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Consequence of Knee Joint Injury in Youth Sport Implica@ons for Osteoarthri@s J.L. WhiEaker, L.J. Woodhouse, J.L. Jaremko, R.

Azzat, J Kang, C.A. Emery Osteoarthri@s (OA) Osteoarthri@s is the most common chronic joint disease for which there is no cure.

1 Consequence of Knee Joint Injury in Youth Sport for J.L. WhiEaker, L.J. Woodhouse, J.L. Jaremko, R. Krawetz, J Ronsky, D Marshall, C McKay, P Doyle- Baker, P Wiley, R Ferber, M Brussoni, A Azzat, J Kang, C.A. Emery Osteoarthri@s (OA) Osteoarthri@s is the most common chronic joint disease for which there is no cure. Progressive joint damage, Loss of range of mo@on, Increasing pain and significant disability. Growing personal and societal burden Lawrence et al 2008, Chen et al 2012, Murray et al 2012, Vos et al

Osteoarthri@s (OA) Tradi@onally associated with aging, however is now

Individual Predisposi@ons Lifestyle Factors (e.g.

Osteoarthri@s Categories of Osteoarthri@s Idiopathic OA (older adults

2 (OA) associated with aging, however is now known to have risk factors & aﬀect all ages. Individual Lifestyle Factors (e.g. (e.g. obesity, Joint Injury Jinks 2007 Categories of Idiopathic OA (older adults o]en those overweight / obese) Post- trauma@c OA (younger adults in response to joint injury) Emery 2003, Misera

Post- Trauma@c Osteoarthri@s Joint Injury Post- trauma@c OA (PTOA) Knee injuries account for

PTOA 10 fold increased OA risk 12-20 years post knee injury Emery 2003, 2006, Englund et al 2003,

Preven$on Ter$ary Preven$on SUSCEPTIBILE Prevent or reduce joint injuries, (sport groups).

3 Post- Joint Injury Post- OA (PTOA) Knee injuries account for 35-40% of all youth sport injuries requiring medical Knee joint is commonly aﬀected by PTOA 10 fold increased OA risk years post knee injury Emery 2003, 2006, Englund et al 2003, Roos 2005, Misera 2014 of PTOA Epidemiological Approach Primary Preven$on Secondary Preven$on Ter$ary Preven$on SUSCEPTIBILE Prevent or reduce joint injuries, (sport groups). PRE- SYMPTOMATIC Slowing or halt disease onset, (post- joint injury). DISEASE Improve & reduce disability. 3

Osteoarthri@s Joint Injury Post- trauma@c OA (PTOA) Improved understanding could facilitate; Chu et al

previous sport knee joint injury & outcomes indica@ve of early onset PTOA (< 10 yrs post- injury).

4 Joint Injury Post- OA (PTOA) Improved understanding could facilitate; Chu et al Early Development of secondary strategies Aim Examine the between previous sport knee joint injury & outcomes of early onset PTOA (< 10 yrs post- injury). Structural MRI Behavioral Physical Physiological Biomarkers Early Knee PTOA Clinical Strength KOOS 4

Objec@ves Determine if young adults with a history of knee injury differ from healthy matched (age, sex, sport) controls in the first 10 yrs post- injury; Structural MRI/USI 1 o MRI OA Knee Score

5 Determine if young adults with a history of knee injury differ from healthy matched (age, sex, sport) controls in the first 10 yrs post- injury; Structural MRI/USI 1 o MRI OA Knee Score (MOAKS) 2 o Blood serum biomarkers KOOS Quadriceps strength Physical ac@vity par@cipa@on Exploratory; addi@onal structural, physiological, clinical, func@onal, behavioral, healthcare u@liza@on outcomes. Behavioral Physical Ac@vity Func@onal Strength Early Knee PTOA Clinical KOOS Physiological Biomarkers % body fat Methods Previous Cohort Studies that Examined Risk Factors Injury in Youth Sports High School Ice Hockey Male / Female Soccer Junior High School Basketball 100 Intra- ar@cular Knee Injury (past 3-10 yrs) 100 Matched Controls (age, sex, sport) Sport Medicine Clinic INTRA- ARTICULAR KNEE INJURY Diagnosis of ligament, meniscal or other intra- femoral or patello- femoral injury that required both medical consulta@ons & resulted in a disrup@on of regular sport par@cipa@on. 5

