Supplemental Online Content
Messier SP, Mihalko SL, Beavers DP, et al. Effect of high-intensity strenght training on knee pain and knee joint compressive forces among adults with knee osteoarthritis: the START randomized clinical trial. JAMA. doi:10.1001/jama.2021.0411
eTable 1 Comparison of Baseline Values of Completers and Noncompleters
eTable 2. Pairwise Between-Group Differences At 18-Month Follow-Up For Pre-Specified Primary And Secondary Outcomes, And Post Hoc Outcome From Multiply Imputed Data eTable 3. Primary Outcome Analyses Mean Values Adjusted For Baseline Frontal Plane Alignment Or Patellofemoral OA
eTable 4. Pre-Specified Secondary Outcomes At 6-month Follow-Up
eTable 5. Unadjusted Changes In Pre-Specified Secondary And Post-Hoc Outcomes At 18-Month Follow-Up
eTable 6. Serious Adverse Events (SAE)
eTable 7. Most Commonly Occurring Adverse Events (AEs) By Group Assignment eTable 8. Adverse Events Related To The Study By Group
eFigure 1. Unadjusted Mean WOMAC Function, and Unadjusted Mean 6-Minute Walk Distance eFigure 2. Unadjusted Mean Knee Extensor Strength, Unadjusted Mean Knee Flexor Strength, and Unadjusted Mean Hip Abductor Strength
eFigure 3. Unadjusted Mean Medial Tibiofemoral Joint Space Width, Unadjusted Mean Thigh Muscle Volume, Unadjusted Mean Thigh Fat Volume, and Unadjusted Mean Log IL-6 Levels eFigure 4. Percent Pain Medication Use By Group
This supplemental material has been provided by the authors to give readers additional information about their work.
eSupplement 2
eTable1. Comparison of baseline values of completers (attended 18 month testing) and
non-completers (no 18 month data) (N=377).
All 18 Month Dropouts n=57 18 Month Completers n=320 Variable N Mean ± SD or N (%) N Mean ± SD or N (%) N Mean ± SD or N (%) P-value Age (yrs) 377 65.0 ± 8.0 57 63.0 ± 9.6 320 65.3 ± 7.7 0.04 BMI (kg/m2) 377 31.4 ± 5.5 57 31.6 ± 4.8 320 31.3 ± 5.6 0.77 Weight (kg) 377 89.0 ± 17.8 57 89.7 ± 17.5 320 88.9 ± 17.9 0.76 Height(cm) 377 168.3 ± 10.1 57 168.3 ± 11.2 320 168.3 ± 9.9 0.98 Fema le Gender 377 151 (40.1) 57 22 (38.6) 320 129 (40.3) 0.81 Ethnicity Hisp 377 3 (0.8) 57 2 (3.5) 320 1 (0.3) 0.08 Ethnicity White 377 296 (78.5) 57 42 (73.7) 320 254 (79.4) Ethnicity Black 377 70 (18.6) 57 12 (21.1) 320 58 (18.1) Ethnicity Other 377 5 (1.3) 57 0 (0.0) 320 5 (1.6) KL Gra de=2 377 184 (48.8) 57 31 (54.4) 320 153 (47.8) 0.60 KL Gra de=3 377 155 (41.1) 57 20 (35.1) 320 135 (42.2) KL Gra de=4 377 38 (10.1) 57 6 (10.5) 320 32 (10.0)
