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Roadmap to Active Healing
Indications*
The EXOGEN® Ultrasound Bone Healing System, is indicated for the
non-invasive treatment of established non-unions† excluding skull
and vertebra.
In addition, EXOGEN is indicated for accelerating the time to a healed
fracture for fresh, closed, posteriorly displaced distal radius fractures and
fresh, closed or Grade I open tibial diaphysis fractures in skeletally
mature individuals when these fractures are orthopedically managed by
closed reduction and cast immobilization.
There are no known contraindications for the EXOGEN device. Safety
and effectiveness has not been established for individuals lacking
skeletal maturity; pregnant or nursing women; patients with cardiac
pacemakers; on fractures due to bone cancer; or on patients with poor
blood circulation or clotting problems. Some patients may be sensitive to
the ultrasound gel.
A non-union is considered to be established when the fracture site
shows no visibly progressive signs of healing
EXOGEN is a registered trademark of Bioventus LLC
Customers Categories
Title
Description
Usage
Number
EXOGEN
Users
Use EXOGEN regularly and
appropriately
2.5
units/month
350
EXOGEN
Dabblers
Use EXOGEN as their BGS of
choice, but only as for “last
resort” cases
1 unit/2
months
7,800
Spreaders
Use whatever BGS is available.
They are all the same
Variable
9,300
E-Stim
users
Use only E-stim.
Variable
8,000
1.8%
13.1%
26.3%
27.2%
31.6%
Non BGS
users
Haven’t prescribed in last 2
years.
Zero
3,900
Each territory has on average 30+ dabblers.
Each dabbler converted to a “user” is worth $60k per year
Potential is therefore $1.8m per rep or $450m nationally
How can you use EXOGEN science to realize some of this potential?
But….Don’t Forget The Spreaders
You have the key messages and tools with which to convince them:
• Unique Technology
• 86% non-union heal rate1
• Only product approved to accelerate the healing of indicated* fresh
fractures
• Only 20 minutes per day
• Peer to peer dialog is key
• Ideal targets for Science Summits and/or local surgeon speaker
meetings
1. Nolte PA, van der Krans A, Patka P, Janssen IM, Ryaby JP, Albers GH. “Low-intensity pulsed ultrasound in the treatment of nonunions.” J
Trauma. 2001;51(4):693-703.
EXOGEN Dabblers
Assumptions
You know your key clinical information
• Heckman, Kristiansen, Nolte, Gebauer, Cook..
You know where to find scientific information
• MOA brochure, Exopedia, sales sheets….
You know the support you have in addition
• Science summits, local meetings (surgeon speakers or Chris)
You are not totally comfortable with when and how to use the science
and when to use the additional support
Process
Meeting
• Run through key science papers
• Discuss when to use
• Demonstrate how to use
• Provide a Roadmap to guide you
• Role play at District Breakout meeting
Post Meeting
• Provide a new White Paper (coming soon) which contains and
explains the new (and old) evidence
• Reps – Identify Dabbler physicians
• Reps/DOSs – Target strategic physicians
• Use provided information
• Use additional resources – Scientific liaison, Science Summits,
Regional speakers
Assumptions
You have convinced them sufficiently that when they decide they need
a bone stimulator they turn to EXOGEN
They don’t understand the product well enough for EXOGEN to be front
of mind when planning treatment
• Surgery is the main consideration
• Biologics mean bone graft, growth factor, stem cell, etc.
Dabblers
Roadmap to Becoming Users
Risk Factors
• Age
• Diabetes
• Smoking
• Osteoporosis
Non-Unions
• Hypertrophic
• Atrophic
Patient Factors:
Fracture Factors: • Comorbidities
• Bone and location
• Lifestyle (e.g. smoking)
• Fracture type and
• Medications
severity
• Soft tissue damage
(Surgical) Technique:
• Reduction
• Stabilization
• Gap filling
• Soft tissue repair
Not Healed
Healed
Often Sufficient
Not Healed
Healed
Sometimes
Enough
Risk
FactorsNot
Lead
to:
FractureUnion
too severe
• • Delayed
Patient factors can’t
• • Non-Union
be addressed by
surgery alone
Not Healed
Healed
Add something to help:
• Bone graft
• Growth Factor
• Stimulation
Not Healed
Healed
EXOGEN
May Help Tip the
Balance
Not Healed
Healed
Risk Factors
Question
Which of these risk factors is most commonly
thought of as a reason to use bone growth
stimulation?
