Conservative Management of Knee osteoarthritis

Treatment of Osteoarthritis
Focus Group
Stephan Esser MD, USPTA

Goals
• From the Sky: 30,000 foot view
• Brief Mini-Medical School
• Orthobiologics in Knee OA Intro
• US Exam and Injection of the Knee
• Bracing Questions
• Wrap Up

Michelangelo’s David:
12 month 20 city tour of the US

https://cpmc.coriell.org/v/Content/RiskReport/Graphs/OA.png

• http://www.cdc.gov/arthritis/temp/pilots-201208/pilot1/online/arthritis-challenge/03-Prevention/primary.htm

Risk of Developing Knee OA
• Lifetime Risk:
– 40% in men, 47% in women
– 60% in those with BMI > 30
– Lifetime risk of symptomatic knee osteoarthritis.Murphy L, Schwartz TA, Helmick CG, Renner JB, Tudor G, Koch G, Dragomir A, Kalsbeek WD,
Luta G, Jordan JMArthritis Rheum. 2008 Sep 15; 59(9):1207-13.
– For a woman of normal height, for every 11 lb weight loss (approximately 2 BMI
units), the risk of knee OA dropped > 50%. Framingham Health Study
– Patients with knee OA, a weight reduction of 10% improved function by
28%http://www.sciencedirect.com/science/article/pii/S1063458404002031
– BUT I CAN”T LOSE WEIGHT……..I CAN’T EXERCISE!.........

• http://annals.org/data/Journals/AIM/19967/16FF1.jpeg

How Common is Knee OA
• Radiographic Knee OA Framingham Study, NHANES Data
• 4.9% > 26
• 19.2% > 45
• 37% > 60
• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920533/

How Common is Knee OA
• Radiographic Knee OA Framingham Study, NHANES Data
• 4.9% > 26
• 19.2% > 45
• 37% > 60
• Symptomatic knee OA Johnston County Osteoarthritis
Project
• 16.7% ≥ 45
• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920533/

• http://www.cdc.gov/arthritis/data_statistics/disabilities-limitations.htm

• http://www.cdc.gov/arthritis/images/data-statistics/national-statistics/charts/functional_limitations_2.0.jpg

National Trends
• Oldest
• Most overweight
• High rate of disability
• Increased rate of surgeries

Risks for Knee OA
• Out of Control:
– Genetics
– Age
– Female gender
– Previous knee injury
– Joint laxity
– Alignment
– Previous knee surgery
• In Control
– Repetitive use of joints
– Mechanics of Movement
– Muscle weakness
– Weight
Overweight/Obesity
– Nutrition: Vitamin D, C,
Omega 3, Selenium

Goals
• Patient Education
• Goal Evaluation and Setting
• Patient Empowerment
• Patient Motivation
GROWGROW

Knee Anatomy
http://www.arthritis-health.com/files/field/image/adult-knee-anatomy-bones-lab.jpg

Knee Anatomy
http://www.newhealthadvisor.com/images/1HT08327/ligaments-of-the-knee.jpg

Knee Anatomy
http://en.wikipedia.org/wiki/File:Gray351.png http://www.exercisereports.com/Anatomy/G348fibularcollaterallig.jpg

• Chondrocyte Dysfunction
– oxidative stress
– induces telomere genomic instability
– replicative senescence
– joint degeneration

ACR Criteria for Knee OA
– Using history, physical examination and laboratory
findings
• Knee pain and 5 of the following
• > 50 years of age
• < 30 minutes of AM stiffness
• Crepitus on active motion
• Bony tenderness
• Bony enlargement
• No palpable warmth of synovium
• ESR < 40mm/hr
• RF < 1:40
M17 Osteoarthritis of knee
M17.0 Bilateral primary osteoarthritis of
knee
M17.1 Unilateral primary osteoarthritis of
knee
M17.10 Unilateral primary osteoarthritis,
unspecified knee
right knee
left knee
M17 Osteoarthritis of knee
M17.0 Bilateral primary osteoarthritis of
knee
M17.1 Unilateral primary osteoarthritis of
knee
unspecified knee
right knee
left knee

Regenerative Potential in Knee OA

• Orthobiologics
– PRP
– Stem Cells

Terms
• Blood by Volume
– RBC’s: 40-45%
– WBC’s: <1%
– Platelets: <1%
– Plasma: 50-55% water, sugar, fat, protein,
minerals

