1 INTRODUCTION

Anterior cruciate ligament (ACL) injury results in short-term disability but also has long-term consequences, with a high risk of posttraumatic knee osteoarthritis (OA), pain, and functional limitations following ACL injury and reconstruction.1-3 The majority of individuals with acute ACL tears are under 30 years of age at the time of injury,4 which increases risk for early onset of posttraumatic knee OA and associated clinical symptoms. This risk has not been shown to be reduced by ACL reconstruction, with a reported 3.6 times greater risk of developing OA of any severity in the ACL reconstructed (ACLR) knee as compared to the uninjured contralateral limb.5 Thus, there is a need to identify markers associated with development of clinical symptoms in these individuals that can assist in the evaluation and development of interventional methods to delay the onset of this disabling disease.

After ACL injury and reconstruction, there are known disruptions in knee biomechanics during walking6, 7 that have been suggested to lead to the development of premature knee OA8 and that may be potential markers of OA risk and targets for intervention. One such variable of interest is the vertical ground reaction force (vGRF), which measures the force applied to the foot from the ground during the stance phase. The vGRF is an attractive mechanical marker because it does not require a full-motion analysis set-up and thus is relatively easier to measure than kinetic or kinematic gait deviations post-ACL reconstruction. Furthermore, the vGRF influences9, 10 kinetic measures (knee adduction and flexion moments) related to OA progression in established disease.11-13 The exact role of the vGRF following ACL reconstruction, however, remains unclear, and both underloading14 and overloading15-17 of the knee, as measured by knee joint contact force, knee kinetics, vGRF, and in vitro mechanical loading, may be detrimental to joint health.

Considering the vGRF as a biomechanical variable of interest for joint degeneration and changes in clinical symptoms in ACL reconstructed individuals is further supported by recent work finding mixed results regarding the influence of vGRF post-ACLR. Pietrosimone et al. found that ACL injured individuals with smaller peak vGRF on the ACLR limb versus the contralateral limb early after surgery (6 months post-ACL reconstruction) had worse patient-reported outcomes 12 months after reconstruction surgery.18 However, other work found that higher peak vGRF in the ACLR limb at 6 months post-ACLR was associated with greater increases in cartilage relaxation times (T1ρ and T2),16 indicative of a deterioration of cartilage health. Furthermore, recent work demonstrated that increases in peak vGRF in the ACLR limb during a drop-landing task from 6 months to 3 years post-surgery were associated with larger increases in T1ρ values in medial knee cartilage over the same period, indicating greater cartilage degeneration.19 The role of the vGRF in joint health following ACL reconstruction may be dependent on timing past surgery.20 Pietrosimone et al.20 found that symptomatic ACLR patients less than 1-year post-surgery underloaded the ACLR limb, while symptomatic patients greater than 2 years post-surgery overloaded the ACLR limb, as compared to asymptomatic individuals. Differences between studies may be due to timing post-ACL reconstruction, as well as whether the vGRF was evaluated in the ACLR limb or as compared to the uninjured contralateral limb. Thus, additional information is needed regarding the influence of the vGRF on clinical outcomes post-ACL reconstruction, particularly at a later time point post-surgery, given the time frame3 to developing joint degeneration post-injury.

The purpose of this study, therefore, was to investigate if side-to-side differences in early stance peak vGRF during walking 2 years after ACL reconstruction are associated with longer-term (10 years post-reconstruction) changes in patient-reported outcome scores. Specifically, we hypothesized that (1) greater peak vGRF of the ACLR knee versus the healthy contralateral knee 2 years post-ACL reconstruction (baseline) was associated with worsening of patient-reported outcomes at 10-year follow-up, and (2) individuals with symptomatic progression, having changes in patient-reported outcomes exceeding minimal detectable changes,21 would have greater baseline peak vGRF than non-progressors.

2 METHODS 2.1 Study design and level of evidence

Prognostic Study, Level II.

2.2 Study participants

Twenty-eight participants with primary unilateral ACL reconstruction participated in this study after providing written informed consent in accordance with the Stanford University Institutional Review Board. Participants were tested at baseline approximately 2 years post-ACL reconstruction (2.2 ± 0.3 years post-surgery) and completed follow-up approximately 10 years post-ACL reconstruction (10.5 ± 0.9 years post-surgery). Study participants were part of a larger group of 42 participants who underwent baseline testing and agreed to further contact by researchers. As long-term follow-up was not part of the original study design, Institutional Review Board approval was obtained to recontact participants. Of the 14 individuals who did not complete 10-year follow-up, 13 did not respond/were unable to be contacted and one was not interested. Baseline inclusion criteria included: (i) successful single-bundle unilateral ACL reconstruction; (ii) no other history of serious lower limb injury; (iii) 18–40 years old at the time of ACL injury; (iv) self-reported history of knee stability; and (v) knee MRI to confirm intact graft. Baseline exclusion criteria included: (i) removal of more than 25% of the meniscus; (ii) a history of other serious ligamentous injuries to either lower limb; (iii) clinical instability of the reconstructed knee; (iv) BMI > 30 kg/m2; (v) significant observable chondral defects by MRI; or (vi) a history of surgical procedures performed on either lower limb or revision operation of the ACL. With at least 28 participants, we expected to detect an effect size of 0.5 with an α of 0.05% and 80% power (G-Power, v3.1.9.4) in univariate correlation tests.