1.
2.
3.
4.
Osteoporosis
Smoking
Advanced age
Diabetes
US
Points allocated
Surgeon view on factors impacting the decision
to use a bone healing adjunct
Q19. Think of the characteristics of all of your fracture patients. Then, please allocate 100 points across the listed characteristics based on their importance in your decision to
treat with non-invasive bone stimulation. The more points you allocate, the more important that characteristic is to you.
DOF 12000.22
17
US
Many of these are patient factors (green) not fracture factors (orange)
Points allocated
The remainder are the key fracture factors for which an adjunct
to surgery may be required
Q19. Think of the characteristics of all of your fracture patients. Then, please allocate 100 points across the listed characteristics based on their importance in your decision to
treat with non-invasive bone stimulation. The more points you allocate, the more important that characteristic is to you.
DOF 12000.22
18
Risk Factors
• Age
• Diabetes
• Smoking
• Osteoporosis
Question
Which of these molecules is an (upstream)
signaling molecule that can lead to up-regulation of
the others?
1.
2.
3.
4.
Alkaline Phosphatase
COX2
VEGF
BMP2
Clinical & Pre-Clinical
Age – The Problem
• Increasing age is a risk factor for
fracture union1,2
• Older animals produce less
*
COX23
• Reduced COX-2 expression in aged
mice is associated with impaired
fracture healing as seen with
reductions in mineral and vascular
volume at the fracture site3
p < 0.02
mRNA levels of COX2 in young (Open bars)
and old (Filled bars) in mice
* p < 0.05 3
1. Heckman et al. 1994. Journal of Bone and Joint Surgery 76A:26–34.
2. Heckman and Sarasohn-Kahn. 1997. Bulletin Hospital Joint Diseases 56(1):63–72.
3. Naik et al., J Bone Miner Res. 2009 Feb;24(2):251-64
Clinical
Age – The EXOGEN Effect
* p < 0.02
p < 0.0001
***
84 days
≤ 30
(n=12)
*
(n=18)
33% Acceleration
LIPUS
Placebo
126 days
84 days
(n=21)
≥ 30
>30
Patient age (years)
42 days
103 days
***
45% Acceleration
187 days
(n=15)
0
30
60
90
120
Days to healing
150
180
• Older patients are at increased risk of delayed fracture healing
• EXOGEN lessened the effect of this risk
Heckman et al. 1994. Journal of Bone and Joint Surgery 76A:26–34.
Heckman and Sarasohn-Kahn. 1997. Bulletin Hospital Joint Diseases 56(1):63–72.
210
In Vivo
Age – The EXOGEN Effect
Day
Day
10
10
14
21
21
28
8 week old mice
•
•
40 week old mice
40 week old mice
with EXOGEN
Older animals are at increased risk of delayed fracture healing
EXOGEN lessened the effect of this risk Radiographs of 8 week old mice were taken in situ,
Katano et al., Exp Anim. 2011;60(4):385-95
while the radiographs of the 40 week old mice were
taken after excision.
Therefore the internal fixation has been removed in the older mice
In Vitro
The EXOGEN Effect – A Possible Explanation
EXOGEN increased COX2 production in osteoblasts, a key fracture
healing factor that is compromised in older animals
Tang Mol Pharmacol. 2006 Jun;69(6):2047-57
Age – Summary
• Age is associated with slower healing
• EXOGEN has been shown, in-vivo and clinically, to reduce this
effect
• Age is related to lower COX-2 production, a factor which EXOGEN
has been shown to upregulate
EXOGEN treatment lessened the effect of age on healing possibly
through counteracting reduced COX2 expression
Diabetes – The Problem
• Patients with diabetes mellitus (DM) have many problems healing
tissues including fracture
• One factor linked to healing problems in diabetics is vascular
insufficiency
Clinical
Diabetes – The EXOGEN Effect
Post marketing data on non-union fractures
• In patients with diabetes the heal rate was 84.2% (n=181/215)
compared to 84.4% (n=3,141/3,722) for all fractures
DOF 12000.01
Question
What is angiogenesis?
1.
2.
3.
4.