High School Ice Hockey Male / Female Soccer Junior High School Basketball 100 Intra- ar@cular Knee Injury (past 3-10 yrs) 100 Matched Controls (age, sex, sport) Sport Medicine Clinic Func$onal (Quads

6 High School Ice Hockey Male / Female Soccer Junior High School Basketball 100 Intra- ar@cular Knee Injury (past 3-10 yrs) 100 Matched Controls (age, sex, sport) Sport Medicine Clinic Func$onal (Quads Diff) Behavioral (PA Par@cipa@on) Structural (MRI, USI) Physiological (Biomarkers, Adiposity) 50 matched pairs (n = 100) Biomarkers KOOS Adiposity Aerobic Fitness Quadriceps Strength PA Par@cipa@on 25 matched pairs (n = 50) VM CSA Clinical (KOOS) 10 matched pairs (n = 20) MRI (MOAKS) Primary Outcome Behavioral (PA Par@cipa@on) Structural (MRI, USI) MRI Knee OA Score (MOAKS) Whole- organ comprehensive inventory of possible abnormali@es related to OA. Func$onal (Quads Diff) Physiological (Biomarkers, Adiposity) + ve MRI outcome; sum 1 of the bone marrow lesion, car@lage loss, synovi@s/ effusion, and meniscal sub- scales. Bilateral clinical imaging series (1.5 Tesla) axial, coronal & sagieal proton density, Clinical (KOOS) proton density fat satura@on Hunter et a. 2011, Roemer et al 2012, Bloecker et al 6

7 Secondary Outcomes Func$onal (Quads Diff) Behavioral (PA Clinical (KOOS) Structural (MRI, USI) Physiological (Biomarkers, Adiposity) Blood Serum Biomarkers Serum OA biomarker profile 99% in adults Knee Injury OA Outcome Score Pain, Symptoms, ADL, Sport Rec, QoL Quadriceps Strength Difference Hand held dynamometry (open chain) Normalized (BW) max. torque Amount of Moderate- Vigorous PA/week Godin Leisure Time Exercise Godin & Shephard 1985, Roos et al 2003, Erhart- Hledic et al 2012, Heard et al Exploratory Outcomes Func$onal (Quadriceps, Balance) Behavioral (PA Structural (USI) Physiological (Adiposity, Aerobic Fitness) Vastus Medialis CSA Sonography Adiposity % Body Fat BMI Waist/height ra@o % body fat (dual- Energy X- ray absorp@ometry) Aerobic Fitness VO 2 max (20m ShuEle run) Clinical (KOOS) Brandt et al 1991, WhiOaker et al

8 Analysis Covariates of entry into the original cohort study) Follow- up Follow- up Covariate Injured Uninjured Age (years) Means (95% CI) or Median (range) Sex Propor@ons (95% CI) Height (cm) Weight (kg) Means (95% CI) or Median (range) Sport Propor@ons (95% CI) *Clinical differences will examined and accounted for in analyses Analysis Follow- up to Recruitment Covariates Follow- up Follow- up Covariate Par$cipants Non- Par$cipants Age (years) Sex Sport Means (95% CI) or Median (range) Propor@ons (95% CI) Propor@ons (95% CI) *Non- par@cipa@on rates will be reported. *Compare covariates for those lost to f/u vs. those remaining in the study. 8

Analysis Primary, Secondary & Exploratory Outcomes Follow- up 2 2014 Follow- up 3 2015 Func$onal (Quads Diff) Behavioral (PA Par@cipa@on) Clinical (KOOS)

PRELIMINARY ANALYSES Descrip@ve Sta@s@cs Mean (95% CI) or Median (95% CI) Propor@ons (95% CI) Risk Ra@os (RR; 95%CI) MOAKS (score > 1) BMI (normal vs.

Injured n=21 Sex (% female, 95%CI) 42 (32,52) 42 (32,52) Age (yrs; mean, 95% CI) 14.4 (13.3,15.4) 14.3 (13.6,15.0) Height (cm; mean 95%CI) 167.5 (161,174) 173.