Knee Extensor Strength (Nm) 371 74.53 ± 31.36 57 71.10 ± 31.44 314 75.15 ± 31.35 0.37
Knee Flexor Strength (Nm) 371 37.08 ± 20.96 57 34.59 ± 20.62 314 37.53 ± 21.02 0.33
Hip Abductor Strength (Nm) 361 64.79 ± 23.63 54 66.30 ± 26.66 307 64.53 ± 23.09 0.61
WOMAC Pa in (0-20) 377 7.16 ± 2.68 57 7.53 ± 2.61 320 7.10 ± 2.69 0.27
WOMAC Function (0-68) 377 25.69 ± 10.45 57 27.09 ± 10.03 320 25.44 ± 10.52 0.27
6 Min Wa lk Dista nce(m) 345 478.7 ± 91.4 50 465.1 ± 89.8 295 480.9 ± 91.6 0.26
Pea k Knee Compressive Force (N) 308 2307 ± 738 46 2233 ± 797 262 2320 ± 728 0.46
Joint Spa ce Width (mm) 347 3.06 ± 1.40 56 3.31 ± 1.52 291 3.02 ± 1.37 0.16
Thigh Muscle Volume (cm3) 347 669 ± 181 47 660 ± 199 300 671 ± 178 0.70
Thigh Fa t Volume (cm3) 347 733 ± 353 47 746 ± 354 300 731 ± 353 0.78 IL6 (pg/mL) 373 3.28 ± 3.23 56 3.81 ± 4.83 317 3.18 ± 2.85 0.18 Log-IL6 (log-pg/mL) 373 0.94 ± 0.65 56 1.02 ± 0.71 317 0.93 ± 0.63 0.33 SF-36 Physica l 363 41.9 ± 5.4 54 41.3 ± 6.0 309 42.1 ± 5.2 0.36 SF-36 Mental 363 47.3 ± 5.8 54 46.8 ± 6.1 309 47.4 ± 5.7 0.50 PASE 370 126.9 ± 52.4 55 119.7 ± 51.6 315 128.2 ± 52.5 0.27
eTable 2. Pairwise Between-Group Differences at 18-Month Follow-Up for Pre-specified Primary and Secondary Outcomes, and Post Hoc
Outcome From Multiply Imputed Data Using Repeated Measures ANCOVA.
Outcome High-Intensity vs Control High vs Con P-value High-Intensity vs Low-Intensity High vs Low
P-value Low-Intensity vs Control
Low vs Con P-value Pre-specified Primary Outcomes
WOMAC Pain (0-20) 0.2 (-0.6, 1.0) .59 0.6 (-0.2, 1.4) .11 -0.4 (-1.2, 0.3) .27
Knee Joint Compressive Force (Newtons) -11 (-220, 198) .92 10 (-218, 238) .93 -21 (-240, 199) .85 Pre-specified Secondary Outcomes
WOMAC Function (0-68) 1.3 (-1.4, 3.9) .36 2.6 (0.2, 5.0) .04 -1.4 (-4.0, 1.3) .32
6 Min Walk Distance (m) -4 (-25, 17) .70 4 (-18, 26) .72 -8 (-29, 13) .43
Knee Extensor Strength (Nm) 12.5 (6.2, 18.9) <.001 4.9 (-1.7, 11.4) .15 7.7 (1.4, 14.0) .02
Hip Abductor Strength (Nm) 5.1 (0.7, 9.5) .02 -1.5 (-5.5, 2.5) .47 6.6 (2.4, 10.7) .002
Thigh Muscle Volume (cm3) 7 (-16, 31) .53 -2 (-26, 21) .85 10 (-10, 30) .34
Thigh Fat Volume (cm3) 10 (-33, 52) .65 -7 (-50, 37) .76 16 (-20, 53) .38
log IL6 0.0 (-0.1, 0.2) .81 0.1 (-0.1, 0.2) .41 -0.0 (-0.2, 0.1) .57
Joint Space Width (mm) 0.2 (-0.0, 0.4) .10 0.1 (-0.1, 0.3) .20 0.0 (-0.2, 0.2) .75
Post Hoc Outcome
eTable 3. Primary outcome analyses mean (95%CI) values adjusted for baseline frontal plane alignment or patellofemoral OA score. P values
represent the overall test of group significance.
