Biology of Fracture Healing Flashcards
(131 cards)
1
Q
osteoporosis
A
loss of bone bass, often associated with menopause and/or aging
2
Q
who does osteoporosis affect
A
women and men
3
Q
osteoporosis is a major medical problem due to (3)
A
aging population, diet, environmental factors
4
Q
Osteoporosis definition -
A
a patient with a BMD
>2.5 standard deviations below average for a
healthy young female or male.
5
Q
those with osteoporosis have an increased susceptibility to
A
fracture
causes ?8.9 million fractures annually
6
Q
Worldwide, — women and — men over 50
will experience osteoporotic fractures
A
1 in 3
1 in 5
7
Q
Hip fractures associated with mortality rates of up
to
A
20-24% in first year after fracture. Greater risk
of dying may persist for at least 5 years
8
Q
In Osteoporosis Bone Formation Can’t Keep up
With
A
Bone Destruction and we Lose Bone (Remo
9
Q
Oral bisphosphonates widely used for treatment of
A
osteoporosis
anti-resorptives
10
Q
I.V. bisphosphonates used for treatment of
particularly if…
A
myeloma/ bone metastatic cancers (e.g. breast, prostate, lung),
particularly if patients have high serum calcium
11
Q
Doses used for — treatment often much higher than those used for —
A
cancer
osteoporosis
12
Q
Bisphosphonates =
A
non-hydrolyzable analogs of
pyrophosphate (PPi) – inhibit mineralization similarly to PPi
13
Q
bisphosphinates have a high affinity for
A
hydroxyapatite
14
Q
BONJ
A
Bisphosphonate Associated Osteonecrosis of the Jaw
15
Q
Vast majority in patients with myeloma/bone metastatic cancers on
A
i.v. bisphosphonates (esp. zoledronate and other N-containing BP’s)
16
Q
Prevalence = –% in cancer population on BPs
A
2-3
17
Q
Prevalence in oral BP (osteoporosis patients) = –%
A
0.1-0.5
18
Q
BONJ affects the (2)
A
maxilla or mandible
19
Q
BONJ definition (American Association of Oral and Maxillofacial Surgeons [AAOMS]): (3)
A
(1) current or previous treatment with a bisphosphonate
(2) exposed, necrotic bone in the maxillofacial region that has been
present for at least 8 weeks
(3) no history of radiation therapy to the jaws
20
Q
BONJ Pathogenesis
A
Not fully understood, but attributed mainly to suppression
of bone turnover due to BP inhibition of osteoclast activity
21
Q
With osteoclast inhibition, bone may be unable to
A
repair in response to trauma
22
Q
BPs may also have — effects on epithelia
A
inhibitory
23
Q
Bisphosphonates may also have an inhibitory effect on
A
orthodontic tooth movement
24
Q
Bone formation during fracture healing recapitulates processes of
A
embryonic bone formation
25
Four Phases of Skeletal Development
1. Migration of preskeletal cells to sites of future
skeletogenesis
2. Interaction of these cells with epithelial cells
3. Interaction leads to mesenchymal condensation
4. Followed by differentiation to chondroblasts or
osteoblasts
26
Endochondral Bone Formation is ---
indirect
27
Indirect in endochondral bone formation because
mesenchyme forms cartilage template first, which is later replaced by bone
28
where does endochondral bone formation occur?
in most bones in the skeleton
| esp bones that ear weight and have joints
29
endochondral bone formation also occurs during
fracture repair
30
Intramembranous Bone Formation is ---
direct
31
intramembranous bone formation is direct because it involves
transformation of mesenchymal cells to osteoblasts (no cartilage intermediate)
32
where does intramembranous bone formation occur? (3)
restricted to cranial vault, some facial bones, parts of the mandible and clavicle
33
intramembranous bone formation contributes to
fracture repair
34
in endochondral bone formation (typically long bone)
Growth plate fusion occurs around age ---
in humans depending on the (2)
14-20
| specific bone and the gender of the individual
35
in endochondral bone formation (typically long bone)
| Vascular endothelial growth factor (VEGF) produced by hypertrophic chondrocytes attracts
blood vessels that invade the cartilage model
36
in endochondral bone formation (typically long bone)
| Secondary ossification center appears around the time of ---
birth
37
in intramembranous bone formation, mesenchymal cells condense to produce ---, which
```
osteoblasts
deposit osteoid (unmineralized) bone matrix
```
38
in intramembranous bone formation, osteoid matrix calcifies/osteoblasts become arranged along
calcified region of the
matrix
39
some osteoblasts trapped in bone matrix, which become
osteocytes
40
First type of bone produced developmentally =
Woven Bone (a.k.a. Primary Bone) (immature)
41
when is woven bone produced?
when osteoblasts need to form bone rapidly
42
examples of when woven bone is formed (3)
embryonic development
fracture healing
disease states (ex pagets disease)
43
Immature woven bone then remodeled and replaced with
Lamellar Bone (a.k.a. Secondary Bone) (mature)
44
woven bone (4)
```
•Disorganized structure
•Collagen fibrils in random
orientation (lower
birefringence w/ polarized
light)
•Increased cell density
•Reduced mineral content
```
45
lamellar bone (4)
```
•Highly organized
•Bone lamellae concentrically
arranged around central canal
(Haversian canal) containing
blood vessels, nerves.
