Osteoarthritis (OA) is the most common joint disorder. The osteoarthritis initiative (OAI) is a multicentre, longitudinal, prospective observational cohort study of knee OA that aims to provide publicly accessible clinical datasets, images and biospecimens, to enable researchers to investigate factors that influence the onset and development of OA, and evaluate biomarkers that predict and track the course of the disease. In this Perspectives, we describe the rationale and design of the OAI and its cohort, discuss imaging protocols and summarize image analyses completed to date. We include descriptive analyses of publicly available longitudinal (2-year) data of changes in cartilage thickness in a core sample of 600 knees from 590 participants in the OAI progression subcohort. Furthermore, we describe published methodological and applied imaging research that has emerged from OAI pilot studies and OAI data releases, and how these studies might contribute to clinical development of biomarkers for assessing the efficacy of intervention trials.

Knee osteoarthritis (OA) is a leading cause of chronic disability worldwide, but no diagnostic or prognostic biomarkers are available. Increasing evidence supports epigenetic dysregulation as a contributor to OA pathogenesis. In this pilot study, we investigated epigenetic patterns in peripheral blood mononuclear cells (PBMCs) as models to predict future radiographic progression in OA patients enrolled in the longitudinal Osteoarthritis Initiative (OAI) study. PBMC DNA was analyzed from baseline OAI visits in 58 future radiographic progressors (joint space narrowing at 24 months, sustained at 48 months) compared to 58 non-progressors. DNA methylation was quantified via Illumina microarrays and beta- and M-values were used to generate linear classification models. Data were randomly split into a 60% development and 40% validation subsets, models developed and tested, and cross-validated in a total of 40 cycles. M-value based models outperformed beta-value based models (ROC-AUC 0.81 ± 0.01 vs. 0.73 ± 0.02, mean ± SEM, comparison p = 0.002), with a mean classification accuracy of 73 ± 1% (mean ± SEM) for M- and 69 ± 1% for beta-based models. Adjusting for covariates did not significantly alter model performance. Our findings suggest that PBMC DNA methylation-based models may be useful as biomarkers of OA progression and warrant additional evaluation in larger patient cohorts.

Historically disease knowledge development and treatment innovation in osteoarthritis (OA) has been considered to be slow. One of the many reasons purported as responsible for this slow pace has been the alleged lack of valid and responsive biomarkers to ascertain efficacy, which itself has been dependent upon the slow evolution of the understanding of the complex nature of joint tissue biology. This narrative review outlines the rationale for why we need OA biomarkers with regard to biomarker validation and qualification. The main biomarkers in current development for OA are biochemical and imaging markers. We describe an approach to biomarker validation and qualification for OA clinical trials that has recently commenced with the Foundation of NIH OA Biomarkers Consortium study cosponsored by the Osteoarthritis Research Society International (OARSI). With this approach we endeavor to identify, develop, and qualify biological markers (biomarkers) to support new drug development, preventive medicine, and medical diagnostics for osteoarthritis.

Objective

To determine the diagnostic performance of standing computerized tomography (SCT) of the knee for osteophytes and subchondral cysts compared with fixed-flexion radiography, using MRI as the reference standard.

Methods

Twenty participants were recruited from the Multicenter Osteoarthritis Study. Participants' knees were imaged with SCT while standing in a knee-positioning frame, and with postero-anterior fixed-flexion radiography and 1T MRI. Medial and lateral marginal osteophytes and subchondral cysts were scored on bilateral radiographs and coronal SCT images using the OARSI grading system and on coronal MRI using Whole Organ MRI Scoring. Imaging modalities were read separately with images in random order. Sensitivity, specificity and accuracy for the detection of lesions were calculated and differences between modalities were tested using McNemar's test.

Results

Participants' mean age was 66.8 years, body mass index was 29.6 kg/m(2) and 50% were women. Of the 160 surfaces (medial and lateral femur and tibia for 40 knees), MRI revealed 84 osteophytes and 10 subchondral cysts. In comparison with osteophytes and subchondral cysts detected by MRI, SCT was significantly more sensitive (93 and 100%; p < 0.004) and accurate (95 and 99%; p < 0.001 for osteophytes) than plain radiographs (sensitivity 60 and 10% and accuracy 79 and 94%, respectively). For osteophytes, differences in sensitivity and accuracy were greatest at the medial femur (p = 0.002).

Conclusions

In comparison with MRI, SCT imaging was more sensitive and accurate for detection of osteophytes and subchondral cysts than conventional fixed-flexion radiography. Additional study is warranted to assess diagnostic performance of SCT measures of joint space width, progression of OA features and the patellofemoral joint.

Objective

To determine whether the amount of physical activity (PA) is a determinant of joint space narrowing (JSN) worsening over 48 months in participants with knee osteoarthritis.

