Technology and Health Care 1998; 6:287-97
Lumbar vertebrae(compression)
Wh
ole
bo
ne
stre
ngt
h (
New
ton
s)
youngold
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20-year-old 80-year-old
Age-related changes in femoral neck cortex and association with hip fracture
Those with hip fractures have:
• Preferential thinning of the inferior anterior cortex
• Increased cortical porosity
Bell et al. Osteoporos Int 1999; 10:248-57
Jordan et al. Bone, 2000; 6:305-13
Mayhew et al, Lancet 2005
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Bone tissue properties during osteoporosis
Organic phase (collagen, non-collagenous proteins andcells) accounts for 35% of bone mass and provides post-yield behaviour and strength
Mineral phase (calcium and phosphorus in the form ofhydroxyapatite crystals) allows the tissue to resistdeformation under applied loading, which is known asthe stiffness of the tissue
overall bone mass and BMD are reduced duringoestrogen deficiency, but the yield strength and elasticmodulus of the remaining tissue increased by 40–90% ofcontrol values
McNamara L. 2005. Musculoskelet. Neuronal Interact. 5, 342–343
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↓ elastic deformation capacity of the bone
↑ type I collagen synthesis
↓ VI and III collagen synthesis
↑ hydroxylation of lysine residues
increase fracture susceptibility by altering the
strength of the collagen network
Collagen
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Non Collagenous Proteins (NCPs)
- act as mineral crystal nucleation siteson the organic matrix
- indirectly regulate the mechanicalproperties of the collagen–mineralinterface
NCPs are altered during post-menopausal osteoporosis.
• Osteocalcin• Osteopontin• Osteonectin• Fibronectin• Thrombospondin-2
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NCPs influence bone fracture independently from bone mass.
play a significant role in the formation of specific morphologies of microdamage.
Nonenzymatic glycation is an important variable in analysis of bone’s fracture resistance, because it significantly alters bone’s organic matrix
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Mineral
conflicting data exist from previous studies; somestudies report a decrease in tissue mineral content andothers reveal an increase in the mineral content
These findings have been shown to differ for trabecularand cortical bone
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Decreased degree of mineralization
increased HA crystal size and perfection
- carbonate content is increased,
- acid phosphate content is decreased infrared imaging spectroscopy
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sequence of events in the bone loss cascade
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Updated Factors affecting fractures
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Future research and conclusions
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bone fracture during post-menopausal osteoporosis has not yet been eliminated.
Future research studies should include multi-disciplinaryanalyses at multiple time points to comprehensivelycharacterize the sequence of changes in molecularsignalling, cell physiology, tissue composition, micro-architecture, damage and bone mass.
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Improving fixation methodsin osteoporotic bones