The Long-Term Risk of Knee Arthroplasty in Patients with Arthroscopically Verified Focal Cartilage Lesions: A Linkage Study with the Norwegian Arthroplasty Register, 1999 to 2020

Focal cartilage lesions are common in the knee and represent a clinical challenge1–3. In the study by Heir et al., patients who were scheduled for cartilage surgery reported Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS QoL) subscores similar to those of patients scheduled for knee arthroplasty4. The intra-articular hyaline cartilage is unable to heal naturally5. Several treatment options (including microfracture, autologous chondrocyte implantation [ACI], and mosaicplasty) are available, but the optimum treatment has yet to be determined6,7. Furthermore, no treatment has been proven to restore hyaline cartilage or decrease the risk of osteoarthritis5.

Patients who have had previous knee surgery undergo knee arthroplasty at a significantly younger age than those who have not8. Several factors have been reported to increase the lifetime risk of knee arthroplasty, including age, body mass index (BMI), body height, sex, manual labor, knee injury, and family history9,10.

Long-term articular cartilage studies have shown that the rate of knee arthroplasty has ranged from 0% to 17% following regenerative cartilage surgical procedures such as microfracture, ACI, chondroplasty, or mosaicplasty11–14. The relative risk of knee arthroplasty in patients with a previous focal cartilage lesion versus the general population remains unknown. Thus, the purposes of the present study were to (1) evaluate the long-term cumulative risk of knee arthroplasty in patients with arthroscopically verified focal cartilage lesions in the knee, (2) to investigate the risk factors for knee arthroplasty in patients with cartilage lesions, and (3) to estimate the relative risk of knee arthroplasty in patients with arthroscopically verified focal cartilage lesions as compared with the risk in the general population.

Materials and Methods Patients and Methods

We identified patients with arthroscopically verified focal cartilage lesions that had been treated at 6 major Norwegian hospitals between 1999 and 2012 (Fig. 1). These hospitals were chosen because they had participated in several prospective clinical cartilage trials in the contemporary period15–18.

fig1Fig. 1:

Flowchart illustrating the inclusion of patients in the cartilage cohort.

The inclusion criteria in this study were (1) an arthroscopically verified and classified focal cartilage lesion in the knee and (2) an age of ≥18 years at the time of surgery. At least 1 preoperative patient-reported outcome measure (PROM) score had to be available. Exclusion criteria were cartilage lesions that were assessed as being osteoarthritis or “kissing lesions” intraoperatively by the surgeon (Fig. 1).

Patients who were found to be eligible for inclusion were contacted by mail. Patients who were listed in the Norwegian Population Register as emigrated or deceased were excluded. Informed consent was obtained. Each patient received a questionnaire regarding their current height, weight, level of education, knee function, additional knee surgery, and level of activity. The PROMs that had been previously used were the KOOS score19, Lysholm score20, and International Cartilage Regeneration & Joint Preservation Society (ICRS) visual analog scale (VAS) for knee pain21.

After informed consent had been obtained, the surgical report and/or trial data for each participant were made available to the main investigator (T.B.). The variables of interest included any previous cartilage surgery; the location, size, and ICRS classification of the cartilage lesions; the type of operative treatment; any additional procedures; and preoperative PROMs. Nine knees in 8 patients who met the exclusion criteria at the time of surgery were then identified and excluded (Fig. 1).

The Norwegian Arthroplasty Register (NAR) has captured data on knee arthroplasty interventions and outcomes in Norway since 1994 and has >95% completeness of reporting22,23. The patients in the current study and in the NAR are identified by their Norwegian unique identification number. Data from the NAR included the date of knee arthroplasty, surgeon-reported cause of knee arthroplasty (i.e., osteoarthritis, posttraumatic arthritis, inflammatory arthritis), type of prothesis, and laterality.

A patient was registered as having a knee arthroplasty when (1) the patient reported an ipsilateral knee arthroplasty in the questionnaire and/or (2) the ipsilateral knee was registered in the NAR.