Methods

Data were obtained from the Osteoarthritis Initiative. PA, measured using the Physical Activity Scale for the Elderly (PASE), was defined as the mean value of the annual measurements conducted prior to development of worsening JSN. Worsening JSN was defined as at least a partial grade increase in the Osteoarthritis Research Society International JSN score over 48 months, in comparison with baseline. Restricted cubic spline function was used to group participants based on the linear association between PA and JSN worsening. A pooled logistic regression model was used to evaluate the association between PA and JSN worsening adjusted for confounders.

Results

A total of 2,167 participants were included. In total, 625 participants (28.8%) had JSN worsening over 48 months. Compared with a PASE score of 141-180, PASE scores of 101-140 and >220 were associated with an increased risk of JSN worsening in men, with odds ratios (ORs) of 1.73 (95% confidence interval [95% CI] 1.07-2.81) and 1.83 (95% CI 1.14-2.93), respectively. Similarly, in participants with Kellgren/Lawrence (K/L) grade 2, compared with a PASE score of 141-180, PASE scores of ≤100 and >220 were associated with increased risks of JSN worsening, with an OR of 1.69 (95% CI 1.13-2.54) and 1.64 (95% CI 1.05-2.56), respectively.

Conclusion

Compared to moderate PA, higher or lower amounts of PA are associated with an elevated risk for JSN worsening in men and in participants with K/L grade 2 knees.

Objective

We examined the association between sleep and odds of developing knee pain, and whether this relationship varied by status of widespread pain (WSP).

Methods

At the 60-month visit of the Multicenter Osteoarthritis Study, sleep quality and restless sleep were each assessed by using a single item from 2 validated questionnaires. Each sleep measure was categorized into 3 levels, with poor/most restless sleep as the reference. WSP was defined as pain above and below the waist on both sides of the body and axially using a standard homunculus, based on the American College of Rheumatology criteria. Outcomes from 60-84 months included (1) knee pain worsening (KPW; defined as minimal clinically important difference in WOMAC pain), (2) prevalent, and (3) incident consistent frequent knee pain. We applied generalized estimating equations in multivariable logistic regression models.

Results

We studied 2329 participants (4658 knees; 67.9 yrs, body mass index 30.9]. We found that WSP modified the relationship between sleep quality and KPW (p = 0.002 for interaction). Among persons with WSP, OR (95% CI) for KPW was 0.53 (0.35-0.78) for those with very good sleep quality (p trend < 0.001); additionally, we found the strongest association of sleep quality in persons with > 8 painful joint sites (p trend < 0.01), but not in those with ≤ 2 painful joint sites. Similar results were observed using restless sleep, in the presence of WSP. The cross-sectional relationship between sleep and prevalence of consistent frequent knee pain was significant.

Conclusion

Better sleep was related to less KPW with coexisting widespread pain.

Objective

Pain persistence following knee replacement (KR) occurs in ∼20-30% of patients. Although several studies have identified preoperative risk factors for persistent post-KR pain, few have focused on post-KR contributing factors. We sought to determine whether altered nociceptive signaling and other peripheral nociceptive drivers present post-operatively contribute to post-KR pain.

Design

We included participants from the Multicenter Osteoarthritis Study who were evaluated ∼12 months after KR. We evaluated the relation of measures of pain sensitivity [pressure pain threshold (PPT), temporal summation (TS), and conditioned pain modulation (CPM)] and the number of painful body sites to post-KR WOMAC knee pain, and of the number of painful sites to altered nociceptive signaling using linear or logistic regression models, as appropriate.

Results

171 participants (mean age 69 years, 62% female) were included. TS was associated with worse WOMAC pain post-KR (β ​= ​0.77 95% CI:0.19-1.35) and reduced odds of achieving patient acceptable symptom state (aOR ​= ​0.54 95%CI:0.34-0.88). Inefficient CPM was also associated with worse WOMAC pain post-KR (β ​= ​1.43 95% CI:0.15-2.71). In contrast, PPT was not associated with these outcomes. The number of painful body sites present post-KR was associated with TS (β ​= ​0.05, 95% CI:0.01, 0.05).

Conclusions

Post-KR presence of central sensitization and inefficient descending pain modulation was associated with post-KR pain. We also noted that presence of other painful body sites contributes to altered nociceptive signaling, and this may thus also contribute to the experience of knee pain post-KR. Our findings provide novel insights into central pain mechanisms and other peripheral pain sources contributing to post-KR persistent knee pain.

Objective

To determine whether intraarticular glucocorticoid (GC) injections are associated with increased knee osteoarthritis (OA) progression compared to hyaluronic acid (HA) injections, which have been reported to delay OA progression and knee replacement.

