Subchondroplasty®

Procedure: Science,

Research and Clinical

Results Peter F. Sharkey, M.D.

Philadelphia, Pennsylvania

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Entity Conflict

Zimmer Biomet Consulting, Royalties

Others:

ConvaTec Consulting

StelKast Royalties

PRN Stock, BOD

Corentec Consulting, Royalties

My Disclaimers

3

Disclaimer

Products represented in this presentation are in

process of obtaining CE mark. At this time, CE mark

is pending.

Background

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• Osteoarthritis describes a “deteriorating” joint (cartilage, synovium,

ligaments, tendons and bone)

• OA affects 15% of world population1

• 20 Million with knee OA in North America2

• In people age 50 and over, 25% have pain in their knees on most days

and percentage is rapidly increasing 3

• OA complaints #1 reason for visits to physicians in US4

Clinical Situation

1. Miller, et al, Subchondroplasty of the ankle: A novel technique, doi 10.3827/faoj.2015.0801.0007

3. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and

current use of primary health care. Ann Rheum Dis.2001;60:91–7. [PMC free article] [PubMed]

2. Arthritis Rheum, 1998 25: 125-33

4. Panush RS, Schmidt C, Caldwell JR, Edwards NL, Longley S, Yonker R, et al. Is running associated with

degenerative joint disease? JAMA. 1986;255(9):1152–1154.

Increasing Population of

Younger TKA Patients

•By 2016 > 50% of TKA pts will be younger

than age 651 in the US

•Fastest growth among pts 45-541

•By 2030 673% increase in patients who are

candidates for primary TKA (3.4 million)1

1. Kurtz et al, Projections of Primary Hip and Knee Arthroplasty in the United States

from 2005 to 2030. Journal of Bone and Joint Surgery. 2007

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Current Treatment Options

• Non-surgical therapeutic methods (NSAID, injection,

bracing) have limited effectiveness for advanced OA

• Role of arthroscopy being questioned

• May help with mechanical symptoms

• Pain relief less predictable

• Osteotomy, UKA, TKA more effective, but more

invasive and not always predictable

• Complications common

• 1 in 6 patients “not satisfied” after TKA, without

obvious cause

Felson & Buckwalter, NEJM 2002

Moseley, et al, NEJM 2002

Kirkley et al., NEJM 2008

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Clinical Situation

…AKA…

• Clinical picture radiographic evaluation

– patient 1: bone on bone but no pain

– patient 2: preservation of joint space, severe pain

≠

• Hallmark sign of OA is loss of cartilage

• Cartilage loss usually noted on plain radiographs

MRI has greatly expanded our knowledge

regarding OA

• MRI demonstrates:

- Bone damage and inflammation

- Non-bone causes of pain

(meniscal tear, synovitis, etc.)

• MRI reveals the primary reported source of

pain: subchondral bone marrow lesion

(BML)

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MRI Changes the Picture

• “The presence or absence of joint space narrowing…was not significantly

associated with knee pain”

Hunter et al, Evolution of semi-quantitative whole joint assessment of

knee OA: MOAKS (MRI Osteoarthritis Knee Score). OA & Cartilage.

2011 Aug; 19(8) 990-1002

• Review of OA symptom predictors found that pain is:

‾ Strongly related to presence of a BML

‾ Moderately related to synovitis & effusion

‾ Weakly related to cartilage volume / thickness

Starr et al, Fundamental subchondral bone changes in

spontaneous knee osteoarthritis. Int J Biochem Cell Biol.

2005;37:224–236.

• Symptoms from BML occur due to irritation or disruption of sensory

nerves of bone marrow

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BML: Main Source of Symptoms

Cicuttini et al, Association of pain with radiological changes in different compartments

and views of the knee joint. OA & Cartilage. 1996; 1063-4584(05)90232-1

BML Definition on MRI

• Region of bone demonstrating

hyper-intense marrow signal

• Recognized on fluid-sensitive,

fat-suppressed sequences

• Sometimes referred to as edema

due to recognition on fluid-

sensitive MRI sequences

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Subchondral Bone

Primary function: shock absorption during joint loading

Subchondral bone = subchondral

bone plate + subarticular spongiosa

(supporting trabeculae)

Madry et al., 2010 The Subchondral Bone in

Articular Cartilage Repair: Current Problems in the

Surgical Management, Knee Surg Sports Trauma

tol Arthrosc 18(4) 434-447

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Microcracks Lead to:

•Targeted remodeling and

removal of damaged tissue

•Stimulation of secondary

centers of ossification –Focal thickening of subchondral

plate

– Increased mineralization density in

some SC regions, but decreased in

others

– Increased vascularity

AC = Articular cartilage

CC = Calcified cartilage

Cr = Microcrack

OC = Osteochondral junction

Arrows = Osteoclasts

Concentration of Joint Forces

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Bone Marrow Lesions (BML)

Different etiologies

Source of pain SUBCHONDRAL

STRESS FRACTURE

“REACTIVE” BME

Knee OA

• Articular cartilage: no pain fibers

• Synovium: some pain fibers; more

baroreceptors

• Ligaments: more proprioceptors

• Meniscus: Pain fibers only in vascular

(peripheral) zone

• Bone: pain fibers

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Primary pain source?