PRP Mechanism of Action
• 1st
Mechanism
–Delivery of Growth Factors

Terms
• Platelet Growth Factors
• PDGF: Chemo-attractive to mesenchymal stem
cells and endothelial cells. Promotes
differentiation for fibroblasts and osteoblasts. Up
regulate effects of other growth factors on cells
such as macrophages.
• TGF-ß: Promotes cell mitosis and differentiation
for connective tissue and bone. Acts on
mesenchymal stem cells, preosteoblasts and
fibroblasts. Inhibits osteoclast formation.
• VEGF: Stimulates angiogenesis and is chemo-
attractive for osteoblasts
• EGF: Induces epithelial development and
promotes angiogenesis and collagen deposition

• 2nd
Mechanism
–“Up regulation” of local GF in tendons
• TGF-Beta1 for 1st
week post prp,
• Increased IGF-1 for 4 weeks tenocytes post prp

• 3rd
Mechanism
–PRP Stimulates HA Release
–PRGF significantly enhanced HA
secretion compared with platelet-poor
preparations, (P < 0.05)
Anitua, et al. Rheumatology 2007 46(12):1769-1772

• 4th
Mechanism
–Chemo-attractant for Stem Cells
–Prompt Migration and Proliferation
http://www.tandfonline.com/doi/abs/10.1080/09537100310001643999

Terms
Stem Cell
– an undifferentiated progenitor/primitive
cell
• A: capable of renewing itself through cell
division, sometimes after long periods of
inactivity
• B: Under certain physiologic or experimental
conditions, it can be induced to become a
tissue- or organ-specific cell with special
functions
http://stemcells.nih.gov/info/basics/pages/basics1.aspx

Terms
Stem cell typeStem cell type DescriptionDescription ExamplesExamples
TotipotentTotipotent
Each cell can develop intoEach cell can develop into
a new individuala new individual
Cells from early (1-3Cells from early (1-3
days) embryosdays) embryos
PluripotentPluripotent
Cells can form any (overCells can form any (over
200) cell types200) cell types
Some cells ofSome cells of
blastocyst (5 to 14blastocyst (5 to 14
days)days)
MultipotentMultipotent
Cells differentiated, butCells differentiated, but
can form a number ofcan form a number of
other tissuesother tissues
Fetal tissue, cordFetal tissue, cord
blood, and adultblood, and adult
stem cellsstem cells

Terms
• Stem Cell
– Mesenchymal Stem Cells (MSC’s)
• Multipotent Stromal Cells capable of differentiating
into osteoblasts, chrondrocytes, myocytes and
adipocytes
– Marrow Derived Stem Cells (MdSC’s)
– Adipose derived Stem Cells (ASC’s)

PRP and Osteoarthritis
• Platelet-rich plasma intra-articular knee injections
for the treatment of degenerative cartilage lesions
and osteoarthritis Knee Surgery, Sports Traumatology,
Arthroscopy April 2011, Volume 19, Issue 4, pp 528-535
• Single PRP injection
• 2 year follow up
• Improved function, pain scores, quality of life

PRP for Osteoarthritis
• Treatment With Platelet-Rich Plasma Is More Effective Than
Placebo for Knee Osteoarthritis A Prospective, Double-Blind,
Randomized Trial Am J Sports Med February 2013 vol. 41 no. 2
356-364
• METHODS: 78 patients divided into 3 groups, 1 PRP injection, 2
PRP injections 3 weeks apart or saline injection
• OUTCOMES:
– WOMAC, Pain visual analog, Overall Satisfaction
– 1 injection as effective as 2 injections. Both
better than saline/placebo. Results ebb around
6 months

PRP vs HA in OA
• Platelet-rich plasma injection is more effective
than hyaluronic acid in the treatment of knee
osteoarthritis Gurler et al. Acta Chirurgiae Orthopaedicae et Traumatologiae
Cechoslovaca [2013, 80(4):278-283]
• METHODS: 90 patients with complaints of knee pain with findings of mild or
moderate degenerative arthritis. In the PRP group (n=45), one intra-articular injection was
applied and in the HA group (n=45), three doses of intra-articular injection were applied.
• OUTCOMES: Clinical evaluation was made by Knee Injury and Osteoarthritis
Outcome Score (KOOS) and a visual pain scale.
• RESULTS: No severe adverse events was observed. Statistically significant better
results in the KOOS score and visual pain scale was determined in PRP group than HA group
at 3 months and 6 months follow up. The cost of the application was less for PRP than HA