High Intensity Low Intensity Control P6 P18
Months Months Months
6 18 6 18 6 18
Primary Results Adjusted for Frontal Plane Alignment or Patellofemoral OA Grade aWOMAC Pain
alignment 5.6 5.1 4.3 4.4 4.9 4.9 .004 .25
95% CI 5.1, 6.1 4.5, 5.7 3.8, 4.8 3.8, 5.0 4.4, 5.4 4.2, 5.5
aKnee Comp Force
(Newtons) alignment 2456 2465 2546 2488 2480 2512 .64 .92 95% CI 2312, 2600 2306, 2624 2409, 2684 2336, 2639 2334, 2625 2352, 2673 aWOMAC Pain patellofemoral OA 5.7 5.0 4.4 4.3 5.0 4.8 .004 0.22 95% CI 5.1, 6.2 4.4, 5.6 3.9, 5.0 3.7, 4.9 4.4, 5.6 4.2, 5.5
a Knee Comp Force
(Newtons) patellofemoral OA
2458 2445 2539 2464 2493 2512 0.71 0.83
95% CI 2308, 2607 2281, 2610 2396, 2682 2307, 2621 2339, 2646 2343, 2681
eTable 4. Pre-specified Secondary Outcomes at 6-month Follow-up in a Study of the Effect of High-intensity Strength Training on Knee
Pain and Knee Joint Compressive Forces Among Patients with Knee Osteoarthritis
Outcome High-Intensity Low-Intensity Control Mean difference P
value Primary outcomes
WOMAC pain (0-20)
Baseline mean (SD) 7.0 (2.7) 7.4 (2.6) 7.2 (2.7)
6-month follow-up (SD), unadjusted 5.5 (3.0) 4.5 (2.8) 5.0 (2.8)
6-month absolute change (95% CI) -1.4 (-1.9 to -0.9) (n = 105) -2.8 (-3.3 to -2.2) (n = 102) -2.3 (-2.9 to -1.7) (n = 103) High-intensity vs controla 0.9 (0.1 to 1.7) .03 High-intensity vs low-intensity 1.4 (0.6 to 2.1) <.001 Low-intensity vs control -0.5 (-1.2 to 0.3) .24
6-month adjusted means (95% CI)b 5.6 (5.1 to 6.1)
(n = 91)c 4.4 (3.9 to 4.9) (n = 86) 4.9 (4.3 to 5.4) (n = 84) High-intensity vs control 0.7 (-0.0 to 1.4) .06 d High-intensity vs low-intensity 1.2 (0.5 to 1.9) .001 Low-intensity vs control -0.5 (-1.3 to 0.2) .18
Knee joint compressive force (Newtons)e
Baseline mean (SD) 2326 (727) 2325 (782) 2261 (691)
6-month follow-up (SD), unadjusted 2426 (735) 2475 (777) 2451 (844) 6-month absolute change (95% CI) 108 (5 to 211)
(n = 66) 163 (50 to 276) (n = 66) 121 (-22 to 263) (n = 64) High-intensity vs controla -13 (-181 to 155) .88 High-intensity vs low-intensity -55 (-222 to 112) .52 Low-intensity vs control 42 (-126 to 210) .62
6-month adjusted means (95% CI) 2453 (2311 to 2595) (n = 50) 2536 (2400 to 2671) (n = 55) 2483 (2338 to 2627) (n = 48) High-intensity vs control -30 (-231 to 172) .77 High-intensity vs low-intensity -83 (-276 to 110) .40 Low-intensity vs control 53 (-144 to 250) .60
eTable 4 con’t. Pre-specified Secondary Outcomes at 6-month Follow-up in a Study of the Effect of High-intensity Strength Training on Knee Pain and Knee Joint Compressive Forces Among Patients with Knee Osteoarthritis
Outcome High-Intensity Low-Intensity Control Mean difference P
value Secondary outcomes
WOMAC function (0-68)
Baseline mean (SD) 25.5 (10.3) 26.6 (10.7) 25.0 (10.3)
6-month follow-up (SD), unadjusted 20.8 (11.4) 16.3 (9.5) 18.0 (9.9) 6-month absolute change (95% CI) -4.5 (-6.3 to -2.6)
(n = 105) -9.8 (-11.6 to -7.9) (n = 102) -7.5 (-9.3 to -5.7) (n = 103) High-intensity vs controla 3.0 (0.4 to 5.6) .02 High-intensity vs low-intensity 5.3 (2.7 to 7.9) <.001 Low-intensity vs control -2.3 (-4.9 to 0.3) .08