Multifactorial;

Structural Correlates of Knee Pain

Dye, et al, Am J Sports Med. 1998

Marrow, mineralized bone and periosteum have rich sensory nerve supply

and sympathetic innervation

Periosteum has densest innervation, but subchondral bone has highest

volume of neural tissue

What Structures in Bone are Most

Innervated with Pain Fibers?

Mach DB, et al. Origins of skeletal pain: sensory and sympathetic innervation of the mouse

femur. Neuroscience. 2002;113:155–166.

Concentration of Joint Forces

• In a non-deteriorated, load is dispersed over a large area

• In a deteriorated joint, load is concentrated in small areas

• Focal loading causes damage in underlying subchondral bone

Diffuse force distribution Deteriorating Joint (load moved

peripherally) Madry et al., 2010

Bone Marrow Lesions and X-Ray

Progression on the Side of the Lesion

(Felson et al, A.I.M. 2003)

% of knees with

progression on side

of lesion

Adjusted OR

(95% CI)

Adjusted OR

including

malalignment

(95% CI)

MEDIAL

PROGRESSION

Medial BML 27/75 (36.1%) 4.7 (2.4,9.2) 3.3 (1.3,8.3)

No Medial BML 12/148 (8.1%) 1 1

LATERAL

PROGRESSION

Lateral BML 10/40 (25.0%) 7.4 (2.9,19.1) 3.7 (1.1,12.5)

No Lateral BML 10/183 (5.5%) 1 1

Histopathology of BML

• Minimal true edema

• Abnormal bone spicules with excessive

fibrosis, small areas of osteonecrosis

• Extensive bony remodeling with reversal lines

• Essentially the pattern often seen

after fatigue fractures in bone

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Zanetti et al, Bone Marrow Edema Pattern in Osteoarthritic Knee: Correlation

Between MR Imaging and Histologic Findings, Radiol 2000; 215:835-840

Histopathology of BML

OA related BMLs represent a healing response to trauma such as

microtrabecular fractures of the subchondral bone.1

1 Eriksen EF, Ringe JD. Bone marrow lesions: a universal bone response to

injury? Rheumatol Int. 2012;32(3):575–584

High-mag histology image

showing subchondral fracture

Micro CT showing the bony

subchondral fractures

Histology of Bone Marrow Lesions

*Taljanovic et al, 2008

Histology of Bone Marrow Lesions

*Taljanovic et al, 2008

The Response to Microtrabecular

Fractures B

on

e S

tren

gth

Time

Remodeling Capacity Exceeded;

Cellular Recruitment

BML & Progression of Disease

BML Grade Odds Ratio of SBA

0 1.0

1 20.2

2 45.2

3 76.5

There was a strong association between prevalent BML

and SBA.

Felson et al, The Association of Bone Marrow Lesions with Pain in Knee

Osteoarthritis; Ann Intern Med. 2001 134 (7):541-9

The identification of BML is the strongest predictor of the presence of pain

associated with knee OA

o “Our results show that bone marrow lesions in knees are associated

with the most important symptom of osteoarthritis, pain.”

Roemer et al. Change in MRI-detected subchondral bone marrow lesions is

associated with cartilage loss: the MOST Study. A longitudinal multicentre

study of knee osteoarthritis. Ann Rheum Dis. 2009;68(9):1461–5.

BML correlate with OA disease progression

o “BML, which are a reflection of increased subchondral metabolism and

remodeling, might lead in some cases to alterations in the subchondral

osseous plate and eventually weakening and deformity.”

BML: Main Source of Symptoms

Scher, et al., Skeletal Radiology. 2008; 37: 609-17 • ~9x More likely to progress rapidly to TKR

Tanamas, et al., Rheumatology. 2010; 12: 2413-9 • Increased patient’s risk of TKR by 57%

Raynauld, et al., Ann Rheum Dis. 2011; 70: 1382-88 • Presence of medial BML is one of the strongest

predictors of TKR

Roemer, et al., Osteoarthritis and Cartilage. 2012;

20: 510-53 • Large medial BML are 2.5x and worsening medial BML

are 3.4x more likely for TKR

Patients with BML

Once a knee OA patient develops BML

without intervention TKA

• “Large bone marrow lesions in the medial femoral condyle or the medial or

lateral plateau were associated with substantially increased odds of

reported pain”

• BML in medial compartments associated with “marked decreases in

walking and stair-climbing performance (p<0.001)”

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Patients with BML

Sowers et al. Associations of Anatomical Measures from MRI with Radiographically

Defined Knee Osteoarthritis Score, Pain, and Physical Functioning, JBJS Am.