The study was approved by the Regional Ethics Committee (2017/1387).

Statistical Analysis

The data were analyzed with use of SPSS Statistics (version 26; IBM). The level of significance was set at p < 0.05.

The cumulative risk of knee arthroplasty was estimated with use of the Kaplan-Meier method24. Cox regression models were used to investigate risk factors for knee arthroplasty in the study population. A graphical causal model (www.dagitty.net/dags.html) was used to identify variables to adjust for, as suggested by Westreich and Greenland25. Preoperative Lysholm and ICRS VAS pain scores were registered for 185 and 114 patients, respectively, and no patient had recorded >1 preoperative PROM. The linear assumption of the Cox model was confirmed for the preoperative VAS pain score with use of the Box-Tidwell procedure. Survival times were calculated as the time between cartilage surgery and knee arthroplasty or the end of the study on December 31, 2020. The proportional hazards assumption was fulfilled for all variables that were investigated except for BMI group and anterior cruciate ligament (ACL) surgery (yes or no). On the basis of a visual inspection of the Kaplan-Meier plot, both variables were analyzed separately according to the duration of follow up (<12 or ≥12 years).

A subgroup of patients without any concomitant procedures at the time of the index procedure were analyzed with use of the same Cox model as described above.

The relative risk of knee arthroplasty after a cartilage injury as compared with the risk in the age-matched general population was estimated. The absolute risk of knee arthroplasty in the cartilage injury cohort was estimated by dividing the number of knee arthroplasties by the total number of knees with cartilage injury in each age-matched group. For the general population, the numerator was the number of all other patients undergoing knee arthroplasty without inflammatory arthritis or previous cartilage surgery as reported to the NAR between January 1, 1999, and December 31, 2020. The denominator was the average number of Norwegian citizens in the same period, retrieved from Statistics Norway. The results were stratified in 10-year groups based on the age at the time of knee arthroplasty.

To further aid the clinical interpretation of the relative risk of knee arthroplasty in the cartilage injury cohort as compared with the general population, we also stratified each 10-year age group at the time of knee arthroplasty according to when the patient underwent the index cartilage procedure. For the general population, the absolute risk was estimated as described in the previous paragraph. In the cartilage injury cohort, the numerator was the number of knee arthroplasties in each 10-year age group (at the time of cartilage surgery) and the denominator was the total number of patients with cartilage injury in the same age group.

A power analysis was performed prior to inclusion. In order to achieve an 80% chance of detecting a 4-times higher rate of knee arthroplasty in the focal cartilage lesion cohort as compared with the general population, we needed to include at least 181 participants.

Source of Funding

The present study was funded by the Norwegian Research Council through the Norwegian Cartilage Project.

Results

Of the 553 patients (563 knees) who were identified, 507 patients (516 knees) were eligible, and, of those, 322 patients (328 knees) consented to participate (Fig. 1). One hundred and sixty-four patients (169 knees) had participated in studies with previously published intermediate to long-term results26–28. Most patients had a pre-enrollment radiograph that did not show any joint-space narrowing. The demographic characteristics of the patients are summarized in Table I. At baseline, there were no significant differences between the responders and nonresponders apart from the responders being a mean of 3.0 years older (p = 0.002).