2.3 Gait analysis

At baseline, participants performed three successful walking trials at a self-selected normal walking speed separately for each limb along a 10-m walkway in their own walking shoes. A trial was considered successful if the foot of the leg being tested fully struck the force plate. The testing order of the limbs was randomly determined. Participants started all trials at the same location to reduce variations in walking speed between trials. Kinematic data were collected using a multi-camera motion capture system (Qualisys Medical) and the point cluster technique, which uses a redundant set of 21 reflective markers.22 Ground reaction forces were collected using a multicomponent floor-embedded force plate (Bertec Corporation). Both systems collected data at 120 Hz. The software application BioMove23 (Stanford University) was used to calculate gait parameters. The stance phase was defined as the time during which the foot is in contact with the floor, determined by a >10-N force plate measurement in the vertical direction. Peak vGRF was defined as the peak value during the first half of the stance phase and was normalized to body weight (%BW). Walking speed was calculated as the average speed of the pelvis along the posterior-anterior axis of the walkway for the entirety of the gait trial when markers were in view. Gait data for the three successful walking trials were averaged for each knee, and the between-limb difference (ACLR – Contralateral) was calculated.

2.4 Patient-reported outcomes

At baseline and follow-up, participants completed the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form24 and Knee Injury and Osteoarthritis Outcome Score25 (KOOS) questionnaire. The IKDC measures symptoms, function, and sports-related activity, and a transformed score of 100 indicates no limitations and the absence of symptoms. The KOOS includes five subscales assessing pain, symptoms, function in daily living (ADL), function in sports and recreation (Sport/Rec), and knee-related quality of life (QOL), with higher transformed scores (maximum score of 100 points) indicating better outcomes. Changes in patient-reported outcomes were calculated as follow-up scores—baseline scores, with worsening in scores indicated as a reduction in score over the follow-up period.

2.5 Data analysis

The Shapiro-Wilks test was used to test for the normality of all data. Changes in patient-reported outcomes from baseline to follow-up were assessed via Wilcoxon Signed Rank Tests. Associations between changes (10–2 years) in patient-reported outcomes and between limb-differences (ACLR – Contralateral) in vGRF were assessed with Pearson or Spearman's ρ (for non-normally distributed data) correlation coefficients. Exploratory backwards elimination multiple linear regression analyses (p out = 0.1) were also performed with changes in patient-reported outcomes as dependent variables and baseline vGRF (ACLR – Contralateral) alongside baseline BMI, baseline age, and additional injury, as independent variables, due to their potential impact as risk factors for OA development after ACL reconstruction.26 Assumptions of linearity, normality, and equality of variances were examined using predicted probability (P-P) plots and residual plots. Multicollinearity of independent variables was assessed using the variance inflation factor (VIF), where a VIF < 5 was considered satisfactory.27 Analyses for hypothesis 1 were repeated on the subset of participants without lower extremity injuries during follow-up.

We also investigated whether the vGRF differed between participants who were defined as symptomatic progressors if the change in either KOOS pain or KOOS symptoms from baseline to follow-up exceeded established minimal detectable changes21 as previously described in the literature.28 The minimal detectable change scores used for KOOS pain and KOOS symptoms were 6.1 and 8.5, respectively.21 Independent t tests, Mann-Whitney U Tests (for non-normally distributed data), and Fisher's exact tests were used to compare demographics, baseline KOOS, and vGRF data between symptomatic progressors and non-progressors. Statistical significance was set at p ≤ 0.05, and all statistical analyses were performed using SPSS version 25 (SPSS Inc.).