The ability of cells to migrate to the fracture
The formation of new blood vessels
The formation of bone without cartilage
The process how bone remodels
In Vivo
The EXOGEN Effect – A Possible Explanation
Ratio of VEGF to Total Protein (ng/mg)
Day 7
Control
0.09
0.08
*
0.07
0.06
0.05
VEGF
0.04
0.03
0.02
0.01
0
Norm
DM
DM + E
E = EXOGEN
VEGF-mediated angiogenesis on the
chicken chorioallantoic membrane
• EXOGEN increased VEGF protein expression in diabetic animals
• VEGF is a potent angiogenic (new blood vessel formation) factor
Coords et al., J Orthop Res. 2011 Feb;29(2):181-8
Ehrbar et al., Circ Res. 2004;94:1124-1132
In Vivo
The EXOGEN Effect – A Possible Explanation
• Diabetic animals have
compromised vascularity
• EXOGEN restored levels to
those of non diabetic
animals
*
New blood vessel production in response to EXOGEN
(w/US) using PECAM (CD-31) to assess day 10
neovascularisation
Coords et al., J Orthop Res. 2011 Feb;29(2):181-8
Diabetes – Summary
• Diabetes mellitus patients are at risk of fracture healing problems
potentially linked to compromised vascularity
• The EXOGEN effect in non-union patients was comparable to the
overall population
• EXOGEN increases growth factors associated with new blood
vessel formation, and with blood vessel formation itself
For patients with diabetes there was no significant change in the
efficacy of EXOGEN possibly through increasing VEGF levels and
vascularity
Question
Which of these effects of smoking is most
implicated in poor healing?
1.
2.
3.
4.
Cancer risk
Compromised blood supply
Reduced lung function
Coronary heart disease risk
Smoking – The Problem
• Smoking is a known risk factor in fracture healing 1
• Cigarette smoking diminishes vascularization at bone
healing sites through the action of nicotine 2
1.Bishop J Am Acad Orthop Surg. 2012 May;20(5):273-82
2. Ueng J. Trauma 1999 47(4) 752-759
Clinical
Smoking – The EXOGEN Effect
Cook et al.
– 41% reduction in healing time for smokers with tibial fractures
– 51% reduction in healing time for smokers with distal radius
fractures
Post marketing data on non-union fractures
• In patients who were currently smoking, the heal rate was 81.3%
(n=615/756) compared to 84.4% (n=3,141/3,722) for all fractures
Cook et al Clin Orthop Relat Res. 1997 Apr;(337):198-207
DOF 12000.01
In Vivo
The EXOGEN Effect – A Possible Explanation
Control
mRNA levels
VEGF
VEGF-mediated angiogenesis on the
chicken chorioallantoic membrane
EXOGEN increased VEGF signaling at the mRNA level
VEGF is a potent angiogenic (new blood vessel formation) factor
Naruse et al., Ultrasound Med Biol. 2010 Jul;36(7):1098-108
Ehrbar et al., Circ Res. 2004;94:1124-1132
Smoking – Summary
• Smoking is a known risk factor in fracture healing linked to
diminished vascularization which delays mineralisation
• EXOGEN lessened this risk in fresh fractures and the effect in nonunion patients was comparable to the overall population
• EXOGEN increases growth factors associated with new blood
vessel formation
EXOGEN accelerated healing in patients who smoke possibly
through increasing VEGF expression and vascularity
Osteoporosis – The Problem
• Osteoporosis is a metabolic condition where sufferers have lower
bone mineral density than normal and are more likely to fracture
• Osteoporotic fracture healing is a problem due to difficulties of
achieving fixation into poor quality bone stock
Clinical
Osteoporosis – The EXOGEN Effect
• The post marketing data on non-union fractures showed that in
patients who suffered from osteoporosis the heal rate was 91.7%
(n=55/60) compared to 84.4% (n=3,141/3,722) for all fractures
DOF 12000.01
In Vivo
The EXOGEN Effect – A Possible Explanation
This paper used a model of osteoporotic fracture repair to assess the
effect of EXOGEN on fracture repair
The paper showed how a number of growth factors are up-regulated
by EXOGEN (BMP2 & VEGF).
Fractures treated with EXOGEN had greater callus formation and
enhanced endochondral ossification.
Cheung J Orthop Res. 2012 Jan;30(1):129-36
Question
What is endochondral ossification?
1.
2.
3.
4.
