1. Roadmap to Active Healing

2. 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
Although you will often see similar language from our indication within medical policies, Medical Policies can and often will differ from our indications
Work with your PR&R team to help maximize these indications

3. Customers Categories Each territory has on average 30+ dabblers.
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.
8,000
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?

4. 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
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):

5. EXOGEN Dabblers

6. 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

7. 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

8. 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.

9. Dabblers Roadmap to Becoming Users
Risk Factors
Age
Diabetes
Smoking
Osteoporosis
Non-Unions
Hypertrophic
Atrophic

10. Lifestyle (e.g. smoking) Medications Fracture Factors:
(Surgical) Technique
Patient Factors:
Comorbidities
Lifestyle (e.g. smoking)
Medications
Fracture Factors:
Bone and location
Fracture type and severity
Soft tissue damage
Patient
Fracture
(Surgical) Technique:
Reduction
Stabilization
Gap filling
Soft tissue repair
Not Healed
Healed

11. Often Sufficient Not Healed Healed Fracture Patient
(Surgical) Technique
Not Healed
Healed

12. Patient factors can’t be addressed by surgery alone
Sometimes Not Enough
Fracture too severe
Patient factors can’t be addressed by surgery alone
Risk Factors Lead to:
Delayed Union
Non-Union
Fracture
Patient
(Surgical) Technique
Not Healed
Healed

13. Active Healing Technology
Fracture
Add something to help:
Bone graft
Growth Factor
Stimulation
Patient
Active Healing Technology
(Surgical) Technique
Not Healed
Healed

14. May Help Tip the Balance
Fracture
EXOGEN
May Help Tip the Balance
Patient
EXOGEN
(Surgical) Technique
Not Healed
Healed

15. Risk Factors

16. Question
Which of these risk factors is most commonly thought of as a reason to use bone growth stimulation?
Osteoporosis
Smoking
Advanced age
Diabetes

17. Surgeon view on factors impacting the decision to use a bone healing adjunct
Points allocated
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

18. Many of these are patient factors (green) not fracture factors (orange)
The remainder are the key fracture factors for which an adjunct to surgery may be required
Points allocated
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

19. Risk Factors
Age
Diabetes
Smoking
Osteoporosis

20. Question
Which of these molecules is an (upstream) signaling molecule that can lead to up-regulation of the others?
Alkaline Phosphatase
COX2
VEGF
BMP2

21. Age – The Problem Clinical & Pre-Clinical *
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
The risk for impaired fracture healing also increases as people age. Studies show that people as young as 30 years of age have diminished bone healing capacity. More than half of the US population is this age or older. Advanced age reduces the number of bone marrow stem cells and inhibits vascularization at bone healing sites.
The effect of advanced age was one of the endpoints in a prospective, randomized, placebo-controlled, double-blind, multicenter, level I study of 33 fractures treated with LIPUS and 34 fractures treated with a placebo device. Patients had an acute closed or Grade I open tibial diaphyseal fracture that was primarily transverse, short oblique, or short spiral and that could be treated effectively with closed reduction and immobilization in a cast.
The graph shows that LIPUS accelerates healing of indicated fresh fractures in younger and older patients. In older patients, LIPUS accelerated healing by more than 10 weeks.
What could your older patients do with an extra 10 weeks of a healed fresh fracture?
mRNA levels of COX2 in young (Open bars)
and old (Filled bars) in mice
* p <
1. Heckman et al Journal of Bone and Joint Surgery 76A:26–34.
2. Heckman and Sarasohn-Kahn Bulletin Hospital Joint Diseases 56(1):63–72.
3. Naik et al., J Bone Miner Res Feb;24(2):251-64 21

22. Age – The EXOGEN Effect Clinical * ***
p < 0.02
***
p <
LIPUS
Placebo
84 days
103 days
(n=21)
(n=12)
(n=18)
(n=15)
126 days
187 days
42 days
33% Acceleration
45% Acceleration
>30
The risk for impaired fracture healing also increases as people age. Studies show that people as young as 30 years of age have diminished bone healing capacity. More than half of the US population is this age or older. Advanced age reduces the number of bone marrow stem cells and inhibits vascularization at bone healing sites.
The effect of advanced age was one of the endpoints in a prospective, randomized, placebo-controlled, double-blind, multicenter, level I study of 33 fractures treated with LIPUS and 34 fractures treated with a placebo device. Patients had an acute closed or Grade I open tibial diaphyseal fracture that was primarily transverse, short oblique, or short spiral and that could be treated effectively with closed reduction and immobilization in a cast.
The graph shows that LIPUS accelerates healing of indicated fresh fractures in younger and older patients. In older patients, LIPUS accelerated healing by more than 10 weeks.
What could your older patients do with an extra 10 weeks of a healed fresh fracture?
Older patients are at increased risk of delayed fracture healing
EXOGEN lessened the effect of this risk
Heckman et al Journal of Bone and Joint Surgery 76A:26–34.
Heckman and Sarasohn-Kahn Bulletin Hospital Joint Diseases 56(1):63–72. 22