TABLE I - Demographic and Descriptive Characteristics of 328 Knees with Focal Cartilage Lesions Treated with Arthroscopic Surgery in 6 Norwegian Hospitals Between 1999 and 2012* No. of knees 328 Sex (male/female) (no. of knees) 188 (57%)/140 (43%) Side (right/left) (no. of knees) 174 (53%)/154 (47%) Age at time of surgery† (yr) 36.8 (35.6-38.0) Time from index procedure to end of study† (yr) 19.8 (19.4-20.2) ICRS grade (no. of knees)  1-2 52 (15.9%)  3-4 276 (84.1%) Size of cartilage lesion† (mm 2 ) 201.3 (178.9-223.7) Preop. Lysholm score (n = 184)† 49.4 (46.9-51.8) Preop. VAS pain score (n = 105)† 44.3 (39.6-49.0) Location of cartilage lesion (no. of knees)  Patellofemoral 73 (22.3%)  Medial 204 (62.2%)  Lateral 51 (15.5%) Type of cartilage lesion (no. of knees)  Traumatic 125 (38.1%)  OCD 17 (5.2%)  Degenerative 4 (1.2%)  Not reported 182 (55.5%) Type of treatment (no. of knees)  No cartilage treatment 93 (28.4%)  Microfracture 124 (37.8%)  Debridement 12 (3.0%)  ACI/MACI 30 (9.1%)  Mosaicplasty 53 (16.2%)  Other 16 (4.9%) Level of education (no. of knees)  High school 155 (47.3%)  Bachelor’s/Master’s degree 164 (50.0%)  Missing information 9 (2.7%) BMI at end of study† (kg/m 2 ) 27.4 (26.9-27.9) BMI category at end of study (no. of knees)  <25 kg/m2 100 (30.5%)  25-29 kg/m2 137 (41.8%)  ≥30 kg/m2 75 (22.9%)  Missing information 16 (4.9%) Ipsilateral ACL reconstruction (no. of knees) 50 (15.2%)  At index surgery 15 (4.6%)  Before or after index surgery 35 (10.7%)  None 278 (84.8%) Ipsilateral meniscal resection (no. of knees) 100 (30.5%)  At index surgery 46 (14.0%)  Before or after index surgery 54 (16.5%)  None 228 (69.5%) Knee arthroplasty (no. of knees) 59 (18.0%)  Male patients (n=188) 30 (16.0%)  Female patients (n=140) 29 (20.7%) Knee arthroplasty procedures (no. of knees) 59 (18.0%)  Total knee arthroplasty (n = 59) 48 (81.4%)  Unicompartmental knee arthroplasty (n = 59) 8 (13.6%)  Patellofemoral knee arthroplasty 3 (5.1%) Age at the time of knee arthroplasty† (yr)  Male patients 56.4 (53.1-59.7)  Female patients 51.9 (47.6-56.1) Time from index cartilage surgery to knee arthroplasty† (yr)  Male patients 13.9 (11.9-16.0)  Female patients 11.4 (9.0-13.8)

*N = 328 unless indicated otherwise. ICRS = International Cartilage Repair & Joint Preservation Society, VAS = visual analog scale, OCD = osteochondritis dissecans, ACI = autologous chondrocyte implantation, MACI = matrix-induced ACI, ACL = anterior cruciate ligament. †The values are given as the mean, with the 95% CI in parenthesis.

The 20-year cumulative risk of knee arthroplasty after arthroscopic verification of a focal cartilage lesion was 19.1% (95% confidence interval [CI], 14.6% to 23.6%). The mean age at the index procedure for the treatment of the focal cartilage lesion was 36.8 years, and the mean duration of follow-up was 19.8 years. The results of the Cox regression model are summarized in Table II. The BMI classifications of overweight and obese at the time of follow-up were the 2 most important risk factors for knee arthroplasty, with an adjusted hazard ratio (aHR) of 3.9 (95% CI, 1.7 to 9.0) and 5.9 (95% CI, 2.4 to 14.3), respectively. The size of the cartilage lesion did not significantly influence the risk of later knee arthroplasty, but ICRS grade-3 and 4 lesions did increase the risk of knee arthroplasty (aHR, 3.1; 95% CI, 1.1 to 8.7). ACI treatment increased the risk of knee arthroplasty (aHR, 3.4; 95% CI, 1.0 to 11.4) compared with no cartilage treatment at index surgery. The preoperative Lysholm and VAS pain scores were analyzed as continuous variables. A low preoperative Lysholm score did not significantly increase the risk of knee arthroplasty, whereas a high preoperative VAS pain score did and was found to be linearly correlated with the risk. ACL reconstruction was not a risk factor for total knee arthroplasty (TKA) at the time of the latest follow-up, but there was an increased risk in the <12-year follow-up group (aHR, 3.2; 95% CI, 1.4 to 7.3) (subanalysis not presented). Increased BMI was a significant risk factor only in the ≥12-year follow-up group.