PRP superior to HA for Knee OA
• Cerza F, Carni S, Carcangiu A, et al. Comparison Between Hyaluronic Acid and
Platelet-Rich Plasma, Intra-articular Infiltration in the Treatment of Gonarthrosis.
The American journal of sports medicine. Dec 2012;40(12):2822-2827.
• Kon E, Mandelbaum B, Buda R, et al. Platelet-rich plasma intra-articular injection
versus hyaluronic acid viscosupplementation as treatments for cartilage
pathology: from early degeneration to osteoarthritis. Arthroscopy : the journal of
arthroscopic & related surgery : official publication of the Arthroscopy Association
of North America and the International Arthroscopy Association. Nov
2011;27(11):1490-1501.
• Sanchez M, Fiz N, Azofra J, et al. A randomized clinical trial evaluating plasma rich
in growth factors (PRGF-Endoret) versus hyaluronic acid in the short- term
treatment of symptomatic knee osteoarthritis. Arthroscopy : the journal of
arthroscopic & related surgery : official publication of the Arthroscopy Association
of North America and the International Arthroscopy Association. Aug
2012;28(8):1070-1078.
• Spakova T, Rosocha J, Lacko M, Harvanova D, Gharaibeh A. Treatment of knee
joint osteoarthritis with autologous platelet-rich plasma in comparison with
hyaluronic acid. American journal of physical medicine & rehabilitation /
Association of Academic Physiatrists. May 2012;91(5):411-41

PRP and Hip OA
• Ultrasound-guided platelet-rich plasma
injections for the treatment of osteoarthritis
of the hip Sanchez et al. Rheumatology 2011
• 40 pts with severe hip OA
• 1 injection of PRP weekly for 3 weeks
• 57% had significant reduction in pain (30-70%)
• Followed up to 6 months with persistent gains

PRP vs HA and Hip OA
• Efficacy of Ultrasound-guided Intra-articular
Injections of Platelet-rich Plasma Versus
Hyaluronic Acid for Hip Osteoarthritis Battaglia et
al. Orthopedics 2013
• 100 pts with unilateral hip OA
• 3 injections of PRP or HA over 6 weeks
• Hip-Harris/VAS improved

PRP in OA
• Platelet-rich plasma: why intra-articular? A systematic review
of preclinical studies and clinical evidence on PRP for joint
degeneration Knee Surgery, Sports Traumatology, Arthroscopy 2013
• “the preclinical literature shows an overall support toward this
PRP application. An intra-articular injection does not just target
cartilage; instead, PRP might influence the entire joint
environment, leading to a short-term clinical improvement.”
• Clinical studies demonstrate most benefit in younger(<65) and
less severely affected (mild-moderate) individuals

PRP Wrap Up
• Great potential
– Mild-moderate OA
– Lasts 6 months-2 years
– Uses appear varied but not a panacea
– More Science needed

http://www.nature.com/aps/journal/v34/n6/full/aps201350a.html
The Science of Stem Cells

Safety
• Safety of autologous bone marrow-derived
mesenchymal stem cell transplantation for
cartilage repair in 41 patients with 45 joints
followed for up to 11 years and 5 months Wakitani et al.
Journal of Tissue Engineering and Regenerative Medicine Volume 5, Issue 2,
pages 146–150, February 2011
• Excellent Safety
• No Cancer, no Infections

Homing and Growth
• Homing and reparative effect of intra-articular injection of
autologus mesenchymal stem cells in osteoarthritic animal
model. Mokbel et al BMC Musculoskelet Disord. 2011 Nov 15;12:259.
• Methods: 27 donkeys (induced arthritis with Amphotericin B)
– MSC harvested and tagged with fluorescent proteins
– Control was HA injection vs HA with MSC’s
• Outcomes: Synovial fluid, histopathologically; articular cartilage structural changes, reduction of articular
cartilage matrix staining, osteophyte formation, and subchondral bone plate thickening were graded
• The reparative effect of MSCs was significant both clinically and radiologically
in all treated groups (P < 0.05) compared to the control groups. Tagged cells
were found integrated within the cartilage surface
• CONCLUSIONS: Homing was confirmed by the incorporation of injected GFP-labeled MSCs within the
repaired newly formed cartilage. Significant recovery proves that the use of IA injection of autologous
MSCs is a viable and a practical option for treating different degrees of osteoarthritis.

• Cartilage regeneration by selected chondrogenic clonal
mesenchymal stem cells in the collagenase-induced monkey
osteoarthritis model. Jiang et al J Tissue Eng Regen Med. 2014 Nov;8(11):896-905
• Methods: Intra-articular cartilage lesions induced by collagenase
injections in monkeys were treated with normal saline (NS) or
stem cells
• Outcomes: Functional parameters, radiographic images,
histological and immunohistochemical examinations at weeks 8,
16 and 24 post-treatment demonstrated that the abrasions of
articular cartilage were significantly improved and repaired by
MSC-based treatment
Reparative Effects of Stem Cell