6-month adjusted means (95% CI)b 20.8 (19.1 to 22.5)
(n = 88)c 16.1 (14.3 to 17.8) (n = 89) 18.1 (16.3 to 19.8) (n = 88) High-intensity vs control 2.8 (0.3 to 5.2) .03 d High-intensity vs low-intensity 4.8 (2.4 to 7.2) <.001 Low-intensity vs control -2.0 (-4.5 to 0.5) .11
6 minute walk distance (m)
Baseline mean (SD) 466 (91) 479 (90) 490 (92)
6-month follow-up (SD), unadjusted 487 (86) 513 (85) 518 (84)
6-month absolute change (95% CI) 14 (2 to 27) (n = 90) 29 (17 to 41) (n = 85) 24 (12 to 35) (n = 77) High-intensity vs controla -9 (-26 to 8) .30 High-intensity vs low-intensity -14 (-31 to 2) .09 Low-intensity vs control 5 (-12 to 23) .56
6-month adjusted means (95% CI) 493 (481 to 506) (n = 73) 514 (502 to 526) (n = 75) 508 (495 to 520) (n = 67) High-intensity vs control -14 (-32 to 3.7) .12 High-intensity vs low-intensity -21 (-38 to -3.6) .02 Low-intensity vs control 6.6 (-11 to 24) .46
aUnadjustedpairwise comparisons based on 6-month changes. bAnalyses were conducted using completers only.
cThe dif ference in the number of participants between the unadjusted and adjusted analyses was due to model-adjusted outcomes using only participants with
complete follow-up data.
dPairwise comparisons were deemed significant at p ≤ .05 from the adjusted ANCOVA model. e1 pound of force is equal to 4.45 Newtons of force.
eTable 5. Unadjusted changes in Pre-specified Secondary and Post-hoc Outcomes at 18-month Follow-up in a Study of the Effect of High-intensity Strength Training on Knee Pain and Knee Joint Compressive Forces Among Patients with Knee Osteoarthritis
Outcome High-Intensity Low-Intensity Control Mean difference
(95% CI)
P value Pre-specified Secondary Outcomes
Secondary outcomes WOMAC function (0-68)
Baseline mean (SD) 25.5 (10.3) 26.6 (10.7) 25.0 (10.3)
18-month f ollow-up (SD), unadjusted 17.2 (11.9) 15.4 (10.9) 15.3 (9.3)
18-month absolute change (95% CI) -8.2 (-10.5 to -6.0) (n = 106) -11.3 (-13.5 to -9.1) (n = 103) -8.7 (-10.7 to -6.7) (n = 99) High-intensity vs controla 0.5 (-2.6 to 3.5) .76 High-intensity vs low-intensity 3.1 (0.1 to 6.1) .05 Low-intensity vs control -2.6 (-5.7 to 0.5) .10
6 minute walk distance (m)
Baseline mean (SD) 466 (91) 479 (90) 490 (92)
18-month f ollow-up (SD), unadjusted 504 (92) 502 (104) 517 (101)
18-month absolute change (95% CI) 27 (9 to 45) (n = 84) 28 (11 to 44) (n = 85) 26 (12 to 41) (n = 81) High-intensity vs control 1 (-22 to 24) .94 High-intensity vs low-intensity -0 (-23 to 23) .99 Low-intensity vs control 1 (-22 to 24) .92
Knee extensor strength (Nm)
Baseline mean (SD) 72.6 (31.2) 75.1 (30.2) 75.9 (32.8)
18-month f ollow-up (SD), unadjusted 95.8 (36.2) 91.8 (35.3) 83.4 (29.2)
18-month absolute change (95% CI) 21.1 (16.1 to 26.1) (n = 92) 15.9 (11.3 to 20.5) (n = 91) 8.2 (3.7 to 12.8) (n = 84) High-intensity vs control 12.9 (6.2 to 19.6) <.001 High-intensity vs low-intensity 5.2 (-1.3 to 11.8) .12 Low-intensity vs control 7.7 (1.0 to 14.4) .03
Hip abductor strength (Nm)
Baseline mean (SD) 62.8 (22.7) 66.9 (25.4) 64.7 (22.6)