TABLE II - Twenty-Year Cumulative Risk (1 − Kaplan-Meier Survival) and Risk Factors Associated with Knee Arthroplasty After Cartilage Injury, 1999 to 2020, in a Focal Cartilage Lesion Cohort Linked to the Norwegian Arthroplasty Register§§§§ No. of Knees No. of Knee Arthroplasties No of Knee Arthroplasties (TKAs/ UKAs/PFs) 20-Year Cumulative Risk (95% CI) Crude HR* (95% CI) Adjusted HR† (95% CI) Total 328 59 (18.0%) of 328 19.1 (14.6-23.6) Age at time of surgery‡ (no. of knees)  18-29 yr 83 (25.3%) 9 (10.8%) of 83 9 (7/0/2) 13.8 (9.7-17.9) 1  30-39 yr 128 (39.0%) 14 (10.9%) of 128 14 (12/2/0) 12.0 (5.7-18.3) 1.08 (0.47-2.50)  ≥40 yr 117 (35.7%) 36 (30.8%) of 117 36 (29/6/1) 32.2 (23.2-41.2) 3.69 (1.78-7.67) Sex‡ (no. of knees)  Male 188 (57.3%) 30 (16.0%) of 188 30 (25/5/0) 14.1 (8.8-19.4) 1  Female 140 (42.7%) 29 (20.7%) of 140 29 (23/3/3) 22.8 (15.4-30.3) 1.38 (0.83-2.30) BMI at end of study§ (no. of knees)  <25 kg/m2 100 (30.5%) 7 (7.0%) of 100 7 (5/1/1) 7.2 (2.1-12.3) 1 1  25-29 kg/m2 137 (41.8%) 27 (19.7%) of 137 27 (20/6/1) 22.2 (14.6-29.8) 3.07 (1.34-7.06) 3.86 (1.65-9.00)  ≥30 kg/m2 75 (22.9%) 19 (25.3%) of 75 19 (17/1/1) 27.1 (16.3-37.9) 4.1 (1.74-9.88) 5.90 (2.43-14.32) Size of lesion# (no. of knees)  <200 mm2 214 (65.2%) 40 (18.7%) of 214 40 (32/5/3) 20.3 (14.6-26.0) 1 1  ≥200 mm2 114 (34.8%) 19 (16.7%) of 114 19 (16/3/0) 16.1 (8.8-23.4) 0.92 (0.53-1.59) 0.99 (0.55-1.78) ICRS grade# (no. of knees)  1-2 52 (15.9%) 4 (7.7%) of 52 4 (4/0/0) 7.7 (0.4-15.0) 1 1  3-4 276 (84.1%) 55 (19.9%) of 276 55 (44/8/3) 21.5 (16.2-26.8) 3.35 (1.21-9.27) 3.09 (1.10-8.70) Level of education** (no. of knees)  High school 155 (47.3%) 33 (21.3%) of 155 33 (24/6/3) 20.8 (14.1-27.5) 1 1  Bachelor’s/Master’s degree 164 (50.0%) 22 (13.4%) of 164 22 (20/2/0) 15.8 (9.7-21.9) 0.62 (0.36-1.06) 0.60 (0.35-1.02) ACL reconstructed at any time†† (no. of knees)  No 278 (84.8%) 50 (18.0%) of 278 50 (39/8/3) 19.1 (14.2-24.0) 1 1  Yes 50 (15.2%) 9 (18.0%) of 50 9 (9/0/0) 19.1 (7.1-31.1) 0.94 (0.46-1.91) 1.62 (0.76-3.47) Meniscal resection at any time‡‡ (no. of knees)  Yes 100 (30.5%) 18 (18.0%) of 100 18 (18/0/0) 21.3 (12.5-30.1) 1 1  No 228 (69.5%) 41 (18%) of 228 41 (30/8/3) 18.1 (12.8-23.4) 1.0 (0.58-1.75) 0.96 (0.53-1.73) Location of cartilage lesion§§ (no. of knees)  Patellofemoral 73 (22.3%) 9 (12.3%) of 73 9 (7/0/2) 13.5 (5.3-21.7) 1 1  Medial 204 (62.2%) 38 (18.6%) of 204 38 (29/8/1) 19.7 (13.8-25.6) 1.53 (0.74-3.17) 1.27 (0.58-2.78)  Lateral 51 (15.5%) 12 (23.5%) of 51 12 (12/0/0) 23.3 (11.1-35.5) 1.8 (0.74-4.30) 1.40 (0.55-3.57) Cartilage lesions## (no. of knees)  1 lesion 244 (74.4%) 33 (13.5%) of 244 33 (24/6/3) 14.2 (9.5-18.9) 1 1  >1 lesion 84 (25.6%) 26 (31.0%) of 84 26 (24/2/0) 31.2 (21.2-41.2) 2.25 (1.34-3.76) 2.05 (1.13-3.71) Treatment at index operation*** (no. of knees)  No cartilage treatment 93 (28.4%) 13 (14.0%) of 93 13 (11/1/1) 14.2 (7.1-21.3) 1 1  Debridement/microfracture 136 (41.5%) 28 (20.6%) of 136 28 (23/3/2) 22.1 (14.5-29.7) 1.8 (0.95-3.56) 1.61 (0.70-3.70)  ACI 30 (9.1%) 7 (23.3%) of 30 7 (5/2/0) 21.0 (5.9-36.1) 2.0 (0.78-5.01) 3.43 (1.03-11.39)  OATS 53 (16.2%) 11 (20.8%) of 53 11 (9/2/0) 21.1 (9.9-32.3) 1.65 (0.74-3.69) 1.95 (0.67-5.69)  Other 16 (4.9%) 0 0 0 0.0 (0-3.89 × 10295) 0.0 (0.0) Preop. VAS pain score†††,‡‡‡ 105 (32.0%) 14 (13.3%) of 105 1.03 (1.01-1.06) 1.08 (1.03-1.14) Preop. Lysholm score†††,‡‡‡ 18 (56.1%) 42 (22.8%) of 184 0.99 (0.97-1.00) 1.0 (0.98-1.02)