9 Analysis Primary, Secondary & Exploratory Outcomes Follow- up Follow- up Func$onal (Quads Diff) Behavioral (PA Par@cipa@on) Clinical (KOOS) Structural (MRI, USI) Physiological (Biomarkers, Adiposity) PLANNED ANALYSES Mul@variate condi@onal logis@c regression Adjust for modifica@on or confounding PRELIMINARY ANALYSES Descrip@ve Sta@s@cs Mean (95% CI) or Median (95% CI) Propor@ons (95% CI) Risk Ra@os (RR; 95%CI) MOAKS (score > 1) BMI (normal vs. overweight/obese) VM CSA (side- to- side asymmetry > 15%) Principal Component Analysis Biomarkers Characteris@cs (n= 38 of 100) Characteris$c Uninjured n=17 Injured n=21 Sex (% female, 95%CI) 42 (32,52) 42 (32,52) Age (yrs; mean, 95% CI) 14.4 (13.3,15.4) 14.3 (13.6,15.0) Height (cm; mean 95%CI) (161,174) (169,178) Weight (kg; mean 95%CI) 55.3 (47.6,63.1) 67.4 (61.5,73.2) Sport; 32% Soccer 32% Hockey 9% Track/running 8% Basketball 4% Volleyball 4% Skiing 4% Football 2% Dancing 2% Rugby 2% Baseball 9

10 (n=100) Characteris$cs Uninjured n=50 Injured n=50 Sex (% female) Age (yrs; median, range) 22 (14-26) 22 (16-26) to Follow- up (yrs; median, range) 7.0 (4.7,9.8) 5.8 (3.6,9.2) Age at Injury (yrs; median, range) - 15 (9-18) Injury to (yrs; median, range) ( ) # Study Knee Surgeries 0 27* # Contralateral Knee Injuries 1 16 # Contralateral Knee Surgeries 0 8 ϕ # Ipsilateral Lower Limb Injuries 5 5 # Contralateral Lower Limb Injuries 8 4 *20 of these were ACL reconstruc@ons; ϕ 3 of these were ACL reconstruc@ons Characteris@cs (n=100) Diagnos$c Category Uninjured n=50 No Injury 50 - Injured n=50 3 o ACL / PCL tear - 20* Meniscal Injury - 9 ϕ Other Ligament (1-3 o MCL, LCL or 1-2 o ACL, PCL) - 4 Fracture - 2 Other Knee Injury (patellar disloca@on and subluxa@ons, etc.) - 15 *all under went ACL reconstruc@on; ϕ 5of these had arthroscopic surgery 10

Primary Objec@ve; MOAKS (n=20) Characteris$c / Outcome Uninjured n=10 Injured n=10 Sex (% female, 95%CI) 60 (36,84) 60 (36,84) Injury age (yrs; median, range) n/a 15 (13-18) Follow- up age (yrs;

11 Primary MOAKS (n=20) Characteris$c / Outcome Uninjured n=10 Injured n=10 Sex (% female, 95%CI) 60 (36,84) 60 (36,84) Injury age (yrs; median, range) n/a 15 (13-18) Follow- up age (yrs; median, range) 23 (18-26) 23 (17-26) Injury to Follow- up (yrs; median, range) n/a 8.1 ( ) MOAKS Score ϕ (median, range) 0 (0-7) 5 (0-41) ϕ Sum of BML, car@lage loss, synovi@s/effusion and meniscal sub- scales Primary Objec@ve; MOAKS (n=20) Uninjured Injured 0 BML Car@lage Synovi@s/Eff Meniscal Ligament Rater was blinded to study group MRI year findings old individuals were pre- clinical with a 4-9 yr history of intra- ar@cular knee injury are more small likely meniscal to have tears, a MOAKS car@lage score defects and 1 than bone healthy marrow sex, edema age and sport matched controls (95%CI; 1.14,7.90) Roemer et al 2009, Koster et al 2011 Preliminary Findings Only 11

Secondary Objec@ve; Inflammatory Biomarkers (n=100) PCA Score Plots by Study Group Uninjured Young (15-26) Injured Young (15-26) PC2 95% Confidence Intervals Healthy Old Healthy Old ( 40) OA Old (

