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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†

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Presentation on theme: "Roadmap to Active Healing. Indications* The EXOGEN ® Ultrasound Bone Healing System, is indicated for the non-invasive treatment of established non-unions†"— Presentation transcript:

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

3 Customers Categories TitleDescriptionUsageNumber 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 SpreadersUse whatever BGS is available. They are all the same Variable9,300 E-Stim users Use only E-stim.Variable8,000 Non BGS users Haven’t prescribed in last 2 years. Zero3,900 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 rate 1 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):

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

11 Not HealedHealed Fracture Patient (Surgical) Technique Often Sufficient

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

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

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

15 Risk Factors

16 Question Which of these risk factors is most commonly thought of as a reason to use bone growth stimulation? 1.Osteoporosis 2.Smoking 3.Advanced age 4.Diabetes

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

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

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? 1.Alkaline Phosphatase 2.COX2 3.VEGF 4.BMP2

21 1. Heckman et al Journal of Bone and Joint Surgery 76A:26– Heckman and Sarasohn-Kahn Bulletin Hospital Joint Diseases 56(1):63– Naik et al., J Bone Miner Res Feb;24(2): * p < 0.02 Age – The Problem Increasing age is a risk factor for fracture union 1,2 Older animals produce less COX2 3 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 site 3 Clinical & Pre-Clinical mRNA levels of COX2 in young (Open bars) and old (Filled bars) in mice * p <

22 Heckman et al Journal of Bone and Joint Surgery 76A:26–34. Heckman and Sarasohn-Kahn Bulletin Hospital Joint Diseases 56(1):63–72. Age – The EXOGEN Effect * p < 0.02 *** p < LIPUS Placebo 84 days 103 days (n=21) (n=12) (n=18) (n=15) 126 days 187 days * *** 84 days 42 days 33% Acceleration 45% Acceleration Clinical Older patients are at increased risk of delayed fracture healing EXOGEN lessened the effect of this risk >30

23 Age – The EXOGEN Effect Day 8 week old mice40 week old mice with EXOGEN In Vivo Older animals are at increased risk of delayed fracture healing EXOGEN lessened the effect of this risk Katano et al., Exp Anim. 2011;60(4): Day 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

24 Tang Mol Pharmacol Jun;69(6): EXOGEN increased COX2 production in osteoblasts, a key fracture healing factor that is compromised in older animals In Vitro The EXOGEN Effect – A Possible Explanation

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 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 Clinical DOF

28 Question What is angiogenesis? 1.The ability of cells to migrate to the fracture 2.The formation of new blood vessels 3.The formation of bone without cartilage 4.The process how bone remodels

29 * Day 7 E = EXOGEN The EXOGEN Effect – A Possible Explanation Coords et al., J Orthop Res Feb;29(2):181-8 Ehrbar et al., Circ Res. 2004;94: In Vivo EXOGEN increased VEGF protein expression in diabetic animals VEGF is a potent angiogenic (new blood vessel formation) factor VEGF-mediated angiogenesis on the chicken chorioallantoic membrane Control VEGF

30 The EXOGEN Effect – A Possible Explanation * Coords et al., J Orthop Res Feb;29(2):181-8 In Vivo 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

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? 1.Cancer risk 2.Compromised blood supply 3.Reduced lung function 4.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 2. Ueng J. Trauma (4) Bishop J Am Acad Orthop Surg May;20(5):273-82

34 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 Clinical Cook et al Clin Orthop Relat Res Apr;(337): DOF

35 The EXOGEN Effect – A Possible Explanation Naruse et al., Ultrasound Med Biol Jul;36(7): Ehrbar et al., Circ Res. 2004;94: In Vivo EXOGEN increased VEGF signaling at the mRNA level VEGF is a potent angiogenic (new blood vessel formation) factor mRNA levels VEGF-mediated angiogenesis on the chicken chorioallantoic membrane Control VEGF

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 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 Clinical DOF

39 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): In Vivo The EXOGEN Effect – A Possible Explanation

40 Question What is endochondral ossification? 1.Something geeky scientists refer to 2.Formation of Bone within cartilage 3.Formation of Bone without cartilage 4.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? 1.Too much movement 2.Over sensitive 3.Above the fracture line 4.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 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 Clinical Nolte et al., J Trauma Oct;51(4): Gebauer et al., Ultrasound Med Biol Oct;31(10):

46 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: Clinical Hypertrophic Non-Unions – The EXOGEN Effect

47 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 The EXOGEN Effect – A Possible Explanation Leung et al., Clin Orthop Relat Res. 2004;(418): In Vitro A&B - human osteoblasts stained with alizarin red to demonstrate calcium formation Lower panel shows image analysis of representative cultures (* p < 0.001) EXOGEN CONTROL

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 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 Clinical Nolte et al., J Trauma Oct;51(4): Gebauer et al., Ultrasound Med Biol Oct;31(10):

52 Question What cell removes / resorbs bone? 1.Osteoblast 2.Osteoclast 3.Osteocyte 4.Pericyte

53 Control EXOGEN 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 Freeman J Orthop Res May;27(5): In Vivo The EXOGEN Effect – A Possible Explanation

54 Naruse et al., Ultrasound Med Biol Jul;36(7): Ehrbar et al., Circ Res. 2004;94: In Vivo EXOGEN increased VEGF signaling at the mRNA level VEGF is a potent angiogenic (new blood vessel formation) factor mRNA levels VEGF-mediated angiogenesis on the chicken chorioallantoic membrane Control VEGF

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 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: Clinical

60 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): In Vitro

61 Tang et al.,Mol Pharmacol 69:2047–2057, 2006 Tang Mol Pharmacol Jun;69(6): 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 In Vitro

62 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): In Vivo

63 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): In Vivo

64 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): In Vivo

65 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 In Vivo

66 Heckman Bull Hosp Jt Dis. 1997;56(1):63-72 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 Clinical

67 Cheung J Orthop Res Jan;30(1): 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 In Vivo


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