ICRS 2016 SORRENTO

Consultant: Vericel Inc. Consultant: Orthospace Inc. Consultant: Cartiheal Inc. Consultant: Aesculap Inc.

Board Member: Virginia Life science Investments LLC

80,000 AMERICANS /YEAR HAVE TREATABLE INJURIES OF AC

880,000 AMERICANS /YEAR HAVE TREATABLE INJURIES OF ARTICULAR CARTILAGE

IF LEFT UNTREATED MANY GO ON TO END STAGE DJD

WHAT CAN WE DO NON OPERATIVELY TO MITIGATE SYMPTOMS - ENHANCE LIFESTYLE -AND AVOID THE NEED FOR END STAGE SURGICAL RX

NSAIDS are effective in blocking pain and inflammatory response Toxicity exists: liver, GI, renal COX-2 Inhibitors: less GI toxicity but more expensive: Liver, Renal toxicity still exists

NO EVIDENCE OF CHONDRO-PROTECTIVE EFFECT -Stanley, Weaver Clin Sp. Med 1998 EVIDENCE OF ANTI-METABOLITE FNT. I.E. INHIBIT GAG SYNTHESIS IN ART. CART. / INHIBITS REPAIR -Abraham,Weissman et al. JNL Rh. & Arthritis 1989

Bone Soft Tissue Articular Cartilage

- cells / matrix Synovial Fluid

Middle arch. zone called “the netting” is made of aggregates of proteoglycans: This netting holds water ie: gives hydrophilic properties

Increase amount of gags to allow tissue repair & slow tissue breakdown Restore visco-elastic prop. of joint fluid Maintain nml. rheologic function promote exchange of wear by-products & encourage cell nutrition Decrease inflammatory cytokines Promote chondrogenesis in defect Avoid Mechanical Wear or Breakdown

Exercise Neutraceuticals Viscosupplementation

Unloading Braces PRP Stem cells (Allo/Auto) Concentrated Autogenous disease modifiers

Inactivity/ sedentary life style yields loss of proteoglycans / chondropenia (both animal & human studies.) (catabolic effect) Animal models show reversibility of these changes w/ exercise. Anabolic effect on cartilage. Rheologic benefit of ROM and exercise accepted. Decrease activity additionally yields obesity and psychologic depression.

RCT: 439 elderly patients disabled from arthritis placed on exercise programs: -JAMA 1997 Ettinger Burns et al

Modest improvements in measure of disability, physical performance and pain were seen with both aerobic and stregnth training programs

Systematic Database search of RCT’s on stregnth training: -Lange, Vanwanseele & Fiatrone Arthritis Care and Research 2008

Resistance Training improved muscle stregnth and significant improvement in all performance based physical function measures except walk time in 75% of studies

ASU (Avocado-Soybean Unsaponifiables)* 300-600 mg Chondroitin* 800-1,600 mg

Glucosamine* 1,500-3,000 mg

Vitamin D3 1,000 IU & up

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Hyaluronic Acid (oral), (Hyal-Joint®) 80 mg/day

SAM-e (s-adenosylmethionine)* 800-1600 mg

Omega-3 Fish Oil 2 gm & up of actual Omega-3

MSM (methylsulfonylmethane, ) 1,500-6,000 mg

Slide generously donated by Dr.

Theo * Also sold as OTC or Prescription drugs in some

countries

AMINO- PRECURSOR TO GAG’S DERIVED FROM CRUSTACEAN SHELLS & THROUGH FERMENTATION In Vitro actions: STIMULATE SYNOVIOCYTES STIMULATE CHONDORCYTE PRODUCTION OF TYPE II COLL.&GAG ANTI-INFLAMMATORY ACTIVITY

- MCNAMARA & BARR 1997

PLACEBO CONTROLLED DB. STUDY 80 IN-PTS IN ITALY GOOD- TO EXCELLENT PAIN RELIEF 69% NO CHANGE IN CBC, BUN, PT,PTT, GLUCOSE LESS THAN 3% SIDE EFFECTS OVERALL INCLUDING HEARTBURN, HEADACHE, NAUSEA, DIARREAH AND DROWSINESS

In vitro studies, there is an anabolic effect in cartilage, both glycosaminoglycans and hyaluronan increased It inhibits the catabolic activity inhibiting metallic proteinase Multiple animal studies have shown an anti-reactive effect in arthritis models