2011;93:241-251

Jacobs CA, et al, Subchondral Bone Marrow Edema Had Greater Effect on

Postoperative Pain After Medial Unicompartmental Knee Arthroplasty Than

Total, J Arthroplasty. 2015, http://dx.doi.org/10.1016/j.arth.2015.09.023

• 71 patients with MRI taken before medial UKA or TKA

• Pain scores for UKA patients with BME were worse (before and after

surgery) than for TKA patients with BME

• Satisfaction rates were lower for UKA patients with BME

• BME did not effect satisfaction rates for TKA patients

Structurally compromised subchondral bone may not predictably support

UKA components

Patients with BML

Insufficiency fracture of tibial plateau may cause knee pain in osteoporotic patients.

BML found in 77.5% of persons with painful knees

Severity of BML associated with progression to TKR

Changes in bone play a role in development of knee pain

Poor clinical outcome after APM associated with bone marrow edema

BML

2010

2008

2001

2011

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Clinical relevance of BML has been studied for >30 years

1983

BML Clinical Relevance

“Changes of subchondral bone are a classic feature of OA….characteristic

processes include microcracks..within the subchondral region.”

Kon E, et al. Bone marrow lesions and subchondral bone pathology of the

knee. European Society of Sports Traumatology, Knee Surgery,

Arthroscopy. 2016; 1797-814.

Summary

• Often a disconnect between clinical picture and plain

radiographic studies

• Presence of BML – highest predictor of clinical symptoms

• When BML are left untreated – progression to TKA likely

• Ideally, find an earlier, minimally-invasive treatment option for

BML defects to perhaps delay or avoid progressing to TKA

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Minimally Invasive More Invasive

Po

ten

tia

l T

rea

tme

nt?

Treatment Options When

Conservative Care Fails?

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Based on Accumulated Knowledge

Philosophical Solution: •Minimally-invasive procedure

•Biological stimulation of bone

• Access and fill bone marrow lesion

• Provide inorganic matrix for remodeling as bone heals

• Procedure that does not compromise bone for later TKA if needed

The Subchondroplasty®

Procedure

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The Subchondroplasty Procedure

1. Preoperative plan, based on MRI

2. Target the BML—translate MRI to intraop fluoro

3. Access lesion with cannula

4. Inject AccuFill® bone substitute material

Preop Plan

• Localize BML relative to

radiographic anatomic

landmarks

• Fat-suppressed MRI (T2FS,

PDFS, STIR) in at least two

planes

• BML typically not visible on

fluoroscopy

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Set Up

OR/Patient setup

for arthroscopy

and fluoroscopy

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Target Bone Marrow Lesion

BML targeted with

fluoroscopy, based

on preop MRI

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Drill Cannula

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Inject AccuFill

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AccuFill Bone Substitute

Material (BSM)

• Hardens in an endothermic reaction at 37°C no tissue necrosis

• Mixed with saline or blood to create injectable material

• Properties similar to the apatite of bone:

Ca10-x(M)x(PO4)6-x(HPO4,CO3)x(OH)2-x

• Macroporous: ~65% porosity, pore size ~300μm

• Compressive strength: ~10MPa, comparable to cancellous bone

• Cell-mediated remodeling as the body heals the defect

The Implant: AccuFill® Bone

Substitute Material (BSM)

Cohen, SB, Sharkey, PF. Subchondroplasty for

Treating Bone Marrow Lesions, Journal of Knee

Surgery, Dec. 2015.

Restrospective review of first 69 patients

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Patient profile

• Chronic, aching pain (VAS ≥ 4/10)

• Failed conservative care

• Candidate for knee replacement

Clinical diagnosis of BML bone

defect could be in combination with

• Meniscal tear / extrusion

• Cartilage thinning / fraying / loss

• Mechanical symptoms / loose bodies

Surgical care

• 1 surgeon, 1 center

• SCP® procedure + arthroscopy

Retrospective Review of

1st 69 Consecutive Patients

General Study Protocol

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Avg Min Max

Age 56 35 76

Length of Symptoms (months) 21.5 2 180

BMI 30.14 20.3 53.2

Treatment prior to SCP® Percentage

Cortisone 63% HA 73% NSAID 46% Scope 28% PMMx 28% PT 12% Bracing 21%

Cohen Clinical Series – 2008-2010

First 69 Patients—Demographics

Location Average Outerbridge Grade

Medial 3.34 Lateral 2.07 PF 2.53 Comp w BML 3.7 Contralateral Comp 1.8 Compartment Implicated Percentage MTP 46% MFC 40% LTP 10% LFC 4% Kissing 33%