18-month f ollow-up (SD), unadjusted 70.3 (25.6) 75.2 (26.9) 65.3 (22.0)
18-month absolute change (95% CI) 7.5 (3.8 to 11.2) (n = 85) 7.3 (4.0 to 10.6) (n = 87) 2.7 (-0.1 to 5.6) (n = 82) High-intensity vs control 4.8 (0.1 to 9.4) .05 High-intensity vs low-intensity 0.2 (-4.4 to 4.8) .93 Low-intensity vs control 4.5 (-0.1 to 9.2) .06
Thigh muscle volume (cm3)
Baseline mean (SD) 662 (183) 685 (188) 661 (171)
18-month f ollow-up (SD), unadjusted 665 (180) 686 (183) 653 (156)
18-month absolute change (95% CI) -2 (-16 to 13) (n = 73) -1 (-22 to 20) (n = 76) -5 (-17 to 6) (n = 75) High-intensity vs control 4 (-19 to 26) .76 High-intensity vs low-intensity -1 (-24 to 22) .92 Low-intensity vs control 5 (-18 to 27) .68
eTable 5 con’t. Unadjusted changes in Pre-specified Secondary and Post-hoc Outcomes at 18-month Follow-up in a Study of the Effect of High-intensity Strength Training on Knee Pain and Knee Joint Compressive Forces Among Patients with Knee Osteoarthritis
Outcome High-Intensity Low-Intensity Control Mean difference
(95% CI)
P value Thigh fat volume (cm3)
Baseline mean (SD) 736 (367) 712 (351) 750 (342)
18-month f ollow-up (SD), unadjusted 731 (390) 678 (339) 751 (368)
18-month absolute change (95% CI) -14 (-42 to 13) (n = 73) 4 (-25 to 32) (n = 76) -18 (-49 to 12) (n = 75) High-intensity vs control 4 (-36 to 45) .84 High-intensity vs low-intensity -18 (-58 to 23) .39 Low-intensity vs control 22 (-18 to 62) .28 Log IL-6b Baseline mean (SD) 1.0 (0.7) 0.9 (0.6) 0.9 (0.7) 18-month f ollow-up (SD) 1.0 (0.6) 0.8 (0.7) 0.9 (0.6)
18-month absolute change (95% CI) -0.1 (-0.2 to 0.1) (n = 92) -0.1 (-0.2 to 0.1) (n = 99) -0.0 (-0.2 to 0.1) (n = 92) High-intensity vs control -0.0 (-0.2 to 0.2) .93 High-intensity vs low-intensity 0.0 (-0.2 to 0.2) .96 Low-intensity vs control -0.0 (-0.2 to 0.2) .89
Joint space width (mm)
Baseline mean (SD) 3.1 (1.3) 3.0 (1.5) 3.0 (1.4)
18-month f ollow-up (SD), unadjusted 3.1 (1.5) 2.8 (1.6) 2.6 (1.5)
18-month absolute change (95% CI) -0.1 (-0.2 to 0.0) (n = 83) -0.2 (-0.4 to -0.1) (n = 84) -0.3 (-0.4 to -0.1) (n = 81) High-intensity vs control 0.2 (-0.0 to 0.4) .07 High-intensity vs low-intensity 0.1 (-0.0 to 0.3) .12 Low-intensity vs control 0.0 (-0.2 to 0.2) .76
Post Hoc Outcome Knee flexor strength (Nm)
Baseline mean (SD) 35.0 (20.1) 38.2 (20.3) 38.1 (22.5)
18-month f ollow-up (SD), unadjusted 50.2 (21.8) 50.8 (23.3) 41.7 (18.8)
18-month absolute change (95% CI) 13.8 (10.5 to 17.1) (n = 92) 12.4 (9.0 to 15.7) (n = 91) 4.7 (1.8 to 7.6) (n = 84) High-intensity vs control 9.1 (4.6 to 13.6) <.001 High-intensity vs low-intensity 1.4 (-3.0 to 5.8) .53 Low-intensity vs control 7.7 (3.2 to 12.2) .001
aUnadjusted pairwise comparisons based on 18-month changes.
bLog transform data presented because IL-6 data in pg/mL do not meet the assumption of normality. This aligns with the statistical comparisons that were based on the log transformed data.
eTable 6. Serious adverse events (SAE). The external safety officer classified all SAEs as unrelated to the study.