FEBS Letti(Netherlands)Jn 2002 - modulates IL-1 : induces articular

chondrocytes at a receptor level to make less receptors:

- inhibits NF Kappa B pathway These effects reverse the decrease in PG

synthesis induced by IL-1( via mRNA up- regulation at the cellular level) in DJD

Randomized controlled study 212 OA pts with grade II or III DJD looking at x-ray changes over a 3 year period Gp 1 got glucosamine Gp2 Placebo

Glucosamine

1500 mg qd

Joint space +.07mm -.31mm

WOMAC OA index +24.3% -9.8% P=.016

Placebo

Most abundant GAG in Cartilage THEORETICAL ACTIONS: Inhibits degradative enzymes Adds to GAG pool thereby yielding anabolic effect on cartilage via mRNA syn) Prevents synoviocyte thrombosis: Positive effect on cell nutrition) Decrease Metalloproteinase & NO in vitro In Summary: Slows matrix degradation post injury

Study was double-blind, placebo-controlled, randomized: Meniscectomy model in 42 rabbits followed for 4 month: Assessed grossly and histologically Significant benefit seen in Cosamin®DS group – no severe lesions and substantial reduction in extent of moderate lesions (p<0.003)

COMBINATION THERAPY: Glucosamine

plus chondroitin sulfate:

Lippiello L, et al 2000

Low serum levels of 25-vitamin D (8-29 ng/ml) = Odds Ratio is 3.2 for developing OA over 8 years7

Vitamin D has been shown to stimulate proteoglycan synthesis by mature chondrocytes in tissue culture 1,2 D Modulates the activity of metalloproteinase enzymes 3-6

Slide generously donated by Dr. Theo

1- Ann Endocrinol (Paris) 1981;42:482-7.

2- Endocrinology 1993;132:1544-52.

3- Calcif Tissue Int 1996;59:109-16.

4- Connect Tissue Res 1996;35:331-6.

5- J Cell Physiol 1996;168:570-9.

6- J Biol Chem 1994;269:28374-81.

7- Lane, N. Arthritis Rheum. 1999;42:854-

60

Safety has been documented: --over 675 published studies

Efficacy has been demonstrated: --28 RCTs/ 3 meta analyses

Questions still persist about associated chondro-protective effect in humans

Several animal studies show potential chondroprotective effects in vitro and in animals: Protection against chondral change after menisectomy seen in sheep model. ACL-deficient canine model: Hi MW HA shown to preserve chondrocyte viability & inc. cartilage matrix production 1 RCT Human study with Low MW Hyaluronon suggests chondroprotective effect -Using high magnification arthroscopy reconstitution of superficial amorphous layer seen plus inc. chondrocyte density with HA vs placebo

After ligament/meniscal trauma can OP-1 (BMP-7) mitigate against rapid downhill trend in chondral health?(Can increase PG synthesis and inhibit cytokine/ IL-1 in vitro) Can PRP effect chondrogenesis or symptom relief in chondral defects or arthritis? What about augmenting autologous inhibitors of IL-1 from peripheral blood?(Orthokine/regenokine) What are our best Stem cell sources?

Non-surgical alternative to unload injured cartilage Single Upright: G-II Double Upright: DJ Ortho/ Breg

DJ Ortho: Adjustable Post Op Unloader for perioperative period

MEAN ADDUCTION MOMENT W/O BRACE = 4.0 + .8% BW X HT. W/ BRACE MAM = 3.6 + .8% BW X HT 10% DECREASE IN ADDUCTION MOMENT- 1 STD. DEV. FROM NORMAL MEAN 9/11 PTS. SHOWED THIS DEC. 5/11 SHOWED > 10% UP TO 32 %

-Lindenfeld, Noyes et al

11 Subjects with medial OA and Varus Knees Valgus Moment could be increased 7.6-11 nm with brace applied at varying positions Statistically Significant VAS Pain score improvement noted vs non braced knees Activity Score improvement noted in braced vs non braced

-Warren, Wickiewicz AOSSM Mtg 7/1/2001

Activity modification: Avoid high impact load but encourage low impact exercise (maintain rheologic fnt) * Cyclic loading Glucosamine/Chondroitin 1500 mg BID Unloading brace for unicondylar defects and malalignment for activity . Annual Injectable: HA-Visco/ PRP/Stem cell (Studies pending in US to determine comparitive

efficacy and gain insurance coverage) Reserve NSAIDS for after athletic challenge