•Collagen fibrils in parallel
orientation (more birefringence
w/ polarized light)
•Mechanically stronger
```
46
Secondary bone = further classified into (2)
Compact (cortical) Bone and Cancellous (trabecular/spongy) Bone
47
Compact
cortical/
| Haversian
48
Cancellous
spongy/
| trabecular
49
Skeletal healing essential for: (3)
•Resolution of orthopedic trauma that has
caused fractures
•Healing of corrective surgeries where bony
injuries are created intentionally to correct
bone deformities, etc
•Bone regeneration in oral surgical
procedures/tooth extractions, etc.
50
```
Development of new treatments to promote
healing of (3)
```
fibrous non-unions,
critically sized defects,
conditions of impaired healing.
51
Failed/delayed healing affects up to --% of
| fracture patients seen clinically
10
52
Can result from inadequate (6)
```
fixation,
infection,
tumor,
hypoxia/poor blood supply,
metabolic dysfunction,
chronic diseases/inherited diseases
```
53
Fracture Healing Requires Coordinated
| Activity of Several Cell Types: (5)
* Inflammatory Cells
* Chondroprogenitors/chondrocytes
* Osteoprogenitors/osteoblasts
* Osteoclasts
* Vascular cells
54
Inflammatory (Reactive) phase:
peaks by 48h and is
| diminished by 1 week
55
Reparative phase:
activated within a few
days and persists for
up to 2-3 months
56
Remodeling phase:
can continue for
| several years
57
```
John Hunter (1935) - Described 4 stages of
fracture repair:
```
reactive: 1) Formation of vascular hematoma
reparative: 2) Formation of (fibrocartilage)
callus
repairative: 3) Tissue metaplasia – callus
replaced by mineralized bone
remodeling: 4) Bone remodeling and turnover
58
Fracture trauma causes
bleeding/formation of hematoma at injury site
59
Hematoma-associated cytokines
| released: (2)
Tumor necrosis factor-α (TNF-α )
| Interleukins (IL-1,-6, -11 and -18)
60
Cytokines lead to recruitment/infiltration
| of
inflammatory cells
61
Inflammatory cells release more --- and recruit --- to fracture site
inflammatory cytokines
| mesenchymal stem cells (MSC)/osteogenic precursors
62
Hematoma Formation/Inflammation occurs within
0-2 days
63
MSC/connective tissue stem cells/blood
| vessels invade ---
hematoma
64
Hematoma ---/Phagocytes
| clear ---
degenerates
| debris
65
Fibrous connective tissue matrix laid
| down by
fibroblasts (granulation tissue)
66
Some MSC differentiate toward --- lineages
chondrogenic/osteogenic
67
At broken ends of bones where blood
| supply was disrupted --- occurs
hypoxia/ tissue necrosis
68
In hypoxic regions MSC differentiate into
| --- which initiates ---
chondrocytes
| endochondral bone formation
69
Intramembranous bone may form in
subperiosteal sites where vascular supply
is intact =
hard (external) callus
70
formation of fibrocartilagenous callus takes
~1 week
71
Cell sources (4)
- Periosteum
- Muscle
- Bone Marrow
- Circulating?
72
Cell types (3)
- Mesenchymal Stem Cell (MSC)
- Pericyte
- Muscle satellite cell
73
```
Intramembranous bone (formed where
vascular supply intact) contributes to
```
bony
| callus
74
Cartilage undergoes --- ---
endochondral
| ossification
75
endochondral
| ossification
hypertrophy>calcification of
cartilage>removal by osteoclasts>
replacement with bone
76
Fracture considered healed when
bone stability restored by bone tissue
completely bridging the original fracture
(“clinical union”)
77
Initial bone formed =
woven bone
78
Formation of Bony Callus takes
~several weeks up to 2-3 months
79
Initial woven bone must be ---
remodeled
80
Osteoclasts resorb woven bone in
fracture callous then osteoblasts lay
down new lamellar bone (Haversian) =
mechanically stronger
81
remodeling restores
marrow cavity
82
remodeling resortes
original contours of bone
83
Biomechanical stability matches that of
| the --- bone
original
84
Same sequence of fracture healing events
| occurs for
healing of alveolar bone in
| tooth socket after tooth extraction
85
remodeling takes
~several weeks/months/years
86
Gene expression profiles/signaling molecules important during
fracture healing
87
Fracture healing includes (4)
inflammation,
endochondral bone formation,
intramembranous bone formation,
osteoclastic bone resorption
88
Gene expression profile =
--- dependent
reflective of these ---
stage dependent
| and reflective of these processes
89
Early Phases of Fracure Healing Include: (5)
* Formation of hematoma
* Recruitment of MSC
* Cell proliferation
* Initiation of chondrogenesis/osteogenesis
* Vascular ingrowth/angiogenesis
90
Signaling Molecules Important in
Fracture Healing:
3 Main categories:
* Pro-inflammatory cytokines
* TGFβ superfamily members
* Angiogenic factors