Something geeky scientists refer to
Formation of Bone within cartilage
Formation of Bone without cartilage
A process that produces BMPs
Osteoporosis – Summary
• Osteoporosis is a potential risk factor for compromised fracture
healing due to poor quality bone stock
• The EXOGEN effect in non-union patients was comparable to the
overall population
• EXOGEN upregulated key growth factors and enhanced
endochondral ossification and callus formation
EXOGEN has been shown to resolve osteoporotic non-unions
possibly through enhanced growth factor expression and callus
formation
Hypertrophic Non-Unions
Question
What does hypertrophic mean?
1.
2.
3.
4.
Too much movement
Over sensitive
Above the fracture line
Enlarged
Hypertrophic Non-Unions – The Problem
• Hypertrophic non-unions are thought to be caused by excessive
motion at the fracture site
• However, if the fracture is grossly stable, then all that is needed is to
enhance the callus to mineralize through endochondral ossification
Clinical
Hypertrophic Non-Unions – The EXOGEN Effect
Nolte
• 80% (n=10/12) of established hypertrophic non-unions healed
successfully with only the addition of 20mins. per day of EXOGEN
treatment
Gebauer
• 100% (n=11/11) of established hypertrophic non-unions healed
successfully with only the addition of 20mins. per day of EXOGEN
treatment
Package Insert
• Summary of non-union clinical data
Nolte et al., J Trauma. 2001 Oct;51(4):693-702
Gebauer et al., Ultrasound Med Biol. 2005 Oct;31(10):1391-402
Clinical
Hypertrophic Non-Unions – The EXOGEN Effect
German study of delayed unions (> 16 weeks)
Key findings:
Bone mineral density was significantly improved
(p=0.002) in the fracture gap of EXOGEN treated
patients
A significant mean reduction in bone gap area
also favored EXOGEN treatment
Mineralization at the fracture site was increased
Schofer et al., BMC 8;11:229 2010
In Vitro
The EXOGEN Effect – A Possible Explanation
CONTROL
The formation of calcium nodules was
significantly greater (p < 0.001) with EXOGEN
treatment
EXOGEN
EXOGEN significantly increased alkaline
phosphatase (p < 0.04) a marker of bone
formation
EXOGEN positively impacted mineralization of
relevant cells
Leung et al., Clin Orthop Relat Res. 2004;(418):253-9.
A&B - human osteoblasts stained with alizarin red
to demonstrate calcium formation
Lower panel shows image analysis of representative
cultures (* p < 0.001)
Hypertrophic Non-Unions - Summary
• Grossly stable hypertrophic non-unions may be resolved via
enhanced mineralization
• Clinical data shows resolution with EXOGEN alone and increased
mineral content at the fracture site
• Both markers of bone formation and mineral content have been
demonstrated to be positively impacted with EXOGEN
EXOGEN has been shown to resolve hypertrophic non-unions
possibly through enhanced callus formation
Atrophic Non-Unions
Atrophic Non-Unions – The Problem
• Healing has stopped, probably due to some aspect of the patients
biology
• The fracture gap still exists on X-Ray and the ends of the bone may
become sclerotic (thickened) and/or avascular (“dead”)
• A surgical option is to remove this bone, find bleeding bone and then
re-unite the ends.
Clinical
Atrophic Non-Unions – The EXOGEN Effect
Nolte
• 80% (n=4/5) of established atrophic non-unions healed successfully
with only the addition of 20 mins. per day of EXOGEN treatment
Gebauer
• 86% (n=30/35) of established atrophic non-unions healed
successfully with only the addition of 20 mins. per day of EXOGEN
treatment
Package Insert
• Summary of non-union clinical data
Nolte et al., J Trauma. 2001 Oct;51(4):693-702
Gebauer et al., Ultrasound Med Biol. 2005 Oct;31(10):1391-402
Question
What cell removes / resorbs bone?
1.
2.
3.
4.
Osteoblast
Osteoclast
Osteocyte
Pericyte
In Vivo
The EXOGEN Effect – A Possible Explanation
This paper showed that bone can be resorbed
biologically by osteoclasts and then remodelled
EXOGEN enhanced bone removal at the fracture site
and this was linked to more osteoclasts
Control
EXOGEN caused improved bone remodelling
Freeman J Orthop Res. 2009 May;27(5):673-9.