12 Secondary Inflammatory Biomarkers (n=100) PCA Score Plots by Study Group Uninjured Young (15-26) Injured Young (15-26) PC2 95% Confidence Intervals Healthy Old Healthy Old ( 40) OA Old ( 40) OA Old Injured Young Uninjured Young * PC2 Value PC1=47% PC2=11% Injured and uninjured study groups had similar profiles however these differed from older ( 40) healthy and OA (radiographic) profiles. Heard et al Secondary Objec@ve; KOOS (n=100) (3-10yrs ago) Mean KOOS Score Uninjured Injured 70 Pain* Symptoms* ADL* Sport/Rec* QoL* KOOS (higher score = beeer) Outcome Uninjured (n=50) Mean (95%CI) Injured (n=50) Mean (95%CI) Pain 97.0 (95.6,98.4) 93.0 (90.5,95.5)* Symptoms 92.4 (90.0,94.8) 82.9 (79.5,86.4)* ADL 99.3 (98.8,99.8) 96.3 (94.4,98.2)* Sport/Rec 97.4 (96.4,98.5) 90.6 (87.8,93.3)* QoL 97.7 (96.6,98.8) 89.7 (87.3,92.1)* 12

Exploratory; Quadriceps Strength / Size (n = 100) (3-10yrs ago) Uninjured Knee Injured Knee Uninjured (n=50) Injured (n=50) Outcome Mean (95%CI) Mean (95%CI) 17-26 year old individuals Quadriceps

8 @mes more likely to have a difference in VM CSA > 15% than Strength Side to Side diff (Nm/kg) 0.35 (0.26,0.45) 0.21 (0.15,0.28) healthy controls (RR = 3.77, 95% CI 1.1,15.0). Strength ra@o 1.07 (0.

Wang et al 2002, Aalund et al, WhiOaker & Emery 2014 Exploratory Objec@ve; Adiposity (n = 100) (3-10yrs ago) Outcome Uninjured (n=50) Mean (95%CI) Injured (n=50) Mean (95%CI) BMI (kg/m 2 ) 23.2 (22.

13 Exploratory; Quadriceps Strength / Size (n = 100) (3-10yrs ago) Uninjured Knee Injured Knee Uninjured (n=50) Injured (n=50) Outcome Mean (95%CI) Mean (95%CI) year old individuals Quadriceps *Strength with (Nm/kg) a 3-10 yr history 1.9 (1.8,2.1) of intra- ar@cular 1.8 knee (1.6,1.9) injury are are more likely to have a difference in VM CSA > 15% than Strength Side to Side diff (Nm/kg) 0.35 (0.26,0.45) 0.21 (0.15,0.28) healthy controls (RR = 3.77, 95% CI 1.1,15.0). Strength ra@o 1.07 (0.98,1.15) 1.02 (0.96,1.07) Vastus Medialis Area (cm 2 ) 2.1 (1.5,2.7) 1.6 (0.5, 2.6) *Study knee (injured knee and corresponding knee of control); 25 matched pairs. Wang et al 2002, Aalund et al, WhiOaker & Emery 2014 Exploratory Objec@ve; Adiposity (n = 100) (3-10yrs ago) Outcome Uninjured (n=50) Mean (95%CI) Injured (n=50) Mean (95%CI) BMI (kg/m 2 ) 23.2 (22.4,24.1) 25.4 (24.3,26.5)* Waist/Height Ra@o 0.45 (0.43,0.46) 0.47 (0.45,0.48) % Body Fat 18.7 (16.9,20.5) 20.8 (18.6,23.1) % Body Lean 77.7 (75.9,79.4) 75.7 (73.6,77.9) year old individuals with a 3-10 yr history of intra- ar@cular knee injury 24 are at a greater risk to have a BMI ra@ng of overweight or obese 23 compared to health matched controls (95%CI; 1.09,3.68) BMI (kg/m 2 ) 20 Uninjured Injured Cole 2000, hop:// 13