§§§§TKA = total knee arthroplasty, UKA = unicompartmental knee arthroplasty, PF = patellofemoral knee arthroplasty, CR = cumulative risk, CI = confidence interval, BMI = body mass index, ICRS = International Cartilage Repair & Joint Preservation Society, ACL = anterior cruciate ligament, ACI = autologous chondrocyte implantation, OATS = osteochondral autograft transplantation system (mosaicplasty), VAS = visual analog scale. *HR = hazard rate ratio from Cox analysis. †Cox-adjusted for variables according to a graphical causal model ‡Not adjusted. §Adjusted for age at time of surgery, sex, level of education. #Adjusted for age at time of surgery, BMI, meniscal resection. **Adjusted for sex. ††Adjusted for age at time of surgery, BMI, sex, level of education. ‡‡Adjusted for ACL reconstruction, age at time of surgery, BMI, sex, level of education. §§Adjusted for ACL reconstruction, age at time of surgery, sex, meniscal resection. ##Adjusted for ACL reconstruction, age at time of surgery, BMI, sex, level of education, meniscal resection, size of lesion. ***Adjusted for age at time of surgery, ICRS grade, level of education, location of lesion, number of lesions, size of lesion. †††Adjusted for ACL reconstruction, age at time of surgery, BMI, sex, ICRS grade, level of education, location of lesion, meniscal resection, number of lesions, size of lesion. ‡‡‡Adjusted for VAS pain and Lysholm scores analyzed as continuous variables.