EXOGEN
The EXOGEN Effect – A Possible
Explanation
In Vivo
mRNA levels
Control
VEGF
VEGF-mediated angiogenesis on the
chicken chorioallantoic membrane
EXOGEN increased VEGF signaling at the mRNA level
VEGF is a potent angiogenic (new blood vessel formation) factor
Naruse et al., Ultrasound Med Biol. 2010 Jul;36(7):1098-108
Ehrbar et al., Circ Res. 2004;94:1124-1132
Atrophic Non-Unions – Summary
• These are characterised by thick and/or dead bone
• Clinical data showed that EXOGEN alone resolved these
• EXOGEN enhanced bone resorption and increased vascularity
necessary to re-initiate healing
EXOGEN has been shown to resolve atrophic non-unions possibly
through enhanced bone resorption and vascularity
Follow Up
EXOGEN Dabblers – Follow Up
• Understanding our data and how it applies to fracture healing is one
of the keys for this group of people.
• Identify these people
• Use the roadmaps to guide your discussions and provide useful
leave behinds
• They are ideal targets for Chris to follow up with and engage in a
dialogue about how the clinical and basic science might inform their
treatment considerations
–
–
–
–
Face to face meetings
Tel-con/Video con to address specific questions
Meet at trade-shows
Follow-up at science summits
Papers
Clinical
Delayed union RCT (> 16 weeks)
(Delayed union has a non-union definition)
Key EXOGEN findings:
Significant increase in bone mineral
density in the fracture gap (p = 0.002)
Significantly smaller fracture gap area
(p = 0.014)
Therefore, EXOGEN increased
mineralization at the fracture site
Schofer et al., BMC 8;11:229 2010
In Vitro
In vitro study (Cells) of human
periosteal cells
Key EXOGEN findings:
Significant increase in VEGF
expression (p < 0.03)
Significantly increased mineralization
(p < 0.001)
Therefore, EXOGEN increased factors
and enhanced processes important for
fracture healing in an animal model
Leung et al., Clin Orthop Relat Res. 2004;(418):253-9.
In Vitro
In vitro study (Cells)
Key EXOGEN findings:
Integrin is essential for transducing
the signal into the cell
Significantly increased COX2 and
PGE2 production (p ≤ 0.05)
Significantly increased
mineralization (p < 0.05)
Tang Mol Pharmacol. 2006 Jun;69(6):2047-57
Therefore, EXOGEN worked
through a well defined pathway to
increase mineralization
Tang et al.,Mol Pharmacol 69:2047–2057, 2006
In Vivo
In vivo (animal) study
Key EXOGEN findings:
Significantly increased number of
osteoclasts in early and middle weeks
(p < 0.05)
Enhanced bone removal at the facture
site
Therefore, EXOGEN caused the
biological removal of bone in an
animal model
Freeman J Orthop Res. 2009 May;27(5):673-9.
In Vivo
In vivo (animal) study of healing of old and
young animals
Key EXOGEN findings:
Accelerated healing response in old
animals compared to young animals
Therefore, EXOGEN lessened the effect
of age on healing time in an animal
model
Katano et al., Exp Anim. 2011;60(4):385-95
In Vivo
In vivo (animal) study
Key EXOGEN findings:
Many growth factors were increased at
the fracture site
These include VEGF and BMP’s
Therefore, EXOGEN increased factors
required for fracture healing in an
animal model
Naruse et al., Ultrasound Med Biol. 2010 Jul;36(7):1098-108
In Vivo
In vivo (animal) study of Type I diabetes
Key EXOGEN findings:
Reversed deficits in VEGF production
Significantly increased the number of
blood vessels (p < 0.017)
Therefore, EXOGEN mitigated the
effects of diabetes on fracture healing
in an animal model
Coords et al., J Orthop Res. 2011 Feb;29(2):181-8
Clinical
Cost analysis of Heckman JBJS
study (1994)
Key EXOGEN findings:
Significantly improved fracture
healing in all patients studied (p =
0.0001)
Maximum benefit in the over 30
group that otherwise healed more
slowly
Heckman Bull Hosp Jt Dis. 1997;56(1):63-72
Therefore, EXOGEN lessened agerelated delays in healing
In Vivo
In Vivo (animal) study of osteoporotic
fracture healing
Key EXOGEN findings:
Increased BMP2 and VEGF
Greater callus formation and
enhanced endochondral ossification
Therefore, EXOGEN enhanced
osteoporotic fracture repair in an
animal model
Cheung J Orthop Res. 2012 Jan;30(1):129-36