14 Exploratory Aerobic Fitness, PA (n=100) (3-10yrs ago) Outcome Uninjured (n=50) Mean (95%CI) Injured (n=50) Mean (95%CI) Aerobic Fitness VO 2 max (ml/kg 2 ) ϕ 44.6 (42.5,46.8) 42.0 (40.3,45.6) Physical Ac@vity Par@cipa@on Moderate to Strenuous Ac@vity (min/wk) No sport par@cipa@on in last year (%) (87.0,115.8) 97.8 (82.9, 112.7) 4.0 (- 2.0, 9.6) 16.0 (5.6,26.4) ϕ Es@mated from Leger 20m shuele run Although not sta@s@cally significant at a 5% significance level there is a trend for poorer aerobic fitness and reduced physical ac@vity par@cipa@on in the injured study group. Summary (3-8 years ago) Young adults who sustained a sport related intra- ar@cular knee injury (3-10 yrs previous) Higher risk of MRI abnormali@es More knee related symptoms (impact daily ac@vi@es, sport/recrea@on and quality of life) Higher risk of structural (func@onal?) asymmetry of the vastus mediallis Higher risk of being categorized as overweight or obese Trends for increased % body fat and reduced physical ac@vity par@cipa@on 14

clinical (KOOS) structural (MOAKS, VM CSA), physiological (inflammatory biomarker, adiposity, aerobic fitness) and behavioral (reduced

15 Joint Injury PTOA and Obesity (3-8 years ago) é Adiposity ê Muscle JOINT INJURY (3-10 yrs previous) OA STRUCTURAL CHANGES OBESITY (meta- (joint load) ê Physical Wluka et al ê Aerobic Fitness Joint Injury PTOA and Obesity (3-8 years ago) There may be clinical (KOOS) structural (MOAKS, VM CSA), physiological (inflammatory biomarker, adiposity, aerobic fitness) and behavioral (reduced physical acsvity parscipason) markers that can be used to and target at risk individuals at a younger age with secondary preven@on interven@ons. 15

Timeline Future Plans COMPLETED 2003-2010/11 2014 2015 2016 Time

years post injury Yearly follow- up tes@ng 1 year Retrospec@ve

related to a relasvely uninvessgated at risk populason which can

16 Timeline Future Plans COMPLETED / Time since injury 3-10 yrs Time since injury 3-10 yrs Follow- up 6 13 years post injury Yearly follow- up tes@ng 1 year Retrospec@ve Conclusion This project is capable of genera@ng new knowledge related to a relasvely uninvessgated at risk populason which can inform early diagnos@cs and interven@ons aimed at reducing the burden of post- trauma@c OA. 16

PRIMARY INVESTIGATOR Carolyn Emery PT PhD CO-INVESTIGATORS Linda Woodhouse PT PhD

Deborah Marshall PhD Carly McKay PhD Patricia Doyle-Baker DrPH Preston Wiley MD

TRAINEES Byan Heard MSc, PhD Candidate Jennifer Baltich MSc, PhD Candidate Payam

Student Jordan Loudon BSc, MSc (Kin) Student Bryn Edgerton BSc (Kin) Student

17 PRIMARY INVESTIGATOR Carolyn Emery PT PhD CO-INVESTIGATORS Linda Woodhouse PT PhD Jackie Whittaker PT PhD Roman Krawetz PhD Jacob Jaremko MD PhD Janet Ronsky PEng PhD Deborah Marshall PhD Carly McKay PhD Patricia Doyle-Baker DrPH Preston Wiley MD Jessica Kupper Reed Ferber PhD Jain King PhD Allison Ezzat PT MSc, PhD Student TRAINEES Byan Heard MSc, PhD Candidate Jennifer Baltich MSc, PhD Candidate Payam Zandiyeh Eng, PhD Candidate Sarah Kenny MSc, PhD Student Kerry MacDonald MSc, PhD Student Jordan Loudon BSc, MSc (Kin) Student Bryn Edgerton BSc (Kin) Student FUNDING; RESEARCH COORDINATORS Gabriella Nasuti MSc Research Coordinator Jamie Rishaug Research Coordinator 17

Preventing Joint Injury & Subsequent Osteoarthritis:

Preventing Joint Injury & Subsequent Osteoarthritis: A Population Health Prospective Carolyn Emery PT, PhD Public Health Burden of Injury in Alberta The leading cause of death and hospitalization in youth