Stem Cells in Shoulder
• A prospective multi-site registry study of a specific protocol of
autologous bone marrow concentrate for the treatment of shoulder
rotator cuff tears and osteoarthritis. Centeno et al. J Pain Res. 2015
Jun 5;8:269-76.
• 115 shoulders in 102 patients
• Dash Score improves 36.1-17.1 , average subjective improvement of
48.8%

• Mesenchymal Stem Cell Implantation in Knee
Osteoarthritis: An Assessment of the Factors
Influencing Clinical Outcomes. Kim et al Am J Sports Med. 2015
Jun 25
• Methods: Retrospective follow up of 49 pts s/p MSC
injection for knee OA
• Inclusion: Isolated full-thickness cartilage lesion and
Kellgren-Lawrence OA grade 1 or 2
• Outcomes: Excellent (43.6%), 17 as good (30.9%), 11 as
fair (20.0%), and 3 as poor (5.5%)
• Poor Predictive factors: Age > 60 and lesion size > 6cm
squared
Stem Cell in Knee OA

A Case Review
• 77 y/p female with Left Knee Pain and Xray with moderate knee
OA
• Tx: NSAIDs, Ice, rest, activity modification, Multiple IA steroid
injections, Eufflexa, Medial mensicectomy in 2014
• Opted for BMAC: At 8 weeks 0% improved

A Case Review
March
2014
April
2014
May 2015

BMAC Injection vs ACI
• Autologous bone marrow-derived
mesenchymal stem cells versus autologous
chondrocyte implantation: An observational
cohort study. Am J Sports Med 38:1110–1116 Nejadnik et al 2010
• 72 matched patients followed for 3, 6, 9, 12, 18, 24
months
• Functional outcomes were equal at 2 years'
follow-up, with less cost and donor site morbidity
noted in the BMAC group

• Long-Term Follow-up of Intra-articular Injection of Autologous
Mesenchymal Stem Cells in Patients with Knee, Ankle, or Hip
Osteoarthritis. Emadedin et al. Arch Iran Med. 2015 Jun;18(6):336-44.
• Methods: 18 patients followed with clinical examinations, MRI
and laboratory tests at 2, 6, 12, and 30 months post-
transplantation
• Outcomes: All patients exhibited therapeutic benefit including
increased walking distance, decreased visual analog scale (VAS),
and total Western Ontario and McMaster Universities OA Index
(WOMAC) scores and MRI findings.
Longevity

Longevity
• Mesenchymal stem cell therapy for knee
osteoarthritis: 5 years follow-up of three
patients. Davatchi et al. Int J Rheum Dis. 2015 May 20
• Outcomes: All parameters improved in
transplant knees at 6 months (walking time,
stair climbing, gelling pain, patella crepitus,
flexion contracture and the visual analogue
score on pain).
– Gradually deteriorated, but at 5 years they were still better than at
baseline. PGA (Patient Global Assessment) improved from baseline to
5 years. The better knee at baseline (no MSC), continued its progression
toward aggravation and at 5 years became the worse knee.

Orthobiologics
• Great potential
• More research needed

What do you use as conservative treatment
options for knee OA?

Do you follow the international guidelines such
as AAOS or OARSI for non-pharmacological
and pharmacological modalities for knee OA
treatment?

Are you using visco-supplementation or HA
injections?

Do you believe there’s a placebo effect with
these injections?
Do patients ask for injections and you give it to
them?

How do you write prescriptions for OA bracing?
Do you write the product name, or is it
general?

How do you think we should get patients to ask
for an Unloader brace?

Where are OA knee braces typically prescribed
in your OA knee protocol?
Is it after or included with NSAIDS,
corticosteroid injections, HA injections, PRP,
insoles or wedges, weight loss/diet, exercise
or PT?

What are the top barriers you have to
prescribing OA knee bracing?
Is it cost, patient compliance, efficacy and
outcomes, insurance and reimbursement,
prescribing habits, or complexity of
ordering/applying a brace?

What factors are important to you when
prescribing a brace?
For example: testimonials, clinical efficacy and
outcomes research, patient support
services/education programs, simplicity for
clinician, patient compliance, patient ease of
use, service/rep relationship, cost of brace to
patient, cost of brace to business, innovation,
brace biomechanics.

Regarding insurance and reimbursement for
bracing, what information would be helpful to
you when prescribing or applying braces?

Would a sample program be helpful in showing
patients the benefits of bracing?

Do you look to any specific periodicals, such as
AJSM or Sports Health, to stay in tune with
new studies or information?

Would an e-newsletter from Össur, on a
quarterly basis, be helpful in highlighting the
new products, data, and clinical information
on our products?

How can Össur help provide additional value to
your practice/business?

Conservative Management of Knee osteoarthritis

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