The subanalysis of patients without any concomitant procedures at the time of the index procedure demonstrated no significant difference in the risk of knee arthroplasty between the treatment groups (see Appendix). Furthermore, an additional Cox analysis including the time period of the index operation (1999 to 2004 or 2005 to 2012) did not alter our findings.

The Cox adjusted survival curves of the knees with a cartilage lesion, with knee arthroplasty as the end point, are presented in Figures 2-A through 2-D. The survival curves are adjusted for the same covariates as in the Cox regression model.

Fig. 2-A through 2-D Cox adjusted survival curves of knees with focal cartilage lesions by World Health Organization BMI classes (adjusted for age at time of surgery, sex, and level of education) (Fig. 2-A), sex (unadjusted) (Fig. 2-B), age group at index surgery (unadjusted) (Fig. 2-C), and cartilage treatment (adjusted for age at time of surgery, ICRS grade, level of education, location of lesion, number of lesions, and size of lesion) (Fig. 2-D), with knee arthroplasty as the end point. Adjustment based on graphical causal model. Mfx = microfracture.

fig2afig2bfig2cfig2d

Table III summarizes the risk of knee arthroplasty in the cartilage cohort as compared with that in the age-matched general population. Table IV summarizes the subsequent risk of knee arthroplasty according to age at the time of cartilage surgery. The risk ratio of subsequent knee arthroplasty in the cartilage cohort versus the age-matched general Norwegian population ranged from 3.6 in the 60 to 69-year age group to 415.7 in the 30 to 39-year age group.

TABLE III - Risk Ratio of Knee Arthroplasty in Cartilage Cohort Versus General Norwegian Population* Cartilage Cohort Age-Matched General Population† Risk Ratio (95% CI) Age at Knee Arthroplasty No. of Knee Arthroplasties No. of Patients in Age Group No. of Knee Arthroplasties,
1999-2020 (per 10 5 ) No. of Knee Arthroplasties,
1999-2019 (per 10 5 ) 30-39 yr 4 20 952.4 2.3 415.69 (168.83-1,023.49) 40-49 yr 15 80 892.9 18.1 49.42 (31.01-78.76) 50-59 yr 25 126 944.8 83.3 11.35 (7.93-16.24) 60-69 yr 11 64 818.5 229.0 3.57 (2.07-6.17) 70-79 yr 3 31 460.8 363.4 1.27 (0.43-3.76)

*The relative risk of knee arthroplasty after a cartilage injury as compared with the general population. The absolute risk of knee arthroplasty in the cartilage cohort was estimated by dividing the number of knee arthroplasties by the total number of knees with cartilage injury in each group. For the general population, the numerator was all other patients with knee arthroplasty without inflammatory arthritis or previous cartilage surgery on the ipsilateral side as reported to the NAR between January 1, 1999, and December 31, 2020. The denominator was the average number of Norwegian citizens in the same period, retrieved from population data from Statistics Norway. One patient was 81 years old at the time of knee arthroplasty and was excluded. †General population excluded patients with previous cartilage surgery.

The rate of knee arthroplasty was significantly increased in all age groups except the 70 to 79-year age group, ranging from 819 to 952 of 100,000 in the cartilage cohort as compared with 2.3 to 229 of 100,000 in the general population (Table III).

TABLE IV - Risk Ratio of Knee Arthroplasty After Cartilage Surgery in Specific Age Ranges Versus Age-Matched General Norwegian Population* Cartilage Cohort Age-Matched General Population† Risk Ratio (95% CI) Age at Cartilage Surgery Age at Knee Arthroplasty No. of Knee Arthroplasties No

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