23. Age – The EXOGEN Effect In Vivo 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,
while the radiographs of the 40 week old mice were
taken after excision.
Therefore the internal fixation has been removed in the older mice
Katano et al., Exp Anim. 2011;60(4):385-95

24. The EXOGEN Effect – A Possible Explanation
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 Jun;69(6):

25. 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

26. 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

27. Diabetes – The EXOGEN Effect
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

28. Question What is angiogenesis?
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

29. The EXOGEN Effect – A Possible Explanation
In Vivo
The EXOGEN Effect – A Possible Explanation *
Day 7
E = EXOGEN
Control
VEGF
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 Feb;29(2):181-8
Ehrbar et al., Circ Res. 2004;94:

30. The EXOGEN Effect – A Possible Explanation
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 Feb;29(2):181-8

31. 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

32. Question
Which of these effects of smoking is most implicated in poor healing?
Cancer risk
Compromised blood supply
Reduced lung function
Coronary heart disease risk

33. 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 May;20(5):273-82
2. Ueng J. Trauma (4)

34. Smoking – The EXOGEN Effect
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 Apr;(337):
DOF

35. The EXOGEN Effect – A Possible Explanation
In Vivo
The EXOGEN Effect – A Possible Explanation
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 Jul;36(7):
Ehrbar et al., Circ Res. 2004;94:

36. 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 non-union 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

37. 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

38. Osteoporosis – The EXOGEN Effect
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

39. The EXOGEN Effect – A Possible Explanation
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 Jan;30(1):129-36

40. Question What is endochondral ossification?
Something geeky scientists refer to
Formation of Bone within cartilage
Formation of Bone without cartilage
A process that produces BMPs

41. 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

42. Hypertrophic Non-Unions

43. Question What does hypertrophic mean? Too much movement Over sensitive
Above the fracture line
Enlarged

44. 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

45. Hypertrophic Non-Unions – The EXOGEN Effect
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 Oct;51(4):
Gebauer et al., Ultrasound Med Biol Oct;31(10):

46. Hypertrophic Non-Unions – The EXOGEN Effect
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:

47. The EXOGEN Effect – A Possible Explanation
In Vitro
The EXOGEN Effect – A Possible Explanation
EXOGEN
EXOGEN significantly increased alkaline phosphatase (p < 0.04) a marker of bone formation
The formation of calcium nodules was significantly greater (p < 0.001) with EXOGEN treatment
EXOGEN positively impacted mineralization of relevant cells
CONTROL
A&B - human osteoblasts stained with alizarin red
to demonstrate calcium formation
Lower panel shows image analysis of representative
cultures (* p < 0.001)
Leung et al., Clin Orthop Relat Res. 2004;(418):253-9.

48. 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

49. Atrophic Non-Unions

50. 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.

51. Atrophic Non-Unions – The EXOGEN Effect
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 Oct;51(4):
Gebauer et al., Ultrasound Med Biol Oct;31(10):

52. Question What cell removes / resorbs bone? Osteoblast Osteoclast
Osteocyte
Pericyte

53. The EXOGEN Effect – A Possible Explanation
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
EXOGEN caused improved bone remodelling
Control
EXOGEN
Freeman J Orthop Res May;27(5):673-9.

54. The EXOGEN Effect – A Possible Explanation
In Vivo
The EXOGEN Effect – A Possible Explanation
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 Jul;36(7):
Ehrbar et al., Circ Res. 2004;94:

55. 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

56. Follow Up

57. 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

58. Papers

59. Therefore, EXOGEN increased mineralization at the fracture site
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:

60. 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.

61. 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)
Therefore, EXOGEN worked through a well defined pathway to increase mineralization
Tang Mol Pharmacol Jun;69(6):
Tang et al.,Mol Pharmacol 69:2047–2057, 2006

62. Enhanced bone removal at the facture site
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 May;27(5):673-9.

63. 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

64. 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 Jul;36(7):

65. 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 Feb;29(2):181-8

66. Clinical
Cost analysis of Heckman JBJS study (1994) Key EXOGEN findings: Significantly improved fracture healing in all patients studied (p = ) Maximum benefit in the over 30 group that otherwise healed more slowly Therefore, EXOGEN lessened age-related delays in healing
Heckman Bull Hosp Jt Dis. 1997;56(1):63-72

67. 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 Jan;30(1):129-36