Cohen Clinical Series –

Demographics/Baseline Data

• Patients chose SCP® Tx as alternative to TKA/UKA

• Regular follow up visits

• Data points collected

– VAS Pain

– IKDC

– Survivorship

Cohen Clinical Series –

Results

Patients followed ≥ 2 years

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The majority of patients experienced clinically significant (>2 pt)

pain relief, including those that converted to TKA

Patients experienced durable pain relief beyond 2 years

Patients experienced durable improvement in IKDC

scores beyond 2 years

70% patients not converted to TKA at/beyond 2 years

In this series of 69 consecutive patients:

•Clinically-significant and durable improvements in pain

•Clinically-significant and durable improvements in function

•70% non-conversion to arthroplasty at minimum 2 years follow up

The SCP Procedure shows potential for patients with symptomatic

BML bone defects

Conclusions

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Current Studies

The Evidence-Based

Approach in Bringing New

Orthopedic Devices to

Market (JBJS 2010)

Scientific & Clinical Basis For SCP Continues to Build

RCT

Cohort

Case Series

Case Reports

Biomechanics / Basic Science

Expert Opinion

Phase IV

Phase III

Phase II

Phase I

Evidence Pyramid

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Current Studies

•Prospective Non-Randomized Knee Trial –5 sites (Rothman, Allegheny, Steadman-Hawkins Greenville,

CORE San Diego, NYU).

–Enrollment: 57 of 70; complete in 2016

–Includes 2 year controlled follow-up with MRI’s.

–1 year MRI publication 2017

–2 year Outcomes 2018

•Knee Observational Cohort Study (Registry) –Enrollment: 218 Subjects at 15 sites

•Academic sites and private practice

–All knee indications; represents real-world use of

SCP

–Goal: 1,000 subjects at 30 sites

–Submission in 2017

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Current Studies

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•201 Subjects; 2 Cohorts:

– Treatment: SCP + Arthroscopy

– Control: Arthroscopy + Sham

incision.

•2 year follow-up with Revision

and Pain Primary Endpoints

•Design Team/Initial Sites:

– Stanford (Dragoo, Vaughn)

– Steadman-Hawkins Carolinas

(Tokish, Wyland)

– Ohio State (Kaeding, Flanigan)

– Rothman (Cohen, Sharkey)

– Rush (Cole).

•Enrollment: 2016-2017

•10-15 Sites

•2 year F/U: 2019

•2 year publication: 2020.

Knee Randomized Controlled Trial

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Pre-Clinical Study

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60

40N impact to

both medial

femoral condyles

12 weeks 3 mos

Assess n=4 Clinical

Function

Pain

XR

MRI

Scope

microCT

Histo

Assess n=4 Clinical

Function

Pain

XR

MRI

Scope

microCT

Histo

6 mos

N=16

Assess n=4 Clinical

Function

Pain

XR

MRI

Scope

microCT

Histo

N= 7 on study

MRI, Scope & Treat

SCP

v

Sham

Assess n=3 Clinical

Function

Pain

XR

MRI

Scope

microCT

Histo

Study Design: James Cook, VMD

1-yr. Results Presented Tomorrow

Additional Clinical Publications

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Knee Arthroplasty After Subchondroplasty: Early Results, Complications, and

Technical Challenges. Yoo JY1, O'Malley MJ1, Matsen Ko LJ1, Cohen SB1, Sharkey

PF1. J Arthroplasty. 2016 May 10. pii: S0883-5403(16)00018-8. doi: 10.1016/j.arth.2015.12.051.

[Epub ahead of print];

• 22 patients (15 TKA, 8 UKA) who had the Subchondroplasty Procedure, then subsequently

had knee arthorplasty

• SCP patients matched 2:1 to a control group of arthroplasty patients, who had no prior

surgery

• No difference in complications or surgical complexity between groups

Additional Publications

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• MRI findings of subchondroplasty of the knee: a two-case report. Nevalainen M,

Sharkey P, Cohen S, Roedl J, Zoga A, Morrison B

Additional Publications

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Discussion

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Indications for Use:

• AccuFill Bone Substitute Material is an injectable, self-setting,

macroporous, osteoconductive, calcium phosphate bone graft substitute

material that is intended for use to fill bony voids or gaps of the skeletal

system of the extremities and the pelvis that are not intrinsic to the

stability of the bony structure. These defects may be surgically created

osseous defects or osseous defects created from traumatic injury to the

bone, including bone marrow lesions. AccuFill® Bone Substitute Material

is a bone graft substitute that resorbs and is replaced with new bone

during the healing process.

The Implant: AccuFill® BSM