91
pro-inflammatory cytokines (4)
− Recruit other inflammatory cells/ promote MSC
recruitment
− Induce apoptosis of hypertrophic chondrocytes
− Recruit fibrogenic cells/promote formation of
granulation tissue/ECM formation
− Can promote osteoclast formation
92
pro inflammatory cytokines are secreted by (3)
macrophages,
mesenchymal cells,
inflammatory cells
93
Mice null for TNF-α receptor show impaired
fracture healing
94
Pro-Inflammatory Cytokines (2)
Tumor necrosis factor-α (TNF-α)
| Interleukins (IL-1,-6, -11 and -18)
95
TGFβ Superfamily Members (3)
Transforming growth factor-β (TGFβ)
Bone morphogenetic protein-2 BMP2 (also 5,6)
Growth and differentiation factor-8 (GDF-8)
96
TGFβ Superfamily Members promote (3)
− Promote ECM synthesis & assembly/initiation of callus formation
− Promote osteogenic differentiation
− GDF-8 – role in cell proliferation
97
TGFβ Superfamily Members produced by (4)
hematoma (platelets)/
granulation tissue/
differentiating MSC/
periosteal callus
98
angiogenic factors (3)
VEGF - Vascular endothelial growth factor
PDGF - Platelet derived growth factor
ANGPT - Angiopoietin
99
Promote vascular ingrowth from vessels in
periosteum (brings oxygen/osteogenic precursors [pericytes])
100
VEGF:
−promotes --- of osteoprogenitors
−upregulated in regions of --- (under control of
transcription factor HIF1α)
−--- overexpressing mice show enhanced bone
regeneration (Wan et al 2008: PNAS 105:686-91)
chemotaxis
hypoxia
HIF1α
101
Vascularization is critical for
fracture repair/bone formation
102
vascularization brings in (2) for mineralization
calcium and phosphate
103
Factors regulating other aspects of fracture
| healing: (3)
* Osteoblastic bone formation
* Osteoclastic bone resorption
* Cartilage formation
104
Fracture stability (mechanical environment) dictates the type of --- that will occur
healing
105
--- --- determines mechanical strain in fracture site
Mechanical stability
106
If strain <2% --- --- --- will occur
intramembranous bone healing
107
If strain is >2% <10% --- --- --- will occur
endochondral bone healing
108
High strain >15% promotes --- ---
fibrous tissue
109
Healing may occur as combination of the above processes depending on
stability throughout the fracture healing process
110
Important to stabilize fracture, but still have some strain on the bone, as zero mechanical loading can
delay healing
111
Bone Repair Could be Enhanced by: (4)
* Improving vascularization
* Attracting progenitor cells
* Accelerating bone formation
* Accelerating remodeling
112
BMPs (recombinant) are evaluated in
preclinical and clinical trials
113
BMPs appear to be an effective alternative to
autologous bone graft for repair of fracture non union/open tibial fractures
114
Controversy about clinical use of BMPs due to (2)
cost
| effectiveness and potential safety drawbacks
115
Platelet Rich Plasma contains
multiple growth factors
116
Platelet Rich Plasma is evaluated in
preclinical and clinical trials
117
Platelet Rich Plasma also appears to be effective in
promoting bone healing
118
FGF signaling also important in (2)
skeletal development/fracture healing
119
--- – shown to enhance
fracture healing in various in vivo experiments
dating back to 1990s
FGF2 (a.k.a. basic FGF)
120
But – continued elevation of FGF2 may impair
mineralization, so --- of treatment needs to be
optimized
timing
121
--- is also promising in preclinical studies
PDGF
123
cell based therapies (2)
Autologous bone marrow
Purified stem cell sources (MSC-mesenchymal
stem cells, EPC - endothelial progenitor cells)
124
Combining these growth factors with --- --- --- may lead to further improvements
tissue engineering techniques
124
cell based therapies (2)
Autologous bone marrow
Purified stem cell sources (MSC-mesenchymal
stem cells, EPC - endothelial progenitor cells)
125
Autologous bone marrow – collected from
iliac crest/injected into non-union site (increases #
| of progenitor cells)
126
cell based therapies (2)
Autologous bone marrow
Purified stem cell sources (MSC-mesenchymal
stem cells, EPC - endothelial progenitor cells)
127
other approaches (3)
* Anti-resorptives (bisphosphonates, denosumab)
* Bone anabolic agents (sclerostin Abs, teriparitide)
* (Gene therapy) – [still experimental]
128
Sclerostin =
inhibitor of Wnt/β-catenin signaling
| important pathway for bone formation
129
Antibodies to sclerostin being developed as
anabolic treatment for osteoporosis (in clinical
| trials)
130
sclerotin is also evaluated in
fracture healing preclinical models – results very promising
131
sclerostin Abs enhanced bone regeneration in rat model of ---
periodontitis