3 RESULTS 3.1 Participant characteristics

The study participants included 11 males and 17 females (baseline age, 28.7 ± 6.4 years; baseline BMI, 24.7 ± 3.5 kg/m2). Fifteen participants had ACL reconstructions on the left knee and 13 participants had ACL reconstructions on the right knee. The mean  ± SD time from injury to surgery was 2.1 ± 1.7 months. Twenty-five participants had reconstructions with Achilles allografts, two participants had reconstructions with bone-patellar tendon-bone autografts, and one participant had a reconstruction with bone-patellar tendon-bone allograft. During the follow-up period, nine participants (32.1%) had additional self-reported knee injuries, including ACL graft rupture and reconstruction (n = 5), meniscectomy (n = 1), ACL sprain (n = 1), contralateral ACL tear and reconstruction (n = 1), and contralateral hamstring surgery (n = 1).

3.2 vGRF and patient-reported outcomes

On average, KOOS ADL significantly worsened over the 10-year follow-up period (p = 0.002, Table 1), with no significant changes in other patient-reported outcomes. Longer-term changes at 10 years in patient-reported outcomes were significantly associated with side-to-side differences in vGRF at baseline 2 years post-ACL reconstruction in univariate analyses (Table 2), with low to moderate29 strength associations observed. Specifically, participants with higher vGRF in the ACLR limb versus the contralateral limb (Figure 1) had worsening of IKDC (p = 0.040), KOOS pain (p = 0.037), KOOS symptoms (p = 0.001), and KOOS QOL (p = 0.014) scores at follow-up. After adjustment for covariates of baseline age, BMI, and additional injuries in multiple linear regression analyses, the side-to-side difference in vGRF at baseline remained significant for the majority of associations (Table 3), and baseline age entered the majority of regressions, with younger age at baseline associated with greater worsening of patient-reported outcome metrics.

Table 1. Patient-reported outcomes at baseline and follow-up Baseline Follow-up p value IKDC 89.0 (10.3) 84.1 (14.3) 0.14 KOOS pain 94.0 (8.5) 91.5 (9.9) 0.20 KOOS symptoms 88.6 (13.9) 85.6 (13.7) 0.31 KOOS ADL 98.9 (2.6) 96.4 (5.2) 0.002 KOOS Sport/Rec 86.6 (17.3) 84.5 (18.8) 0.67 KOOS QOL 73.7 (22.7) 75.0 (19.6) 0.77 Tegner — 4.6 (1.8) — Note: Data presented as mean (SD). The Tegner activity scale was not collected at baseline. Tegner scores range from 0 to 10, where 0 is “on sick leave/disability” and 10 is “participation in competitive sports such as soccer at a national elite level.” Abbreviations: ADL, activities of daily living; IKDC, International Knee Documentation Committee; KOOS, Knee Injury and Osteoarthritis Outcome Score QOL, quality of life. Table 2. Associations (Pearson/Spearman's ρ correlation coefficients) between side-to-side differences in vGRF (ACLR – Contralateral) at 2-years post-ACL reconstruction and changes in patient-reported outcomes from 2 to 10 years post-ACL reconstruction (10–2 years) Change in patient-reported outcome (10–2 years) IKDC KOOS pain KOOS symptoms KOOS ADL KOOS Sports/Rec KOOS QOL All participants (n = 28) Correlation coefficient −0.391 −0.396 a −0.572 a −0.139a −0.303a −0.458 p value 0.040 0.037 0.001 0.481 0.117 .014 Participants without subsequent injuries (n = 19) Correlation coefficient −0.440 −0.584 −0.595 −0.144a −0.505 −0.511 p value 0.059 0.009 0.007 0.557 0.027 0.025 Note: Results shown are for all 28 participants, as well as for the 19 participants without additional injuries during the follow-up period. Significant associations are expressed in bold. Abbreviations: ACL, anterior cruciate ligament; ACLR, ACL reconstructed; ADL, activities of daily living; IKDC, International Knee Documentation Committee; KOOS, Knee Injury and Osteoarthritis Outcome Score; QOL, quality of life; Sports/Rec, sports and recreation; vGRF, vertical ground reaction force.

Associations between side-to-side differences in vGRF at 2-years post-ACL reconstruction (T1) and change in (A) KOOS symptoms (Spearman's ρ = −0.57) and (B) KOOS QOL (R = −0.46) from 2 years (T1) to 10 years (T2) post-ACL reconstruction. Greater vGRF in the ACLR knee as compared to the contralateral knee and improved outcome in patient-reported scores at 10 years are shown as positive values. ACL, anterior cruciate ligament; ACLR, ACL reconstructed; BW, body weight; KOOS, Knee Injury and Osteoarthritis Outcome Score; QOL, quality of life; vGRF, vertical ground reaction force