High-intensity Low-intensity Control
Event Description *No.
Participants (%)** Events*** *No. Participants (%)** Events*** *No. Participants (%)** Events*** Cancer 2 1.83 2 0 0.00 0 1 0.97 1 Knee Replacement 1 0.92 1 1 0.93 1 1 0.97 1 Hip Replacement 0 0.00 0 0 0.00 0 2 1.94 2
Myocardial Inf arction 1 0.92 1 0 0.00 0 1 0.97 1
High/Uncontrollable Blood Pressure 0 0.00 0 1 0.93 1 0 0.00 0
Stroke 0 0.00 0 1 0.93 1 0 0.00 0
TIA 1 0.92 1 0 0.00 0 0 0.00 0
*- number of participants experienced SAE (participant is to be counted only once for each SAE) ** % of total number of participants enrolled
*** - number of events
2 persons experiencing SAEs did not complete the study: 1-Cancer (HI); 1-High/Uncontrollable Blood Pressure (LI) Relatedness is determined based on participant description, timing of AE, previous history.
eTable 7 . Most commonly occurring AEs by group assignment.
High-intensity Low-intensity Control
Event Description *No.
Participants (%)** Events*** *No. Participants (%)** Events*** *No. Participants (%)** Events*** Body Pain 12 11.01 12 7 6.48 7 1 0.97 1 Fall 11 10.09 11 6 5.56 6 2 1.94 2 Muscle Strain 7 6.42 8 2 1.85 2 0 0.00 0 Cataract 4 3.67 4 0 0.00 0 0 0.00 0 Twisted Leg 1 0.92 2 2 1.85 2 0 0.00 0 Hernia 1 0.92 1 2 1.85 2 0 0.00 0 Accident/Injury
(dropped weight on foot) 1 0.92 1 1 0.93 1 0 0.00 0
Baker's Cyst 1 0.92 1 1 0.93 1 0 0.00 0
Bruise 1 0.92 1 1 0.93 1 0 0.00 0
Diabetes 0 0.00 0 2 1.85 2 0 0.00 0
Fracture 0 0.00 0 1 0.93 1 1 0.97 1
Thyroid 1 0.92 1 1 0.93 1 0 0.00 0
* - number of participants experienced AE (participant is to be counted only once for each AE) ** % of total number of participants enrolled
eTable 8. Adverse events related to the study by group assignment. The external safety officer approved the designation of possibly or
definitely related to the study.
High-intensity Low-intensity Control
Event Description Related *No.
Participants (%)** Events***
*No.
Participants (%)** Events***
*No.
Participants (%)** Events***
Body Pain Possibly 4 3.67 4 2 1.85 2 0 0.00 0
Bruise Possibly 1 0.92 1 0 0.00 0 0 0.00 0
Fainting/Dizziness Possibly 1 0.92 1 0 0.00 0 0 0.00 0
Body Pain Def initely 6 5.50 6 3 2.78 3 0 0.00 0
Muscle Strain Def initely 5 4.59 6 1 0.93 1 0 0.00 0
Accident/Injury
(dropped weight on foot) Def initely 1 0.92 1 1 0.93 1 0 0.00 0
Bruise Def initely 0 0.00 0 1 0.93 1 0 0.00 0
Fall Def initely 0 0.00 0 1 0.93 1 0 0.00 0
Headache Def initely 1 0.92 1 0 0.00 0 0 0.00 0
* - number of participants experienced AE (participant is to be counted only once for each AE) ** % of total number of participants enrolled
*** - number of events
eFigure 3a. Unadjusted Mean Medial Tibiofemoral Joint Space Width, 3b. Unadjusted Mean Thigh Muscle Volume, 3c. Unadjusted Mean Thigh Fat
Volume, and 3d. Unadjusted Mean Log IL-6 Levels.