Methods

We identified participants from 2 large cohort studies, the Osteoarthritis Initiative (OAI) and the Multicenter Osteoarthritis Study. Study visits were performed at regular intervals and included questionnaires about intraarticular GC or HA injection use in the previous 6 months and incident total knee replacement (TKR). Knee radiographs were obtained at each study visit and interpreted in a similar manner. Outcome measures were radiographic progression based on Kellgren/Lawrence (K/L) grade and joint space narrowing (JSN) for both cohorts and based on medial joint space width for OAI participants, and incident TKR. We compared preinjection and postinjection radiographs to generate rate ratios of progression comparing GC injection with HA injection. A Cox proportional hazards model was used to estimate the rate of TKR for both groups.

Results

We studied 791 participants (980 knees) with knee OA, of whom 629 reported GC injection use and 162 HA injection use. Rate ratios of progression were similar between those receiving GCs and those receiving HA for JSN (1.00 [95% confidence interval (95% CI) 0.83-1.21]), K/L grade (1.03 [95% CI 0.83-1.29]), and medial joint space width (1.03 [95% CI 0.72-1.48]). Hazard of TKR was slightly lower for those receiving intraarticular GC compared to those receiving HA (hazard ratio 0.75 [95% CI 0.51-1.09]).

Conclusion

Intraarticular GC injections are not associated with an increased risk of knee OA progression compared to HA.

Background

Medial meniscus root tears (RTs) are associated with the development and worsening of knee osteoarthritis (OA), but little is known about their progression when compared with meniscal tears that spare the root (nonroot tears; NRTs).

Purpose

To compare radiographic worsening of OA in knees with RTs versus NRTs and to identify factors associated with radiographic worsening of OA in knees with RTs.

Study design

Cohort study; Level of evidence, 3.

Methods

Using the Osteoarthritis Initiative database, we included knees with medial meniscus RTs and NRTs present at the baseline visit (baseline tears) and new RTs and NRTs observed at 12- to 48-month annual follow-up visits (incident tears). Worsening of radiographic OA was defined for baseline tears as an increase in Kellgren-Lawrence grade (KLG) during the subsequent 12 months of follow-up; for incident tears, worsening was defined as either concurrent (increase in KLG over the 12 months preceding tear appearance on magnetic resonance imaging) or subsequent (increase in KLG during the 12 months after tear appearance). Odds ratios (ORs), adjusted for covariates, were calculated for the association of worsening by type of tear.

Results

Included were 39 knees with baseline RTs, 633 knees with baseline NRTs, 33 knees with incident RTs, and 234 knees with incident NRTs. Radiographic OA worsening subsequent to meniscal tear identification was no different for baseline RTs (15%) or baseline NRTs (14%; adjusted OR, 1.34; 95% CI, 0.52-3.47), nor did subsequent worsening differ for incident RTs (19%) versus incident NRTs (18%; adjusted OR, 0.52; 95% CI, 0.15-1.83). Concurrent radiographic OA worsening was seen at a significantly higher rate for incident RTs (64%) versus incident NRTs (21%; adjusted OR, 3.00; 95% CI, 1.21-7.47). Incident RTs in knees without radiographic OA (KLG 0-1) before the tear had a high rate of worsening (94%, n = 16) and were more likely to worsen than those in knees with radiographic OA (KLG ≥2) present before the tear.

Conclusion

Compared with NRTs, incident RTs were associated with a significantly increased risk of worsening radiographic OA over a 12-month period concurrent with the appearance of the tear. Incident RTs in knees without radiographic OA at baseline had a high rate of worsening.

Abstract

As the population ages, there is a growing burden owing to musculoskeletal diseases, such as knee osteoarthritis, and subsequent functional decline. In the absence of a cure, there is a need to identify factors amenable to intervention to prevent or slow this process. The Multicenter Osteoarthritis Study cohort was developed for this purpose. In this study, associations between variability in peak knee flexor and extensor torque at baseline and worsening of pain and physical function over the subsequent 60 mos were assessed in a cohort of 2680 participants. The highest quartile of baseline knee flexor torque variability was found to be associated longitudinally with worsening pain (fourth quartile ß estimate, mean ± SE, 0.49 ± 0.19; P = 0.0115; with R2 = 0.28 and P for trend across quartiles = 0.0370) and physical function scores (fourth quartile ß estimate, mean ± SE, 1.39 ± 0.64; P = 0.0296; with R2 = 0.25 and P for trend across quartiles = 0.0371), after adjusting for baseline knee osteoarthritis and maximum knee flexor torque. There were no associations between baseline knee extensor torque and worsening pain or physical function by 60 mos. The presence of greater variability in maximum knee flexor strength may identify patients who may benefit from therapies aimed at preventing worsening knee pain and physical function.