Table 3. Results of multiple linear regression (backwards elimination, p out = 0.1). Results are shown for all 28 participants, as well as for the 19 participants without additional injuries during the follow-up period All participants (n = 28) Participants without additional injuries (n = 19) Independent measures in model Overall model Independent measures in model Overall model Change in patient-reported outcome measure Name Standardized coefficient p value R value p value Name Standardized coefficient p value R value p value IKDC Baseline age 0.508 0.004 0.627 0.002 Baseline age 0.545 0.016 0.545 0.016 vGRF −0.287 0.082 Pain Baseline age 0.439 0.011 0.620 0.002 Baseline age 0.394 0.047 0.699 0.005 vGRF −0.367 0.030 vGRF −0.497 0.015 Symptom Baseline age 0.468 0.002 0.736 <0.001 Baseline age 0.419 0.031 0.722 0.003 vGRF −0.491 0.002 vGRF −0.503 0.012 ADL — — — — — Baseline BMI 0.514 0.024 0.514 0.024 Sport/Rec Baseline age 0.444 0.012 0.593 0.004 Baseline age 0.467 0.024 0.680 0.007 vGRF −0.322 0.060 vGRF −0.402 0.048 QOL Baseline age 0.473 0.005 0.664 0.001 Baseline age 0.386 0.045 0.745 0.006 vGRF −0.389 0.017 vGRF −0.425 0.030 Baseline BMI 0.385 0.041 Note: Overall models are considered significant and bolded when the overall model's p value ≤ .05. Independent measures are considered significant and are bolded when p value ≤ 0.05. vGRF is the between-limb difference (ACLR – Contralateral) in vGRF at baseline testing 2 years post-ACL reconstruction. Abbreviations: ADL, activities of daily living; BMI, body mass index; IKDC, International Knee Documentation Committee; QOL, quality of life; Sports/Rec, sports and recreation; vGRF, vertical ground reaction force. — Indicates no variable remained in the backward elimination model for ADL (all participants).

When considering the subset of 19 participants without additional lower extremity injuries during follow-up, the univariate association of side-to-side difference in vGRF with IKDC was no longer significant (p = 0.059), however moderate29 associations (Table 2) were observed with worsening of KOOS pain (p = 0.009), symptoms (p = 0.007), Sports/Rec (p = 0.027) and QOL (p = 0.025) scores with greater vGRF in the ACLR limb versus the contralateral limb. After adjustment for covariates in multiple linear regression analyses, the side-to-side difference in vGRF at baseline remained a significant predictor for the observed univariate associations in this subset of participants (Table 3).

At baseline (2 years post-ACLR) no significant difference (p = 0.96) was observed on average overall participants between vGRF in the ACLR and contralateral limbs (ACLR: 115.1 ± 9.0%BW; Contralateral: 115.0 ± 9.1%BW; p = 0.96). Thirteen of the 28 participants (46%) had smaller vGRF in the ACLR limb, and 15 participants (54%) had a greater vGRF in the ACLR limb as compared to the contralateral limb. The average walking speed was 1.36 ± 0.14 m/s for the ACLR limb trials and 1.37 ± 0.13 m/s for the contralateral limb trials.

3.3 Symptomatic progression

Ten participants (35.7%) had worsening of either KOOS pain and/or KOOS symptoms at 10-year follow-up that exceeded the minimal detectable changes for these scales21 and were defined as symptomatic progressors. Two participants displayed progression in KOOS pain, four participants displayed progression in KOOS symptoms, and four participants displayed progression in both KOOS pain and symptoms. Symptomatic progressors had greater vGRF in the ACLR limb as compared to the contralateral limb at baseline than non-progressors (p = 0.023, Table 4). Symptomatic progressors were also younger at baseline testing than those without symptomatic progression (p = 0.011). No other significant differences were observed in demographics, additional injuries during the follow-up period, or baseline patient-reported outcomes (Table 4).

Table 4. Demographics, baseline patient-reported outcomes, and vGRF (ACLR – Contralateral) of the symptomatic progressors and non-progressors Progressors (n = 10) Non-progressors (n = 18) p value Age (years) 24.8 (4.3) 30.8 (6.4) 0.011 Gender (male/female) 3M/7F 8M/10F 0.69 BMI (kg/m2) 24.7 (3.7) 24.7 (3.5) 0.99 Additional Injuries (n) 5 (50%) 4 (22%) 0.21 Baseline IKDC 93.4 (6.9) 86.6 (11.2) 0.09 Baseline KOOS pain 97.2 (3.8) 92.3 (9.9) 0.20 Baseline KOOS symptoms 91.1 (10.1) 87.3 (15.7) 0.61 Baseline KOOS ADL 99.1 (1.4) 98.8 (3.2) 0.64 Baseline KOOS Sports/Rec 91.5 (13.6) 83.9 (18.9) 0.18 Baseline KOOS QOL 76.9 (17.2) 71